Enzymatically-inactive Tissue-type Plasminogen Activator Reverses Disease Progression in the Dextran Sulfate Sodium Mouse Model of Inflammatory Bowel Disease
Enzymatically-inactive tissue-type plasminogen activator (EI-tPA) does not activate fibrinolysis but still interacts with the NMDA Receptor (NMDA-R) and LRP1 in macrophages to block innate immune system responses mediated by Toll-like Receptors. Herein, we examined the ability of EI-tPA to treat colitis in mice induced by Dextran Sulfate Sodium (DSS). In two separate studies, designed to generate colitis of differing severity, a single dose of EI-tPA administered after inflammation was established significantly improved disease parameters. (Source: American Journal of Pathology)
Source: American Journal of Pathology - January 16, 2021 Category: Pathology Authors: Lipsa Das, Michael A. Banki, Pardis Azmoon, Donald Pizzo, Steven L. Gonias Tags: Short Communication Source Type: research

CCL1 Derived from Tumor-Associated Macrophages Contributes to Esophageal Squamous Cell Carcinoma Progression via CCR8-mediated Akt/PRAS40/mTOR Pathway
Tumor-associated macrophages (TAMs) promote tumor progression. The number of infiltrating TAMs is associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) patients; however, the mechanism underlying this phenomenon is unclear. Our previous cDNA microarray analysis had revealed that the expression of C-C motif chemokine ligand 1 (CCL1) is upregulated in peripheral blood monocyte (PBMo)-derived macrophages stimulated using conditioned media from ESCC cells (TAM-like macrophages). (Source: American Journal of Pathology)
Source: American Journal of Pathology - January 15, 2021 Category: Pathology Authors: Masataka Fujikawa, Yu-ichiro Koma, Masayoshi Hosono, Naoki Urakawa, Kohei Tanigawa, Masaki Shimizu, Takayuki Kodama, Hiroki Sakamoto, Mari Nishio, Manabu Shigeoka, Yoshihiro Kakeji, Hiroshi Yokozaki Source Type: research

Administration of a CXCR2 antagonist, SCH527123, together with oseltamivir suppresses NETosis and protects mice from lethal influenza and piglets from swine-influenza infection.
Excessive neutrophil influx, their released neutrophil extracellular traps (NETs) and extracellular histones are associated with disease severity in influenza-infected patients. Neutrophil chemokine receptor CXCR2 is a critical target for suppressing neutrophilic inflammation. Here, we investigated temporal dynamics of neutrophil activity and NETosis to determine the optimal timing of treatment with the CXCR2 antagonist, SCH527123 and we tested its efficacy together with antiviral agent, oseltamivir in murine and piglet influenza-pneumonia models. (Source: American Journal of Pathology)
Source: American Journal of Pathology - January 13, 2021 Category: Pathology Authors: Harshini K. Ashar, Sivasami Pulavendran, Jennifer M. Rudd, Prasanthi Maram, Mallika Achanta, Vincent TK. Chow, Jerry R. Malayer, Timothy A. Snider, Narasaraju Teluguakula Tags: Regular Article Source Type: research

Host Cxcr2-dependent regulation of pancreatic cancer growth, angiogenesis, and metastasis
In this report, we examined whether tumor angiogenesis, growth, and metastasis of CXCR2-ligands expressing PDAC cells are regulated in vivo by a host CXCR2-dependent mechanism. (Source: American Journal of Pathology)
Source: American Journal of Pathology - January 13, 2021 Category: Pathology Authors: Abhilasha Purohit, Sugandha Saxena, Michelle Varney, Dipakkumar R. Prajapati, Jessica A. Kozel, Audrey Lazenby, Rakesh K. Singh Source Type: research

Pigment epithelium-derived factor enhances the suppressive phenotype of regulatory T-cells in a murine model of dry eye disease.
In this study, we evaluate the effect of PEDF on the immunosuppressive characteristics of regulatory T-cells (Tregs), which are functionally impaired in DED. (Source: American Journal of Pathology)
Source: American Journal of Pathology - January 13, 2021 Category: Pathology Authors: Rohan Bir Singh, Tomas Blanco, Sharad K. Mittal, Hamid Alemi, Sunil K. Chauhan, Yihe Chen, Reza Dana Tags: Regular Article Source Type: research

