Cerebral Small Vessel Disease in Sporadic and Familial Alzheimer Disease
Alzheimer ’s disease is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary pathology and neurodegeneration. However, current evidence suggests various features of small vessel disease (SVD) are part and parcel of and cove rtly modify both sporadic and familial AD. Neuroimaging studies suggest white matter hyperintensities (WMH) explained by vascular mechanisms occur frequently in the AD spectrum. Recent advances have further emphasised that frontal periventricular and posterior WMH are associated with cerebral amyloi d angiopat...
Source: American Journal of Pathology - July 27, 2021 Category: Pathology Authors: Raj N. Kalaria, Diego Sepulveda-Falla Tags: Review Source Type: research

Interplay between brain pericytes and endothelial cells in dementia
Dementia is becoming an increasingly important disease due to an aging population and limited treatment options. Cerebral small vessel disease (cSVD) and Alzheimer ’s disease (AD) are the two most common causes of dementia with vascular dysfunction being a large component of both their pathophysiologies. The neurogliovascular unit (NVU), and in particular the blood-brain barrier (BBB) are required for maintaining brain homeostasis. A complex interaction exis ts between the endothelial cells, which line the blood vessels and pericytes, which surround them in the NVU. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 27, 2021 Category: Pathology Authors: Tessa V. Procter, Anna Williams, Axel Montagne Tags: Review Source Type: research

Trajectory of Growth of SARS-CoV-2 Variants in Houston, Texas, January through May 2021 Based on 12,476 Genome Sequences
We report SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist healthcare system diagnosed from January 1 through May 31, 2021. Prevalence of the B.1.1.7 (Alpha) variant increased rapidly and caused 63%-90% of new cases in the latter half of May. Eleven B.1.1.7 genomes had an E484K replacement in spike protein, a change also identified in other SARS-CoV-2 lineages. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 22, 2021 Category: Pathology Authors: Randall J. Olsen, Paul A. Christensen, S. Wesley Long, Sishir Subedi, Parsa Hodjat, Robert Olson, Marcus Nguyen, James J. Davis, Prasanti Yerramilli, Matthew Ojeda Saavedra, Layne Pruitt, Kristina Reppond, Madison N. Shyer, Jessica Cambric, Ryan Gadd, Ras Source Type: research

Myeloid cells are enriched in tonsillar crypts providing insight into the host tropism of HPV
Viruses are the second leading cause of cancer worldwide, and human papillomavirus (HPV)-associated head and neck cancers are increasing in incidence in the United States. HPV preferentially infects the crypts of the tonsils rather than the surface epithelium. The present study sought to characterize the unique microenvironment within the crypts to better understand the host tropism of HPV to a lymphoid rich organ. Laser-capture microdissection of distinct anatomic areas (crypts, surface epithelium, and germinal centers) of the tonsil coupled with transcriptional analysis and multi-parameter immunofluorescence staining was...
Source: American Journal of Pathology - July 22, 2021 Category: Pathology Authors: Austin K. Mattox, Jessica Roelands, Talia M. Saal, Yang Cheng, Darawan Rinchai, Wouter Hendrickx, Geoffrey D. Young, Thomas J. Diefenbach, Alan E. Berger, William H. Westra, Justin A. Bishop, William C. Faquin, Francesco M. Marincola, Mikael J. Pittet, Da Tags: Regular Article Source Type: research

Serum Antibodies to N-Glycolylneuraminic Acid Are Elevated in Duchenne Muscular Dystrophy and Correlate with Increased Disease Pathology in Cmah −/−mdx Mice
Humans cannot synthesize the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) because of an inactivating deletion in the cytidine-5'-monophospho-(CMP) –N-acetylneuraminic acid hydroxylase (CMAH) gene responsible for its synthesis. Human Neu5Gc deficiency can lead to development of anti-Neu5Gc serum antibodies, the levels of which can be affected by Neu5Gc-containing diets and by disease. Metabolic incorporation of dietary Neu5Gc into human tissu es in the face of circulating antibodies against Neu5Gc-bearing glycans is thought to exacerbate inflammation-driven diseases like cancer and atherosclerosis. ...
Source: American Journal of Pathology - July 20, 2021 Category: Pathology Authors: Paul T. Martin, Kunio Kawanishi, Anna Ashbrook, Bethannie Golden, Annie Samraj, Kelly E. Crowe, Deborah A. Zygmunt, Jonathan Okerblom, Hai Yu, Agatha Maki, Sandra Diaz, Xi Chen, Paul M.L. Janssen, Ajit Varki Tags: Regular article Source Type: research

