Heparanase level and procoagulant activity are increased in thalassemia and attenuated by JAK-2 inhibition
Patients with thalassemia demonstrate an increased risk of thrombotic events that is augmented following splenectomy. Heparanase protein, aside from enhancing cancer progression, angiogenesis and inflammation, is shown to activate the coagulation system through direct interaction with tissue factor (TF). Additionally, erythropoietin, elevated in anemic patients, is found to upregulate heparanase expression via the JAK-2 pathway. The study aim was to explore the heparanase profile in thalassemia. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 31, 2020 Category: Pathology Authors: Hussam Ghoti, Shanny Ackerman, Stefano Rivella, Carla Casu, Yona Nadir Tags: Regular Article Source Type: research

Medical treatment can unintentionally alter the Treg compartment in patients with widespread pathophysiologic conditions
Regulatory T cells (Tregs) are non-redundant mediators of immune tolerance, critical to prevent autoimmune disease and promote an anti-inflammatory tissue environment. Many individuals experience diseases of a chronic nature and physiological changes associated with aging requiring long-term medication. Unfortunately, side-affects accompany every pharmacologic intervention and may impact overall outcomes. Here we focus on medications typically prescribed during the treatment of prevalent chronic diseases/disorders including cardiovascular disease, autoimmune disease, and menopausal symptoms affecting>200 million individ...
Source: American Journal of Pathology - July 31, 2020 Category: Pathology Authors: Sabrina N. Copsel, Thomas R. Malek, Robert B. Levy Tags: Review Source Type: research

ACE gene polymorphism and severe lung injury in patients with COVID-19
COVID-19 has markedly varied clinical presentations, with the majority of patients being asymptomatic or having mild symptoms. However, severe acute respiratory disease caused by SARS-CoV-2 is common and associated with mortality in patients who require hospitalization. The etiology of susceptibility to severe lung injury remains unclear. Angiotensin II, converted by angiotensin-converting enzyme (ACE) from angiotensin I and metabolized by angiotensin converting enzyme 2 (ACE2), plays a pivotal role in the pathogenesis of lung injury. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 28, 2020 Category: Pathology Authors: Haoyi Zheng, J. Jane Cao Tags: Mini-Review Source Type: research

“Retinoid-related orphan receptor RORγt in CD4+T cell–mediated intestinal homeostasis and inflammation.”
ROR γt, a retinoid orphan nuclear receptor and the master transcription factor of the Th17 subset of CD4+T helper cells, is one of the most promising targets to treat a host of autoimmune diseases. This includes the inflammatory bowel diseases (IBD)—Crohn’s disease (CD) and ulcerative colitis (UC)— caused by untoward reactivity of the immune system to the components of the intestinal microbiome. The mammalian intestinal tract is a highly complex and compartmentalized organ with specialized functions, and is a privileged site for the generation of both peripherally induced regulatory CD4+ T cel ls (T...
Source: American Journal of Pathology - July 28, 2020 Category: Pathology Authors: Michel Edwar Mickael, Suniti Bhaumik, Rajatava Basu. Tags: Review Source Type: research

Editorial Board
(Source: American Journal of Pathology)
Source: American Journal of Pathology - July 23, 2020 Category: Pathology Source Type: research

Table of Contents
(Source: American Journal of Pathology)
Source: American Journal of Pathology - July 23, 2020 Category: Pathology Source Type: research

Knockout of the tachykinin receptor 1 in the Mdr2-/- mouse model of primary sclerosing cholangitis reduces biliary damage and liver fibrosis
Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated (BDL) and Mdr2-/- mice through enhanced transforming growth factor- β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for microRNA (miR)-31 in TGF-β1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with d ouble knockout of Mdr2-/- and NK1R to further address the role of the SP/NK1R axis during chronic cho...
Source: American Journal of Pathology - July 22, 2020 Category: Pathology Authors: Ludovica Ceci, Heather Francis, Tianhao Zhou, Thao Giang, Zhihong Yang, Fanyin Meng, Nan Wu, Lindsey Kennedy, Konstantina Kyritsi, Vik Meadows, Chaodong Wu, Suthat Liangpunsakul, Antonio Franchitto, Amelia Sybenga, Burcin Ekser, Romina Mancinelli, Paolo O Tags: Regular Article Source Type: research

Association of neutrophil extracellular traps with the development of idiopathic osteonecrosis of the femoral head
Idiopathic osteonecrosis of the femoral head (ONFH) is defined as necrosis of osteocytes due to a non-traumatic ischemia of the femoral head. Iatrogenic glucocorticoid administration and habitual alcohol intake are regarded as risk factors. It has been suggested that glucocorticoid-induced activation of platelets contribute to the local blood flow disturbance of the femoral head. Both activated platelets and alcohol can induce neutrophil extracellular traps (NETs). To determine the association of NETs with the development of idiopathic ONFH, surgically resected femoral heads of patients with idiopathic ONFH and osteoarthri...
Source: American Journal of Pathology - July 20, 2020 Category: Pathology Authors: Mayu Nonokawa, Tomohiro Shimizu, Miku Yoshinari, Yamato Hashimoto, Yusuke Nakamura, Daisuke Takahashi, Tsuyoshi Asano, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Norimasa Iwasaki, Akihiro Ishizu Source Type: research