Small Blood Vessel Disease in the Brain Theme Issue Overlapping protein accumulation profiles of CADASIL and CAA: Is there a common mechanism driving cerebral small vessel disease?
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and CAA (cerebral amyloid angiopathy) are two distinct vascular angiopathies that share several similarities in clinical presentation and vascular pathology. Given the clinical and pathological overlap, we explored the molecular overlap between CADASIL and CAA. We compared CADASIL and CAA protein profiles in recently published proteomics-based and immuno-based studies to investigate the potential for shared disease mechanisms. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 29, 2020 Category: Pathology Authors: Kelly Z. Young, Gang Xu, Simon G. Keep, Jimo Borjigin, Michael M. Wang Tags: Review Source Type: research

Loss of fibroblast growth factor receptor 2 (FGFR2) leads to defective bladder urothelial regeneration after Cyclophosphamide injury
Cyclophosphamide may cause hemorrhagic cystitis and eventually bladder urothelial cancer. Genetic determinants for poor outcomes are unknown. We assessed actions of fibroblast growth factor receptor 2 (FGFR2) in urothelium after Cyclophosphamide. Conditional urothelial deletion of Fgfr2 (Fgfr2KO) did not affect injury severity or proliferation of Keratin 14+ (KRT14+) Basal progenitors or other urothelial cells one day after Cyclophosphamide. Three days after Cyclophosphamide, Fgfr2KO urothelium had defective regeneration, fewer cells, larger Basal cell bodies and nuclei, paradoxical increases in proliferation markers and e...
Source: American Journal of Pathology - December 29, 2020 Category: Pathology Authors: Sridhar Tatarao Narla, Daniel Scott Bushnell, Caitlin Marie Schaefer, Mehdi Nouraie, Justin T. Tometich, Timothy W. Hand, Carlton Matthew Bates Tags: Regular Article Source Type: research

Adrenomedullin-RAMP2 system ameliorates subretinal fibrosis by suppressing epithelial-mesenchymal transition in age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti-VEGF drugs are used to treat AMD, but they may induce subretinal fibrosis. We have focused on adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein, RAMP2, which regulate vascular homeostasis and suppress fibrosis. Here, the therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis and macrophage invasion were all enhanced in both AM and RAMP2 knockout (KO) mice as compared to wild-ty...
Source: American Journal of Pathology - December 29, 2020 Category: Pathology Authors: Masaaki Tanaka, Shinji Kakihara, Kazutaka Hirabayashi, Akira Imai, Yuichi Toriyama, Yasuhiro Iesato, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Megumu Tanaka, Nanqi Cui, Yangxuan Wei, Yunlu Zhao, Kohsuke Aruga, Akihiro Yamauch Source Type: research

Activation of Hepatic Stellate Cells Requires Dissociation of E-Cadherin –Containing Adherens Junctions with Hepatocytes
Hepatic stellate cells (HSCs) are resident mesenchymal cells in the space of Disse interposed between liver sinusoidal endothelial cells and hepatocytes. Thorn-like microprojections, or spines, project out from the cell surface of HSCs, crossing the space of Disse, to establish adherens junctions with neighboring hepatocytes. Although HSC activation is initiated largely from stimulation by adjacent cells, isolated HSCs also activate spontaneously in primary culture on plastic. Therefore, other unknown HSC-initiating factors apart from paracrine stimuli may promote activation. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 23, 2020 Category: Pathology Authors: Hayato Urushima, Hideto Yuasa, Tsutomu Matsubara, Noriyuki Kuroda, Yaiko Hara, Kouji Inoue, Kenjiro Wake, Tetsuji Sato, Scott L. Friedman, Kazuo Ikeda Tags: Regular article Source Type: research

Treatment of experimental choroidal neovascularization via RUNX1 inhibition
This study demonstrates RUNX1 expression in critical cell types involved in laser-induced model of CNV in mice. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 23, 2020 Category: Pathology Authors: Lucia Gonzalez-Buendia, Santiago Delgado-Tirado, Miranda An, Michael O ’Hare, Dhanesh Amarnani, Hannah Whitmore, Guannan Zhao, Jose M. Ruiz-Moreno, Joseph F. Arboleda-Velasquez, Leo A. Kim Tags: Short Communication Source Type: research

