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Publisher: Elsevier   (Total: 3160 journals)

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Showing 1 - 200 of 3160 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 37, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 25, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 97, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 37, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 427, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 28, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.128, CiteScore: 0)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 288, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 6, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 17, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 11, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 176, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 16, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 10, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 14, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 32, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 28, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in Digestive Medicine     Open Access   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 43, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 49, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 61, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 20, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 10, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 24, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 23)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 18, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 7, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 25, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 12)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 66)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 1, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 413, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 12, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 35, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 19)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 49, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 362, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 11, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 470, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 17, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 43, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 11)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 52, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 57, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 62, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 44, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 11)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 13, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 34, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 35, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 48)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 231, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 29, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 63, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 20, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 200, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 12, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 206, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 6, SJR: 0.937, CiteScore: 2)

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Similar Journals
Journal Cover
American Journal of Pathology
Journal Prestige (SJR): 2.139
Citation Impact (citeScore): 4
Number of Followers: 29  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0002-9440
Published by Elsevier Homepage  [3160 journals]
  • Transient Receptor Potential Vanilloid 4 (TRPV4) is required for foreign
           body response and giant cell formation
    • Abstract: Publication date: Available online 21 May 2019Source: The American Journal of PathologyAuthor(s): Rishov Goswami, Rakesh Arya, Debabrata Biswas, Xiaoping Zhu, Shaik O. Rahaman The presence of biomaterials and devices implanted into soft tissue is associated with development of a foreign body response (FBR), a chronic inflammatory condition that can ultimately lead to implant failure, which may cause harm to or death of the patient. Development of FBR includes activation of macrophages at the tissue-implant interface, generation of destructive foreign body giant cells (FBGCs), and generation of fibrous tissue that encapsulates the implant. However, the mechanisms underlying the FBR remain poorly understood, as neither the materials comprising the implants nor their chemical properties can explain triggering of the FBR. Here, we report that genetic ablation of TRPV4, a Ca2+-permeable mechanosensitive cation channel in the transient receptor potential vanilloid family, protects TRPV4 KO mice from FBR-related events. The mice showed diminished collagen deposition along with reduced macrophage accumulation and FBGC formation compared to WT mice in a subcutaneous implantation model. Analysis of macrophage markers in spleen tissues and peritoneal cavity showed that the TRPV4 deficiency did not impair basal macrophage maturation. Furthermore, genetic deficiency or pharmacologic antagonism of TRPV4 blocked cytokine-induced FBGC formation, which was restored by lentivirus-mediated TRPV4 reintroduction. Taken together, these results suggest an important, previously unknown role for TRPV4 in FBR.
       
  • E-cadherin is important for Meibomian gland function as revealed by a new
           human ex vivo slice culture model
    • Abstract: Publication date: Available online 20 May 2019Source: The American Journal of PathologyAuthor(s): Vera Rötzer, Francesca Melega, Fabian Garreis, Friedrich Paulsen, Jens WaschkeABSTRACTMeibomian glands within the eyelid are important for the maintenance of the integrity and health of the ocular surface. Patients with the blistering skin disease pemphigus vulgaris (PV), which is caused by autoantibodies against desmosomal cadherins, often suffer from Dry Eye Disease (DED). Therefore, we studied regulation of cell cohesion in human Meibomian gland epithelial cells (HMGEC). During serum-induced differentiation for 1d up to 6d, HMGEC drastically enhanced intercellular cohesion whereas lipid production did not change. The expression profiles of the desmosomal PV-antigens desmoglein (Dsg) 3 and 1 but not of the adherens junction component E-cadherin (Ecad) was dependent on the presence of serum. Surprisingly, after 1d but not after 6d of serum-induced differentiation, an inhibitory antibody against Ecad drastically reduced intercellular cohesion and blocked lipid production of HMGEC. In contrast, antibodies against desmosomal cadherins including human and mouse pemphigus autoantibodies had no effect on monolayer integrity and lipid production. Because in Meibomian glands from Dsg3-deficient mice lipid production was unaltered, we established an ex vivo slice culture model of human eyelids to allow studies in a more physiological environment. Here, the inhibitory antibody against Ecad but not a Dsg3-specific PV-antibody interfered with stimulated lipid production. Together, these data demonstrate that cell cohesion is maintained differently in Meibomian gland cells and indicate that E-cadherin is important for Meibomian gland function.
       
  • Endothelial HIF-1α Is Required for Vascular Repair and Resolution of
           Inflammatory Lung Injury through FoxM1
    • Abstract: Publication date: Available online 20 May 2019Source: The American Journal of PathologyAuthor(s): Xiaojia Huang, Xianming Zhang, David X. Zhao, Jun Yin, Guochang Hu, Colin E. Evans, You-Yang Zhao Endothelial barrier dysfunction is a central factor in the pathogenesis of persistent lung inflammation and protein-rich edema formation, the hallmarks of acute respiratory distress syndrome. However, little is known about the molecular mechanisms that are responsible for vascular repair and resolution of inflammatory injury after sepsis challenge. Here we show that hypoxia inducible factor-1α (HIF-1α) expressed in endothelial cells (ECs) is the critical transcriptional factor mediating vascular repair and resolution of inflammatory lung injury. Following sepsis challenge, HIF-1α but not HIF-2α expression was rapidly induced in lung vascular ECs, and mice with EC-restricted disruption of Hif1α (Hif1af/f/Tie2Cre+) exhibited defective vascular repair, persistent inflammation, and increased mortality in contrast to the WT littermates following polymicrobial sepsis or endotoxemia challenge. Hif1af/f/Tie2Cre+ lungs exhibited marked decrease of EC proliferation during recovery following sepsis challenge, which was associated with inhibited expression of FoxM1, a reparative transcription factor. Therapeutic restoration of endothelial FoxM1 expression via liposomal delivery of FoxM1 plasmid DNA to Hif1af/f/Tie2Cre+ mice resulted in re-activation of the vascular repair program, and improved survival. Together, our studies for the first time delineate the essential role of endothelial HIF-1α in driving the vascular repair program. Thus, therapeutic activation of HIF-1α-dependent vascular repair may represent a novel and effective therapy to treat inflammatory vascular diseases such as sepsis and acute respiratory distress syndrome.
       
  • Heart inflammation: immune cells roles and roads to the heart.
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Francisco J. Carrillo-Salinas, Njabulo Ngwenyama, Marina Anastasiou, Kuljeet Kaur, Pilar AlcaideHeart failure (HF) has been traditionally viewed as a disease of the cardiac muscle associated with systemic inflammation. Burgeoning evidence implicates immune effector mechanisms that include immune cell activation and trafficking to the heart. Immune cell infiltration in the myocardium can have adverse effects in the heart and contribute to the pathogenesis of HF. Both innate and adaptive immunity operate sequentially, and the specificity of these responses depends on the initial trigger sensed by the heart. While the role of the immune system in the initial inflammatory response to infection and injury is well studied, what sets the trajectory to HF from different etiologies, and the role of immunity once HF has been established is less understood. Here, we review experimental and clinical knowledge of cardiac inflammation induced by different triggers that often result in HF from different etiologies. We focus on the mechanisms of immune cell activation systemically, and in the pathways immune cells use to traffic to the heart.
       
  • Invasive Ductular Reaction Operates Hepatobiliary Junctions upon
           Hepatocellular Injury in Rodents and Humans
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Laure-Alix Clerbaux, Rita Manco, Noémi Van Hul, Caroline Bouzin, Amedeo Sciarra, Christine Sempoux, Neil D. Theise, Isabelle A. LeclercqDuctular reaction (DR) is observed in virtually all liver diseases both in humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. Upon severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Here, we proposed that invasive DR could contribute to operating hepatobiliary junctions upon hepatocellular injury. We used the choline-deficient ethionine-supplemented (CDE) mouse model of hepatocellular injury and human liver samples to evaluate the hepatobiliary junctional role of the invasive form of DR. We showed that CDE-induced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting non-invasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug-induced or metabolic) in which DR invaded the lobule but not in biliary diseases (obstruction or cholangitis) in which DR was contained within the portal mesenchyme. In conclusion, our data in rodents and humans support that invasive DR plays a hepatobiliary junctional role to maintain structural continuity between hepatocytes and ducts in disorders affecting hepatocytes.
       
  • Progranulin Promotes Bleomycin-Induced Skin Sclerosis by Enhancing
           TGF-β/Smad3 Signaling through Up-Regulation of TGF-β Type I Receptor
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Ting Yang, Xuemei Zhang, Aijun Chen, Yunju Xiao, Si Sun, Jurong Yan, Yuwei Cao, Jin Chen, Fengzeng Li, Kun HuangProgranulin (PGRN) is an autocrine growth factor with numerous physiological and pathological roles. Previous reports demonstrated PGRN could increase dermal fibroblasts in wound healing and activate cancer associated fibroblasts in some cancers. Because systemic sclerosis (SSc) is a prototypical fibrosis-related disorder, here, our aim was to clarify the role and mechanism of PGRN in bleomycin (BLM)-induced model of SSc for the first time. We observed that the serum PGRN levels were increased in SSc patients compared with healthy controls. Immunohistology and RT-qPCR demonstrated that PGRN was also elevated in the lesion from mice model of BLM-induced dermal fibrosis. Additionally, in BLM-treated mice, PGRN deficiency not only attenuated dermal fibrosis but also decreased the differentiation of myofibroblasts. The reduced progression of skin sclerosis in PGRN-deficient mice was associated with downregulation of TGF-β receptor I (TβR I) and decreased level of p-Smad3, with correspondingly impaired the expression of its downstream target gene connective tissue growth factor(CTGF) in skin lesion. In contrast, exogenous PGRN significantly increased the level of TβR I and p-Smad3 in cultured mouse fibroblasts.This study demonstrates that PGRN plays a promoting role in the development of dermal fibrosis through the activation of the TGF-β/Smad3 signaling via upregulation of TβR I. PGRN may be a new therapeutic target in SSc.
       