The guanine nucleotide exchange factor, LARG, and RhoC play a role in glioblastoma cell invasion and resistance
Glioblastoma (GBM) is the most common primary malignant brain cancer in adults. A hallmark of GBM is aggressive invasion of tumor cells into the surrounding normal brain. The current standard of care therapy, as well as targeted therapies, have largely failed to specifically address this issue. Therefore, identifying key regulators of GBM cell migration and invasion is of particular interest. The leukemia-associated RhoGEF (LARG) has previously been implicated in cell invasion in other tumor types; however, the role of LARG in GBM pathobiology remains undefined. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 18, 2020 Category: Pathology Authors: Zonghui Ding, Zhiwan Dong, Yuping Yang, Shannon P. Fortin Ensign, Hemragul Sabit, Mitsutoshi Nakada, Rosamaria Ruggieri, Jean M. Kloss, Marc Symons, Nhan L. Tran, Joseph C. Loftus Source Type: research

Glaucoma after ocular surgery or trauma: the role of infiltrating monocytes and their response to cytokine inhibitors.
Glaucoma is a frequent and devastating long-term complication following ocular trauma, including corneal surgery, open globe injury, chemical burn, infection, etc. Post-event inflammation and neuroglial remodeling plays a key role in subsequent ganglion cell apoptosis and glaucoma. To this end, this study was designed to investigate the amplifying role of monocyte infiltration into the retina. By using 3 different ocular injury mouse models (corneal suture, penetrating keratoplasty, and globe injury) and monocyte fate mapping techniques we show that ocular trauma or surgery can cause robust infiltration of bone marrow-deri...
Source: American Journal of Pathology - July 18, 2020 Category: Pathology Authors: Xiaoniao Chen, Fengyang Lei, Chengxin Zhou, James Chodosh, Liqiang Wang, Yifei Huang, Claes H. Dohlman, Eleftherios I. Paschalis Source Type: research

This Month in AJP
The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 17, 2020 Category: Pathology Tags: This Month in AJP Source Type: research

This Month in AJP (TMIA)
Galectin-3 May Facilitate Cardiac Wound Healing (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 17, 2020 Category: Pathology Authors: Chhavi Chauhan Tags: This Month in AJP Source Type: research

Lacrimal Gland Myoepithelial Cells Are Altered in a Mouse Model of Dry Eye Disease
The purpose of this study was to determine the pathogenic changes that occur in myoepithelial cells (MECs) from lacrimal glands of a mouse model of Sjogren ’s syndrome. MECs were cultured from lacrimal glands of C57BL/6J (wild type, WT), and thrombospondin 1 null (TSP1-/-) mice, and from mice expressing smooth muscle actin-GFP (SMA-GFP) that labels MECs. MECs were stimulated with cholinergic and α1-adrenergic agonists, vasoactive intestinal peptide (VIP), and the purinergic (P)2 agonists, ATP and UTP. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 14, 2020 Category: Pathology Authors: Laura Garc ía-Posadas, Robin R. Hodges, Tor P. Utheim, Ole Kristoffer Olstad, Vanessa Delcroix, Helen Makarenkova, Darlene A. Dartt Tags: Regular Article Source Type: research

Expression of DNA methyltransferase 1 is a hallmark of melanoma, correlates with response to BRAF and MEK inhibition and with proliferation in melanocytic tumors.
Aberrant DNA methylation is an epigenetic hallmark of melanoma and hypomethylating drugs with immunomodulatory activity are currently investigated in clinical trials. DNA methyltransferase 1 (DNMT1) is the major maintenance methyltransferase but its expression in melanocytic tumors is unknown. We analyzed DNMT1 expression in primary melanocytes, melanoma cell lines and 83 melanocytic tumors and explored its association with proliferation, mutational status and response to BRAF and MEK inhibition. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 14, 2020 Category: Pathology Authors: Maximilian Gassenmaier, Maximilian Rentschler, Birgit Fehrenbacher, Thomas Kurt Eigentler, Kristian Ikenberg, Corinna Kosnopfel, Tobias Sinnberg, Heike Niessner, Hans B ösmüller, Nikolaus Benjamin Wagner, Martin Schaller, Claus Garbe, Martin Röcken Tags: Regular Article Source Type: research

Lysosome Associated Protein Transmembrane 4B (LAPTM4B)-24 is the predominant protein isoform in human tissues and undergoes rapid, nutrient-regulated turnover
Studies of Lysosome Associated Protein Transmembrane 4B (LAPTM4B) have mainly focused on the 35 kDa isoform and its association with poor prognosis in cancers. Here, by employing a novel monoclonal antibody we found that the 24 kDa LAPTM4B isoform predominated in most, both healthy and malignant, human cells and tissues studied. LAPTM4B-24 lacks the extreme N-terminus and contrary to LAPTM4B-35, failed to promote cell migration. The endogenous LAPTM4B-24 protein was subject to rapid turnover with a t1/2 ∼1 h. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 14, 2020 Category: Pathology Authors: Kecheng Zhou, Andrea Dichlberger, Elina Ikonen, Tomas Blom Tags: Regular Article Source Type: research