Vascular endothelial growth factor mediates the sprouted axonogenesis of breast cancer in rat
Nerve infiltration into the tumor is a common feature of the tumor microenvironment. The mechanisms of axonogenesis in breast cancer remain unclear. We hypothesized that vescular endothelial growth factor (VEGF) as well as nerve growth factor (NGF) is involved in the axonogenesis of breast cancer. Here, we used a N-Methyl-N-Nitrosourea (MNU)-induced rat model of breast cancer to explore the presence of axonogenesis in breast tumor and the involvement of VEGF as well as NGF in the axonogenesis of breast tumor. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 23, 2020 Category: Pathology Authors: Hongxiu Han, Chunxue Yang, Yuan Zhang, Changhao Han, Guohua Zhang Source Type: research

Activation of Hepatic Stellate Cells Requires Dissociation of E-Cadherin-Containing Adherens Junctions with Hepatocytes
Hepatic stellate cells (HSCs) are resident mesenchymal cells in the space of Disse interposed between liver sinusoidal endothelial cells (LSECs) and hepatocytes. Thorn-like microprojections, or spines, project out from the cell surface of HSCs, crossing the space of Disse to establish adherens junctions with neighboring hepatocytes. Although HSC activation is initiated largely from stimulation by adjacent cells, isolated HSCs also activate spontaneously in primary culture on plastic. Therefore, other unknown HSC initiating factors apart from paracrine stimuli may promote activation. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 23, 2020 Category: Pathology Authors: Hayato Urushima, Hideto Yuasa, Tsutomu Matsubara, Noriyuki Kuroda, Yaiko Hara, Kouji Inoue, Kenjiro Wake, Tetsuji Sato, Scott L. Friedman, Kazuo Ikeda Source Type: research

Three-dimensional vessel segmentation in whole-tissue and whole-block imaging using a deep neural network: Proof of concept study
In the field of pathology, micro computed tomography (micro-CT) has become attractive imaging modality because it enables full analysis of the three-dimensional (3D) characteristics of a tissue sample or organ in a non-invasive manner. However, due to the complexity of the 3D information, understanding would be improved by development of analytical methods and software such as those implemented for clinical CT. As the accurate identification of tissue components is critical for this purpose, we have developed a deep neural network (DNN) to analyze whole-tissue images (WTI) and whole-block images (WBI) of neoplastic cancer ...
Source: American Journal of Pathology - December 23, 2020 Category: Pathology Authors: Takashi Ohnishi, Alexei Teplov, Noboru Kawata, Kareem Ibrahim, Peter Ntiamoah, Canan Firat, Hideaki Haneishi, Meera Hameed, Jinru Shia, Yukako Yagi Source Type: research

This Month in AJP
The lack of relevant animal models has limited our understanding of COVID-19 pathobiology and testing possible interventions. Using aged African green monkeys (AGMs) infected with SARS-CoV-2, Blair et al (Am J Pathol, AJPA-D-20-00470) modeled acute respiratory distress syndrome (ARDS), which is a common symptom in severely ill COVID-19 patients, and often a cause of death. Eight aged AGMs were exposed to SARS-CoV2 and they exhibited mild to severe COVID-19 with increased levels of plasma interleukin-6, a predictive biomarker and potential therapeutic target. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 18, 2020 Category: Pathology Tags: This Month in AJP Source Type: research

Lack of Annexin A6 Exacerbates Liver Dysfunction and Reduces Lifespan of Niemann-Pick Type C Protein –Deficient Mice
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by cholesterol accumulation caused by loss-of-function mutations in the Npc1 gene. NPC disease primarily affects the brain, causing neuronal damage and affecting motor coordination. In addition, considerable liver malfunction in NPC disease is common. Recently, we found that the depletion of annexin A6 (ANXA6), which is most abundant in the liver and involved in cholesterol transport, ameliorated cholesterol accumulation in Npc1 mutant cells. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 17, 2020 Category: Pathology Authors: Elsa Meneses-Salas, Marta Garcia-Forn, Carla Castany-Pladevall, Albert Lu, Alba Fajardo, Jaimy Jose, Mohamed Wahba, Marta Bosch, Albert Pol, Francesc Tebar, Andr és D. Klein, Silvana Zanlungo, Esther Pérez-Navarro, Thomas Grewal, Carlos Enrich, Carles R Tags: Regular article Source Type: research

