Keratinocyte growth factor reduces injury and leads to early recovery from cyclophosphamide bladder injury
Keratinocyte growth factor (KGF) improves outcomes after cyclophosphamide-induced bladder injury. To understand the underlying mechanisms, we subcutaneously administered KGF to mice 24 hours prior to intraperitoneal cyclophosphamide administration, followed by histological assays and immunostaining. In vehicle (PBS)-pretreated mice, non-apoptotic superficial urothelial cell death from two to six hours and apoptosis in intermediate and basal cells from four to 24 hours was observed post cyclophosphamide treatment. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 22, 2019 Category: Pathology Authors: Sridhar Tatarao Narla, Daniel Scott Bushnell, Caitlin Marie Schaefer, Mehdi Nouraie, Carlton Matthew Bates Tags: Regular Article Source Type: research

Interleukin17 –CXCR2 axis facilitates breast cancer progression by up-regulating neutrophil recruitment
Recent evidence suggests that interactions among pro-inflammatory cytokines, chemokines, and cancer cell –recruited neutrophils result in enhanced metastasis and chemotherapy resistance. Nonetheless, the detailed mechanism remains unclear. Our aim was to discover the role of interleukin 17 (IL-17), CXCR2 ligands, and cancer-associated neutrophils in chemotherapy resistance and metastasis in breast ca ncer. Mice were injected with Cl66 murine mammary tumor cells, Cl66 cells resistant to doxorubicin (Cl66-Dox), or paclitaxel (Cl66-Pac). (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 22, 2019 Category: Pathology Authors: Lingyun Wu, Mohammad Awaji, Sugandha Saxena, Michelle L. Varney, Bhawna Sharma, Rakesh K. Singh Tags: Regular Article Source Type: research

A guide for the use of the ferret model for influenza virus infection
As influenza viruses continue to jump species barriers to cause human infection, assessments of disease severity and viral replication kinetics in vivo provide crucial information for public health professionals. The ferret model is a valuable resource for evaluating influenza virus pathogenicity; thus, understanding the most effective sample collection and usage techniques, as well as the full spectrum of attainable data following experimental inoculation in this species, is paramount. This is especially true for scheduled necropsy of virus-infected ferrets, a standard component in evaluation of influenza virus pathogenic...
Source: American Journal of Pathology - October 22, 2019 Category: Pathology Authors: Jessica A. Belser, Alissa M. Eckert, Thanhthao Huynh, Joy M. Gary, Jana M. Ritter, Terrence M. Tumpey, Taronna R. Maines Tags: Review Source Type: research

Long Intervening Noncoding 00467 RNA Contributes to Tumorigenesis by Acting as a Competing Endogenous RNA against miR-107 in Cervical Cancer Cells
In this study, we aimed to identify the role of long intervening noncoding 00467 (LINC00467) in epithelial-mesenchymal transition (EMT), invasion and migration of cervical cancer cells by regulating miR-107 and kinesin family member 23 (KIF23). Microarray analyses were used to detect cervical cancer –related differentially expressed genes, followed by determination of LINC00467, miR-107, and KIF23 levels and subcellular location of LINC00467. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 20, 2019 Category: Pathology Authors: Guang-Cai Li, Li Xin, Yong-Sheng Wang, Ying Chen Tags: Regular article Source Type: research

Long Noncoding RNA LINC01133 Confers Tumor-Suppressive Functions in Ovarian Cancer by Regulating Leucine-Rich Repeat Kinase 2 as an miR-205 Sponge
This study aimed to clarify the molecular mechanism of LINC01133 in the progression of ovarian cancer. Initially, microarray-based analysis was used to screen differentially expressed long noncoding RNAs and miRNAs, with LINC01133 and miR-205 obtained for this study. The biological functions of LINC01133, miR-205, and leucine-rich repeat kinase 2 (LRRK2) were validated on cell proliferation, migration, and invasion of ovarian cancer through gain-of-function and loss-of-function experiments. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 20, 2019 Category: Pathology Authors: Min Liu, Cuiping Shen, Changxiu Wang Tags: Regular article Source Type: research

Jay McKay McDonald, M.D., 1943 –2019
This In Memoriam highlights the life of Jay McKay McDonald, a leader, educator, mentor, and a committed researcher. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 20, 2019 Category: Pathology Authors: Gene P. Siegal, Kevin A. Roth, Robert W. Hardy Tags: In memoriam Source Type: research

Editorial Board
(Source: American Journal of Pathology)
Source: American Journal of Pathology - October 20, 2019 Category: Pathology Source Type: research