Decidual Vasculopathy Identification in Whole Slide Images Using Multiresolution Hierarchical Convolutional Neural Networks
After a child is born, the examination of the placenta by a pathologist for abnormalities, such as infection or maternal vascular malperfusion, can provide important information about the immediate and long-term health of the infant. Detection of the pathologic placental blood vessel lesion decidual vasculopathy (DV) has been shown to predict adverse pregnancy outcomes, such as preeclampsia, which can lead to mother and neonatal morbidity in subsequent pregnancies. However, because of the high volume of deliveries at large hospitals and limited resources, currently a large proportion of delivered placentas are being discar...
Source: American Journal of Pathology - July 13, 2020 Category: Pathology Authors: Daniel Clymer, Stefan Kostadinov, Janet Catov, Lauren Skvarca, Liron Pantanowitz, Jonathan Cagan, Philip LeDuc Tags: Regular article Source Type: research

Decidual Vasculopathy Identification in Whole Slide Images Using Multi-Resolution Hierarchical Convolutional Neural Networks
After a child is born, the examination of the placenta by a pathologist for abnormalities such as infection or maternal vascular malperfusion can provide important information about the immediate and long-term health of the infant. Detection of the pathologic placental blood vessel lesion decidual vasculopathy (DV) has been shown to predict adverse pregnancy outcomes such as pre-eclampsia, which can lead to mother and neonatal morbidity in subsequent pregnancies. However, due to the high volume of deliveries at large hospitals and limited resources, currently a large proportion of delivered placentas are being discarded wi...
Source: American Journal of Pathology - July 13, 2020 Category: Pathology Authors: Daniel Clymer, Stefan Kostadinov, Janet Catov, Lauren Skvarca, Liron Pantanowitz, Jonathan Cagan, Philip LeDuc Tags: Regular Article Source Type: research

Eicosanoids
Severe coronavirus disease 2019 (COVID-19) symptoms, including systemic inflammatory response and multisystem organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum stress response and subsequent eicosanoid and cytokine storms. Although proinflammatory eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are critical mediators of physiological processes, such as inflammation, fever, allergy, and pain, their role in COVID-19 is poorly characterized. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Bruce D. Hammock, Weicang Wang, Molly M. Gilligan, Dipak Panigrahy Tags: Mini-review Source Type: research

WITHDRAWN: ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITH OUTCOME AND SYMPTOMS
The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.ajpath.2020.07.001. The duplicate article has therefore been withdrawn.The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Kimon V. Argyropoulos, Antonio Serrano, Jiyuan Hu, Margaret Black, Xiaojun Feng, Guomiao Shen, Melissa Call, Min Jae Kim, Andrew Lytle, Brendan Belovarac, Theodore Vougiouklakis, Lawrence Hsu Lin, Una Moran, Adriana Heguy, Andrea Troxel, Matija Snuderl, I Source Type: research

Tenascin-C induces phenotypic changes in fibroblasts to myofibroblasts with high contractility through the integrin αvβ1/TGF-β/SMAD signaling axis in human breast cancer
Tenascin-C (TNC) is strongly expressed by fibroblasts and cancer cells in breast cancer. To assess the effects of TNC on stromal formation, we examined phenotypic changes in human mammary fibroblasts (HMFs) treated with TNC. The addition of TNC significantly up-regulated α-smooth muscle actin (SMA) and calponin. TNC increased the number of α-SMA- and/or calponin-positive cells with well-developed stress fibers in immunofluorescence, which enhanced contractile ability in collagen gel contraction. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Daisuke Katoh, Yuji Kozuka, Aya Noro, Tomoko Ogawa, Kyoko Imanaka-Yoshida, Toshimichi Yoshida Tags: Regular Article Source Type: research

The common microRNA signatures associated with mitochondrial dysfunction in different muscular dystrophies
Secondary mitochondrial damage in skeletal muscles is a common feature of different neuromuscular disorders (NMD), which fall outside the mitochondrial cytopathies. The common cause of mitochondrial dysfunction and structural changes in skeletal muscle tissue remains to be discovered. Although they are associated with different clinical, genetic, and pathological backgrounds, the pathomechanisms underlying NMDs might be attributed to the complex interaction and crosstalk between mitochondria and the associated microRNAs (miRNAs). (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Evrim Aksu-Menges, Yeliz Zulfiye Akkaya-Ulum, Didem Dayangac-Erden, Banu Balci-Peynircioglu, Ayse Yuzbasioglu, Haluk Topaloglu, Beril Talim, Burcu Balci-Hayta Tags: Regular Article Source Type: research