A Deep Learning-Based Approach for Glomeruli Instance Segmentation from Multistained Renal Biopsy Pathologic Images
Glomeruli instance segmentation from pathologic images is a fundamental step in the automatic analysis of renal biopsies. Glomerular histologic manifestations vary widely among diseases and cases, and several special staining methods are necessary for pathologic diagnosis. A robust model is needed to segment and classify glomeruli with different staining methods and apply in cases with various glomerular pathologic changes. Herein, pathologic images from renal biopsy slides stained with three basic special staining methods were used to build the data sets. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 20, 2021 Category: Pathology Authors: Lei Jiang, Wenkai Chen, Bao Dong, Ke Mei, Chuang Zhu, Jun Liu, Meishun Cai, Yu Yan, Gongwei Wang, Li Zuo, Hongxia Shi Tags: Regular article Source Type: research

Correction
In the article entitled, “Increased M2 Isoform of Pyruvate Kinase in Fibroblasts Contributes to the Growth, Aggressiveness, and Osteoclastogenesis of Odontogenic Keratocysts” (Volume 191, pages 857–871 of the May 2021 issue of The American Journal of Pathology; DOI: https://doi.org/10.1016/j.ajpath.2021.02.010) the au thors have requested an update to the legend of Figure 3F and G to note that the extracellular lactate production (panel F) and intracellular lactate production (panel G) in OKC-F's is being shown with or without PKM2 knockdown. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 20, 2021 Category: Pathology Tags: Correction Source Type: research

Editorial Board
(Source: American Journal of Pathology)
Source: American Journal of Pathology - July 20, 2021 Category: Pathology Source Type: research

Table of Contents
(Source: American Journal of Pathology)
Source: American Journal of Pathology - July 20, 2021 Category: Pathology Source Type: research

This Month in AJP
COVID-19 patients often complain about lack of taste; however, it is unclear if SARS-CoV-2 can directly infect taste receptor cells. Using biopsied fungiform papillae (FP) from a symptomatic SARS-CoV-2+ patient who reported of taste changes and circumvallate papilla from COVID-19 patients who consented to autopsy, Doyle et al (Am J Pathol, AJPA-D-21-00001) studied this possibility. In situ hybridization (ISH) probe and an antibody specific to angiotensin-converting enzyme- 2 (ACE2) —the cell surface receptor facilitating viral entry—confirmed the co-localization of replicating SARS-CoV-2 and ACE2 in type II cel...
Source: American Journal of Pathology - July 15, 2021 Category: Pathology Authors: Chhavi Chauhan Tags: This Month in AJP Source Type: research

Ethics of AI in Pathology: Current Paradigms and Emerging Issues
Deep learning has rapidly advanced artificial intelligence (AI) and algorithmic decision-making (ADM) paradigms, impacting many traditional fields of medicine. Pathology is a heavily data-centric specialty of medicine. The structured nature of pathology data repositories makes it highly attractive to AI researchers to train deep learning models to improve healthcare delivery. Equally, there are enormous financial incentives driving adoption of AI and ADM due to promise of increased efficiency of the healthcare delivery process. (Source: American Journal of Pathology)
Source: American Journal of Pathology - July 9, 2021 Category: Pathology Authors: Chhavi Chauhan, Rama R. Gullapalli Tags: Review Source Type: research

Methionine- and Choline-deficient Diet-induced Non-alcoholic Steatohepatitis Is Associated with Increased Intestinal Inflammation
Inflammation drives the development and progression of non-alcoholic steatohepatitis (NASH). The present study examined changes in intestinal inflammation during NASH. In male C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in severe hepatic steatosis and inflammation relative to feeding a chow diet (CD). Also, MCD-fed mice revealed characteristics of mucosal and submucosal inflammatory responses and increased CD68-postive cells compared with CD-fed mice. Moreover, intestinal phosphorylation states of c-Jun N-terminal protein kinase (JNK) p46 and mRNA levels of interleukin (IL) 1 beta (IL1B),...
Source: American Journal of Pathology - July 6, 2021 Category: Pathology Authors: Destiny R. Matthews, Honggui Li, Jing Zhou, Qingsheng Li, Shannon Glaser, Heather Francis, Gianfranco Alpini, Chaodong Wu Source Type: research

Photoreceptor cell calcium dysregulation and calpain activation promote pathogenic photoreceptor oxidative stress and inflammation in prodromal diabetic retinopathy.
In this study, we test the hypothesis that diabetes promotes a greater than normal cytosolic calcium level in rod cells that activates a Ca2+-sensitive protease, calpain, resulting in oxidative stress and inflammation, two pathogenic factors of early diabetic retinopathy (DR). Nondiabetic and 2-months diabetic C57Bl/6J and calpain1 knockout (Capn1-/-) mice were studied; subgroups were treated with a calpain inhibitor (CI). Ca2+ content was measured in photoreceptors using Fura-2. Retinal calpain expression was studied by qTR-PCR and immunohistochemistry. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 29, 2021 Category: Pathology Authors: Aicha Saadane, Yunpeng Du, Wallace B. Thoreson, Masaru Miyagi, Emma M. Lessieur, Jianying Kiser, Xiangyi Wen, Bruce A. Berkowitz, Timothy S. Kern Tags: Regular Article Source Type: research