  • Neutrophil Elastase Damages the Pulmonary Endothelial Glycocalyx in
           Lipopolysaccharide-Induced Experimental Endotoxemia
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Kodai Suzuki, Hideshi Okada, Genzou Takemura, Chihiro Takada, Ayumi Kuroda, Hirohisa Yano, Ryogen Zaikokuji, Kentaro Morishita, Hiroyuki Tomita, Kazumasa Oda, Saori Matsuo, Akihiro Uchida, Tetsuya Fukuta, So Sampei, Nagisa Miyazaki, Tomonori Kawaguchi, Takatomo Watanabe, Takahiro Yoshida, Hiroaki Ushikoshi, Shozo YoshidaNeutrophil elastase (NE) is necessary for effective sterilization of phagocytosed bacterial and fungal pathogens; however, NE itself increases alveolocapillary permeability, and induces proinflammatory cytokine production in sepsis-induced acute respiratory distress syndrome. Under septic conditions, the pulmonary endothelial glycocalyx covering on the healthy endothelium surface is injured, but the contribution of NE to this injury remains unknown. Our aim was to examine whether NE-induced pulmonary endothelial injury is associated with endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 9–12-week-old granulocyte colony-stimulating factor knockout (G-CSFKO) mice, which harbor few neutrophils, and littermate control mice; in a second assay, mice were injected with the NE-inhibitor sivelestat (0.2 mg/kg) at 3, 6, 9, and 12 hours after LPS administration. Subsequently, vascular endothelial injury was evaluated through ultrastructural analysis. At 48 hours post-LPS injection, survival rate was>3-fold higher among G-CSFKO than control mice, and degradation of both thrombomodulin and syndecan-1 was markedly attenuated in G-CSFKO compared to control mice. Ultrastructural analysis revealed attenuated vascular endothelial injury and clear preservation of the endothelial glycocalyx in G-CSFKO mice. Moreover, after LPS exposure, survival rate was ∼9-fold higher among sivelestat-injected mice than control mice, and sivelestat treatment potently preserved vascular endothelial structures and the endothelial glycocalyx. In conclusion, NE is associated with pulmonary endothelial injury under LPS-induced endotoxemic conditions.
       
  • Environmental Cadmium Enhances Lung Injury by Respiratory Syncytial Virus
           Infection
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Xin Hu, Ki-hye Kim, Youri Lee, Jolyn Fernandes, M. Ryan Smith, Yujin Jung, Michael Orr, Sang-Moo Kang, Dean P. Jones, Young-Mi Go Cadmium (Cd) is a naturally occurring environmental toxicant that disrupts mitochondrial function at occupational exposure levels. The impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Human respiratory syncytial virus (RSV) causes severe morbidity which can require hospitalization and result in death in young children and elderly populations. The impacts of environmental Cd exposure on the severity of RSV disease are unknown. Herein, we used a mouse model to examine whether Cd pre-exposure at a level of dietary intake potentiates pulmonary inflammation upon subsequent infection with RSV. Mice were given Cd or saline in drinking water for 28 days. Subsets of these mice were infected with RSV at 5 days before the end of the study. Cd pre-exposure caused relatively subtle changes in lung; however, it elevated IL-4 level and altered metabolites associated with fatty acid metabolism. After RSV infection, mice pre-exposed to Cd had elevated lung RSV titer and increased inflammation as measured by histopathology, immune cell infiltration, cytokines and chemokines. RSV infection following Cd pre-exposure also caused widespread perturbation in metabolism of glycerophospholipids and amino acids (Trp, Met, Cys, branched chain amino acids), as well as carnitine shuttle associated with mitochondrial energy metabolism. The results show that Cd burden by dietary intake potentiates RSV infection and severe disease with associated mitochondrial metabolic disruption.
       
  • CD55 Is Essential for CD103+ Dendritic Cell Tolerogenic Responses that
           Protect against Autoimmunity
    • Abstract: Publication date: Available online 17 May 2019Source: The American Journal of PathologyAuthor(s): Michael Strainic, Jinbo Liu, Fengqi An, Erin Bailey, Andrew Esposito, Jörg Hamann, Peter S. Heeger, M. Edward MedofRecent studies traced inflammatory bowel disease in some patients to deficiency of CD55 [decay accelerating factor (DAF)], but the mechanism underlying the linkage remains unclear. Herein, we studied the importance of DAF in enabling processes that program tolerance in the gut and the eye, two immune-privileged sites where immunosuppressive responses are continuously elicited. Unlike oral feeding or ocular injection of ova in wild-type (WT) mice, which induced dominant immune tolerance, identical treatment of DAF–/– mice or DAF–/–to WT bone marrow chimeras did not. Although 10% to 30% of mesenteric and submandibular lymph node CD4+ cells became robust Tregs in WT Foxp3-GFP mice, few in either site became Tregs with little suppressor activity in DAF–/– Foxp3-GFP mice. Phenotyping of CD103+ dendritic cells (DCs) from the ova fed DAF-/- mice showed impaired expression of ICOS ligand, PD1-L1, Cx3CR1, CCR7, and CCR9. Analyses of elicited DAF-/- Foxp3+ T regulatory cells (Tregs) showed reduced expression of IRF-8/Aldh1a2 and GARP/LAP associated with Treg transforming growth factor-β production and presentation, as well as Itg-β6/Itg-β8 integrins associated with Treg and CD103+ DC transforming growth factor-β release. Thus, DAF is required for the properties of CD103+ DCs and their naïve CD4+ cell partners that together program tolerance.
       
  • This Month in AJP
    • Abstract: Publication date: Available online 17 May 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
       
  • Apolipoprotein E/Aβ Complex Accumulates in AD Cortical Synapses via apoE
           Receptors and Is Enhanced by APOE4
    • Abstract: Publication date: Available online 17 May 2019Source: The American Journal of PathologyAuthor(s): Tina Bilousova, Mikhail Melnik, Emily Miyoshi, Bianca L. Gonzalez, Wayne W. Poon, Harry V. Vinters, Carol A. Miller, Maria M. Corrada, Claudia Kawas, Asa Hatami, Ricardo Albay, Charles Glabe, Karen Hoppens GylysApolipoprotein E (apoE) co-localizes with amyloid-beta (Aβ) in Alzheimer’s disease (AD) plaques and in synapses, and evidence suggests that direct interactions between apoE and Aβ are important for apoE’s effects in AD. The present work examines the hypothesis that apoE receptors mediate uptake of apoE/Aβ complex into synaptic terminals. Western analysis shows multiple SDS-stable assemblies in synaptosomes from human AD cortex; apoE/Aβ complex was markedly increased in AD compared to aged control samples. Complex formation between apoE and Aβ was confirmed by co-immunoprecipitation experiments. The apoE receptors low density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) were quantified in synaptosomes using flow cytometry, revealing up-regulation of LRP1 in early- and late-stage AD. Dual labeling flow cytometry analysis of LRP1- and LDLR-positives indicate a majority (∼65%) of LDLR and LRP1 is associated with PSD-95-positive synaptosomes, indicating that remaining LRP1 and LDLR receptors are exclusively presynaptic. Flow cytometry analysis of Nile Red labeling revealed a reduction in cholesterol esters in AD synaptosomes. Dual labeling experiments showed apoE and Aβ concentration into LDLR and LRP1-positive synaptosomes, along with free and esterified cholesterol. Synaptic Aβ was increased by apoE4 in control and AD samples. These results are consistent with uptake of apoE/Aβ complex and associated lipids into synaptic terminals, with subsequent Aβ clearance in control synapses and accumulation in AD synapses.
       
  • Pathogen Colonization Resistance in the Gut and Its Manipulation for
           Improved Health
    • Abstract: Publication date: Available online 14 May 2019Source: The American Journal of PathologyAuthor(s): Joseph M. Pickard, Gabriel NúñezMammals have coevolved with a large community of symbiotic, commensal, and some potentially pathogenic microbes. The trillions of bacteria and hundreds of species in our guts form a relatively stable community that resists invasion by outsiders, including pathogens. This powerful protective force is referred to as colonization resistance. We discuss the variety of proposed or demonstrated mechanisms that can mediate colonization resistance and some potential ways to manipulate them for improved human health. Instances in which certain bacterial pathogens can overcome colonization resistance are also discussed.
       
  • Syntaphilin Is a Novel Biphasic Biomarker of Aggressive Prostate Cancer
           and a Metastasis Predictor
    • Abstract: Publication date: Available online 9 May 2019Source: The American Journal of PathologyAuthor(s): Michael J. Hwang, Kelly G. Bryant, Jae H. Seo, Qin Liu, Peter A. Humphrey, Mary Ann C. Melnick, Dario C. Altieri, Marie E. RobertEasily accessible biomarkers that may inform on the metastatic potential of localized prostate cancer are urgently needed. Herein, we show that syntaphilin (SNPH), a molecule originally identified as a negative regulator of mitochondrial dynamics in neurons, is abundantly expressed in prostate cancer. SNPH distribution in prostate cancer is spatially biphasic, with high expression at the invasive front, correlating with increased proliferative rates, as determined by Ki-67 labeling, and reduced levels in the central tumor bulk, which are further decreased in patients with distant metastases. Higher levels of SNPH are observed with increasing Gleason grade. Prostate tumors predominantly express a novel, extraneuronal isoform of SNPH that accumulates in mitochondria and maintains oxidative metabolism and tumor cell proliferation. These data suggest that SNPH is a novel marker of high Gleason grade prostate cancer, differentially expressed at the invasive front compared with the central tumor bulk, and is potentially down-regulated in metastatic disease. This biphasic pattern of expression may reflect a dual function of SNPH in controlling the balance between cell proliferation and invasion in tumors.
       
  • Membrane Metalloendopeptidase (MME) Suppresses Metastasis of Esophageal
           Squamous Cell Carcinoma (ESCC) by Inhibiting FAK-RhoA Signaling Axis
    • Abstract: Publication date: Available online 2 May 2019Source: The American Journal of PathologyAuthor(s): Mengqing Li, Ling Wang, Yuting Zhan, Tingting Zeng, Xu Zhang, Xin-Yuan Guan, Yan LiEsophageal squamous cell carcinoma (ESCC) is a typical neoplastic disease and a frequent cause of death in China. Although great achievements have been made in diagnostic strategies and combination therapies in recent years, the prognosis of ESCC is still poor. Metastasis/recurrence has been the major factor responsible for poor prognosis. However, the underlying mechanism of ESCC dissemination remains elusive. Membrane metalloendopeptidase (MME) is a transmembrane glycoprotein that degrades a number of substrates. Our results indicated that the down-regulation of MME is significantly associated with advanced clinical stage (P < 0.05) and lymph node metastasis (P < 0.05). The down-regulation of MME in ESCC tumor tissues is correlated to poorer prognosis of the patients. Functional studies demonstrated that MME could significantly inhibit ESCC tumor cell metastasis in vitro and in vivo. MME overexpression could also interrupt ESCC tumor cell adhesion. Mechanistically, MME inhibits the phosphorylation of FAK thus interrupting the FAK-RhoA axis, which is important in cell movement. Taken together, these data show that MME regulates ESCC via FAK-RhoA axis. High expression of MME may indicate a beneficial outcome for patients.
       