Myogenic cell expression of intercellular adhesion molecule-1 (ICAM-1) contributes to muscle regeneration after injury
We investigated intercellular adhesion molecule-1 (ICAM-1), a membrane protein that mediates cell-to-cell adhesion and communication, as a mechanism through which the inflammatory response facilitates muscle regeneration after injury. Toxin-induced muscle injury to tibialis anterior muscles of wild type mice caused ICAM-1 to be expressed by a population of satellite cells/myoblasts and myofibers. Myogenic cell expression of ICAM-1 contributed to the restoration of muscle structure after injury, as regenerating myofibers were more abundant and myofiber size was larger for wild type compared to ICAM-1-/- mice during 28 d of ...
Source: American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Ryan A. Martin, Kole H. Buckley, Drew C. Mankowski, Benjamin M. Riley, Alena N. Sidwell, Stephanie L. Douglas, Randall G. Worth, Francis X. Pizza Tags: Regular Article Source Type: research

Eicosanoids: the Overlooked Storm in COVID-19?
Severe coronavirus-19 (COVID-19) symptoms, including systemic inflammatory response and multi-system organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum (ER) stress response and subsequent eicosanoid and cytokine storms. While pro-inflammatory eicosanoids including prostaglandins, thromboxanes, and leukotrienes are critical mediators of physiological processes such as inflammation, fever, allergy, and pain, their role in COVID-19 are poorly characterized. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Bruce D. Hammock, Weicang Wang, Molly M. Gilligan, Dipak Panigrahy Tags: Mini-Review Source Type: research

ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITH OUTCOME AND SYMPTOMS.
The dynamics of viral load (VL) of the 2019 novel coronavirus (SARS-CoV-2) and its association with different clinical parameters remain poorly characterized in the United States patient population. Herein we investigate associations between VL and parameters such as severity of symptoms, disposition (admission vs direct discharge), length of hospitalization, and admission to the intensive care unit, length of need for oxygen support and overall survival in a cohort of 205 patients from a tertiary care center in New York City. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Kimon V. Argyropoulos, Antonio Serrano, Jiyuan Hu, Margaret Black, Xiaojun Feng, Guomiao Shen, Melissa Call, Min Jae Kim, Andrew Lytle, Brendan Belovarac, Theodore Vougiouklakis, Lawrence Hsu Lin, Una Moran, Adriana Heguy, Andrea Troxel, Matija Snuderl, I Tags: Regular Article Source Type: research

Association of Initial Viral Load in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Patients with Outcome and Symptoms
The dynamics of viral load (VL) of the 2019 novel coronavirus (severe acute respiratory syndrome coronavirus 2) and its association with different clinical parameters remain poorly characterized in the US patient population. Herein, we investigate associations between VL and parameters, such as severity of symptoms, disposition (admission versus direct discharge), length of hospitalization, admission to the intensive care unit, length of need for oxygen support, and overall survival in a cohort of 205 patients from a tertiary care center in New York City. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 2, 2020 Category: Pathology Authors: Kimon V. Argyropoulos, Antonio Serrano, Jiyuan Hu, Margaret Black, Xiaojun Feng, Guomiao Shen, Melissa Call, Min J. Kim, Andrew Lytle, Brendan Belovarac, Theodore Vougiouklakis, Lawrence H. Lin, Una Moran, Adriana Heguy, Andrea Troxel, Matija Snuderl, Ima Tags: Regular article Source Type: research

ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITH OUTCOME AND SYMPTOMS
The dynamics of viral load (VL) of the 2019 novel coronavirus (SARS-CoV-2) and its association with different clinical parameters remain poorly characterized in the United States patient population. Herein we investigate associations between VL and parameters such as severity of symptoms, disposition (admission vs direct discharge), length of hospitalization, and admission to the intensive care unit, length of need for oxygen support and overall survival in a cohort of 205 patients from a tertiary care center in New York City. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 2, 2020 Category: Pathology Authors: Kimon V. Argyropoulos, Antonio Serrano, Jiyuan Hu, Margaret Black, Xiaojun Feng, Guomiao Shen, Melissa Call, Min Jae Kim, Andrew Lytle, Brendan Belovarac, Theodore Vougiouklakis, Lawrence Hsu Lin, Una Moran, Adriana Heguy, Andrea Troxel, Matija Snuderl, I Tags: Regular Article Source Type: research

Hepatic Stellate Cell –Specific Platelet-Derived Growth Factor Receptor-α Loss Reduces Fibrosis and Promotes Repair after Hepatocellular Injury
Platelet-derived growth factor receptor (PDGFR)- α plays roles in cell survival, proliferation, and differentiation; however, its function in chronic liver injury sequelae, such as fibrosis, is unknown. Hepatic stellate cells (HSCs), the primary mediators of fibrosis, undergo activation, which entails differentiation to myofibroblasts, proliferat ion, migration, and collagen deposition, partially in response to PDGFs. To examine the role of PDGFR-α in HSCs, we bred lecithin retinol acyltransferase (Lrat)–Cre recombinase and Pdgfra-floxed mice to generate Lrat-Cre Pdgfra−/− (knockout) animals, ...
Source: American Journal of Pathology - June 29, 2020 Category: Pathology Authors: Alexander Kikuchi, Sucha Singh, Minakshi Poddar, Toshimasa Nakao, Heidi Marie Schmidt, Jenesis D. Gayden, Toshifumi Sato, Gavin E. Arteel, Satdarshan P. Monga Tags: Full length article Source Type: research