Lack of Annexin A6 exacerbates liver dysfunction and reduces lifespan of NPC1-deficient mice
Niemann-Pick type C disease (NP-C) is a lysosomal storage disorder characterized by cholesterol accumulation caused by loss-of-function mutations in the Npc1 gene. NP-C disease primarily affects the brain, causing neuronal damage and affecting motor coordination. In addition, considerable liver malfunction in NP-C disease is common. Recently, we demonstrated that the depletion of annexin A6 (ANXA6), which is most abundant in the liver and involved in cholesterol transport, ameliorated cholesterol accumulation in Npc1 mutant cells. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 17, 2020 Category: Pathology Authors: Elsa Meneses-Salas, Marta Garcia-Forn, Carla Castany-Pladevall, Albert Lu, Alba Fajardo, Jaimy Jose, Mohamed Wahba, Marta Bosch, Albert Pol, Francesc Tebar, Andr és D. Klein, Silvana Zanlungo, Esther Pérez-Navarro, Thomas Grewal, Carlos Enrich, Carles R Source Type: research

Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment
Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia worldwide. There is considerable evidence of age-related disruption of proteostasis being responsible for the development of AD. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and an age-related decline in its activity has been implicated in age-related pathologies. Although proteasomal dysfunction is assumed to be a key AD hallmark, it remains unclear whether its role in disease onset is causative or secondary. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 15, 2020 Category: Pathology Authors: Utano Tomaru, Tomoki Ito, Yu Ohmura, Kei Higashikawa, Syota Miyajima, Ruka Tomatsu, Tsunehito Higashi, Akihiro Ishizu, Yuji Kuge, Mitsuhiro Yoshioka, Masanori Kasahara Tags: Regular article Source Type: research

Pathology, Publishing, and a Pandemic
As scientists, we are all aware of past pandemics and the great toll that they have taken in terms of mortality. Many of us also are knowledgeable about the biological forces that drive global outbreaks of infectious diseases. But the overwhelming impact of pandemics on every aspect of life, from the trivial to the profound, was hard to appreciate until we found ourselves in the midst of one. Like every institution worldwide, The American Journal of Pathology (AJP) had to adapt rapidly to an unimaginable and constantly shifting new landscape. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 15, 2020 Category: Pathology Authors: Emily H. Essex, Chhavi Chauhan, Martha B. Furie Tags: Editorial Source Type: research

Correction
This article is being corrected to replace the center image on the top row. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 15, 2020 Category: Pathology Tags: Correction Source Type: research

Editorial Board
(Source: American Journal of Pathology)
Source: American Journal of Pathology - December 15, 2020 Category: Pathology Source Type: research

Table of Contents
(Source: American Journal of Pathology)
Source: American Journal of Pathology - December 15, 2020 Category: Pathology Source Type: research

Instructions to Authors
(Source: American Journal of Pathology)
Source: American Journal of Pathology - December 15, 2020 Category: Pathology Source Type: research

Scientific Integrity Policy
(Source: American Journal of Pathology)
Source: American Journal of Pathology - December 15, 2020 Category: Pathology Source Type: research

Insulin-induced gene 2 expression is associated with breast cancer metastasis
Insulin-induced gene 2 (INSIG2) functions as a blocker of cholesterol biosynthesis and has been shown to be involved in colon and pancreatic cancer pathogenesis. Cholesterol is a risk factor for breast cancer pathophysiology; however, the underlying mechanisms are not well defined. Hence, our goal was to determine the role of INISG2 in breast cancer. INSIG2 mRNA and protein expression was correlated to metastatic potential of breast cancer cell lines. Knockdown of INSIG2 inhibited epithelial to mesenchymal (EMT) transition. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 12, 2020 Category: Pathology Authors: Ning Lu, Mei Zhang, Lu Lu, Yan-zhao Liu, Xiao-dong Liu, Hai-hong Zhang Source Type: research

Differences in the Immune Response of the Nonmetastatic Axillary Lymph Nodes Between Triple-Negative and Luminal A Breast Cancer Surrogate Subtypes
Breast cancer (BC) comprises four immunohistochemical surrogate subtypes of which triple-negative breast cancer (TNBC) has the highest risk of mortality. Axillary lymph nodes (ALNs) are the regions where BC cells first establish before distant metastasis, and the presence of tumor cells in the ALN causes an immune tolerance profile that contrasts with that of the nonmetastatic ALN(ALN −). However, few studies have compared the immune components of the ALNs− in BC subtypes. The present study aimed to determine whether differences between immune populations in the primary tumor and ALNs− were associated wit...
Source: American Journal of Pathology - December 9, 2020 Category: Pathology Authors: Carlos L ópez, Albert Gibert-Ramos, Ramón Bosch, Anna Korzynska, Marcial García-Rojo, Gloria Bueno, Joan Francesc García-Fontgivell, Salomé Martínez González, Laia Fontoura, Andrea Gras Navarro, Esther Sauras Colón, Júlia Casanova Ribes, Lukasz R Tags: Regular article Source Type: research