Table of Contents
(Source: American Journal of Pathology)
Source: American Journal of Pathology - October 20, 2019 Category: Pathology Source Type: research

This Month in AJP
There are no reported biomarkers to predict progression of small renal masses (SRMs). Using peptidomics, Di Meo et al (Am J Pathol, AJPA_2019_399) identified new non-invasive urinary peptide biomarkers for early-stage renal cell carcinoma (RCC)-SRMs. Urinary peptides distinguished clear cell RCC-SRM from healthy controls and renal oncocytoma. These non-invasive diagnostic and prognostic biomarkers may help improve clinical decision-making as well as patient management. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 16, 2019 Category: Pathology Authors: Chhavi Chauhan Tags: This Month in AJP Source Type: research

Lymphotoxin-beta receptor signaling is crucial for the vascularization of transplanted metanephros
This commentary highlights the article by Francipane et al that studied the molecular signals supporting kidney vascularization in host lymphoid sites and omenta. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 16, 2019 Category: Pathology Authors: Valerio Brizi, Christodoulos Xinaris Tags: Commentary Source Type: research

Non-SMC condensin I complex subunit D2 is a prognostic factor in triple-negative breast cancer for the ability to promote cell cycle and enhance invasion
Triple-negative breast cancer (TNBC) is a heterogeneous disease with an unfavorable prognosis and no specific targeted therapies. The role of non-SMC condensin I complex subunit D2 (NCAPD2), a regulatory subunit of the condensin I complex that mainly participates in chromosome condensation and segregation, has not been reported in cancer. We therefore evaluated the prognostic value and biological function of NCAPD2 in TNBC. The expression of NCAPD2 was studied in 179 TNBC tissues by immunohistochemistry and associations among NCAPD2 expression, clinicopathological features, and the prognosis information of TNBC patients we...
Source: American Journal of Pathology - October 12, 2019 Category: Pathology Authors: Yajing Zhang, Fangfang Liu, Chengli Zhang, Meijing Ren, Manchao Kuang, Ting Xiao, Xuebing Di, Lin Feng, Li Fu, Shujun Cheng Tags: Regular article Source Type: research

Cell of Origin and Immunological Events in the Pathogenesis of Breast Implant –Associated Anaplastic Large Cell Lymphoma
Breast implant –associated anaplastic large cell lymphoma (BIA-ALCL) is a CD30-positive, anaplastic lymphoma kinase–negative T-cell lymphoma. Nearly all cases have been associated with textured implants. Most cases are of effusion-limited, indolent disease, with an excellent prognosis following implant and cap sule removal. However, capsular invasion and tumor mass has a more aggressive course, and a fatal outcome risk. This review summarizes the current knowledge on BIA-ALCL cell of origin and immunological factors underlying its pathogenesis. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Suzanne D. Turner, Giorgio Inghirami, Roberto N. Miranda, Marshall E. Kadin Tags: Review Source Type: research

Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma
Tumor stroma resembles a fibrotic microenvironment, being characterized by the presence of myofibroblast-like cancer-associated fibroblasts (CAFs). In wild-type mice injected with melanoma cells, we show that the stem cell transcription factor Sox2 is expressed by tumor cells and induced in CAFs derived from synthetic fibroblasts. These fibroblasts were labeled postnatally with green fluorescent protein using mice expressing a tamoxifen-dependent Cre recombinase under the control of a fibroblast-specific promoter/enhancer. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Matthew Tsang, Katherine Quesnel, Krista Vincent, James Hutchenreuther, Lynne-Marie Postovit, Andrew Leask Tags: Regular article Source Type: research

RNA Expression Profiling of Lymphoepithelioma-Like Carcinoma of the Bladder Reveals a Basal-like Molecular Subtype
Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare subtype of urothelial carcinoma consisting of undifferentiated epithelial cells within a dense inflammatory cell infiltrate. We set out to molecularly characterize LELC-B through RNA expression profiling as well as immunohistochemistry to understand its underlying biology. Sixteen cases of LELC-B were identified at Johns Hopkins University. RNAseq was performed on 14 cases. Immunohistochemical staining for PD-L1 and mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 was performed. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Ujjawal Manocha, Jordan Kardos, Sara Selitsky, Mi Zhou, Steven M. Johnson, Cori Breslauer, Jonathan I. Epstein, William Y. Kim, Sara E. Wobker Tags: Regular article Source Type: research