Exposure to microbial metabolite butyrate prolongs the survival time and changes the growth pattern of HPV16 E6/E7-immortalized keratinocytes in vivo
Human papillomavirus (HPV) is a ubiquitous human pathogen that can be cleared by host immunity. Nonetheless, a small percentage of the patients develop persistent infection with oncogenic HPV, which poses an increased risk of developing HPV-associated malignancy. While cell-mediated immunity is a known systemic factor, local factors that influence persistent HPV infection have not been fully investigated. HPV-related head/neck cancers have a strong site preference for the oropharynx, suggesting the existence of unique local factors that promote HPV-induced oncogenesis. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 28, 2021 Category: Pathology Authors: Mengtao Li, Eva M. McGhee, Lauryn Shinno, Kellie Lee, Yi-Ling Lin Tags: Regular Article Source Type: research

Anaplastic lymphoma kinase (ALK) overexpression is associated with aggressive phenotypic characteristics of ovarian high-grade serous carcinoma
Deregulated full-length anaplastic lymphoma kinase (ALK) overexpression has been found in some primary solid tumors, but little is known about its role in ovarian high-grade serous carcinoma (HGSC). Here we focused on the functional roles of ALK in HGSC. Cytoplasmic ALK immunoreactivity without chromosomal rearrangement and gene mutations was significantly higher in HGSC as compared to non-HGSC type ovarian carcinomas, and was significantly associated with several unfavorable clinicopathological factors and poor prognosis. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 28, 2021 Category: Pathology Authors: Toshihide Matsumoto, Yusuke Oda, Yoshinori Hasegawa, Miki Hashimura, Yasuko Oguri, Hisako Inoue, Ako Yokoi, Masataka Tochimoto, Mayu Nakagawa, Zesong Jiang, Makoto Saegusa Source Type: research

Use of convolutional neural networks for the detection of u-serrated patterns in direct immunofluorescence images to facilitate the diagnosis of epidermolysis bullosa acquisita
The objective of this study is to investigate the feasibility of using convolutional neural networks (CNNs) for the recognition of u-serrated patterns that can assist in diagnosis of EBA.Nine most commonly used CNNs are trained and validated by using 220,800 manually delineated DIF image patches from 106 images of 46 different patients. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 27, 2021 Category: Pathology Authors: Chenyu Shi, Joost M. Meijer, George Azzopardi, Gilles F.H. Diercks, Jiapan Guo, Nicolai Petkov Tags: Short Communication Source Type: research

Funding sources: NoneUse of convolutional neural networks for the detection of u-serrated patterns in direct immunofluorescence images to facilitate the diagnosis of epidermolysis bullosa acquisita
The objective of this study is to investigate the feasibility of using convolutional neural networks (CNNs) for the recognition of u-serrated patterns that can assist in diagnosis of EBA.Nine most commonly used CNNs are trained and validated by using 220,800 manually delineated DIF image patches from 106 images of 46 different patients. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 27, 2021 Category: Pathology Authors: Chenyu Shi, Joost M. Meijer, George Azzopardi, Gilles F.H. Diercks, Jiapan Guo, Nicolai Petkov Tags: Short Communication Source Type: research

Retinal and choroidal pathologies in aged BALB/c mice following systemic neonatal murine cytomegalovirus infection
While pathologies associated with acute virus infections have been extensively studied, the effects of long-term latent virus infections are less well understood. Human cytomegalovirus (HCMV), which infects 50 to 80% of humans, is usually acquired during early life and persists in a latent state for the lifetime. The purpose of this study was to determine if systemic murine cytomegalovirus (MCMV) infection acquired early in life disseminates to and becomes latent in the eye and if ocular MCMV can trigger in situ inflammation and occurrence of ocular pathology. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 27, 2021 Category: Pathology Authors: Jinxian Xu, Xinglou Liu, Xinyan Zhang, Brendan Marshall, Zheng Dong, Sylvia B. Smith, Diego G. Espinosa-Heidmann, Ming Zhang Tags: Regular Article Source Type: research

Malondialdehyde-acetaldehyde adduct formation decreases immunoglobulin A transport across airway epithelium in smokers who abuse alcohol
Alcohol misuse and smoking are risk factors for pneumonia, yet the impact of combined cigarette smoke and alcohol on pneumonia remains understudied. Smokers who misuse alcohol form lung malondialdehyde-acetaldehyde (MAA) protein adducts and have decreased levels of anti-MAA secretory IgA (sIgA). Transforming growth factor beta (TGF β) downregulates polymeric Ig receptor (pIgR) on mucosal epithelium, resulting in decreased sIgA transcytosis to the mucosa. It is hypothesized that MAA-adducted lung protein increases TGFβ, preventing expression of epithelial cell pIgR and decreasing sIgA. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 26, 2021 Category: Pathology Authors: Todd A. Wyatt, Kristi J. Warren, Tanner J. Wetzel, Troy Suwondo, Gage P. Rensch, Jane M. DeVasure, Deanna D. Mosley, Kusum K. Kharbanda, Geoffrey M. Thiele, Ellen L. Burnham, Kristina L. Bailey, Samantha M. Yeligar Tags: Regular Article Source Type: research