  • A Noncanonical Role for Plasminogen Activator Inhibitor Type 1 in
           Obesity-Induced Diabetes
    • Abstract: Publication date: Available online 2 May 2019Source: The American Journal of PathologyAuthor(s): Gina M. Coudriet, John Stoops, Anne V. Orr, Bharat Bhushan, Kelly Koral, Sojin Lee, Dana M. Previte, H. Henry Dong, George K. Michalopoulos, Wendy M. Mars, Jon D. PiganelliObesity is a major risk factor for type 2 diabetes due to chronic hepatic inflammation and resultant insulin resistance. Hepatocyte growth factor (HGF) is responsible for resetting hepatic homeostasis after injury following activation by urokinase-type plasminogen activator (u-PA, encoded by the PLAU gene). Plasminogen activator inhibitor type-1 (PAI-1, encoded by the SERPINE1 gene), a u-PA inhibitor and anti-fibrinolytic agent, is often elevated in obesity and is linked to cardiovascular events. We hypothesized that in addition to its role in preventing fibrinolysis, elevated PAI-1 inhibits HGF’s activation by u-PA and the resultant anti-inflammatory and hepato-protective properties. Wild-type (WT) and PAI-1 knockout (KO) mice on high fat diet both became significantly heavier than lean controls; however, the obese KO mice demonstrated improved glucose metabolism as compared to WT. Obese KO mice also exhibited an increase in conversion of latent single chain HGF to active two-chain HGF, coinciding with an increase in the phosphorylation of HGF receptor, MET, as well as dampened inflammation. These results strongly suggest that in addition to its other functions, PAI-mediated inhibition of HGF activation prohibits the resolution of inflammation in the context of obesity-induced type 2 diabetes.
       
  • High temperature requirement A1 protease as a rate-limiting factor in the
           development of osteoarthritis
    • Abstract: Publication date: Available online 30 April 2019Source: The American Journal of PathologyAuthor(s): Peter. H. Chen, Tian. Tang, Chenlu. Liu, Beiyu. Wang, Michelle. Mian, Chio. Oka, Maria. Baquerizo, Yefu Li, Lin XuPreserving of the mature articular cartilage of joints is a critical focus in the prevention and treatment of osteoarthritis. We determined whether the genetic inactivation of high temperature requirement A1 (HtrA1) can significantly attenuate the degradation of articular or condylar cartilage. Two types of mouse models of osteoarthritis were used, a spontaneous mutant mouse model (type XI collagen-haploinsufficiency, Col11a1+/- mice) and two post-traumatic mouse models (destabilization of the medial meniscus, DMM, on knee and a partial discectomy, PDE, on temporomandibular joint). Three different groups of mice were generated: i) HtrA1 was genetically deleted from Col11a1+/- mice (HtrA1-/-;Col11a1+/-), ii) HtrA1-deficient mice (HtrA1-/-) were subjected to DMM, and iii) HtrA1-/- mice were subjected to PDE. Knee and temporomandibular joints from the mice were characterized for evidence of cartilage degeneration. The degradation of articular or condylar cartilage was significantly delayed in HtrA1-/-;Col11a1+/- mice and HtrA1-/- mice following DMM or PDE. The amount of collagen type VI was significantly higher in the articular cartilage in HtrA1-/-;Col11a1+/- mice, compared with that in Col11a1+/- mice. The genetic removal of HtrA1 may delay the degradation of articular or condylar cartilage in mice.
       
  • Choriocapillaris Degeneration in Geographic Atrophy
    • Abstract: Publication date: Available online 30 April 2019Source: The American Journal of PathologyAuthor(s): Elliott H. Sohn, Miles J. Flamme-Wiese, S. Scott Whitmore, Grefachew Workalemahu, Alexander G. Marneros, Erin A. Boese, Young H. Kwon, Kai Wang, Michael D. Abramoff, Budd A. Tucker, Edwin M. Stone, Robert F. MullinsEarly age-related macular degeneration (AMD) is characterized by degeneration of the choriocapillaris, the vascular supply of retinal photoreceptor cells. We assessed vascular loss during disease progression in the choriocapillaris and larger vessels in the deeper choroid. Human donor maculas from controls (n=99), early AMD (n=35), or clinically diagnosed with geographic atrophy (GA; n=9, collected from outside the zone of retinal pigment epithelium degeneration) were evaluated using Ulex europaeus agglutinin-I labeling to discriminate between vessels with intact endothelial cells and ghost vessels. Morphometric analyses of choriocapillaris density (cross sectional area of capillary lumens divided by length) and of vascular lumen-to-stroma ratio in the outer choroid were performed. Choriocapillaris loss was observed in early AMD (Bonferroni corrected P (pcorr)=0.024) with greater loss in GA (pcorr 0.05), suggesting that changes in the choriocapillaris are more prevalent in AMD than those in the outer choroid. In addition, vascular endothelial growth factor-A levels were negatively correlated with choriocapillaris vascular density. These findings support the concept that choroidal vascular degeneration contributes to dry AMD, and that these changes are predominant in the microvasculature. Addressing the capillary loss in AMD remains an important translational target.
       
  • Breast Ductal Carcinoma in Situ: Precursor to Invasive Breast
           Cancer
    • Abstract: Publication date: May 2019Source: The American Journal of Pathology, Volume 189, Issue 5Author(s): William B. Coleman
       
  • Receptor-Interacting Serine/Threonine Kinase 3 (RIP3)–Mixed Lineage
           Kinase Like Protein (MLKL)–Mediated Necroptosis Contributes to
           Ischemia-Reperfusion Injury of Steatotic Livers
    • Abstract: Publication date: Available online 23 April 2019Source: The American Journal of PathologyAuthor(s): Hong-Min Ni, Xiaojuan Chao, Joshua Kaseff, Fengyan Deng, Shaogui Wang, Ying-Hong Shi, Tiangang Li, Wen-Xing Ding, Hartmut JaeschkeIncreased hepatic ischemia-reperfusion (IR) injury in steatotic livers is a major reason for rejecting the use of fatty livers for liver transplantation. Necroptosis is implicated in the pathogenesis of fatty liver diseases. Necroptosis is regulated by three key proteins: receptor-interacting serine/threonine kinase 1 (RIP1; official name RIPK1), RIP3, and mixed lineage kinase like protein (MLKL). Here, we found that western diet (WD) induced marked steatosis in mouse livers, which was associated with the inhibition of hepatic proteasome activities and increased levels of key necroptosis proteins. Mice fed a WD had more severe liver injury as demonstrated by increased serum alanine aminotransferase levels and liver necrosis areas after IR than mice fed with a control diet (CD). Although hepatic steatosis was not different between Mlkl knockout mice and wild type mice, Mlkl knockout mice had decreased hepatic neutrophil infiltration and inflammation and were protected from hepatic IR injury in both CD and WD fed mice. Intriguingly, RIP3 knockout or RIP3 kinase dead knockin mice were only protected against IR injury at the late phase but not the early phase in mice either fed with a CD or WD. Overall, our findings indicate that liver steatosis exacerbates hepatic IR injury via increased MLKL-mediated necroptosis. Targeting MLKL-mediated necroptosis may help to improve the outcomes of steatotic liver transplantation.
       
  • Automated identification and quantification of signals in multichannel
           immunofluorescence images: the SignalFinder platform
    • Abstract: Publication date: Available online 23 April 2019Source: The American Journal of PathologyAuthor(s): Daniel Barnett, Johnathan Hall, Brian HaabMultimarker fluorescence analysis of tissue specimens offers the opportunity to probe the expression levels and locations of multiple markers in a single sample. Software is needed to fully capitalize on the advantages of this technology for sensitive, quantitative, and multiplexed data collection. A major challenge has been the automated identification and quantification of signals. We report software, called SignalFinder, which meets that need. SignalFinder employs a newly-developed algorithm called Segment-Fit Thresholding that demonstrated robust performance for automated signal identification in side-by-side comparisons with several current methods. Two utilities provided with SignalFinder enable downstream analyses. The first allows the quantification and mapping of relationships between an unlimited number of markers through user-defined sequences of AND, OR, and NOT operators. The second produces composite pictures of the signals or colocalization analysis on brightfield heamtoxylin and eosin images, which is useful for understanding the morphologies and locations of cells meeting specific marker criteria. SignalFinder enables high-throughput, rigorous analyses of whole-slide, multimarker data, and it promises to open new possibilities in many research and clinical applications.
       
  • Network Medicine In Pathobiology
    • Abstract: Publication date: Available online 20 April 2019Source: The American Journal of PathologyAuthor(s): Laurel Yong-Hwa Lee, Joseph Loscalzo The past decade has witnessed exponential growth in the generation of high-throughput human data across almost all known dimensions of biological systems. The discipline of network medicine has rapidly evolved in parallel, providing an unbiased, comprehensive biological framework through which to interrogate and integrate systematically these large-scale multi-omic data in order to enhance our understanding of disease mechanisms and to design drugs that reflect a deep knowledge of molecular pathobiology. In this review, we discuss the key principles of network medicine and the human disease network, and explore the latest applications of network medicine in this multi-omic era. We also highlight the current conceptual and technological challenges, which, in turn, serve as exciting opportunities by which to improve and expand the network-based applications beyond the artificial boundaries of the current state of human pathobiology.
       
