This Month in AJP.
Authors: Abstract The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID: 31759881 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 21, 2019 Category: Pathology Tags: Am J Pathol Source Type: research

Glucagon Like Peptide-1 Receptor Agonism Improves Nephrotoxic Serum Nephritis by Inhibiting T Cell Proliferation.
, Eller K Abstract Glucagon like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, we tested the anti-inflammatory action of Glp1r-agonism in a non-diabetic, T-cell-mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r-/- mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r-/- mice...
Source: The American Journal of Pathology - November 21, 2019 Category: Pathology Authors: Moschovaki Filippidou F, Kirsch AH, Thelen M, Kétszeri M, Artinger K, Aringer I, Schabhüttl C, Mooslechner AA, Frauscher B, Pollheimer M, Niedrist T, Meinitzer A, Drucker DJ, Pieber TR, Eller P, Rosenkranz AR, Heinemann A, Eller K Tags: Am J Pathol Source Type: research

Thrombospondin-1 exacerbates acute liver failure and hepatic encephalopathy pathology in mice by activating transforming growth factor beta 1.
Abstract Severe hepatic insults can lead to acute liver failure and the development of hepatic encephalopathy (HE). Transforming growth factor beta 1 (TGFβ1) has been demonstrated to contribute to HE from acute liver failure; however, TGFβ1 must be activated to bind its receptor and generate downstream effects. One protein that can activate TGFβ1 is thrombospondin-1 (TSP-1). Therefore, the aim of this study was to assess the role of TSP-1 in acute liver failure and HE pathogenesis. C57Bl/6 or TSP-1 knockout (TSP-1-/-) mice were injected with azoxymethane (AOM) to induce acute liver failure and HE. L...
Source: The American Journal of Pathology - November 14, 2019 Category: Pathology Authors: Jefferson B, Ali M, Grant S, Frampton G, Ploof M, Andry S, DeMorrow S, McMillin M Tags: Am J Pathol Source Type: research

Next-generation sequencing reveals potential predictive biomarkers and targets of therapy for urothelial carcinoma in situ of the urinary bladder.
;chel R Abstract Bacillus Calmette-Guérin instillation following removal of the tumor is the first-line of treatment for urothelial carcinoma in situ (CIS), the precursor lesion of most muscle-invasive bladder cancers. Bacillus Calmette-Guérin therapy fails in>50% of cases and second-line radical cystectomy is associated with overtreatment and drastic lifestyle consequences. Given the need for alternative bladder-preserving therapies, we identified genomic alterations (GAs) in urothelial CIS having the potential to predict response to targeted therapies. Laser-capture microdissection was applied t...
Source: The American Journal of Pathology - November 14, 2019 Category: Pathology Authors: Garczyk S, Ortiz-Brüchle N, Schneider U, Lurje I, Guricova K, Gaisa NT, Lorsy E, Lindemann-Docter K, Heidenreich A, Knüchel R Tags: Am J Pathol Source Type: research

Mycobacterial Trehalose 6,6'-Dimycolate Induced M1-Type Inflammation.
Abstract Murine models of Mycobacterium tuberculosis (Mtb) infection demonstrate progression of M1-like (pro-inflammatory) and M2-like (anti-inflammatory) macrophage morphology following primary granuloma formation. The Mtb cell wall cording factor, trehalose 6,6'-dimycolate (TDM), is a physiologically-relevant and useful molecule for modeling early macrophage-mediated events during establishment of the tuberculosis-induced granuloma pathogenesis. Here we show that TDM is a major driver of the early M1-like macrophage response as seen during initiation of the granulomas of primary pathology. Pro-inflammatory cytok...
Source: The American Journal of Pathology - November 14, 2019 Category: Pathology Authors: Nguyen TKT, d'Aigle J, Chinea L, Niaz Z, Hunter RL, Hwang SA, Actor JK Tags: Am J Pathol Source Type: research

Cecal tumorigenesis in AhR-deficient mice depends on cecum-specific MAPK pathway activation and inflammation.
Abstract The aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. Recently, Ahr-/- mice were revealed to develop cecal tumors with inflammation and Wnt/β-catenin pathway activation. However, whether β-catenin degradation is AhR-dependent remains unclear. To determine whether other signaling pathways function in Ahr-/- cecal tumorigenesis, we investigated histological characteristics of the tumors, cytokine/chemokine production in tumors and Ahr-/- peritoneal macrophages. AhR expression was also assessed in human colorectal carcinomas. Ten of the 28 Ahr-/- mice developed c...
Source: The American Journal of Pathology - November 14, 2019 Category: Pathology Authors: Matoba H, Takamoto M, Fujii C, Kawakubo M, Kasuga E, Matsumura T, Natori T, Misawa K, Taniguchi S, Nakayama J Tags: Am J Pathol Source Type: research