Corrections
In the article entitled, “Oxidative Phosphorylation Promotes Primary Melanoma Invasion” (Volume 190, pages 1108-1117 of the May 2020 issue of The American Journal of Pathology; DOI: https://doi.org/10.1016/j.ajpath.2020.01.012) the authors have requested an update to the funding information. The NYU Melanoma Specialized Program of Research Excellence (SPORE) grant is being changed from P50 CA16087 to P50 CA225450. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 20, 2021 Category: Pathology Tags: Correction Source Type: research

Correction
In the article entitled, “Lack of Annexin A6 Exacerbates Liver Dysfunction and Reduces Lifespan of Niemann-Pick Type C Protein–Deficient Mice” (Volume 191, pages 475-486 of the March 2021 issue of The American Journal of Pathology; DOI: https://doi.org/10.1016/j.ajpath.2020.12.009) the authors have requested an update to the funding information. Grant number RTI2018-098593-B-I00, awarded to Albert Pol is being added to the funding statement: (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 20, 2021 Category: Pathology Tags: Correction Source Type: research

Editorial Board
(Source: American Journal of Pathology)
Source: American Journal of Pathology - June 20, 2021 Category: Pathology Source Type: research

Table of Contents
(Source: American Journal of Pathology)
Source: American Journal of Pathology - June 20, 2021 Category: Pathology Source Type: research

Rictor/Mammalian Target of Rapamycin Complex 2 Signaling Protects Colonocytes from Apoptosis and Prevents Epithelial Barrier Breakdown
Epithelial barrier impairment is a hallmark of several pathologic processes in the gut, including inflammatory bowel diseases. Several intracellular signals prevent apoptosis in intestinal epithelial cells. Herein, we shown that in colonocytes, rictor/mammalian target of rapamycin complex 2 (mTORC2) signaling is a prosurvival stimulus. Mechanistically, mTORC2 activates Akt, which, in turn, inhibits apoptosis by phosphorylating Bad and preventing caspase-3 activation. Nevertheless, during inflammation, rictor/mTORC2 signaling declines and Akt activity is reduced. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 14, 2021 Category: Pathology Authors: Felipe Castro-Martinez, Aurora Candelario-Martinez, Maria del Rocio Encarnacion-Garcia, Zayda Piedra-Quintero, Raul Bonilla-Moreno, Abigail Betanzos, Rocio Perez-Orozco, Maria de los Angeles Hernandez-Cueto, Jose E. Mu ñoz-Medina, Genaro Patiño-Lopez, M Tags: Regular article Source Type: research

Rictor/mTORC2 signaling protects colonocytes from apoptosis and prevents epithelial barrier breakdown.
Epithelial barrier impairment is a hallmark of several pathological processes in the gut, including inflammatory bowel diseases. Several intracellular signals prevent apoptosis in intestinal epithelial cells. Here we shown that in colonocytes, rictor/mTORC2 signaling is a pro-survival stimulus. Mechanistically, mTORC2 activates Akt which in turns inhibits apoptosis by phosphorylating Bad and preventing caspase-3 activation. Nevertheless, during inflammation, rictor/mTORC2 signaling declines and Akt activity is reduced. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 14, 2021 Category: Pathology Authors: Felipe Castro-Martinez, Aurora Candelario-Martinez, Maria del Rocio Encarnacion-Garcia, Zayda Piedra-Quintero, Raul Bonilla-Moreno, Abigail Betanzos, Rocio Perez-Orozco, Maria de los Angeles Hernandez-Cueto, Jose Esteban Mu ñoz-Medina, Genaro Patiño-Lop Tags: Regular Article Source Type: research

Artificial Intelligence in Pathology: Easing the Burden of Annotation
capsule networks (27) and compositional learning (28). LeCun, who is the father of (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 12, 2021 Category: Pathology Authors: Benjamin R. Mitchell, Marion C. Cohen, Stanley Cohen Tags: Mini-Review Source Type: research