  • CD147/Basigin deficiency prevents the development of podocyte injury
           through FAK signaling
    • Abstract: Publication date: Available online 20 April 2019Source: The American Journal of PathologyAuthor(s): Tomoki Yoshioka, Tomoki Kosugi, Tomohiro Masuda, Tomoharu Watanabe, Akihiro Ryuge, Hiroshi Nagaya, Maeda Kayaho, Yuka Sato, Takayuki Katsuno, Noritoshi Kato, Takuji Ishimoto, Yukio Yuzawa, Shoichi Maruyama, Kenji Kadomatsu Podocytes, which are susceptible to injury by various stimuli and stress, are critical regulators of proteinuric kidney diseases, regardless of the primary disease and pathogenesis. We further confirmed a significant correlation between urinary CD147/Basigin (Bsg) levels and proteinuria in patients with focal segmental glomerulosclerosis. However, the molecular mechanism of podocyte injury involving Bsg is not fully understood. Here, we elucidated the involvement of Bsg in the pathogenesis of podocyte injury. Healthy podocytes rarely express Bsg protein. In two independent mouse models, including adriamycin-induced nephropathy and Nω-nitro-l-arginine methylester (L-NAME)-induced endothelial dysfunction, Bsg induction in injured podocytes caused podocyte effacement, which led to the development of proteinuria. Bsg silencing in cultured podocytes exposed to transforming growth factor-β suppressed focal adhesion rearrangement and cellular motility via the activation of β1 integrin–focal adhesion kinase–matrix metallopeptidase signaling. In addition, induction of vascular endothelial growth factor and endothelin-1, which are implicated in podocyte-to-endothelial cross-communication, was lower in the supernatants of cultured Bsg-silenced podocytes stimulated with transforming growth factor-β. In this setting, Bsg may be involved in a physiological positive feedback loop that accelerates podocyte cell motility and depolarization. The current study thus suggests that Bsg silencing via suppression of β1 integrin–focal adhesion kinase–matrix metallopeptidase signaling may be an attractive therapeutic strategy for the maintenance of podocytes in patients with proteinuric kidney diseases.
       
  • Pericytes: key players in spinal cord injury
    • Abstract: Publication date: Available online 20 April 2019Source: The American Journal of PathologyAuthor(s): Caroline C. Picoli, Leda M.C. Coimbra-Campos, Daniel A.P. Guerra, Walison N. Silva, Pedro H.D.M. Prazeres, Alinne C. Costa, Luiz A.V. Magno, Marco A. Romano-Silva, Akiva Mintz, Alexander Birbrair Spinal cord injury results in locomotor impairment due to the formation of an inhibitory fibrous scar, which prevents axonal regeneration following trauma. The scarcity of knowledge about the molecular and cellular mechanisms involved in scar formation following spinal cord lesion impede the design of effective therapies. Recent studies, by using state-of-art technologies, including genetic tracking and blockage of pericytes in combination with optogenetics, reveal that pericytes blockage facilitates axonal regeneration, and neuronal integration into the local neural circuitry. Strikingly, a pericyte subset is essential during scarring after spinal cord injury, and its arrest results in motor performance improvement. The arising knowledge from current research will contribute to novel approaches to develop therapies for spinal cord injury. Here, we review novel advances in our understanding of pericyte biology in the spinal cord.
       
  • Stimulating Type 1 Angiotensin Receptors on T Lymphocytes Attenuates Renal
           Fibrosis
    • Abstract: Publication date: Available online 15 April 2019Source: The American Journal of PathologyAuthor(s): Yi Wen, Nathan P. Rudemiller, Jiandong Zhang, Alexander D. Jeffs, Robert Griffiths, Xiaohan Lu, Jiafa Ren, Jamie Privratsky, Steven D. CrowleyMost forms of chronic kidney disease culminate in renal fibrosis that heralds organ failure. In contrast to the protective effects of globally blocking type 1 angiotensin (AT1) receptors throughout the body, activating AT1 receptors directly on immune cells may serve protective functions. However, the effects of stimulating the T-cell AT1 receptor on the progression of renal fibrosis remain unknown. In this study, mice with T-cell–specific deletion of the dominant murine AT1 receptor isoform Lck-Cre Agtraflox/flox [total knockout (TKO)] and wild-type (WT) controls were subjected to the unilateral ureteral obstruction model of kidney fibrosis. Compared with WT controls, obstructed kidneys from TKO mice at day 14 had increased collagen 1 deposition. CD4+ T cells, CD11b+Ly6Chi myeloid cells, and mRNA levels of Th1 inflammatory cytokines are elevated in obstructed TKO kidneys, suggesting that augmented Th1 responses in the TKO mice may exaggerate renal fibrosis by driving proinflammatory macrophage differentiation. In turn, T-bet deficient (T-bet knockout) mice lacking Th1 responses have attenuated collagen deposition after unilateral ureteral obstruction. We conclude that activating the AT1 receptor on T cells mitigates renal fibrogenesis by inhibiting Th1 differentiation and renal accumulation of profibrotic macrophages.
       
  • Uterine Epithelial Development and EZH2: It’s Important for More
           than Just Cancer
    • Abstract: Publication date: Available online 13 April 2019Source: The American Journal of PathologyAuthor(s): Xiyin Wang, Shannon M. Hawkins
       
  • This Month in AJP
    • Abstract: Publication date: Available online 13 April 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
       
  • Centrosomal proteins in urothelial tumors: new pathways in disease
           pathogenesis
    • Abstract: Publication date: Available online 13 April 2019Source: The American Journal of PathologyAuthor(s): Zoran Culig
       
  • Cognitive Decline, Cerebral-Spleen Tryptophan Metabolism, Oxidative
           Stress, Cytokine Production, and Regulation of the Txnip Gene in 3xTg-AD
           Mice
    • Abstract: Publication date: Available online 10 April 2019Source: The American Journal of PathologyAuthor(s): Emre Fertan., Gloria Rodrigues, Ryan V. Wheeler, Donna Goguen, Aimee A. Wong, Hana James, Andrew Stadnyk, Richard E. Brown, Ian C.G. WeaverPathological inflammation in response to injury, infection, or oxidative stress is a proposed mechanism relating cognitive decline to dementia. The kynurenine pathway and thioredoxin-interacting protein (TXNIP) activity regulate inflammation and neurotoxicity in Alzheimer disease (AD). We examined cognitive deficits, kynurenine pathway mediators, TXNIP, and oxidative damage in the cerebrum and spleen, as well as inflammatory cytokine production by stimulated splenocytes, from female 3xTg-AD mice in early and late stages of disease progression. We also characterized tissue-specific epigenetic regulation of Txnip gene expression in the cerebrum and spleen. Here we show that cognitive deficits in 7-month–old 3xTg-AD mice are associated with a stable increase in cerebrum and spleen tryptophan metabolites, with a concomitant increase in Aβ40/Aβ42 and tau/p-tau pathologies and a coordinated reduction in spleen pro-inflammatory cytokine production in 17-month–old mice. The enhanced cerebrum TXNIP expression is associated with increased histone acetylation, transcription factor (Aβ42, CTCF) binding and Txnip promoter hypomethylation, whereas the attenuated spleen TXNIP expression is associated with increased histone methylation, reduced CTCF binding, and Txnip promoter hypermethylation. These results suggest a causal relationship among epigenomic state, TXNIP expression, cerebral-spleen tryptophan metabolism, inflammatory cytokine production, and cognitive decline, and provide a potential mechanism for Txnip gene regulation in normal and pathological conditions, suggesting TXNIP levels may be a useful predictive or diagnostic biomarker for Aβ40/Aβ42 targeted AD therapies.
       
  • USP15 Maintains Transforming Growth Factor-β Pathway Activity by
           Deubiquitinating TGF-β Receptor I (TBR1) during Wound Healing
    • Abstract: Publication date: Available online 10 April 2019Source: The American Journal of PathologyAuthor(s): Yixuan Zhao, Zi Wang, Chiakang Ho, Guoyou Zhang, Qingfeng LiWound healing is a process of cutaneous barrier reconstruction that occurs after skin injury and involves diverse cytokines and cell types. Similar to several deubiquitinating enzymes, ubiquitin-specific peptidase 15 (USP15) can remove ubiquitin chains from specific proteins to rescue them from degradation. However, the regulatory role of USP15 in wound healing remains unclear. We investigated the dynamic function of USP15 in wound healing. First, in USP15 knockout mice, we observed a significant delay in wound closure. In addition, inhibition of cell proliferation and migration was observed in USP15-silenced human dermal fibroblasts. Through RNA sequencing, it was revealed that the transforming growth factor-β (TGF-β) pathway was suppressed after USP15 knockdown. Furthermore, co-immunoprecipitation (Co-IP) demonstrated that USP15 could interact with TGF-β receptor I (TBR1) and promote its deubiquitination, thereby maintaining TGF-β signalling pathway activity by enhancing TBR1 stability. These observations shed light on the function and mechanisms of USP15-mediated modulation of the TGF-β signalling pathway during wound healing, thus providing a novel potential target for the treatment of refractory wounds.
       
  • EZH2 Is Required for Uterine Epithelial Integrity
    • Abstract: Publication date: Available online 5 April 2019Source: The American Journal of PathologyAuthor(s): Xin Fang, Nan Ni, John P. Lydon, Ivan Ivanov, Kayla J. Bayless, Monique Rijnkels, Qinglei Li Normal proliferation and differentiation of uterine epithelial cells are critical for uterine development and function. EZH2, a core component of Polycomb Repressive Complexes 2, possesses histone methyltransferase activity that catalyzes the trimethylation of lysine 27 of histone H3. EZH2 has been involved in epithelial to mesenchymal transition (EMT), a key event in development and carcinogenesis. However, its role in uterine epithelial cell function remains unknown. To determine the role of uterine EZH2, Ezh2 was conditionally deleted using progesterone receptor Cre recombinase, which is expressed in both epithelial and mesenchymal compartments of the uterus. Loss of EZH2 promoted stratification of uterine epithelium, an uncommon and detrimental event in the uterus. The abnormal epithelium expressed basal cell markers including p63, KRT5, KRT6A, and KRT14. These results suggest that EZH2 serves as a guardian of uterine epithelial integrity partially via inhibiting the differentiation of basal-like cells and preventing epithelial stratification. The observed epithelial abnormality was accompanied by fertility defects, altered uterine growth and function, and the development of endometrial hyperplasia. Thus, the Ezh2 conditional knockout mouse model may be useful to explore mechanisms that regulate endometrial homeostasis and uterine function.
       