Differences in the immune response of the non-metastatic axillary lymph nodes between triple-negative and luminal A breast cancer surrogate subtypes
Breast cancer (BC) comprises four immunohistochemical surrogate subtypes, of which triple-negative breast cancer (TNBC) has the highest risk of mortality. Axillary lymph nodes (ALNs) are the regions where BC cells first establish before distant metastasis, and the presence of tumor cells in the ALN gives rise to an immune tolerance profile that contrasts with that of the non-metastatic ALN (ALN-). However, few studies have compared the immune components of the ALNs- in BC subtypes. The present study aimed to determine whether differences between immune populations in the primary tumor and ALNs- were associated with the lum...
Source: American Journal of Pathology - December 9, 2020 Category: Pathology Authors: Carlos L ópez, Albert Gibert-Ramos, Ramón Bosch, Anna Korzynska, Marcial García-Rojo, Gloria Bueno, Joan Francesc García-Fontgivell, Salomé Martínez González, Laia Fontoura, Andrea Gras Navarro, Esther Sauras Colón, Júlia Casanova Ribes, Lukasz R Tags: Regular article Source Type: research

An RGDKGE-Containing Cryptic Collagen Fragment Regulates Phosphorylation of Large Tumor Suppressor Kinase-1 and Controls Ovarian Tumor Growth by a Yes-Associated Protein –Dependent Mechanism
The growth and spread of malignant tumors, such as ovarian carcinomas, are governed in part by complex interconnected signaling cascades occurring between stromal and tumor cells. These reciprocal cross-talk signaling networks operating within the local tissue microenvironment may enhance malignant tumor progression. Understanding how novel bioactive molecules generated within the tumor microenvironment regulate signaling pathways in distinct cellular compartments is critical for the development of more effective treatment paradigms. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 8, 2020 Category: Pathology Authors: Xiang H. Han, Jennifer M. Caron, Christine W. Lary, Pradeep Sathyanarayana, Calvin Vary, Peter C. Brooks Tags: Regular article Source Type: research

Hypoxia and Hypoxia-Inducible Factor-1 α Regulate Endoplasmic Reticulum Stress in Nucleus Pulposus Cells
Endoplasmic reticulum (ER) stress is shown to promote nucleus pulposus (NP) cell apoptosis and intervertebral disc degeneration. However, little is known about ER stress regulation by the hypoxic disc microenvironment and its contribution to extracellular matrix homeostasis. NP cells were cultured under hypoxia (1% partial pressure of oxygen) to assess ER stress status, and gain-of-function and loss-of-function approaches were used to assess the role of hypoxia-inducible factor (HIF)-1 α in this pathway. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 8, 2020 Category: Pathology Authors: Emanuel J. Novais, Hyowon Choi, Vedavathi Madhu, Kaori Suyama, Sandra I. Anjo, Bruno Manadas, Irving M. Shapiro, Ant ónio J. Salgado, Makarand V. Risbud Tags: Regular article Source Type: research

PIM kinases promote survival and immune escape in primary mediastinal large B-cell lymphoma through modulation of JAK-STAT and NF κB activity
Primary mediastinal large B-cell lymphoma (PMBL) cells depend on the constitutive activity of NF κB and STAT transcription factors, which drive expression of multiple molecules essential for their survival. We have previously showed that in a molecularly-related B-cell malignancy, classical Hodgkin lymphoma (cHL), tumor Reed-Sternberg (RS) cells overexpress oncogenic PIM1/2/3 kinases (PIMs) in a NFκB- and STAT-dependent manner, and that PIMs enhance survival and expression of immunomodulatory molecules. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 8, 2020 Category: Pathology Authors: Maciej Szyd łowski, Sonia Dębek, Monika Prochorec-Sobieszek, Małgorzata Szołkowska, Andrea M. Tomirotti, Przemysław Juszczyński, Anna Szumera-Ciećkiewicz Source Type: research