YAP Accelerates NOTCH Driven Cholangiocarcinogenesis via mTORC1 in Mice
Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy with limited therapeutic options. Previously, we demonstrated that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. Here, we show that activation of the Yap protooncogene occurs during Notch1 driven iCCA progression. After co-expressing activated Notch1 (Nicd) and Yap (YapS127A) in the mouse liver, rapid iCCA formation and progression occurred in Nicd/Yap mice. Mechanistically, an increased expression of amino acid transporters and activation of the mTORC1 signaling pathway was detected in Nicd/Yap mouse liver tumors. ...
Source: American Journal of Pathology - June 12, 2021 Category: Pathology Authors: Xinjun Lu, Baogang Peng, Ge Chen, Mario G. Pes, Silvia Ribback, Cindy Ament, Hongwei Xu, Rajesh Pal, Pedro M. Rodrigues, Jesus M. Banales, Matthias Evert, Diego F. Calvisi, Xin Chen, Biao Fan, Jingxiao Wang Source Type: research

This Month in AJP
Obliterative bronchiolitis lesions caused by bronchiolitis obliterans syndrome (BOS) may lead to organ failure post lung transplant; however, the molecular composition of these lesions is unclear. Using proteomics approach, M üller et al (Am J Pathol, AJPA-D-20-00499) analyzed the protein composition of the lesions in explanted lungs from four end-stage BOS patients. Protein signatures were established for 14 bronchiolitis obliterans lesions. A set of 39 proteins were identified in over 75% of lesions, with every lesion exhibiting some common features and a unique composition of proteins. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 12, 2021 Category: Pathology Tags: This Month in AJP Source Type: research

Artificial Intelligence and Cellular Segmentation in Tissue Microscopy Images
With applications in object detection, image feature extraction, image classification, and image segmentation, artificial intelligence is enabling high-throughput analysis of image data in a variety of biomedical imaging disciplines, ranging from radiology and pathology to cancer biology and immunology. Specifically, a growth in research surrounding deep learning has led to widespread application of computer vision techniques to analyze and mine data from biomedical images. The availability of open-source software packages and the development of novel, trainable deep neural network architectures has led to an increase in a...
Source: American Journal of Pathology - June 12, 2021 Category: Pathology Authors: Madeleine S. Durkee, Rebecca Abraham, Marcus R. Clark, Maryellen L. Giger Tags: Mini-Review Source Type: research

Artificial Intelligence in Pathology: Easing the Burden of Annotation Running Title: AI Annotation Reduction
capsule networks (27) and compositional learning (28). LeCun, who is the father of (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 12, 2021 Category: Pathology Authors: Benjamin R. Mitchell, Marion C. Cohen, Stanley Cohen Tags: Mini-Review Source Type: research

Vitamin C Deficiency Inhibits Nonalcoholic Fatty Liver Disease Progression through Impaired de Novo Lipogenesis
Despite the increasing clinical importance of nonalcoholic fatty liver disease (NAFLD), little is known about its underlying pathogenesis or specific treatment. The senescence marker protein 30 (SMP30), which regulates the biosynthesis of vitamin C (VC) in many mammals, except primates and humans, was recently recognized as a gluconolactonase. However, the precise relation between VC and lipid metabolism in NAFLD is not completely understood. Therefore, we aimed to clearly reveal the role of VC in NAFLD progression. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 11, 2021 Category: Pathology Authors: Seoung-Woo Lee, Su-Min Baek, Kyung-Ku Kang, A-Rang Lee, Tae-Un Kim, Seong-Kyoon Choi, Yoon-Seok Roh, Il-Hwa Hong, Sang-Joon Park, Tae-Hwan Kim, Kyu-Shik Jeong, Jin-Kyu Park Tags: Regular article Source Type: research

Multiple Lesions Contribute to Infertility in Males Lacking Autoimmune Regulator
Male factors, including those of autoimmune origin, contribute to approximately 50% of infertility cases in humans. However, the mechanisms underlying autoimmune male infertility are poorly understood. Deficiency in autoimmune regulator (AIRE) impairs central immune tolerance because of diminished expression of self-antigens in the thymus. Humans with AIRE mutations and mice with engineered ablation of Aire develop multiorgan autoimmunity and infertility. To determine the immune targets contributing to infertility in male Aire-deficient ( −/−) mice, we paired Aire−/− or wild-type (WT) males with WT ...
Source: American Journal of Pathology - June 11, 2021 Category: Pathology Authors: Bryce D. Warren, Soo H. Ahn, Kathryn Brittain, Manjunatha K. Nanjappa, Hao Wang, Jianrong Wang, Gustavo Blanco, Gladis Sanchez, Yong Fan, Brian K. Petroff, Paul S. Cooke, Margaret G. Petroff Tags: Regular article Source Type: research

Vitamin C deficiency inhibits non-alcoholic fatty liver disease progression through impaired de novo lipogenesis
Despite the increasing clinical importance of nonalcoholic fatty liver disease (NAFLD), little is known about its underlying pathogenesis or specific treatment. The senescence marker protein 30 (SMP30), which regulates the biosynthesis of vitamin C in many mammals except primates and humans, was recently recognized as a gluconolactonase. However, the precise relation between vitamin C and lipid metabolism in NAFLD is not completely understood. Therefore, we aimed to clearly reveal the role of vitamin C in NAFLD progression. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 11, 2021 Category: Pathology Authors: Seoung-Woo Lee, Su-Min Baek, Kyung-Ku Kang, A-Rang Lee, Tae-Un Kim, Seong-Kyoon Choi, Yoon-Seok Roh, Il-Hwa Hong, Sang-Joon Park, Tae-Hwan Kim, Kyu-Shik Jeong, Jin-Kyu Park Tags: Regular Article Source Type: research