  • Carboxyl Ester Lipase May Not Mediate Lipotoxic Injury during Severe Acute
           Pancreatitis
    • Abstract: Publication date: Available online 5 April 2019Source: The American Journal of PathologyAuthor(s): Biswajit Khatua, Ram N. Trivedi, Pawan Noel, Krutika Patel, Ravinder Singh, Cristiane de Oliveira, Shubham Trivedi, Vivek Mishra, Mark Lowe, Vijay P. Singh Acute lipolysis of visceral fat or circulating triglycerides may worsen acute pancreatitis–associated local and systemic injury. The pancreas expresses pancreatic triacylglycerol lipase (PNLIP), pancreatic lipase related protein 2 (PNLIPRP2), and carboxyl ester lipase (CEL), which may leak into the visceral fat or systemic circulation during pancreatitis. We thus aimed to determine the pancreatic lipase(s) regulating lipotoxicity during acute pancreatitis. For this acute pancreatitis–associated fat necrosis (FN) was analyzed using western blotting. Bile acid (liquid chromatography-tandem mass spectrometry/mass spectrometry) and fatty acid (using gas chromatography) concentrations were measured in human FN. The FN milieu was simulated in vitro using glyceryl trilinoleate, since linoleic acid is increased in FN. The bile acid requirements to effectively hydrolyze glyceryl trilinoleate were studied using exogenous or overexpressed lipases. The renal cell line (HEK 293) was used to study lipotoxic injury. Since dual pancreatic lipase knockouts are lethal, exocrine parotid acini lacking lipases were used to verify the results. PNLIP, PNLIPRP2, and CEL were increased in fat necrosis. Although PNLIP and PNLIPRP2 were equipotent in inducing lipolysis and lipotoxic injury, CEL required bile acid concentrations higher than in human fat necrosis. The high bile acid requirements for effective lipolysis make CEL an unlikely mediator of lipotoxic injury in acute pancreatitis. It remains to be explored whether PNLIP or PNLIPRP2 worsens acute pancreatitis severity in vivo.
       
  • Functional organotypic cultures of prostate tissues: a relevant
           preclinical model that preserves hypoxia sensitivity and calcium signaling
           
    • Abstract: Publication date: Available online 5 April 2019Source: The American Journal of PathologyAuthor(s): Sandy Figiel, Côme Pasqualin, Fanny Bery, Veronique Maupoil, Christophe Vandier, Marie Potier-Cartereau, Isabelle Domingo, Roseline Guibon, Franck Bruyere, Karine Maheo, Gaelle Fromont In prostate cancer research, there is a lack of valuable preclinical models. Tumor cell heterogeneity and sensitivity to microenvironment signals, such as hypoxia or extracellular calcium concentration, are difficult to reproduce. Here, we developed and characterized an ex vivo tissue culture model preserving these properties. Prostate tissue slices from 26 patients were maintained ex vivo under optimized culture conditions. The expression of markers associated with proliferation, androgen receptor signaling, and hypoxia was assessed by immunostaining. A Macro Zoom System Microscope was used to achieve real-time calcium fluorescence optical imaging. Tissue morphology was successfully maintained without necrosis for 5 days. Compared to native tumors and tissue cultured with androgens, androgen deprivation in the medium led to decreased expression of both androgen receptor and its target gene products, PSA and ERG. Ex vivo cultured slices were also sensitive to hypoxia since CAIX and Zeb1 protein levels increased in 1% oxygen. Exposure of slices to supra-physiological extracellular Ca2+ concentration induced a robust and rapid Ca2+ entry, with a greater response in tumor compared to non tumor tissue. This ex vivo model reproduces the morphological and functional characteristics of human prostate cancer, including sensitivity to androgen deprivation and induced response to hypoxia and extracellular Ca2+. It could therefore become an attractive tool for drug response prediction studies.
       
  • Hepatitis C virus infection and cholangiocarcinoma: An insight into
           epidemiological evidences and hypothetical mechanisms of oncogenesis
    • Abstract: Publication date: Available online 4 April 2019Source: The American Journal of PathologyAuthor(s): Maria-Cristina Navas, Shannon Glaser, Harshil Dhruv, Scott Celinski, Gianfranco Alpini, Fanyin Meng Hepatitis C Virus (HCV) infection is a global public health problem since it is a main cause of liver cirrhosis and hepatocellular carcinoma (HCC). This human oncogenic virus is also associated with the development of non-Hodgkin lymphoma and cholangiocarcinoma (CCA). The association between HCV infection and CCA has been examined in a number of epidemiological studies. However, in vivo and in vitro results demonstrating the oncogenic mechanisms of HCV in CCA development and progression are insufficient. Here, we review the epidemiological association of HCV and CCA and recent publications of studies of HCV infection of cholangiocytes and CCA cell lines as well as studies of viral infection performed with liver samples obtained from patients. In addition, we also discuss the preliminary results of in vitro assays of HCV protein expression in CCA cell lines. Finally, we discuss the hypothetical role of HCV infection in CCA development by induction of epithelial-mesenchymal transition and up-regulation of hedgehog signaling, and consequently biliary tree inflammation and liver fibrosis. Further studies are required to demonstrate these hypothesis and therefore to elucidate the mechanisms of HCV as a risk factor for CCA.
       
  • Overexpression of CEP72 Promotes Bladder Urothelial Carcinoma Cell
           Aggressiveness via Epigenetic CREB-Mediated Induction of SERPINE1
    • Abstract: Publication date: Available online 4 April 2019Source: The American Journal of PathologyAuthor(s): XiangDong Li, Pei Dong, WenSu Wei, LiJuan Jiang, ShengJie Guo, ChaoWen Huang, ZeFu Liu, JieWei Chen, FangJian Zhou, Dan Xie, ZhuoWei Liu A vital constituent of the centrosome involved in regulating the activity of the organelle during the cell cycle is Centrosomal protein 72 (CEP72), whose function in the case of human cancer yet lacks clarity. Expression dynamics of CEP72 and its clinical impact were examined in a large cohort of bladder tissues. Several experiments at both in vitro and in vivo levels on urothelial carcinoma of the bladder (UCB) cells were conducted to understand the role of this molecule along with the mechanisms. Overexpression of CEP72 in UCB was linked with the acquisition of an aggressive phenotype, which was associated with poor prognosis. In UCB cell lines, knockdown of CEP72 using short hairpin RNA was sufficient to inhibit cell invasiveness/metastasis, whereas ectopic overexpression of CEP72 promoted cell invasiveness and/or metastasis both in vitro and in vivo. CEP72 was demonstrated to induce UCB cell aggressiveness via up-regulation of an important target downstream, the serpin family member 1 (SERPINE1) gene (also known as plasminogen activator inhibitor, PAI1), ultimately leading to increased cancer cell invasiveness. Particularly, overexpression of CEP72 caused a sizeable increase of CREB binding at the SERPINE1 promoter leading to increased SERPINE1 transcription. Such observations are suggestive of the potential use of CEP72 as a therapeutic tool for UCB.
       
  • Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic
           Liver Injury
    • Abstract: Publication date: Available online 28 March 2019Source: The American Journal of PathologyAuthor(s): Patrick D. Wilkinson, Frances Alencastro, Evan R. Delgado, Madeleine P. Leek, Matthew P. Weirich, P. Anthony Otero, Nairita Roy, Whitney K. Brown, Michael Oertel, Andrew W. DuncanThe liver contains diploid and polyploid hepatocytes (tetraploid, octaploid, etc.), with polyploids comprising ≥90% of the hepatocyte population in adult mice. Polyploid hepatocytes form multipolar spindles in mitosis, which lead to chromosome gains/losses and random aneuploidy. The effect of aneuploidy on liver function is unclear, and the degree of liver aneuploidy is debated, with reports showing aneuploidy affects 5% to 60% of hepatocytes. To study the relationship between liver polyploidy, aneuploidy, and adaptation, mice lacking E2f7 and E2f8 in the liver (LKO), which have a polyploidization defect, were used. Polyploids were reduced 4-fold in LKO livers, and LKO hepatocytes remained predominantly diploid following extensive proliferation. Moreover, nearly all LKO hepatocytes were euploid compared to control hepatocytes, suggesting polyploid hepatocytes are required for production of aneuploid progeny. To determine if reduced polyploidy impairs adaptation, LKO mice were bred onto a tyrosinemia background, a disease model where the liver can develop disease-resistant, regenerative nodules. Although tyrosinemic LKO mice were more susceptible to morbidities and death associated with tyrosinemia-induced liver failure, they developed regenerating nodules similar to controls. Analyses revealed that the nodules in the tyrosinemic livers were generated via aneuploidy and inactivating mutations. In summary, we identified new roles for polyploid hepatocytes and demonstrated that they are required for the formation of aneuploid progeny and can facilitate adaptation to chronic liver disease.
       
  • Loss of the Na+/H+ exchange regulatory factor 1 increases susceptibility
           to cisplatin-induced acute kidney injury
    • Abstract: Publication date: Available online 27 March 2019Source: The American Journal of PathologyAuthor(s): Adrienne Bushau-Sprinkle, Michelle Barati, Caryl Conklin, Tess Dupre, Kenneth B. Gagnon, Syed Jalal Khundmiri, Barbara Clark, Leah Siskind, Mark A. Doll, Madhavi Rane, Michael Brier, Susan Coventry, Eleanor LedererABSTRACTThe Na+/H+ exchange regulatory factor 1 (NHERF1) is a scaffolding protein that anchors multiple membrane proteins in renal proximal tubules. Cultured proximal tubule cells deficient in NHERF1 and proximal tubules from NHERF1 deficient mice exhibit aberrant trafficking. NHERF1 deficient cells also exhibit altered transcription pattern and worse survival. These observations suggest the hypothesis that NHERF1 loss increases susceptibility to acute kidney injury (AKI). Male and female WT C57BL/6J and NHERF1 KO mice were treated with saline or cisplatin (20 mg/kg dose IP) to induce AKI and euthanized after 72 hours. Blood was collected for blood urea nitrogen (BUN). Urine was collected for neutrophil gelatinase-associated lipocalin. Kidneys were harvested for histology (hematoxylin and eosin, periodic acid-schiff), TUNEL assay, KIM1 mRNA assessment, and Western Blot for cleaved caspase 3. Cisplatin caused significantly greater severity of kidney injury in KO compared to WT mice as demonstrated by semi-quantitative injury score (WT: 1.89, KO: 2.8) (P < 0.001), BUN levels (WT: 97.8 mg/dL ± 10.1, KO: 151.8 mg/dL ± 17.2) (P < 0.05), and neutrophil gelatinase-associated lipocalin urine protein (WT: 2.7 μg/mL ± 0.53, KO: 55.6 μg/mL ± 21.3) (P < 0.05). Apoptosis markers were significantly increased in cisplatin-treated NHERF1 KO and WT mice compared to respective controls. These data demonstrate NHERF1 loss increases susceptibility to AKI.
       