An RGDKGE containing cryptic collagen fragment regulates phosphorylation of LATS1 and controls ovarian tumor growth by a YAP-dependent mechanism
The growth and spread of malignant tumors such as ovarian carcinomas are governed in part by complex interconnected-signaling cascades occurring between stromal and tumor cells. These reciprocal cross-talk signaling networks operating within the local tissue microenvironment may enhance malignant tumor progression. Understanding how novel bioactive molecules generated within the tumor microenvironment regulate signaling pathways in distinct cellular compartments is critical for the development of more effective treatment paradigms. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 8, 2020 Category: Pathology Authors: XiangHua Han, Jennifer M. Caron, Christine W. Lary, Pradeep Sathyanarayana, Calvin Vary, Peter C. Brooks Tags: Regular Article Source Type: research

Image-based machine learning algorithms for disease characterization in the human type 1 diabetes pancreas
Emerging data suggest that type 1 diabetes affects not only the β-cell-containing islets of Langerhans, but also the surrounding exocrine compartment. Using digital pathology, machine learning algorithms were applied to provide high-resolution, whole-slide images of human pancreata to determine if the tissue composition in individuals with or at-risk for type 1 diabetes differs from those without diabetes. Transplant grade pancreata from organ donors were evaluated from 16 non-diabetic autoantibody negative controls, 8 non-diabetic autoantibody positive subjects who have increased-type 1 diabetes risk, and 19 persons ...
Source: American Journal of Pathology - December 8, 2020 Category: Pathology Authors: Xiaohan Tang, Irina Kusmartseva, Shweta Kulkarni, Amanda Posgai, Stephan Speier, Desmond A. Schatz, Michael J. Haller, Martha Campbell-Thompson, Clive H. Wasserfall, Bart O. Roep, John S. Kaddis, Mark A. Atkinson Tags: Regular article Source Type: research

The gain-of-function mutation p53R248W suppresses cell proliferation and invasion of oral squamous cell carcinoma through the down-regulation of KRT17
This study was conducted to investigate the correlation between KRT17 expression and TP53 mutants. First, we found that Ca9-22 cells, which exhibit low KRT17 expression, carried mutant p53 (p53R248W) and that p53R248W knockdown promoted KRT17 expression. Then, we demonstrated t hat p53R248W knockdown in Ca9-22 cells promoted migration and invasion activity. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 8, 2020 Category: Pathology Authors: Mayu Enaka, Masako Nakanishi, Yasuteru Muragaki Tags: Regular article Source Type: research

Hypoxia and HIF-1 α regulate endoplasmic reticulum (ER) stress in nucleus pulposus cells: Implications of ER stress for extracellular matrix secretion
ER stress is shown to promote nucleus pulposus (NP) cell apoptosis and intervertebral disc degeneration. However, little is known about ER stress regulation by the hypoxic disc microenvironment and its contribution to extracellular matrix homeostasis. NP cells were cultured under hypoxia (1% pO2) to assess ER stress status and gain- and loss-of-function approaches were used to assess the role of HIF-1 α in this pathway. Additionally, the contribution of ER stress induction on the NP cell secretome was assessed by a non-targeted quantitative proteomic analysis by SWATH-mass spectrometry. (Source: American Journal of Pathology)
Source: American Journal of Pathology - December 8, 2020 Category: Pathology Authors: Emanuel J. Novais, Hyowon Choi, Vedavathi Madhu, Kaori Suyama, Sandra I. Anjo, Bruno Manadas, Irving M. Shapiro, Ant ónio J. Salgado, Makarand V. Risbud Source Type: research

Effects of Electronic Nicotine Delivery Systems and Cigarettes on Systemic Circulation and Blood-Brain Barrier
Electronic nicotine delivery systems (often known as e-cigarettes) are a novel tobacco product with growing popularity, particularly among younger demographics. The implications for public health are twofold, as these products may represent a novel source of tobacco-associated disease but may also  provide a harm reduction strategy for current tobacco users. There is increasing recognition that e-cigarettes impact vascular function across multiple organ systems. Herein, we provide a comparison of evidence regarding the role of e-cigarettes versus combustible tobacco in vascular disease and i mplications for blood-brai...
Source: American Journal of Pathology - December 4, 2020 Category: Pathology Authors: Nathan A. Heldt, Nancy Reichenbach, Hannah M. McGary, Yuri Persidsky Tags: Review Source Type: research