Multiple lesions contribute to infertility in males lacking autoimmune regulator (AIRE)
Male factors, including those of autoimmune origin, contribute to approximately 50% of infertility cases in humans. However, the mechanisms underlying autoimmune male infertility are poorly understood. Deficiency in autoimmune regulator (AIRE) impairs central immune tolerance because of diminished expression of self-antigens in the thymus. Humans with AIRE mutations and mice with engineered ablation of Aire develop multi-organ autoimmunity and infertility. To determine the immune targets contributing to infertility in male Aire-deficient (-/-) mice, we paired Aire-/- or wild-type (WT) males with WT females. (Source: Americ...
Source: American Journal of Pathology - June 11, 2021 Category: Pathology Authors: Bryce D. Warren, Soo Hyun Ahn, Kathryn Brittain, Manjunatha K. Nanjappa, Hao Wang, Jianrong Wang, Gustavo Blanco, Gladis Sanchez, Yong Fan, Brian K. Petroff, Paul S. Cooke, Margaret G. Petroff Tags: Regular Article Source Type: research

Understanding the Role of Blood Vessels in the Neurological Manifestations of COVID-19
SARS-CoV-2 was originally identified as an outbreak in Wuhan, China towards the end of 2019 and quickly became a global pandemic, with a large death toll. Originally identified as a respiratory disease, similar to previously discovered SARS and MERS type viruses, concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain-barrier. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 11, 2021 Category: Pathology Authors: Hannah A.B. Whitmore, Leo A. Kim Tags: Review Source Type: research

Nondegradable Collagen Increases Liver Fibrosis but Not Hepatocellular Carcinoma in Mice
Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. By studying in  vivo and in vitro models of HCC using Colr/r mice (that produce a collagenase-resistant type I collagen) or wild-type (WT) mice, we aimed to assess the relationship between type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Colr/r mice or Hepa 1 to 6 cells were engrafted into WT and Colr/r livers. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 10, 2021 Category: Pathology Authors: Jacopo Baglieri, Cuili Zhang, Shuang Liang, Xiao Liu, Takahiro Nishio, Sara B. Rosenthal, Debanjan Dhar, Hua Su, Min Cong, Jidong Jia, Mojgan Hosseini, Michael Karin, Tatiana Kisseleva, David A. Brenner Tags: Regular article Source Type: research

Decreased portal circulation augments fibrosis and ductular reaction in nonalcoholic fatty liver disease in mice
Nonalcoholic fatty liver disease (NAFLD) often progresses to cirrhosis and causes liver cancer, but mechanisms of its progression have not been elucidated. Although NAFLD is often associated with abnormal portal circulation, there have not been any experimental studies to test its pathogenic role. Here, we examined whether decreased portal circulation affected the pathology of nonalcoholic steatohepatitis (NASH) using congenital portosystemic shunt (PSS) in C57BL/6J mice. Whereas PSS significantly attenuated free radical-mediated CCl4 injury, it augmented pericellular fibrosis in the centrilobular area induced by a 0.1% me...
Source: American Journal of Pathology - June 10, 2021 Category: Pathology Authors: Lingtong Meng, Masanori Goto, Hiroki Tanaka, Yuki Kamikokura, Yumiko Fujii, Yoko Okada, Hiroyuki Furukawa, Yuji Nishikawa Source Type: research

CUL4high lung adenocarcinomas are dependent on the CUL4-p21 ubiquitin signaling for proliferation and survival
In this study, we report that both CUL4A and CUL4B are highly expressed in non-small cell lung cancer (NSCLC) patients, and high expression of both is associated with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 10, 2021 Category: Pathology Authors: Yannan Wang, Fan Yan, Abu Nasar, Zhe-Sheng Chen, Nasser Khaled Altorki, Brendon Stiles, Navneet Narula, Pengbo Zhou Source Type: research

Non-degradable collagen increases liver fibrosis but not hepatocellular carcinoma in mice
Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. By studying in vivo and in vitro models of HCC using Colr/r mice (that produce a collagenase resistant Type I collagen) or WT mice, we aim to assess the relationship between Type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Colr/r mice or Hepa 1-6 cells were engrafted into WT and Colr/r livers. The effect of Hepatic Stellate Cells (HSCs) from WT and Colr/r mice on the growth of Hepa 1-6 cells was studied by using multicellul...
Source: American Journal of Pathology - June 10, 2021 Category: Pathology Authors: Jacopo Baglieri, Cuili Zhang, Shuang Liang, Xiao Liu, Takahiro Nishio, Sara B. Rosenthal, Debanjan Dhar, Hua Su, Min Cong, Jidong Jia, Mojgan Hosseini, Michael Karin, Tatiana Kisseleva, David A. Brenner Source Type: research