Hepatic stellate cell-specific platelet-derived growth factor receptor α loss reduces fibrosis and promotes repair following hepatocellular injury
Platelet-derived growth factor receptor α (PDGFRα) plays roles in cell survival, proliferation, and differentiation, however its function in chronic liver injury sequelae like fibrosis is unknown. Hepatic stellate cells (HSCs), the primary mediators of fibrosis, undergo activation, which entails differentiation to myofibroblasts, prolif eration, migration and collagen deposition, partially in response to PDGFs. To examine the role of PDGFRα in HSCs, we bred lecithin retinol acyltransferase (Lrat)-Cre recombinase and Pdgfra-floxed mice to generate Lrat-Cre Pdgfra-/- (KO) animals which were subjected to chr...
Source: American Journal of Pathology - June 29, 2020 Category: Pathology Authors: Alexander Kikuchi, Sucha Singh, Minakshi Poddar, Toshimasa Nakao, Heidi Marie Schmidt, Jenesis D. Gayden, Toshifumi Sato, Gavin E. Arteel, Satdarshan P. Monga Source Type: research

Structural Integrity of the Alveolar-Capillary Barrier in Cynomolgus Monkeys Challenged with Fully Virulent and Toxin-Deficient Strains of Bacillus Anthracis
Inhalational anthrax, a disease caused by inhaling Bacillus anthracis spores, leads to respiratory distress, vascular leakage, high-level bacteremia, and often death within days. Anthrax lethal toxin (LT) and edema toxin (ET), which are composed of protective antigen (PA) plus either lethal factor (LF) or edema factor (EF), respectively, play an important yet incompletely defined role in the pulmonary pathophysiology. To better understand their contribution, we examined the structural integrity of the alveolar capillary barrier in archival formalin-fixed lungs of cynomolgus monkeys challenged with the fully virulent B. (So...
Source: American Journal of Pathology - June 26, 2020 Category: Pathology Authors: Felice D ’Agnillo, Xiaoyuan Zhang, Matthew C. Williams Tags: Regular Article Source Type: research

The Renin-Angiotensin-Aldosterone System (RAAS) is One of the Effectors by Which Vascular Endothelial Growth Factor (VEGF)/anti-VEGF Controls the Endothelial Cell Barrier
Leakage of retinal blood vessels, which is an essential element of diabetic retinopathy (DR), is driven by chronic elevation of vascular endothelial growth factor (VEGF). VEGF quickly relaxes the endothelial cell barrier by triggering signaling events that post-translationally modify preexisting components of intercellular junctions. VEGF also changes expression of genes, which are known to regulate barrier function. This project ’s goal was to identify effectors by which VEGF and anti-VEGF control the endothelial cell barrier in cells that were chronically exposed to VEGF (hours instead of minutes). (Source: America...
Source: American Journal of Pathology - June 23, 2020 Category: Pathology Authors: Yueru Li, Zhonghao Yan, Komal Chaudhry, Andrius Kazlauskas Source Type: research

Characterization of tumor blood vasculature expression of human invasive bladder cancer by laser capture microdissection and transcriptional profiling
Tumor –associated blood vessels differ from normal vessels and play key roles in tumor progression. We aimed at identifying biomolecules that are differentially expressed in human bladder cancer-associated blood vessels in order to find novel biomarkers and mechanisms involved in tumor-associated angiog enesis.We compared the transcriptome of tumor blood vasculature from human invasive bladder carcinoma (I-BLCA) and normal bladder tissue vasculature and performed differential expression and unsupervised hierarchical clustering analyses. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 22, 2020 Category: Pathology Authors: Filip Roudnicky, Cedric Poyet, Lorenz Buser, Karim Saba, Peter Wild, Vivianne I. Otto, Michael Detmar Source Type: research

Retraction notice to Plexin-B1 and Semaphorin 4D Cooperate to Promote Perineural Invasion in a RhoA/ROK-Dependent Manner Am J Pathol 180 (2012) 1232 –1242
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article is being retracted following correspondence from the Office of Accountability and Compliance at the University of Maryland, Baltimore.An internal investigation into this manuscript by the University of Maryland, Baltimore, found evidence that there are errors with the presentation of the standard deviations and statistical significance shown in Figure  6 which are not supported by the original data, and that these inaccuracies warrant retraction to cor...
Source: American Journal of Pathology - June 20, 2020 Category: Pathology Authors: Nada O. Binmadi, Ying-Hua Yang, Hua Zhou, Patrizia Proia, Yi-Ling Lin, Alfredo M. Batista De Paula, Andr é L. Sena Guimarães, Fabiano O. Poswar, Devaki Sundararajan, John R. Basile Tags: Retraction notice Source Type: research