  • Expression and Localization of DDX3 in Prostate Cancer Progression and
           Metastasis
    • Abstract: Publication date: Available online 27 March 2019Source: The American Journal of PathologyAuthor(s): Jordan E. Vellky, Emily A. Ricke, Wei Huang, William A. RickeABSTRACTSurvival rates drop significantly when localized prostate cancer (CaP) becomes metastatic, emphasizing the need for improved targeted therapies. DDX3, an RNA helicase, has widespread functions in RNA regulation, both in the nucleus and cytoplasm. Although DDX3 has been implicated as a prognostic marker for many cancers including primary CaP, its expression, localization, and function in metastatic CaP has not been interrogated. Analysis of meta-data and cell line models showed increased DDX3 expression in metastatic vs primary CaP and benign prostate. Quantification of DDX3 expression in 320 human prostate samples representing different stages of CaP progression, showed an increase in epithelial whole cell, cytoplasmic, and nuclear DDX3 in primary CaP compared to benign prostate. In metastatic tissues, cytoplasmic DDX3 remained highly expressed, whereas nuclear DDX3 significantly decreased compared to primary CaP, suggesting a potential role for cytoplasmic DDX3 in metastatic CaP. Genetic and pharmacologic loss of function for DDX3 in metastatic CaP showed a significant decrease in cell viability, proliferation, and motility, but did not affect apoptosis. The data suggest cytoplasmic DDX3 is highly expressed in metastatic CaP, and inhibiting DDX3 affects metastatic growth by decreasing proliferation and motility. These findings introduce a novel role for cytoplasmic DDX3 in CaP progression and provide a foundation for clinically targeting DDX3 in metastatic CaP.
       
  • An Overview of the Derivation and Function of Multinucleated Giant Cells
           and Their Role in Pathological Processes
    • Abstract: Publication date: Available online 27 March 2019Source: The American Journal of PathologyAuthor(s): Patricia Joyce Brooks, Michael Glogauer, Christopher Allan McCullochMonocyte lineage cells play important roles in health and disease. Their differentiation into macrophages is crucial for a broad array of immunological processes that regulate inflammation, neoplasia, and infection. In certain pathological conditions, such as foreign body reactions and peripheral inflammatory lesions, monocytes fuse to form large, multinucleated giant cells (MGCs). Currently, our knowledge of the fusion mechanisms of monocytes and the regulation of MGC formation and function in discrete pathologies is limited. Here we consider the types and function of MGCs in disease and assess the mechanisms by which monocyte fusion contributes to the formation of MGCs. An improved understanding of the cellular origins and metabolic functions of MGCs will facilitate their identification and ultimately the treatment of diseases and disorders that involve MGCs.
       
  • A novel combination of prion strain co-occurrence in patients with
           sporadic Creutzfeldt-Jakob disease
    • Abstract: Publication date: Available online 27 March 2019Source: The American Journal of PathologyAuthor(s): Atsushi Kobayashi, Yasushi Iwasaki, Masaki Takao, Yuko Saito, Toru Iwaki, Zechen Qi, Ryouta Torimoto, Taishi Shimazaki, Yoshiko Munesue, Norikazu Isoda, Hirofumi Sawa, Keisuke Aoshima, Takashi Kimura, Hinako Kondo, Shirou Mohri, Tetsuyuki Kitamoto Six subgroups of sporadic Creutzfeldt-Jakob disease have been identified by distinctive clinicopathological features, genotype at polymorphic codon 129 (methionine/valine, M/V) of the PRNP gene, and type of abnormal prion proteins (type 1 or 2). In addition to the pure subgroups, mixed neuropathological features and co-existence of two types of abnormal prion proteins in the same patient have also been reported. Here, we found that a portion of the patients previously diagnosed as MM1 had neuropathological characteristics of MM2 thalamic form, ie, neuronal loss of the inferior olivary nucleus of the medulla. Furthermore, co-existence of biochemical features of MM2 thalamic form was also confirmed in the identified cases. In addition, in transmission experiments using prion protein–humanized mice, the brain material from the identified case showed weak infectivity and generated characteristic abnormal prion proteins in the inoculated mice resembling those after inoculation with a brain material of MM2 thalamic form. Taken together, these results show that the co-occurrence of MM1 and MM2 thalamic form is a novel entity of sporadic Creutzfeldt-Jakob disease prion strain co-occurrence. The present study raises the possibility that the co-occurrence of MM2 thalamic form might have been overlooked so far due to scarcity of abnormal prion protein accumulation and restricted neuropathology.
       
  • Lack of P2X7 receptors protects against renal fibrosis after
           pyelonephritis with α-hemolysin producing Escherichia coli
    • Abstract: Publication date: Available online 27 March 2019Source: The American Journal of PathologyAuthor(s): Jacob Rudjord Therkildsen, Mette Graversgård Christensen, Stine Julie Tingskov, Julia Wehmöller, Rikke Nørregaard, Helle A. PraetoriusSevere urinary tract infections are commonly caused by sub-strains of Escherichia coli secreting the pore-forming virulence factor α-hemolysin (HlyA). Repeated or severe cases of pyelonephritis can cause renal scarring that subsequently can lead to progressive failure. We have previously demonstrated that HlyA releases cellular ATP directly through its membrane pore and that acute HlyA-induced cell damage is completely prevented by blocking ATP-signaling. Local ATP signaling and P2X7 receptor activation play a key role in the development of tissue fibrosis. This study investigated the effect of P2X7 receptors on infection-induced renal scarring in a murine model of pyelonephritis. Pyelonephritis was induced by injecting 100 million HlyA-producing, uropathogenic E. coli into the urinary bladder of BALB/cJ mice. Similar degree of pyelonephritis and mortality was confirmed at day 5 postinfection in P2X7+/+ and P2X7−/− mice. Fibrosis was first observed two weeks postinfection and the data clearly demonstrated that P2X7−/− mice and mice exposed to the P2X7 antagonist BBG show markedly less renal fibrosis 14 days postinfection compared to controls (P < 0.001). Immunohistochemistry revealed comparable early neutrophil infiltration in renal cortex from P2X7+/+ and P2X7−/− mice. Interestingly, lack of P2X7 receptors resulted in diminished macrophage infiltration and reduced neutrophil clearance in the cortex of P2X7−/− mice. Hence, this study suggests the P2X7 receptor to be an appealing antifibrotic target following renal infections.
       
  • Understanding Hepatic and Pulmonary Veno-Occlusive Disease: Similarities
           and Differences
    • Abstract: Publication date: Available online 26 March 2019Source: The American Journal of PathologyAuthor(s): Sven Günther, Frédéric Perros, Pierre-Emmanuel Rautou, Barbara Girerd, Maria-Rosa Ghigna, Dominique Cazals-Hatem, Edmund M. Lau, Peter Dorfmüller, Olivier Sitbon, Dominique C. Valla, Marc Humbert, David MontaniHepatic veno-occlusive disease (HVOD), also known as sinusoidal obstruction syndrome, may develop as a complication of chemotherapy in the setting of hematopoietic stem cell transplantation. HVOD is less frequently described after exposure to chemotherapy in the non-transplant setting and can also be a complication following ingestion of toxins such as pyrrolizidine alkaloids. Veno-occlusive disease may also affect the lungs, and is therefore termed pulmonary veno-occlusive disease (PVOD). Similarly, PVOD can develop after exposure to chemotherapeutic agents in the treatment of solid and hematologic malignancies. In addition, PVOD has also been linked to autoimmune disorders and occupational solvent exposure. Finally, the heritable form of PVOD is due to bi-allelic mutations of the EIF2AK4 gene. Both HVOD and PVOD share common histopathologic features and pathophysiologic mechanisms. Both clinical disorders are rare complications that can appear after exposure to the common inciting trigger of chemotherapeutic agents. The present review aims to summarize the current knowledge of HVOD and PVOD, and to describe both similarities as well as differences regarding both conditions.
       
  • Plexiform Arteriopathy in Rodent Models of Pulmonary Arterial Hypertension
    • Abstract: Publication date: Available online 26 March 2019Source: The American Journal of PathologyAuthor(s): Brandon L. Carman, Dan Predescu, Roberto Machado, Sanda A. PredescuAs time progresses, our understanding of disease pathology is propelled forward by technological advancements. Much of the advancements that aid in understanding disease mechanics are based on animal studies. Unfortunately, animal models often fail to recapitulate the entirety of the human disease. This is especially true with animal models used to study pulmonary arterial hypertension (PAH), a disease with two distinct phases. The first phase is defined by non-specific medial and adventitial thickening of the pulmonary artery, and is commonly reproduced in animal models including the classical models [ie, hypoxia-induced pulmonary hypertension, and monocrotaline lung injury model]. However, many animal models, including the classical models, fail to capture the progressive, or second phase of PAH. This is a stage defined by plexogenic arteriopathy, resulting in obliteration and occlusion of the small- to mid-sized pulmonary vessels. Each of these two phases results in severe pulmonary hypertension that directly leads to right ventricular hypertrophy, decompensated right heart failure, and death. Fortunately, newly developed animal models have begun to address the second, more severe side of PAH and aid in our ability to develop new therapeutics. Moreover, p38 MAPK activation emerges as a central molecular mediator of plexiform lesions in both, experimental models and human disease. Therefore, this review will focus on plexiform arteriopathy in experimental animal models of PAH.
       
  • This Month in AJP
    • Abstract: Publication date: Available online 19 March 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
       
  • Immediate Release of Gastrin-Releasing Peptide Mediates, Delayed
           Radiation-Induced Pulmonary Fibrosis
    • Abstract: Publication date: Available online 18 March 2019Source: The American Journal of PathologyAuthor(s): Robert M. Tighe, Karissa Heck, Erik Soderblom, Shutang Zhou, Anastasiya Birukova, Kenneth Young, Douglas Rouse, Jessica Vidas, Miglena K. Komforti, Christopher B. Toomey, Frank Cuttitta, Mary E. Sunday Radiation-induced pulmonary fibrosis is a progressive, serious condition in many subjects treated for thoracic malignancies or following accidental nuclear exposure. No biomarker exists for identifying the irradiated subjects most susceptible to pulmonary fibrosis. Previously, we determined that gastrin-releasing peptide (GRP) was elevated within days after birth in newborns exposed to hyperoxia that later developed chronic lung disease. The goal of the current study was to test whether radiation exposure triggers GRP release in mice and whether this contributes to RT-induced pulmonary fibrosis in vivo. We determined urine GRP levels and lung GRP immunostaining in mice 0-24 hours post-thoracic radiation (15 Gy). Urine GRP levels were significantly elevated between 24 hours post-radiation; GRP-blocking MoAb 2A11 given minutes post-radiation abrogated urine GRP levels by 6-12 hours and also altered phosphoprotein signaling pathways at 24 hours post-radiation. Strong extracellular GRP immunostaining was observed in lung at 6 hours post-radiation. Mice given one dose of GRP MoAb 2A11 24 hours post-radiation had significantly reduced myofibroblast accumulation and collagen deposition 15 weeks later, indicating protection against lung fibrosis. Therefore, elevation of urine GRP could be predictive of radiation-induced pulmonary fibrosis development. Additionally, transient GRP-blockade could mitigate pulmonary fibrosis in normal lung following therapeutic or accidental radiation exposure.
       