Coronavirus Disease 2019 during Pregnancy
Despite occasional reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vertical transmission during pregnancy, the question of placental infection and its consequences for the newborn remain questionable. Herein, we analyzed the placentas of 31 coronavirus disease 2019 –positive mothers by reverse transcriptase PCR, immunohistochemistry, and in situ hybridization. We only detected one case of placental infection, which was associated with intrauterine demise of the fetus. We then isolated and differentiated primary trophoblasts from nonpathologic human placentas at term, and exposed them to SARS-C...
Source: American Journal of Pathology - June 7, 2021 Category: Pathology Authors: Arthur Colson, Christophe L. Depoix, G éraldine Dessilly, Pamela Baldin, Olivier Danhaive, Corinne Hubinont, Pierre Sonveaux, Frédéric Debiève Source Type: research

Primary Osteoarthritis Early Joint Degeneration Induced by Endoplasmic Reticulum Stress Is Mitigated by Resveratrol
Given the increasing number of people living with osteoarthritis (OA), due to population aging and rising rates of obesity, there is an urgent need to identify effective treatment and preventions. Two top risk factors for OA, age and obesity, are associated with endoplasmic reticulum (ER) stress. The I-ERS mouse, an ER stress –driven model of primary OA, was developed to study the role of ER stress in primary OA susceptibility. The I-ERS mouse has the unique ability to induce ER stress in healthy adult I-ERS mouse articular chondrocytes and cartilage, driving joint degeneration that mimics early primary OA. (Source: ...
Source: American Journal of Pathology - June 7, 2021 Category: Pathology Authors: Jacqueline T. Hecht, Alka C. Veerisetty, Juliana Wu, Francoise Coustry, Mohammad G. Hossain, Frankie Chiu, Francis H. Gannon, Karen L. Posey Tags: Regular Article Source Type: research

Down-Regulation of a Profibrotic Transforming Growth Factor- β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis
Idiopathic subglottic stenosis (iSGS) is a progressive fibrotic disease characterized by life-threatening airway narrowing. Although the molecular underpinnings are unknown, our previous reports showing that subglottic serial intralesional steroid injections (SILSIs) improve clinical outcomes suggests a steroid-sensitive pathway in iSGS. We conducted a prospective study to determine the changes in profibrotic markers during SILSI to identify steroid-sensitive profibrotic drivers. Seven newly diagnosed iSGS patients were recruited for SILSI. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 7, 2021 Category: Pathology Authors: J. Humberto Trevi ño-Villarreal, Justin S. Reynolds, P. Kent Langston, Andrew Thompson, James R. Mitchell, Ramon A. Franco Tags: Regular article Source Type: research

COVID-19 during Pregnancy: Clinical and In Vitro Evidence against Placenta Infection at Term by SARS-CoV-2
Despite occasional reports of SARS-CoV-2 vertical transmission during pregnancy, the question of placental infection and its consequences for the newborn remain questionable. Here, we analyzed the placentas of 31 COVID-19-positive mothers by RT-PCR, immunohistochemistry and in situ hybridization. We only detected one case of placental infection, which was associated with intrauterine demise of the fetus. We then isolated and differentiated primary trophoblasts from non-pathological human placentas at term, and exposed them to SARS-CoV-2 virions. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 7, 2021 Category: Pathology Authors: Arthur Colson, Christophe L. Depoix, G éraldine Dessilly, Pamela Baldin, Olivier Danhaive, Corinne Hubinont, Pierre Sonveaux, Frédéric Debiève Source Type: research

Recombinant antithrombin attenuates acute respiratory distress syndrome in experimental endotoxemia
Sepsis-induced endothelial acute respiratory distress syndrome (ARDS) is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was intraperitoneally injected into 10-week-old male C57BL/6 mice, and saline or rAT was intraperitoneally administrated at 3 and 24 h after LPS administrat...
Source: American Journal of Pathology - June 7, 2021 Category: Pathology Authors: Haruka Okamoto, Isamu Muraki, Hideshi Okada, Hiroyuki Tomita, Kodai Suzuki, Chihiro Takada, Yugo Wakayama, Ayumi Kuroda, Hirotsugu Fukuda, Yuki Kawasaki, Ayane Nishio, Maho Matsuo, Yuto Tamaoki, Risa Inagawa, Shigeo Takashima, Toshiaki Taniguchi, Akio Suz Tags: Regular Article Source Type: research