Effects of electronic nicotine delivery systems and cigarettes on systemic circulation and blood brain barrier: implications for cognitive decline
Electronic nicotine delivery systems (often known as e-cigarettes) are a novel tobacco product with growing popularity, particularly among younger demographics. The implications for public health are two-fold, as these products may represent a novel source of tobacco-associated disease but may also provide a harm reduction strategy for current tobacco users. There is increasing recognition that e-cigarettes impact vascular function across multiple organ systems. Here we provide a comparison of evidence regarding the role of e-cigarettes versus combustible tobacco in vascular disease and implications for BBB dysfunction and...
Source: American Journal of Pathology - December 4, 2020 Category: Pathology Authors: Nathan A. Heldt, Nancy Reichenbach, Hannah M. McGary, Yuri Persidsky Tags: Review Source Type: research

Title Page
(Source: American Journal of Pathology)
Source: American Journal of Pathology - December 1, 2020 Category: Pathology Source Type: research

Table of Contents
(Source: American Journal of Pathology)
Source: American Journal of Pathology - December 1, 2020 Category: Pathology Source Type: research

Meeting Abstracts
(Source: American Journal of Pathology)
Source: American Journal of Pathology - December 1, 2020 Category: Pathology Source Type: research

Author Index
(Source: American Journal of Pathology)
Source: American Journal of Pathology - December 1, 2020 Category: Pathology Source Type: research

Challenges in the Development, Deployment, and Regulation of Artificial Intelligence in Anatomic Pathology
Significant advances in artificial intelligence (AI), deep learning, and other machine-learning approaches have been made in recent years, with applications found in almost every industry, including health care. AI has proved to be capable of completing a spectrum of mundane to complex medically oriented tasks previously performed only by boarded physicians, most recently assisting with the detection of cancers difficult to find on histopathology slides. Although computers will not replace pathologists any time soon, properly designed AI-based tools hold great potential for increasing workflow efficiency and diagnostic acc...
Source: American Journal of Pathology - November 23, 2020 Category: Pathology Authors: Jerome Y. Cheng, Jacob T. Abel, Ulysses G.J. Balis, David S. McClintock, Liron Pantanowitz Tags: Mini-review Source Type: research

Endoplasmic Reticulum Calcium Homeostasis in Kidney Disease
Calcium (Ca2+) homeostasis is a crucial determinant of cellular function and survival. Endoplasmic reticulum (ER) acts as the largest intracellular Ca2+ store that maintains Ca2+ homeostasis through the ER Ca2+ uptake pump, sarco/ER –Ca2+ ATPase, ER Ca2+ release channels, inositol 1,4,5-trisphosphate receptor channel, ryanodine receptor, and Ca2+-binding proteins inside of the ER lumen. Alterations in ER homeostasis trigger ER Ca2+ depletion and ER stress, which have been associated with the development of a variety of diseas es. (Source: American Journal of Pathology)
Source: American Journal of Pathology - November 23, 2020 Category: Pathology Authors: Sun-Ji Park, Chuang Li, Ying M. Chen Tags: Mini-review Source Type: research

Myeloid-Derived IL-33 Limits the Severity of Dextran Sulfate Sodium –Induced Colitis
IL-33 is an IL-1 family cytokine that signals through its cognate receptor, ST2, to regulate inflammation. It is controversial whether IL-33 serves a pathogenic or protective role during inflammatory bowel disease. Herein, two different strains of cell-specific conditionally deficient mice were used to compare the role of myeloid- versus intestinal epithelial cell –derived IL-33 during dextran sodium sulfate–induced colitis. Data show that loss of CD11c-restricted IL-33 exacerbated tissue pathology, coinciding with increased tissue Il6 levels and loss of intestinal Foxp3+ regulatory T cells, but surprisingly, t...
Source: American Journal of Pathology - November 23, 2020 Category: Pathology Authors: Li-Yin Hung, Christopher F. Pastore, Bonnie Douglas, De ’Broski R. Herbert Tags: Short communication Source Type: research

Myeloid-derived Interleukin-33 limits the severity of dextran sulfate sodium (DSS)-induced colitis
Interleukin (IL)-33 is an IL-1 family cytokine that signals through its cognate receptor ST2 to regulate inflammation. It is controversial whether IL-33 serves pathogenic or protective role during inflammatory bowel disease (IBD). Here, two different strains of cell-specific conditionally deficient mice were used to compare the role of myeloid- versus intestinal epithelial cell (IEC)-derived IL-33 during dextran sodium sulfate-induced colitis. Data show that loss of CD11c-restricted IL-33 exacerbated tissue pathology coinciding with increased tissue Il6 levels and loss of intestinal Foxp3+Treg, but surprisingly, the lack o...
Source: American Journal of Pathology - November 23, 2020 Category: Pathology Authors: Li-Yin Hung, Christopher F. Pastore, Bonnie Douglas, De ’Broski R. Herbert Tags: Short Communication Source Type: research