  • MRPL35 is up-regulated in colorectal cancer and regulates colorectal
           cancer cell growth and apoptosis
    • Abstract: Publication date: Available online 9 March 2019Source: The American Journal of PathologyAuthor(s): Litao Zhang, Peifen Lu, Lihong Yan, Lijun Yang, Yutao Wang, Junjun Chen, Jie Dai, Yahui Li, Zhiming Kang, Tao Bai, Yanfeng Xi, Jun Xu, Gongqin Sun, Tao Yang Mitochondrial ribosome proteins (MRPs), which are encoded by the nuclear genomic DNA, are important for mitochondrial-encoded protein synthesis and mitochondrial function. Emerging evidence suggests that several MRPs also exhibit important extra-mitochondrial functions, such as involvement in apoptosis, protein biosynthesis, and signal transduction. In this study, we demonstrate a significant role of mitochondrial ribosomal protein L35 in colorectal cancer (CRC). The expression of MRPL35 was higher in CRC tissues than in matched cancer-adjacent tissues and higher in CRC cells than in normal mucosal epithelial cells. Higher MRPL35 expression in CRC tissue correlated with shorter overall survival for CRC patients. In vitro, down-regulation of MRPL35 led to increased production of reactive oxygen species (ROS) together with DNA damage, loss of cell proliferation, G2/M arrest, a decrease in mitochondrial membrane potential, apoptosis, and autophagy induction. MRPL35 knockdown inhibited tumor proliferation in a CRC xenograft nude mouse model. Furthermore, overexpression of MRPL35 or treatment of cells with the ROS scavenger, N-acetyl cysteine (NAC), abrogated ROS production, cell cycle arrest, and apoptosis in vitro. These findings suggest that MRPL35 plays an essential role in the development of CRC and may be a potential therapeutic target for CRC.
       
  • TEA domain transcription factor 4 (TEAD4) is the major mediator of Yap
           oncogenic activity in mouse and human hepatoblastoma
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Jie Zhang, Pin Liu, Junyan Tao, Pan Wang, Yi Zhang, Xinhua Song, Li Che, Pavel Sumazin, Silvia Ribback, Andras Kiss, Zsuzsa Schaff, Antonio Cigliano, Frank Dombrowski, Carla Cossu, Rosa M. Pascale, Diego F. Calvisi, Satdarshan P. Monga, Xin Chen Hepatoblastoma (HB) is the most common type of pediatric liver cancer. Activation of Yes-associated protein (YAP) has been implicated in HB molecular pathogenesis. The transcriptional co-activator Yap regulates downstream gene expression through interaction with the TEA domain (TEAD) proteins. Nonetheless, YAP also displays functions that are independent of its transcriptional activity. The underlying molecular mechanisms by which Yap promotes HB development remain elusive. In the current study, we demonstrated that blocking TEAD function via the dominant negative form of TEAD2 (dnTEAD2) abolishes Yap-driven HB formation in mice and restrains human HB growth in vitro. When TEAD2 DNA binding domain was fused with VP16 transcriptional activation domain (TEAD2VP16), it synergized with activated β-catenin (ΔN90-β-catenin) to promote HB formation in vivo. Among TEAD genes, silencing of TEAD4 consistently inhibited tumor growth and Yap target gene expression in HB cell lines. Furthermore, TEAD4 mRNA expression was significantly higher in human HB lesions when compared with corresponding non-tumorous liver tissues. Human HB specimens also exhibited strong nuclear immunoreactivity for TEAD4. Altogether, data demonstrate that TEAD-mediated transcriptional activity is both sufficient and necessary for Yap-driven HB development. TEAD4 is the major TEAD isoform and Yap partner in human HB. Targeting TEAD4 may represent an effective treatment option for human HB.
       
  • Epidermis Activated Gsdma3 Enhances Thermogenesis of Brown Adipose Tissue
           through Interleukin-6/Stat3 Signaling
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Qin Chen, Peiliang Shi, Dingyu Wang, Qiyao Liu, Xu Li, Yufang Wang, Dayuan Zou, Zan Huang, Xiang Gao, Zhaoyu LinMissense mutations in the Gasdermin-A3 (Gsdma3) gene are associated with skin inflammation and hair loss in mice. However, the physiological function of Gsdma3 remains unclear. Here we reported that mice carrying the Gsdma3 Y344H mutation that encodes a presumptive activated form of Gsdma3, show increased heat production along with lower body fat percentages. Detailed analysis indicated that this metabolic phenotype is mediated by serum interleukin-6–induced up-regulation of thermogenesis in brown adipose tissue. The mutant form of Gsdma3 promotes the expression of interleukin-6 in the epidermis in a JNK signaling–dependent manner. The higher whole-body heat production in AE mice (alopecia and excoriation) could be suppressed by an interleukin-6 receptor/GP130 inhibitor. Our results uncovered Gsdma3/interleukin-6–dependent cross-talk between the skin and brown adipose tissue.
       
  • Genetic strain and sex differences in a hyperoxia-induced mouse model of
           varying severity of bronchopulmonary dysplasia
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Sean Leary, Pragnya Das, Devasena Ponnalagu, Harpreet Singh, Vineet BhandariBronchopulmonary dysplasia (BPD) is a disease prevalent in preterm babies with a need for supplemental oxygen resulting in impaired lung development and dysregulated vascularization. Epidemiological studies have shown that males are more prone to BPD and have a delayed recovery compared to females for reasons unknown. Here, we tried to recapitulate mild, moderate, and severe BPD, using two different strains of mice: CD1 (outbred) and C57BL/6 (inbred), in males and females. Aside from higher body weight in the CD1 strain, there were no other gross morphological differences with respect to alveolar development between the two strains. With respect to lung morphology after oxygen exposure, females had less injury with better preservation of alveolar chord length and decreased alveolar protein leak and inflammatory cells in the bronchoalveolar lavage fluid. In addition, housekeeping genes, which are routinely used as loading controls, were expressed differently in males and females. In the BPD mouse model, gonadotropin-releasing hormone was increased in females as compared to males. Specific microRNAs (miR146 and miR34a) were expressed differently in the sexes. In the severe BPD mouse model, administering miR146-mimic to males attenuated lung damage while administering miR-146 inhibitor to females increased pulmonary injury.
       
  • Intrinsic Bone Defects in Cystinotic Mice
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Giulia Battafarano, Michela Rossi, Laura Rita Rega, Gianna Di Giovamberardino, Anna Pastore, Matteo D'Agostini, Ottavia Porzio, Nathalie Nevo, Francesco Emma, Anna Taranta, Andrea Del FattoreCystinosis is a rare lysosomal storage disorder caused by loss of function mutations of the CTNS gene, encoding cystinosin, a symporter that mediates cystine efflux from lysosomes. About 95% of patients with cystinosis display renal Fanconi syndrome, short stature, osteopenia, and rickets . In this study, we investigated whether the absence of cystinosin primarily affects bone remodeling activity, apart from the influences of the Fanconi syndrome on bone mineral metabolism. Using micro-computed tomography, histomorphometric and bone serum biomarkers analysis, we evaluated the bone phenotype of one-month–old ctns-/- (KO) male mice without tubulopathy. In vitro study was performed to characterize the effects of cystinosin deficiency on osteoblasts and osteoclasts. Micro-computed tomography analysis showed a reduction of trabecular bone volume, bone mineral density, number and thickness in KO mice compared to wild-type animals; histomorphometric analysis revealed a reduction of osteoblast and osteoclast parameters in tibias of cystinotic mice. Decreased levels of serum P1NP and TRAcP in KO mice confirmed reduced bone remodeling activity. In vitro experiments showed an impairment of ctns-/- osteoblasts and osteoclasts. In conclusion, cystinosin deficiency primarily affects bone cells, leading to a bone loss phenotype of KO mice, independent from renal failure.
       
  • β-Catenin and yes-associated protein 1 cooperate in hepatoblastoma
           pathogenesis
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Qian Min, Laura Molina, Jing Li, Adeola O. Adebayo Michael, Jacquelyn O. Russell, Morgan E. Preziosi, Sucha Singh, Minakshi Poddar, Madlen Matz-Soja, Sarangarajan Ranganathan, Aaron W. Bell, Rolf Gebhardt, Frank Gaunitz, Jinming Yu, Junyan Tao, Satdarshan P. Monga Hepatoblastoma (HB), the most common pediatric primary liver neoplasm, show nuclear localization of β-catenin and yes-associated protein1 (YAP1) in almost 80% of the cases. Co-expression of constitutively active S127A-YAP1 and ΔN90 deletion-mutant-β-catenin (YAP1-ΔN90-β-catenin) causes HB in mice. Since heterogeneity in downstream signaling is being identified owing to mutational differences even in β-catenin gene alone, we investigated if co-expression of point-mutants of β-catenin (S33Y or S45Y) with S127A-YAP1 led to similar tumors as YAP1-ΔN90-β-catenin. Co-expression of S33Y/S45Y-β-catenin and S127A-YAP1 led to activation of Yap and Wnt signaling and development of HB with 100% mortality by 13 to 14 weeks. Co-expression with YAP1-S45Y/S33Y-β-catenin of the dominant-negative (dn) TCF4 or dnTEAD2, the respective surrogate transcription factors, prevented HB development. Although histologically similar, HB in YAP1-S45Y/S33Y-β-catenin, unlike YAP1-ΔN90-β-catenin HB were glutamine synthetase (GS)-positive. However, both ΔN90-β-catenin and point-mutant-β-catenin comparably induced GS-luciferase reporter in vitro. Finally, using a previously reported 16-gene signature, it was shown that YAP1-ΔN90-β-catenin HB tumors exhibit genetic similarities with more proliferative, less differentiated, GS-negative HB patient tumors, whereas YAP1-S33Y/S45Y-β-catenin HB exhibit heterogeneity and clustered with both well-differentiated GS-positive and proliferative GS-negative patient tumors. Thus, we demonstrate that β-catenin point mutants can also collaborate with YAP1 in HB development, albeit with distinct molecular profile from the deletion mutant, which may have implications in both biology and therapy.
       