Primary OA early joint degeneration induced by ER-stress is mitigated by resveratrol
Given the increasing number of people living with OA, due to population aging and rising rates of obesity, there is an urgent need to identify effective treatment and preventions. Two top risk factors for OA, age and obesity, are associated with ER stress. The I-ERS mouse, an ER stress driven model of primary OA, was developed to study the role of ER stress in primary OA susceptibility. The I-ERS mouse has the unique ability to induce ER stress in healthy adult I-ERS mouse articular chondrocytes and cartilage, driving joint degeneration that mimics early primary OA. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 7, 2021 Category: Pathology Authors: Jacqueline T. Hecht, Alka C. Veerisetty, Juliana Wu, Francoise Coustry, Mohammad G. Hossain, Frankie Chiu, Francis H. Gannon, Karen L. Posey Tags: Regular Article Source Type: research

Downregulation of a Profibrotic TGF β1/CCN2/MMP9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis
Idiopathic subglottic stenosis (iSGS) is a progressive fibrotic disease characterized by life-threatening airway narrowing. While the molecular underpinnings are unknown, our previous reports showing that subglottic Serial Intra-Lesional Steroid Injections (SILSI) improves clinical outcomes suggests a steroid-sensitive pathway in iSGS. We conducted a prospective study to determine the changes in profibrotic markers during SILSI to identify steroid-sensitive profibrotic drivers. Seven newly diagnosed iSGS patients were recruited for SILSI. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 7, 2021 Category: Pathology Authors: J. Humberto Trevi ño-Villarreal, Justin S. Reynolds, P. Kent Langston, Andrew Thompson, James R. Mitchell, Ramon A. Franco Source Type: research

Protein signatures of remodeled airways in transplanted lungs with Bronchiolitis Obliterans Syndrome obtained using laser capture microdissection
Bronchiolitis obliterans syndrome (BOS), a common form of chronic lung allograft dysfunction, is the major limitation to long-term survival after lung transplantation. The histological correlate is progressive, fibrotic occlusion of small airways, obliterative bronchiolitis lesions, ultimately leading to organ failure. The molecular composition of these lesions is unknown. By laser-capture microdissection and optimized sample preparation protocols for mass spectrometry the protein composition of the lesions in explanted lungs from four end-stage BOS patients were analysed. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 7, 2021 Category: Pathology Authors: Catharina M üller, Oskar Rosmark, Emma Åhrman, Hans Brunnström, Katharina Wassilew, Annika Nybom, Barbora Michaliková, Hillevi Larsson, Leif T. Eriksson, Hans Henrik Schultz, Michael Perch, Johan Malmström, Jenny Wigén, Martin Iversen, Gunilla Weste Source Type: research

The Role of R-Ras Proteins in Normal and Pathologic Migration and Morphologic Change
The contributions that the R-Ras subfamily (R-Ras, R-Ras2/TC21 and M-Ras) of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome, a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular and nervous systems. Consistent with the abnormalities seen in Noonan syndrome, a host of new studies have implicated R-Ras proteins in physiologic and pathologic changes ...
Source: American Journal of Pathology - June 6, 2021 Category: Pathology Authors: Shannon M. Weber, Steven L. Carroll Tags: Review Source Type: research

Human Type II Taste Cells Express Angiotensin-Converting Enzyme 2 and Are Infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Chemosensory changes are well-reported symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The virus targets cells for entry by binding of its spike protein to cell-surface angiotensin-converting enzyme 2 (ACE2). It was not known whether ACE2 is expressed on taste receptor cells (TRCs) or if TRCs are infected directly. Using an in situ hybridization probe and an antibody specific to ACE2, ACE2 is present on a subpopulation of TRCs (namely, type II cells in taste buds in taste papillae). (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 5, 2021 Category: Pathology Authors: M áire E. Doyle, Ashley Appleton, Qing-Rong Liu, Qin Yao, Caio H. Mazucanti, Josephine M. Egan Tags: Short Communication Source Type: research

Human Type II Taste Cells Express ACE2 and are Infected by SARS-CoV-2
Chemosensory changes are well-reported symptoms of SARS-CoV-2 infection. The virus targets cells for entry by binding of its spike protein to cell-surface angiotensin-converting enzyme- 2 (ACE2). It was not known whether ACE2 is expressed on taste receptor cells (TRCs) nor if TRCs are infected directly. Using an in-situ hybridization (ISH) probe and an antibody specific to ACE2, ACE2 is present on a subpopulation of TRCs, namely, Type II cells in taste buds in taste papillae. Fungiform papillae (FP) of a SARS-CoV-2+ patient exhibiting symptoms of COVID-19, including taste changes, were biopsied. (Source: American Journal of Pathology)
Source: American Journal of Pathology - June 5, 2021 Category: Pathology Authors: M áire E. Doyle, Ashley Appleton, Qing-Rong Liu, Qin Yao, Caio Henrique Mazucanti, Josephine M. Egan Tags: Short Communication Source Type: research