Involvement of Transcription Factor 21 in the Pathogenesis of Fibrosis in Endometriosis
This study aimed to determine whether transcription factor 21 (TCF21) is involved in the development of endometriosis as an upstream regulatory gene of periostin. Formalin-fixed, paraffin-embedded tissue samples (normal endometrium of women without endometriosis, NE; eutopic endometrium of women with endometriosis, EE; ovarian endometriosis, OE; deep infiltrating endometriosis, DIE) and respective cells were analyzed. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Umida Ganieva, Tomoko Nakamura, Satoko Osuka, Bayasula, Natsuki Nakanishi, Yukiyo Kasahara, Nobuyoshi Takasaki, Ayako Muraoka, Shotaro Hayashi, Takashi Nagai, Tomohiko Murase, Maki Goto, Akira Iwase, Fumitaka Kikkawa Tags: Regular Article Source Type: research

Intestinal epithelial chemokine (C-C motif) ligand 7 overexpression enhances acetaminophen-induced hepatotoxicity in mice
Acetaminophen (APAP) overdose –induced hepatotoxicity is the leading cause of drug-induced liver injury worldwide. The related injury pathogenesis is mainly focused on the liver. Here, we report that gut barrier disruption may also be involved in APAP hepatotoxicity. APAP administration led to gut leakiness and colonic epithel ial chemokine (C-C motif) ligand 7 (CCL7) up-regulation. Intestinal epithelial cell (IEC)-specific CCL7 transgenic mice (CCL7tgIEC mice) showed markedly increased myosin light chain kinase (MLCK) phosphorylation and elevated gut permeability and bacterial translocation into the liver compared t...
Source: American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Mengwei Niu, Zhihong Luo, Shenhai Gong, Sanda Win, Neil Kaplowitz, Yong Jiang, Peng Chen Source Type: research

Ferroptosis affects the progression of non-alcoholic steatohepatitis via the modulation of lipid peroxidation –mediated cell death in mice
Oxidative stress and its-associated lipid peroxidation play a key role in non-alcoholic steatohepatitis (NASH). Ferroptosis is a recently recognized type of cell death characterized by an iron dependent and lipid peroxidation –mediated non-apoptotic cell death. We demonstrate the impact of ferroptosis on the progression of NASH induced by methionine/choline-deficient diet (MCD) feeding for 10 days. RSL-3 (a ferroptosis inducer) treatment showed decreased hepatic expression of GPX4, and conversely increased 12/15-lipoxy genase, and apoptosis inducing factor, indicating that ferroptosis plays a key role in NASH-related...
Source: American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Jing Qi, Jong-Won Kim, Zixiong Zhou, Chae Woong Lim, Bumseok Kim Source Type: research

Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis
This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal specific SIRT1 deletion (SIRT1iKO) and flox control (WT) mice with a chronic-plus-binge ethanol feeding protocol. (Source: American Journal of Pathology)
Source: American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Zhou Zhou, Ting Jie Ye, Elizabeth DeCaro, Brian Buehler, Zachary Stahl, Gregory Bonavita, Michael Daniels, Min You Source Type: research

Host Lymphotoxin- β Receptor Signaling Is Crucial for Angiogenesis of Metanephric Tissue Transplanted into Lymphoid Sites
The mouse lymph node (LN) can provide a niche to grow metanephric kidney to maturity. Here, we show that signaling through the lymphotoxin- β receptor (LTβR) is critical for kidney organogenesis both in the LN and the omentum. By transplanting kidney rudiments either in the LNs of mice undergoing LTβR antagonist treatment or in the omenta of LTBR knockout (LTβR−/−) mice, the host LTβR signals were found to be crucial for obtain ing a well-vascularized kidney graft. Indeed, defective LTβR signaling correlated with decreased expression of endothelial and angiogenic markers in kidney ...
Source: American Journal of Pathology - October 1, 2019 Category: Pathology Authors: Maria Giovanna Francipane, Bing Han, Eric Lagasse Source Type: research

Age-related pathology associated with H1N1 A/California/07/2009 influenza virus infection
Influenza virus infection causes a spectrum of diseases ranging from mild upper respiratory tract infection to severe lower respiratory tract infection that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia following 2009 H1N1 influenza virus infection in newly weaned, adult, and ag...
Source: American Journal of Pathology - October 1, 2019 Category: Pathology Authors: Stephanie J. Bissel, Chalise E. Carter, Guoji Wang, Scott K. Johnson, Lauren P. Lashua, Alyson Kelvin, Clayton A. Wiley, Elodie Ghedin, Ted M. Ross Tags: Regular Article Source Type: research