Editorial Board
(Source: American Journal of Pathology)
Source: American Journal of Pathology - June 20, 2020 Category: Pathology Source Type: research

Table of Contents
(Source: American Journal of Pathology)
Source: American Journal of Pathology - June 20, 2020 Category: Pathology Source Type: research

This Month in AJP
Choroidal neovascularization (CNV) may lead to irreversible vision loss in patients with age-related macular degeneration (AMD) —the leading cause of blindness in the seniors. Using a 3’ RNA sequencing approach, Schlecht and Boneva et al (Am J Pathol, AJPA-D-19-00238) analyzed CNV and archived control specimens to characterize global gene expression. One-hundred and fifty-eight differentially-expressed genes (DEG) that w ere significantly increased in CNV compared to control tissue were identified. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 20, 2020 Category: Pathology Tags: This Month in AJP Source Type: research

Acoustic Trauma Causes Cochlear Pericyte-to-Myofibroblast –Like Cell Transformation and Vascular Degeneration, and Transplantation of New Pericytes Prevents Vascular Atrophy
Acoustic trauma disrupts cochlear blood flow and damages sensory hair cells. Damage and regression of capillaries after acoustic trauma have long been observed, but the underlying mechanism of pathology has not been understood. We show herein that loud sound causes change of phenotype from neural/glial antigen 2 positive/ α-smooth muscle actin negative to neural/glial antigen 2 positive/α-smooth muscle actin positive in some pericytes (PCs) on strial capillaries that is strongly associated with up-regulation of transforming growth factor-β1. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 17, 2020 Category: Pathology Authors: Zhiqiang Hou, Lingling Neng, Jinhui Zhang, Jing Cai, Xiaohan Wang, Yunpei Zhang, Ivan A. Lopez, Xiaorui Shi Tags: Regular article Source Type: research

Acoustic trauma causes cochlear pericyte-to-myofibroblast-like cell transformation and vascular degeneration, and transplantation of new pericytes prevents vascular atrophy
Acoustic trauma disrupts cochlear blood flow and damages sensory hair cells. Damage and regression of capillaries after acoustic trauma have long been observed, but the underlying mechanism of pathology has not been understood. We show here that loud sound causes change of phenotype from NG2+/ α-SMA- to NG2+/α-SMA+ in some pericytes (PCs) on strial capillaries that is strongly associated with up-regulation of TGF-β1. The acoustic trauma also causes a reduction of capillary density and increased deposition of matrix proteins, particularly in tne vicinity of transformed PCs. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 17, 2020 Category: Pathology Authors: Zhiqiang Hou, Lingling Neng, Jinhui Zhang, Jing Cai, Xiaohan Wang, Yunpei Zhang, Ivan A. Lopez, Xiaorui Shi Tags: Regular Article Source Type: research

Up-Regulation of Matrix Metalloproteinase-2 by Scleral Monocyte –Derived Macrophages Contributes to Myopia Development
Myopia is a leading cause of visual impairment worldwide. This sight-compromising condition is associated with scleral thinning, extracellular matrix remodeling, and inappropriate optical axial length elongation. Although macrophages are present in the sclera, their involvement in this condition is unknown. By using a form-deprivation myopia (FDM) mouse model, we found that both the scleral macrophage density and their matrix metalloproteinase-2 (MMP-2) expression levels increased in myopic eyes. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 15, 2020 Category: Pathology Authors: Fei Zhao, Hao Wu, Peter S. Reinach, Yi Wu, Ying Zhai, Yi Lei, Li Ma, Yongchao Su, Yizhong Chen, Fen Li, Xing Liu, Nethrajeith Srinivasalu, Jia Qu, Xiangtian Zhou Tags: Regular article Source Type: research

Resolvin E1 Reduces Leukotriene B4 –Induced Intracellular Calcium Increase and Mucin Secretion in Rat Conjunctival Goblet Cells
Leukotriene B4 (LTB4) is a major proinflammatory mediator important in host defense whereas resolvins (Rvs) are produced during the resolution phase of inflammation. We determined the actions of both RvE1 and RvD1 on LTB4-induced responses of goblet cells cultured from rat conjunctiva. The responses measured were an increase in the intracellular [Ca2+] ([Ca2+]i) and high molecular weight glycoprotein secretion. Treatment with RvE1 or RvD1 for 30 min significantly blocked the LTB4-induced [Ca2+]i increase. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 15, 2020 Category: Pathology Authors: Menglu Yang, Jeffrey A. Bair, Robin R. Hodges, Charles N. Serhan, Darlene A. Dartt Tags: Regular Article Source Type: research