Endoplasmic Reticulum Calcium Homeostasis in Kidney Disease: Pathogenesis and Therapeutic Targets
Calcium (Ca2+) homeostasis is a critical determinant of cellular function and survival. Endoplasmic reticulum (ER) acts as the largest intracellular Ca2+ store that maintains Ca2+ homeostasis through ER Ca2+ uptake pump, sarco/ER –Ca2+ ATPase (SERCA), ER Ca2+ release channels, inositol 1,4,5-trisphosphate receptor channel (IP3R) and ryanodine receptor (RyR), and Ca2+-binding proteins inside the ER lumen. Alterations in ER homeostasis triggers ER Ca2+ depletion and ER stress, which is associated with development of a variet y of diseases. (Source: American Journal of Pathology)
Source: American Journal of Pathology - November 23, 2020 Category: Pathology Authors: Sun-Ji Park, Chuang Li, Ying Maggie Chen Tags: Mini-Review Source Type: research

Challenges in the Development, Deployment & Regulation of Artificial Intelligence (AI) in Anatomical Pathology
Artificial intelligence (AI), deep learning, and other machine learning approaches have made significant advances in recent years, finding applications in almost every industry, including healthcare. AI has proven to be capable of a spectrum of mundane to complex medically oriented tasks previously only performed by boarded physicians, most recently assisting detection of difficult-to-find cancer on histopathology slides. Although computers will not replace pathologists anytime soon, properly designed AI-based tools hold great potential to increase workflow efficiency and diagnostic accuracy in the practice of pathology. (...
Source: American Journal of Pathology - November 23, 2020 Category: Pathology Authors: Jerome Y. Cheng, Jacob T. Abel, Ulysses G.J. Balis, David S. McClintock, Liron Pantanowitz Tags: Mini-Review Source Type: research

Heat Shock Protein 27 Enhances SUMOylation of Heat Shock Protein B8 to Accelerate the Progression of Breast Cancer
This study investigated the potential role of heat shock protein 27 (HSP27, also known as HSPB1) in breast cancer through heat shock protein B8 (HSPB8). The correlation between HSP27 and HSPB8 was identified by using co-immunoprecipitation, immunoprecipitation, and SUMOylation assays. Through gain- and loss-of-function approaches in MCF-7 cells, the effect of HSP27 on HSPB8 expression, SUMOylation level, and protein stability of HSPB8, as well as on cell proliferation, migration, and stemness, was elucidated. (Source: American Journal of Pathology)
Source: American Journal of Pathology - November 20, 2020 Category: Pathology Authors: Shuai Wang, Xinyan Zhang, Haiwei Wang, Yang Wang, Peng Chen, Longgang Wang Tags: Regular article Source Type: research

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

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

Characterizing Viral Infection by Electron Microscopy
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, causing coronavirus disease 2019 (COVID-19), has presented many challenges and spurred intense investigations into the pathogenesis of this disease. In addition to respiratory disease, many patients with SARS-CoV-2 infection are experiencing systemic illnesses, including kidney failure, heart failure, liver injury, neurologic dysfunction, and skin manifestations (eg, COVID toe). The etiology and pathogenesis of these sequelae are the current focus of intense research and speculation. (Source: American Journal of Pathology)
Source: American Journal of Pathology - November 20, 2020 Category: Pathology Authors: Shreeram Akilesh, Roberto F. Nicosia, Charles E. Alpers, Maria Tretiakova, Tien-Ying Hsiang, Michael Gale, Kelly D. Smith Tags: Biological Perspectives Source Type: research

Animal and Cell Culture Models for Cystic Fibrosis
Over the past 30 years, a range of cystic fibrosis (CF) animal models have been generated for research purposes. Species, including mice, rats, ferrets, rabbits, pigs, sheep, zebra fish, and fruit flies, have all been used to model CF disease. Access to such a variety of animal models is a luxury for any research field, but it also complicates the decision-making process when it comes to selecting the right model for an investigation. The purpose of this review is to provide a guide for selecting the most appropriate CF animal model for any given application. (Source: American Journal of Pathology)
Source: American Journal of Pathology - November 20, 2020 Category: Pathology Authors: Alexandra McCarron, David Parsons, Martin Donnelley Tags: Review Source Type: research