Host Lymphotoxin-Beta Receptor Signaling is Crucial for Angiogenesis of Metanephric Tissue Transplanted into Lymphoid Sites
The mouse lymph node (LN) can provide a niche to grow metanephric kidney to maturity. Here, we show that signaling through the lymphotoxin-beta receptor (LT βR) is critical for kidney organogenesis both in the LN and the omentum. By transplanting kidney rudiments either in the LNs of mice undergoing LTβR antagonist treatment or in the omenta of LTβR knockout (LTβR-/-) mice, the host LTβR signals were found to be crucial for obtaining a well-vascula rized kidney graft. Indeed, defective LTβR signaling correlated with decreased expression of endothelial and angiogenic markers in kidney grafts as...
Source: American Journal of Pathology - October 1, 2019 Category: Pathology Authors: Maria Giovanna Francipane, Bing Han, Eric Lagasse Source Type: research

Endogenous Specialized Proresolving Mediator Profiles in a Novel Experimental Model of Lymphatic Obstruction and Intestinal Inflammation in African Green Monkeys
Changes in the intestinal lymphatic vascular system, such as lymphatic obstruction, are characteristic features of inflammatory bowel diseases. The lymphatic vasculature forms a conduit to enable resolution of inflammation; this process is driven by specialized endogenous proresolving mediators (SPMs). To evaluate contributions of lymphatic obstruction to intestinal inflammation and to study profiles of SPMs, we generated a novel animal model of lymphatic obstruction using African green monkeys. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 21, 2019 Category: Pathology Authors: Felix Becker, Emily Romero, Jason Goetzmann, Dana L. Hasselschwert, Beth Dray, John Vanchiere, Jane Fontenot, J. Winny Yun, Paul C. Norris, Luke White, Melany Musso, Charles N. Serhan, J. Steven Alexander, Felicity N.E. Gavins Tags: Regular article Source Type: research

Editorial Board
(Source: American Journal of Pathology)
Source: American Journal of Pathology - September 21, 2019 Category: Pathology Source Type: research

Table of Contents
(Source: American Journal of Pathology)
Source: American Journal of Pathology - September 21, 2019 Category: Pathology Source Type: research

Wasf3 deficiency reveals involvement in metastasis in a mouse model of breast cancer
The WASF3 gene has been implicated in cancer cell movement, invasion, and metastasis by regulating genetic pathways important in these processes. Invasion and metastasis assays, however, are largely centered on xenograft models in immune compromised mice. To facilitate analysis of the role of WASF3 in spontaneous development of cancer cell metastasis, we generated a Wasf3 null strain by deleting exons 4 and 5, which encode essential motifs for Wasf3 function. On exposure to cre-recombinase a stop codon is generated immediately downstream in exon 6. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 19, 2019 Category: Pathology Authors: Haiyan Qin, Sumin Lu, Muthusamy Thangaraju, John K. Cowell Source Type: research

Detection of Lung Cancer Lymph Node Metastases from Whole-Slide Histopathologic Images Using a Two-Step Deep Learning Approach
In this study, a novel two-step deep learning algorithm was developed to address the issue of false-positive prediction while maintaining accurate cancer detection. Three-hundred and forty-nine whole-slide lung cancer lymph node images, including 233 slides for algorithm training, 10 slides for validation, and 106 slides for evaluation, were collected. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Hoa Hoang Ngoc Pham, Mitsuru Futakuchi, Andrey Bychkov, Tomoi Furukawa, Kishio Kuroda, Junya Fukuoka Source Type: research

Serum Amyloid P and a Dendritic Cell –Specific Intercellular Adhesion Molecule-3–Grabbing Nonintegrin Ligand Inhibit High-Fat Diet–Induced Adipose Tissue and Liver Inflammation and Steatosis in Mice
High-fat diet (HFD) –induced inflammation is associated with a variety of health risks. The systemic pentraxin serum amyloid P (SAP) inhibits inflammation. SAP activates the high-affinity IgG receptor Fcγ receptor I (CD64) and the lectin receptor dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (CD209). Herein, we show that for mice on an HFD, injections of SAP and a synthetic CD209 ligand (1866) reduced HFD-increased adipose and liver tissue inflammation, adipocyte differentiation, and lipid accumulation in adipose tissue. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Darrell Pilling, Nehemiah Cox, Megan A. Thomson, Tejas R. Karhadkar, Richard H. Gomer Tags: Regular article Source Type: research