Up-regulation of Matrix Metalloproteinase-2 by Scleral Monocyte-derived Macrophages Contributes to Myopia Development
Myopia is a leading cause of visual impairment worldwide. This sight compromising condition is associated with scleral thinning, extracellular matrix (ECM) remodeling and inappropriate optical axial length elongation. Even though macrophages are present in the sclera, their involvement in this condition is unknown. By using a form-deprivation myopia (FDM) mouse model, we found that both the scleral macrophage density and their matrix metallopeptidase-2 (MMP-2) expression levels rose in myopic eyes. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 15, 2020 Category: Pathology Authors: Fei Zhao, Hao Wu, Peter S. Reinach, Yi Wu, Ying Zhai, Yi Lei, Li Ma, Yongchao Su, Yizhong Chen, Fen Li, Xing Liu, Nethrajeith Srinivasalu, Jia Qu, Xiangtian Zhou Source Type: research

Perivascular Fibro-Adipogenic Progenitor Tracing during Post-Traumatic Osteoarthritis
Perivascular mural cells surround capillaries and microvessels, and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well-known pathologic feature of osteoarthritis, yet transgenic animals for use in visualizing perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreERT2 reporter mice were subjected to joint-destabilization surgery in order to induce arthritic changes, and cell lineage was traced over an 8-week period with a focus on the joint-associated fat pad. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 10, 2020 Category: Pathology Authors: Takashi Sono, Ching-Yun Hsu, Yiyun Wang, Jiajia Xu, Masnsen Cherief, Simone Marini, Amanda K. Huber, Sarah Miller, Bruno P éault, Benjamin Levi, Aaron W. James Tags: Regular article Source Type: research

Perivascular fibro-adipogenic progenitor tracing during post-traumatic osteoarthritis.
Perivascular mural cells surround capillaries and microvessels, and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well known pathologic feature of osteoarthritis, yet transgenic animals to visualize perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreERT2 reporter mice were subjected to joint destabilization surgery in order to induce arthritic changes, and cell lineage traced over an 8 week period with a focus on the joint-associated fat pad. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 10, 2020 Category: Pathology Authors: Takashi Sono, Ching-Yun Hsu, Yiyun Wang, Jiajia Xu, Masnsen Cherief, Simone Marini, Amanda K. Huber, Sarah Miller, Bruno P éault, Benjamin Levi, Aaron W. James Tags: Regular Article Source Type: research

Lung and Eye Disease Develop Concurrently in Supplemental Oxygen –Exposed Neonatal Mice
Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are two debilitating disorders that develop in preterm infants exposed to supplemental oxygen to prevent respiratory failure. Both can lead to lifelong disabilities, such as chronic obstructive pulmonary disease and vision loss. Because of the lack of a standard experimental model of coincident disease, the underlying associations between BPD and ROP are not well characterized. To address this gap, we used the robust mouse model of oxygen-induced retinopathy exposing C57BL/6 mice to 75% oxygen from postnatal day 7 to 12. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 8, 2020 Category: Pathology Authors: Lakshanie C. Wickramasinghe, Maverick Lau, Devy Deliyanti, Timothy A. Gottschalk, Peter van Wijngaarden, Dean Talia, Chad Johnson, Jennifer L. Wilkinson-Berka, Evelyn Tsantikos, Margaret L. Hibbs Tags: Regular article Source Type: research

Lung and eye disease develop concurrently in supplemental oxygen-exposed neonatal mice
Bronchopulmonary dysplasia and retinopathy of prematurity are two debilitating disorders that develop in preterm infants exposed to supplemental oxygen to prevent respiratory failure. Both can lead to lifelong disabilities such as chronic obstructive pulmonary disease and vision loss. Due to the lack of a standard experimental model of coincident disease, the underlying associations between BPD and ROP are not well characterized. To address this gap, the robust mouse model of oxygen-induced retinopathy was employed exposing C57BL/6 mice to 75% oxygen from postnatal day (PN) 7 to 12. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 8, 2020 Category: Pathology Authors: Lakshanie C. Wickramasinghe, Maverick Lau, Devy Deliyanti, Timothy A. Gottschalk, Peter van Wijngaarden, Dean Talia, Chad Johnson, Jennifer L. Wilkinson-Berka, Evelyn Tsantikos, Margaret L. Hibbs Source Type: research

The membrane protein sortilin can be targeted to inhibit pancreatic cancer cell invasion
In this study, we found that sortilin expression was higher in pancreatic cell lines vs normal pancreatic ductal epithelial cells, as demonstrated by Western blot and mass spectrometry. The increased sortilin level in pancreatic cancer cells was confirmed by immunohistochemistry in a series of 99 human pancreatic adenocarcinomas vs 48 normal pancreatic tissues (p=0.0014). (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 7, 2020 Category: Pathology Authors: Fangfang Gao, Nathan Griffin, Sam Faulkner, Xiang Li, Simon J. King, Phillip Jobling, Jim W. Denham, Chen Chen Jiang, Hubert Hondermarck Tags: Regular Article Source Type: research