  • Identification of CCDC180 and LRRC4 as Potential Immunohistochemical
           Markers for Liposarcoma Based on Proteomic Analysis Using Formalin-Fixed,
           Paraffin-Embedded Tissue
    • Abstract: Publication date: Available online 18 February 2019Source: The American Journal of PathologyAuthor(s): Tomoyuki Aoyama, Akira Takasawa, Kumi Takasawa, Yusuke Ono, Makoto Emori, Masaki Murata, Takahiro Hayasaka, Naoki Fujitani, Makoto Osanai, Toshihiko Yamashita, Tadashi Hasegawa, Norimasa SawadaRecent technical improvements in both mass spectrometry and protein extraction have made it possible to use formalin-fixed, paraffin-embedded (FFPE) tissues for proteome analysis. In this study, comparable proteome analysis of FFPE tissues revealed multiple candidate marker molecules for differentiating atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) from lipoma. One-hundred and eighty-one unique proteins were identified for ALT/WDL. Of the identified proteins, coiled-coil domain-containing protein 180 (CCDC180) and leucine-rich repeat-containing protein 4 (LRRC4) were studied as candidate markers of ALT/WDL. CCDC180 and LRRC4 immunohistochemistry clearly stained tumor cells of ALT/WDL and dedifferentiated liposarcoma and could differentiate them from lipoma with high accuracy. Cell biological methods were used to further examine the expression of the candidate marker molecules in liposarcoma cells. In liposarcoma cells, knockdown of CCDC180 and LRRC4 inhibited cell proliferation. CCDC180 inhibited cell migration, invasion, and apoptosis resistance in WDL cells. Adipogenic differentiation suppressed the expression of CCDC180 and LRRC4 in WDL cells. These results indicated that LRRC4 and CCDC180 are novel immunohistochemical markers for differentiating ALT/WDLS. Their expression was associated with adipocyte differentiation and contributed to malignant potentials of WDL cells. Proteome analysis using a standard stock of FFPE tissues can reveal novel biomarkers for various diseases, which contributes to the progress of molecular pathology.
       
  • Macrophage-Mediated Phagocytosis and Dissolution of Amyloid-Like Fibrils
           in Mice, Monitored by Optical Imaging
    • Abstract: Publication date: Available online 6 February 2019Source: The American Journal of PathologyAuthor(s): Tina Richey, James S. Foster, Angela D. Williams, Anna Bryn Williams, Alexa Stroh, Sallie Macy, Craig Wooliver, R. Eric Heidel, Siva Karthik Varanasi, Elizabeth N. Ergen, Dianne J. Trent, Stephen A. Kania, Stephen J. Kennel, Emily B. Martin, Jonathan S. WallLight chain–associated amyloidosis is characterized by the extracellular deposition of amyloid fibrils in abdominothoracic organs, skin, soft tissue, and peripheral nerves. Phagocytic cells of the innate immune system appear to be ineffective at clearing the material; however, human light chain amyloid extract, injected subcutaneously into mice, is rapidly cleared in a process that requires neutrophil activity. To better elucidate the phagocytosis of light chain fibrils, a potential method of cell-mediated dissolution, amyloid-like fibrils were labeled with the pH-sensitive dye pHrodo red and a near infrared fluorophore. After injecting this material subcutaneously in mice, optical imaging was used to quantitatively monitor phagocytosis and dissolution of fibrils concurrently. Histological evaluation of the residual fibril masses revealed the presence of CD68+, F4/80+, Iba-1- macrophages containing Congo red–stained fibrils as well as neutrophil-associated proteins with no evidence of intact neutrophils. These data suggest an early infiltration of neutrophils followed by extensive phagocytosis of the light chain fibrils by macrophages leading to dissolution of the mass. Optical imaging of this novel murine model, coupled with histological evaluation can be used to study the cellular mechanisms underlying dissolution of synthetic amyloid-like fibrils and human amyloid extracts. In addition, it may serve as a test bed to evaluate investigational opsonizing agents that might serve as therapeutic agents for light chain–associated amyloidosis.
       
  • MBD2 inhibits the malignant characteristic of lung adenocarcinoma through
           the epigenetic modulation of TET1 and mir-200s
    • Abstract: Publication date: Available online 5 February 2019Source: The American Journal of PathologyAuthor(s): Yao-fei Pei, Xiang-nan Xu, Zhi-fei Wang, Fu-wei Wang, Wei-ding Wu, Jun-feng Geng, Xi-qiang Liu It has been reported that disorders of epigenetic modulation play a critical role in carcinogenesis. MBD2 is known to act as an epigenetic modulator in various types of tumors; however, the role of MBD2 in lung adenocarcinoma (LUAD) remains unclear. Here, we demonstrated the down-regulation of MBD2 in LUAD compared with adjacent nontumor tissues. The down-regulation of MBD2 in LUAD was correlated with metastasis and poor survival. Additionally, MBD2 inhibited tumor metastasis by maintaining the expression of the mir-200s, which suppressed the invasive properties of tumors. Also, MBD2 positively correlated with 5-hmC content in mir-200s promoter. The conventional view is that MBD2 acts as a transcriptional suppressor. However, the data revealed that MBD2 may act as transcriptional activator by recruiting TET1 and forming a chromatin-remodeling complex. The MBD2-TET1 complex locates to the TET1 promoter and removes the methyl residues in this region, thereby activating TET1 transcription. TET1 also acted as tumor suppressor in LUAD. Taken together, the data demonstrate the correlation between MBD2, mir-200s, and TET1, and tumor suppressive effect of MBD2 through up-regulation of TET1 and the mir-200s.
       
  • Molecular Evaluation of Breast Ductal Carcinoma in Situ with
           Oncotype DX DCIS
    • Abstract: Publication date: Available online 31 December 2018Source: The American Journal of PathologyAuthor(s): Sharon Nofech-Mozes, Wedad Hanna, Eileen Rakovitch A subset of patients with ductal carcinoma in situ of the breast develop ipsilateral invasive breast cancer following breast conserving surgery with or without adjuvant radiotherapy. Risk assessment and PgRediction of adverse outcomes for individual patients based on traditional clinical and pathological parameters are limited. The Oncotype DCIS Score is a commercially available multigene assay that has been independently validated in PgRospective clinical trial and a population-based cohort. The score helps to identify a subset of women age>50 years with unifocal disease that carries
       
  • Morphologic and Molecular Features of Breast Ductal Carcinoma In Situ
    • Abstract: Publication date: Available online 29 October 2018Source: The American Journal of PathologyAuthor(s): Souzan Sanati Ductal carcinoma in situ (DCIS) encompasses a highly heterogeneous group of lesions that differ with regard to their clinical presentations, histologic features, biomarker profiles, genetic abnormalities, and potential for progression. DCIS is a non-obligatory precursor for invasive carcinoma. With the advent of screening mammography the incidence of DCIS has significantly increased. There is an argument that many of these lesions will not progress to invasive carcinoma within the lifetime of a patient. In addition, many studies have shown enormous heterogeneity within DCIS. There is a need for biomarkers that can stratify patients with DCIS into different prognostic groups based on the biology of the disease. Estrogen and progesterone receptors are the established biomarkers that are used for clinical decision making. In addition, a number of biomarkers such as HER2, p53 tumor suppressor gene, ki67 proliferation marker, and tumor infiltrating lymphocytes have been shown to carry prognostic significance although their use is considered investigational and has not been transferred to clinical practice. On the molecular level low-grade and high-grade DCIS have different molecular alterations and the intrinsic molecular subtypes that exist in invasive carcinoma also exist in DCIS with prognostic implications. In this manuscript we review the morphologic features, prognostic biomarkers, and molecular features of ductal carcinoma in situ.
       
  • Ductal Carcinoma in Situ Biomarkers in a Precision Medicine Era: Current
           and Future Molecular-Based Testing
    • Abstract: Publication date: Available online 29 October 2018Source: The American Journal of PathologyAuthor(s): Kevin Shee, Kristen E. Muller, Jonathan Marotti, Todd W. Miller, Wendy A. Wells, Gregory J. Tsongalis Historically, ductal carcinoma in situ (DCIS) of the breast has been managed aggressively with surgery and radiation due to a risk of progression to invasive ductal carcinoma. However, this treatment paradigm has been challenged by overtreatment concerns and evidence suggesting that DCIS can be stratified according to risk of recurrence, or risk of progression to invasive disease. Traditional methods of risk stratification include histologic grade and hormone receptor status. Recent technological advancements have enabled an era of precision medicine, where DCIS can be molecularly analyzed by tools such as next-generation DNA and RNA sequencing to identify molecular biomarkers for risk stratification. These findings have led to the development of tools such as the Oncotype DXBreast DCIS Score, a gene expression-based assay with the potential to prevent overtreatment in low-risk disease.
       
  • Functional Role of microRNAs in the Progression of Breast Ductal Carcinoma
           in situ
    • Abstract: Publication date: Available online 29 September 2018Source: The American Journal of PathologyAuthor(s): Bethany N. Hannafon, Wei-Qun Ding microRNAs (miRNAs) are small RNAs that influence gene expression by targeting messenger RNAs (mRNAs). Depending on the function of their target genes, miRNAs may regulate the expression of oncogenes and tumor suppressors, thereby contributing to the promotion or inhibition of tumor progression. Ductal carcinoma in situ (DCIS), although often diagnosed as breast cancer, is a potential precursor to invasive ductal carcinoma. Many of the genetic events required for the invasive progression of DCIS occur at the pre-invasive stage, and these events include changes to the expression of miRNAs. Aberrant expression of miRNAs can influence specific oncogenic or tumor suppressive pathways required for breast cancer progression. miRNAs in DCIS have been shown to influence hormone signaling, cell-cell adhesion, epithelial to mesenchymal transition, TGF-β signaling, maintenance of cancer stem cells, and modulation of the extracellular matrix. Additionally, extracellular DCIS miRNAs, such as those found in exosomes, may promote invasive progression by modifying the tumor microenvironment. Here, we review the miRNAs that have been identified in DCIS and how they may contribute to the progression to invasive disease. We also touch on the current state of miRNA therapeutic development, including the current challenges, and discuss the key future perspectives for research into miRNA function for the purpose of miRNA therapeutic development against DCIS.
       
 
 
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