Spatiotemporal Gradient of Cortical Neuron Death Contributes to Microcephaly in Knock-In Mouse Model of Ligase 4 Syndrome
Cells of the developing central nervous system are particularly susceptible to formation of double-stranded DNA breaks (DSBs) arising from physiological and/or environmental insults. Therefore, efficient repair of DSBs is especially vital for maintaining cellular health and proper functioning in the developing brain. Here, increased expression of DSB initiating and nonhomologous end joining repair machinery in newborn neurons in the developing brains of both mouse and human are demonstrated. In parallel, the first characterization is provided of the brain phenotype in the Lig4R278H/R278H (Lig4R/R) mouse model of DNA Ligase...
Source: American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Melody P. Lun, Morgan L. Shannon, Sevgi Keles, Ismail Reisli, Nicole Luche, Douglas Ryan, Kelly Capuder, Luigi D. Notarangelo, Maria K. Lehtinen Source Type: research

Serum amyloid P and a DC-SIGN ligand inhibit high fat diet –induced adipose tissue and liver inflammation and steatosis in mice
High-fat diet (HFD)-induced inflammation is associated with a variety of health risks. The systemic pentraxin serum amyloid P (SAP) inhibits inflammation. SAP activates the high affinity IgG receptor Fc γ receptor I (FcγRI; CD64) and the lectin receptor DC-SIGN (CD209). Here, we show that for mice on a HFD, injections of SAP and a synthetic CD209 ligand (1866) reduced HFD-increased adipose and liver tissue inflammation, adipocyte differentiation, and lipid accumulation in adipose tissue. HFD wors ened glucose tolerance tests and caused increased adipocyte size; for mice on a HFD, SAP improved glucose tolerance ...
Source: American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Darrell Pilling, Nehemiah Cox, Megan A. Thomson, Tejas R. Karhadkar, Richard H. Gomer Tags: Regular Article Source Type: research

Spatio-temporal gradient of cortical neuron death contributes to microcephaly in knock-in mouse model of ligase 4 syndrome
Cells of the developing central nervous system are particularly susceptible to formation of double-stranded DNA breaks (DSBs) arising from physiological and/or environmental insults. Therefore, efficient repair of DSBs is especially vital for maintaining cellular health and proper functioning in the developing brain. Here, we demonstrate increased expression of DSB initiating and non-homologous end joining repair machinery in newborn neurons in the developing brains of both mouse and human. In parallel, we provide the first characterization of the brain phenotype in the Lig4R278H/R278H (Lig4R/R) mouse model of DNA Ligase 4...
Source: American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Melody P. Lun, Morgan L. Shannon, Sevgi Keles, Ismail Reisli, Nicole Luche, Douglas Ryan, Kelly Capuder, Luigi D. Notarangelo, Maria K. Lehtinen Source Type: research

Endogenous calcitonin gene –related peptide deficiency exacerbates postoperative lymphedema by suppressing lymphatic capillary formation and M2 macrophage accumulation
Lymphedema is a chronic condition caused by disruption of lymphatic vessels, which often occurs after invasive surgery. Calcitonin gene –related peptide (CGRP) is a 37-amino acid peptide produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene. CGRP was initially identified as a neuropeptide released primarily from sensory nerves and involved in regulating pathophysiological nociceptive pain. However, recent studies have shown CGRP is also released from a variety of other cells and possesses multiple functions. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Shuhei Matsui, Megumu Tanaka, Akiko Kamiyoshi, Takayuki Sakurai, Yuka Ichikawa-Shindo, Hisaka Kawate, Kun Dai, Nanqi Cui, Yangxuan Wei, Masaaki Tanaka, Shinji Kakihara, Keisei Nakamura, Akihiro Yamauchi, Kumiko Ishida, Satoshi Tanaka, Mikito Kawamata, Tak Source Type: research

Detection of lung cancer lymph node metastases from whole-slide histopathological images using a two-step deep learning approach
In this study, a novel two-step deep learning algorithm was developed to address the issue of false-positive prediction while maintaining accurate cancer detection. Three-hundred and forty-nine whole-slide lung cancer lymph node images, including 233 slides for algorithm training, 10 slides for validation, and 106 slides for evaluation, were collected. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Hoa Hoang Ngoc Pham, Mitsuru Futakuchi, Andrey Bychkov, Tomoi Furukawa, Kishio Kuroda, Junya Fukuoka Source Type: research

Achaete-Scute Homologue 2 –Regulated Follicular Helper T Cells Promote Autoimmunity in a Murine Model for Sjögren Syndrome
Follicular helper T (Tfh) cells contribute to various immune responses as well as to the pathogenesis of several immune diseases. However, the precise mechanism underlying the onset or development of autoimmunity via Tfh cells remains unclear. Herein, the detailed relationship between autoimmune disease and Tfh cells was analyzed using a murine model for Sj ögren syndrome (SS) wherein the mice underwent neonatal thymectomy. Germinal center (GC) development was promoted in this SS model along with an increase of Tfh cells and GC B cells. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Kunihiro Otsuka, Akiko Yamada, Masako Saito, Aya Ushio, Mami Sato, Satoru Kisoda, Wenhua Shao, Takaaki Tsunematsu, Yasusei Kudo, Rieko Arakaki, Naozumi Ishimaru Tags: Regular article Source Type: research