Genetic Deletion of Galectin-3 Alters the Temporal Evolution of Macrophage Infiltration and Healing Affecting the Cardiac Remodeling and Function after Myocardial Infarction in Mice
We studied the role of galectin-3 (Gal-3) in the expression of alternative activation markers (M2) on macrophage, cytokines, and fibrosis through the temporal evolution of healing, ventricular remodeling, and function after myocardial infarction (MI). C57BL/6J and Gal-3 knockout mice (Lgals3-/-) were subjected to permanent coronary ligation or sham. We studied i) mortality, ii) macrophage infiltration and expression of markers of alternative activation, iii) cytokine, iv) matrix metalloproteinase-2 activity, v) fibrosis, and vi) cardiac function and remodeling. (Source: American Journal of Pathology)
Source: American Journal of Pathology - May 28, 2020 Category: Pathology Authors: Pablo Cassaglia, Federico Penas, Celeste Betazza, Florencia Fontana Estevez, Ver ónica Miksztowicz, Nadia Martínez Naya, María Clara Llamosas, Sofía Noli Truant, Luciana Wilensky, Verónica Volberg, Ágata C. Cevey, Vanessa Touceda, Eliana Cicale, Gab Tags: Regular article Source Type: research

Filoviruses Infect Rhesus Macaque Synoviocytes in  Vivo and Primary Human Synoviocytes in Vitro
The most commonly reported symptom of post –Ebola virus disease syndrome in survivors is arthralgia, yet involvement of the joints in acute or convalescent Ebola virus infection is not well characterized in human patients or animal models. Through immunohistochemistry, we found that the lining synovial intima of the stifle (knee) is a targ et for acute infection by Ebola virus/Kikwit, Ebola virus/Makona-C05, and Marburg virus/Angola in the rhesus macaque model. Furthermore, histologic analysis, immunohistochemistry, RNAscope in situ hybridization, and transmission electron microscopy showed that synoviocytes of the s...
Source: American Journal of Pathology - May 28, 2020 Category: Pathology Authors: Timothy K. Cooper, James Logue, David X. Liu, Donna L. Perry, Randy J. Hart, Amanda M.W. Hischak, John G. Bernbaum, Dawn M. Gerhardt, Oscar Rojas, J. Kyle Bohannon, Katie R. Hagen, Reed F. Johnson, Ian Crozier, Peter B. Jahrling, Lisa E. Hensley, Richard Tags: Regular article Source Type: research

Platelet C-Type Lectin-Like Receptor 2 Reduces Cholestatic Liver Injury in Mice
This study focused on the functions of the C-type lectin-like receptor 2 (CLEC-2), a new special platelet receptor that binds with podoplanin-activating platelets. The role of CLEC-2 and podoplanin in cholestatic liver injury was investigated. Mice were injected intraperitoneally with weekly doses of anti –CLEC-2 antibody (2A2B10) to achieve effective CLEC-2 inhibition in their platelets. (Source: American Journal of Pathology)
Source: American Journal of Pathology - May 28, 2020 Category: Pathology Authors: Suguru Maruyama, Hiroshi Kono, Shinji Furuya, Hiroki Shimizu, Ryo Saito, Katsutoshi Shoda, Hidenori Akaike, Naohiro Hosomura, Yoshihiko Kawaguchi, Hidetake Amemiya, Hiromichi Kawaida, Makoto Sudo, Shingo Inoue, Toshiaki Shirai, Katsue Suzuki-Inoue, Daisuk Tags: Regular article Source Type: research

Filoviruses Infect Rhesus Macaque Synoviocytes in  Vivo and Primary Human Synoviocytes in Vitro
The most commonly reported symptom of post –Ebola virus disease syndrome in survivors is arthralgia, yet involvement of the joints in acute or convalescent Ebola virus infection has not been well characterized in human patients or animal models. Through the use of immunohistochemistry, we found that the lining synovial intima of the stifle (knee) is a target for acute infection by Ebola virus/Kikwit, Ebola virus/Makona-C05, and Marburg virus/Angola in the rhesus macaque model. Furthermore, we found through histologic analysis, immunohistochemistry, RNAscope in situ hybridization, and transmission electron microscopy ...
Source: American Journal of Pathology - May 28, 2020 Category: Pathology Authors: Timothy K. Cooper, James Logue, David X. Liu, Donna L. Perry, Randy J. Hart, Amanda M.W. Hischak, John G. Bernbaum, Dawn M. Gerhardt, Oscar Rojas, J. Kyle Bohannon, Katie R. Hagen, Reed F. Johnson, Ian Crozier, Peter B. Jahrling, Lisa E. Hensley, Richard Tags: Regular article Source Type: research

Restoration of Regulatory T-cell Function in Dry Eye Disease by Antagonizing Substance P/Neurokinin-1 Receptor
This study examined the phenotypic and functional changes in Tregs in response to SP in DED. (Source: American Journal of Pathology)
Source: American Journal of Pathology - May 28, 2020 Category: Pathology Authors: Yukako Taketani, Anna Marmalidou, Thomas Dohlman, Rohan Bir Singh, Afsaneh Amouzegar, Sunil Chauhan, Yihe Chen, Reza Dana Tags: Regular article Source Type: research