Transforming growth factor- β receptor internationalization via caveolae is regulated by tubulin-β2 and tubulin-β3 during endothelial-mesenchymal transition
This study is the first to demonst rate that glycosylation of tubulin-β2 (TUBB2) and tubulin-β3 (TUBB3) in microtubules enhances sensitivity to TGF-β1 stimulation in human microvascular endothelial cells. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Katarzyna Sobierajska, Marta Ewelina Wawro, Wojciech Micha ł Ciszewski, Jolanta Niewiarowska Source Type: research

Klotho deficiency induces arteriolar hyalinosis in a trade-off with vascular calcification
Hyalinosis is a vascular lesion affecting the renal vasculature and contributing to ageing-related renal function decline. We assessed whether arteriolar hyalinosis is caused by Klotho deficiency – a state known to induce both renal and vascular phenotypes associated with ageing. Histochemistry was used to assess hyalinosis in Klotho-/- kidneys, compared to Klotho+/- and wild-type littermates. Immunohistochemistry was used to investigate vascular lesion composition and the different layers of the vascular wall. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Rik Mencke, Anja T. Umbach, Lucas M. Wiggenhauser, Jakob Voelkl, Hannes Olauson, Geert Harms, Marian Bulthuis, Guido Krenning, Leticia Quintanilla-Martinez, Harry van Goor, Florian Lang, Jan-Luuk Hillebrands Tags: Regular Article Source Type: research

Elevated miR-615-3p expression predicts adverse clinical outcome and promotes proliferation and migration of prostate cancer cells
In this study, we investigated the clinical and biological relevance of miR-615-3p in PC. The expression of miR-615-3p was measured in PC tissue specimens from 239 men who underwent radical prostatectomy (RP) and it was investigated if miR-615-3p could predict post-operative biochemical recurrence (BCR). (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Emma Bollmann Laursen, Jacob Freds øe, Linnéa Schmidt, Siri Strand, Helle Kristensen, Anne Karin Ildor Rasmussen, Tina Fuglsang Daugaard, Peter Mouritzen, Søren Høyer, Gitte Kristensen, Hein Vincent Stroomberg, Klaus Brasso, Martin Andreas Røder, Mic Source Type: research

Ascl2-Regulated Follicular Helper T Cells Promote Autoimmunity in a Murine Model for Sj ögren’s Syndrome
Follicular helper T (Tfh) cells contribute to various immune responses as well as to the pathogenesis of several immune diseases. However, the precise mechanism underlying the onset or development of autoimmunity via Tfh cells remains unclear. Here, the detailed relationship between autoimmune disease and Tfh cells was analyzed using a murine model for Sj ögren’s syndrome (SS) wherein the mice underwent neonatal thymectomy. Germinal center (GC) development was promoted in this SS model along with an increase of Tfh cells and GC B cells. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Kunihiro Otsuka, Akiko Yamada, Masako Saito, Aya Ushio, Mami Sato, Satoru Kisoda, Wenhua Shao, Takaaki Tsunematsu, Yasusei Kudo, Rieko Arakaki, Naozumi Ishimaru Tags: Regular Article Source Type: research

RelB regulates lymphatic endothelial cells during vessel maturation and is required for lymphatic vessel function in adult mice
NF- κB signals through canonical RelA/p50 and noncanonical RelB/p52 pathways. The RelA/p50 is involved in basal and inflammatory lymphangiogenesis. However, the role of RelB/p52 in lymphatic vessel biology is unknown. Here, we investigated changes in lymphatic vessels (LVs) in mice deficient in noncano nical NF-κB signaling, and the function of RelB in lymphatic endothelial cells (LECs). LVs were examined in Relb-/-, p52-/-, or control mice, and the gene expression profiles in LECs with RelB knockdown. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Qianqian Liang, Li Zhang, Ronald W. Wood, Rui-Cheng Ji, Brendan F. Boyce, Edward.M. Schwarz, Yongjun Wang, Lianping Xing Tags: Regular Article Source Type: research

Effects of High Glucose –Induced Lysyl Oxidase Propeptide on Retinal Endothelial Cell Survival
Diabetic retinopathy (DR) is characterized by apoptotic cell loss in the retinal vasculature. Lysyl oxidase propeptide (LOX-PP), released during LOX processing, has been implicated in promoting apoptosis in various diseased tissues. However, its role in the development and progression of DR is unknown. We investigated whether high glucose (HG) or diabetes alters LOX-PP expression and thereby influences AKT pathway and affects retinal endothelial cell survival. Rat retinal endothelial cells were grown in normal medium, normal medium and exposed to recombinant LOX-PP (rLOX-PP) or HG medium and examined for LOX-PP expression,...
Source: American Journal of Pathology - September 16, 2019 Category: Pathology Authors: Dongjoon Kim, Dayeun Lee, Philip C. Trackman, Sayon Roy Tags: Regular article Source Type: research

Bioactive lipids in shoulder tendon tears
This commentary highlights the article by Dakin et al that demonstrates critical roles of bioactive lipids in the resolution of inflammation in shoulder tendon tears. (Source: American Journal of Pathology)
Source: American Journal of Pathology - September 14, 2019 Category: Pathology Authors: Undurti N. Das Tags: Commentary 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 - September 13, 2019 Category: Pathology Authors: Chhavi Chauhan Tags: This Month in AJP Source Type: research

Lactoferrin CpG Island Hypermethylation and Decoupling of mRNA and Protein Expression in the Early Stages of Prostate Carcinogenesis
Lactoferrin (LTF) is an iron binding protein canonically known for its innate and adaptive immune functions. LTF may also act as a tumor suppressor with anti-proliferative action. LTF is inactivated genetically or epigenetically in various cancers, and a CpG island spanning the transcriptional start site of LTF is hypermethylated in prostate cancer cell lines. We therefore hypothesized that LTF expression is silenced via CpG island hypermethylation in the early stages of prostate tumorigenesis. Targeted methylation analysis was performed using a combination of methylated-DNA precipitation and methylation-sensitive restrict...
Source: American Journal of Pathology - September 6, 2019 Category: Pathology Authors: Corey M. Porter, Michael C. Haffner, Ibrahim Kulac, Janielle P. Maynard, Javier A. Baena-Del Valle, William B. Isaacs, Srinivasan Yegnasubramanian, Angelo M. De Marzo, Karen S. Sfanos Source Type: research

Down-Regulation of Circular RNA_000926 Attenuates Renal Cell Carcinoma Progression through miRNA-411 –Dependent CDH2 Inhibition
This study intends to uncover the implication of a novel circRNA, circ_000926 in RCC, and how it affects tumorigenesis. Microarray-based circRNA/gene expression profiling of RCC was used to identify differentially expressed circRNAs/genes in RCC and normal tissues. miRNAs targeting the screened circRNAs/genes were predicted online, followed by analyzing circ_000926 expression in RCC. (Source: American Journal of Pathology)
Source: American Journal of Pathology - August 30, 2019 Category: Pathology Authors: Dong Zhang, Xiao-Jie Yang, Qi-Dong Luo, De-Lai Fu, Zhao-Lun Li, Peng Zhang, Tie Chong Tags: Regular article Source Type: research

Smooth Muscle α-actin Deficiency Leads to Decreased Liver Fibrosis via Impaired Cytoskeletal Signaling in Hepatic Stellate Cells
In the liver, smooth muscle α-actin (SM α-actin) is up-regulated in hepatic stellate cells (HSCs) as they transition to myofibroblasts during liver injury and the wound healing response. Whether SM α-actin has specific functional effects on cellular effectors of fibrosis such as HSC is controversial. Here, we focused on the relationship between SM α-actin and type 1 collagen expression (COL1A1), a major extracellular matrix protein important in liver fibrosis and demonstrate that knockout of SM α-actin leads to reduced liver fibrosis and COL1 expression. (Source: American Journal of Pathology)
Source: American Journal of Pathology - August 30, 2019 Category: Pathology Authors: Don C. Rockey, Qinghong Du, Zengdun Shi Tags: Regular article Source Type: research

Down-Regulation of Circular RNA_000926 Attenuates Renal Cell Carcinoma Progression through microRNA-411-Dependent CDH2 Inhibition
This study intends to uncover the implication of a novel circRNA circ_000926 in RCC, and how it affects tumorigenesis. Microarray-based circRNA/gene expression profiling of RCC was employed to identify differentially expressed circRNAs/genes in RCC and normal tissues. miRNAs targeting the screened circRNAs/genes were predicted online, followed by analyzing circ_000926 expression in RCC. (Source: American Journal of Pathology)
Source: American Journal of Pathology - August 30, 2019 Category: Pathology Authors: Dong Zhang, Xiao-Jie Yang, Qi-Dong Luo, De-Lai Fu, Zhao-Lun Li, Peng Zhang, Tie Chong Tags: Regular Article Source Type: research

The role of MET in melanoma and melanocytic lesions
Melanoma is the leading cause of death due to cutaneous malignancy and its incidence is on the rise. Several signaling pathways have been recognized to have an etiopathogenetic role in precursor melanocytic lesions and malignant melanoma development and progression, including receptor tyrosine kinases. Among those, MET/HGF axis is emerging as a critical player not only in the tumor itself but also in the immune microenvironment in which the tumor grows and advance in its development. Moreover, this pathway ’s activation has emerged as a paradigm of tumor resistance to modern targeted therapies and assessment of its e...
Source: American Journal of Pathology - August 30, 2019 Category: Pathology Authors: Yan Zhou, Kyu Young Song, Alessio Giubellino Tags: Review Source Type: research

Neutrophil-derived reactive oxygen orchestrates epithelial cell signaling events during intestinal repair
Recent evidence has demonstrated that reactive oxygen, eg, hydrogen peroxide, can activate host cell signaling pathways that function in repair. We show that mice deficient in their capacity to generate reactive oxygen by the Nox2 holoenzyme, an enzyme complex highly expressed in neutrophils and macrophages, have disrupted capacity to orchestrate signaling events that function in mucosal repair. Similar observations were made for mice after neutrophil depletion, pinpointing this cell type as the source of the reactive oxygen driving redox protein signaling in the epithelium. (Source: American Journal of Pathology)
Source: American Journal of Pathology - August 28, 2019 Category: Pathology Authors: Jason D. Matthews, Joshua A. Owens, Crystal R. Naudin, Bejan J. Saeedi, Ashfaqul Alam, April R. Reedy, Benjamin H. Hinrichs, Ronen Sumagin, Andrew S. Neish, Rheinallt M. Jones Tags: Regular Article Source Type: research

Tissue Iron Promotes Wound Repair via M2 Macrophage Polarization and the Chemokine (C-C Motif) Ligands 17 and 22
Macrophages are important for effective iron recycling and erythropoiesis, but they also play a crucial role in wound healing, orchestrating tissue repair. Recently, we demonstrated a significant accumulation of iron in healing wounds and a requirement of iron for effective repair. Herein, we sought to determine the influence of iron on macrophage function in the context of wound healing. Interestingly, wound macrophages extensively sequestered iron throughout healing, associated with a prohealing M2 phenotype. (Source: American Journal of Pathology)
Source: American Journal of Pathology - August 27, 2019 Category: Pathology Authors: Holly N. Wilkinson, Elizabeth R. Roberts, Amber R. Stafford, Kayleigh L. Banyard, Paolo Matteucci, Kimberly A. Mace, Matthew J. Hardman Source Type: research

Tissue iron promotes wound repair via M2 macrophage polarisation and the chemokines CCL17 and CCL22
Macrophages are important for effective iron recycling and erythropoiesis, but also play a crucial role in wound healing, orchestrating tissue repair. Recently, we demonstrated a significant accumulation of iron in healing wounds, and a requirement of iron for effective repair. Here, we sought to determine the influence of iron on macrophage function in the context of wound healing. Interestingly, wound macrophages extensively sequestered iron throughout healing, associated with a pro-healing M2 phenotype. (Source: American Journal of Pathology)
Source: American Journal of Pathology - August 27, 2019 Category: Pathology Authors: Holly Nicola Wilkinson, Elizabeth Rose Roberts, Amber Rose Stafford, Kayleigh Louise Banyard, Paolo Matteucci, Kimberly Ann Mace, Matthew James Hardman Source Type: research

Vitamin D and Calcium Supplementation Accelerates Randall's Plaque Formation in a Murine Model
Most kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla, is considered to at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth. We analyzed whether long-term exposure of Abcc6 −/− mice (a murine model of Randall's plaque) to vitamin D supplementation, with or without a calcium-rich diet, would accelerate the formation of Randall's plaque. Eight groups of mice (including Abcc6−/− and wild type) received vitamin D alone (100,000 UI/kg every 2 weeks), a calcium-enric hed diet alone (cal...
Source: American Journal of Pathology - August 23, 2019 Category: Pathology Authors: Elise Bouderlique, Ellie Tang, Jo ëlle Perez, Amélie Coudert, Dominique Bazin, Marie-Christine Verpont, Christophe Duranton, Isabelle Rubera, Jean-Philippe Haymann, Georges Leftheriotis, Ludovic Martin, Michel Daudon, Emmanuel Letavernier Tags: Regular article Source Type: research