Two distinct tumorigenic processes in endometrial endometrioid adenocarcinoma.
Abstract Endometrial endometrioid adenocarcinoma (EEA) is conventionally considered to be a single pathological entity that develops through a hyperplasia-carcinoma sequence under the influence of estrogen. Previously, another EEA subtype was described and proposed to arise directly from normal endometrium. These conventional and de novo subtypes are designated groups 1 and 2, respectively. To identify the molecular mechanisms of these distinct tumorigenic processes, we conducted comprehensive integrated analyses of genomic data with hormonal status for group-1 paired carcinoma and hyperplasia and group-2 carcinom...
Source: The American Journal of Pathology - November 13, 2019 Category: Pathology Authors: Sugiyama Y, Gotoh O, Fukui N, Tanaka N, Hasumi K, Takazawa Y, Noda T, Mori S Tags: Am J Pathol Source Type: research

Role of Mechanistic Target of Rapamycin and Autophagy in Alcohol-Induced Adipose Atrophy and Liver Injury.
In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice. PMID: 31733185 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 13, 2019 Category: Pathology Authors: Li Y, Chao X, Wang S, Williams JA, Ni HM, Ding WX Tags: Am J Pathol Source Type: research

Total absence of dystrophin expression exacerbates ectopic myofiber calcification, fibrosis, and alters macrophage infiltration patterns.
ki DC Abstract Duchenne muscular dystrophy (DMD) causes severe disability and death of young men due to progressive muscle degeneration aggravated by sterile inflammation. DMD is also associated with cognitive and bone-function impairments. This complex phenotype results from the cumulative loss of a spectrum of dystrophin isoforms expressed from the largest human gene. Although there is evidence for the loss of shorter isoforms having impact in the central nervous system, their role in muscle is unclear. We found that at eight weeks, the active phase of pathology in dystrophic mice, dystrophin-null mice (mdx&beta...
Source: The American Journal of Pathology - November 11, 2019 Category: Pathology Authors: Young CN, Gosselin MR, Rumney R, Oksiejuk A, Chira N, Bozycki L, Matryba P, Łukasiewicz K, Kao AP, Dunlop J, Robson SC, Zabłocki K, Górecki DC Tags: Am J Pathol 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. Cervical cancer cells were treated with a series of siRNA and mimics to measure the regulatory role of LINC00467, miR-107, and KIF23 in EMT, cell invasion, migration and proliferation,...
Source: The American Journal of Pathology - October 25, 2019 Category: Pathology Authors: Li GC, Xin L, Wang YS, Chen Y Tags: Am J Pathol 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.
In conclusion, because of its role as an miR-205 sponge, LINC01133 repressed the development of ovarian cancer by up-regulating LRRK2. PMID: 31640854 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - October 25, 2019 Category: Pathology Authors: Liu M, Shen C, Wang C Tags: Am J Pathol Source Type: research

Lymphotoxin-beta receptor signaling is crucial for the vascularization of transplanted metanephros.
Abstract This commentary highlights the article by Francipane et al that studied the molecular signals supporting kidney vascularization in host lymphoid sites and omenta. PMID: 31628902 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - October 16, 2019 Category: Pathology Authors: Brizi V, Xinaris C Tags: Am J Pathol Source Type: research

This Month in AJP.
PMID: 31628903 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - October 16, 2019 Category: Pathology Authors: Chauhan C Tags: Am J Pathol Source Type: research

Cell of Origin and Immunological Events in the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma.
Abstract 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 capsule 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. Cytokine expression profiling of BIA-ALCL cell lines and clinic...
Source: The American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Turner SD, Inghirami G, Miranda RN, Kadin ME Tags: Am J Pathol Source Type: research

Intestinal epithelial chemokine (C-C motif) ligand 7 overexpression enhances acetaminophen-induced hepatotoxicity in mice.
Abstract 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 epithelial 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 ...
Source: The American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Niu M, Luo Z, Gong S, Win S, Kaplowitz N, Jiang Y, Chen P Tags: Am J Pathol Source Type: research

RNA Expression Profiling of Lymphoepithelioma-Like Carcinoma of the Bladder Reveals a Basal-like Molecular Subtype.
Abstract 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. Transcriptomic profiling of LELC-B showed that they are en...
Source: The American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Manocha U, Kardos J, Selitsky S, Zhou M, Johnson SM, Breslauer C, Epstein JI, Kim WY, Wobker SE Tags: Am J Pathol 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. Basal, transiently stimulated, and knocked down periostin and TCF21 concentrations in stromal cells of women with or without endometriosis were examined. Periostin and TCF21 expressions were undetected in NE,...
Source: The American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Ganieva U, Nakamura T, Osuka S, Bayasula, Nakanishi N, Kasahara Y, Takasaki N, Muraoka A, Hayashi S, Nagai T, Murase T, Goto M, Iwase A, Kikkawa F Tags: Am J Pathol 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. Following ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared to WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attribut...
Source: The American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Zhou Z, Ye TJ, DeCaro E, Buehler B, Stahl Z, Bonavita G, Daniels M, You M Tags: Am J Pathol Source Type: research

Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma.
Abstract 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. Conversely, fibroblast activation was impaired in mice with a fibroblast-specific d...
Source: The American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Tsang M, Quesnel K, Vincent K, Hutchenreuther J, Postovit LM, Leask A Tags: Am J Pathol 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.
Abstract 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 o...
Source: The American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Zhang Y, Liu F, Zhang C, Ren M, Kuang M, Xiao T, Di X, Feng L, Fu L, Cheng S Tags: Am J Pathol Source Type: research

Ferroptosis affects the progression of non-alcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice.
Abstract 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-lipoxygenase, and apoptosis inducing factor, indicating that ferroptosis plays a key role in NA...
Source: The American Journal of Pathology - October 11, 2019 Category: Pathology Authors: Qi J, Kim JW, Zhou Z, Lim CW, Kim B Tags: Am J Pathol Source Type: research

Age-related pathology associated with H1N1 A/California/07/2009 influenza virus infection.
Abstract 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 wea...
Source: The American Journal of Pathology - October 1, 2019 Category: Pathology Authors: Bissel SJ, Carter CE, Wang G, Johnson SK, Lashua LP, Kelvin A, Wiley CA, Ghedin E, Ross TM Tags: Am J Pathol Source Type: research

Host Lymphotoxin-Beta Receptor Signaling is Crucial for Angiogenesis of Metanephric Tissue Transplanted into Lymphoid Sites.
Abstract 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 (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 LTβR knockout (LTβR-/-) mice, the host LTβR signals were found to be crucial for obtaining a well-vascularized kidney graft. Indeed, defective LTβR signaling correlated with decreased expression of endothelial and angiogenic markers in ...
Source: The American Journal of Pathology - October 1, 2019 Category: Pathology Authors: Francipane MG, Han B, Lagasse E Tags: Am J Pathol Source Type: research

Endogenous Specialized Proresolving Mediator Profiles in a Novel Experimental Model of Lymphatic Obstruction and Intestinal Inflammation in African Green Monkeys.
Abstract 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. Follow-up studies were performed at 7, 21, and 61 days. Inflammation was determined by histology. Luminex assay...
Source: The American Journal of Pathology - September 26, 2019 Category: Pathology Authors: Becker F, Romero E, Goetzmann J, Hasselschwert DL, Dray B, Vanchiere J, Fontenot J, Yun JW, Norris PC, White L, Musso M, Serhan CN, Alexander JS, Gavins FNE Tags: Am J Pathol Source Type: research

Wasf3 deficiency reveals involvement in metastasis in a mouse model of breast cancer.
Abstract 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. Using a CMV-cre strain, Wasf3 was constitutively inactiva...
Source: The American Journal of Pathology - September 19, 2019 Category: Pathology Authors: Qin H, Lu S, Thangaraju M, Cowell JK Tags: Am J Pathol Source Type: research

Endogenous calcitonin gene-related peptide deficiency exacerbates postoperative lymphedema by suppressing lymphatic capillary formation and M2 macrophage accumulation.
In this study, CGRP knockout (-/-) mice were used to show the actions of endogenous CGRP in postoperative lymphedema. After generating a mouse postoperative tail lymphedema model, the edema was observed to be more severe in CGRP-/- than wild-type mice. Numbers of LYVE-1-positive lymphatic capillaries were decreased and lymphatic capillary formation-related factors were down-regulated in CGRP-/- mice. In addition, accumulation of M2, but not M1 macrophages was selectively reduced in the edematous tissue of CGRP-/- mice. Selective depletion of M2 macrophages decreased lymphatic capillary formation and worsened lymphedema in ...
Source: The American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Matsui S, Tanaka M, Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Kawate H, Dai K, Cui N, Wei Y, Tanaka M, Kakihara S, Nakamura K, Yamauchi A, Ishida K, Tanaka S, Kawamata M, Shindo T Tags: Am J Pathol 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. In the first step, a deep learning algorithm was used to eliminate frequently misclassified noncancerous regions (lymphoid follicles). In the second step, a deep learning classifier was developed to detect cancer cells. Using this two-step approach, errors were reduced by 36...
Source: The American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Pham HHN, Futakuchi M, Bychkov A, Furukawa T, Kuroda K, Fukuoka J Tags: Am J Pathol Source Type: research

Spatio-temporal gradient of cortical neuron death contributes to microcephaly in knock-in mouse model of ligase 4 syndrome.
Abstract 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 mod...
Source: The American Journal of Pathology - September 18, 2019 Category: Pathology Authors: Lun MP, Shannon ML, Keles S, Reisli I, Luche N, Ryan D, Capuder K, Notarangelo LD, Lehtinen MK Tags: Am J Pathol Source Type: research

RelB regulates lymphatic endothelial cells during vessel maturation and is required for lymphatic vessel function in adult mice.
Abstract 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 noncanonical 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. Relb-/-, but not p52-/- mice, exhibited multiple LV abnormalities. They include i) increased c...
Source: The American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Liang Q, Zhang L, Wood RW, Ji RC, Boyce BF, Schwarz EM, Wang Y, Xing L Tags: Am J Pathol Source Type: research

Ascl2-Regulated Follicular Helper T Cells Promote Autoimmunity in a Murine Model for Sj ögren's Syndrome.
In conclusion, our results indicate that abnormal Tfh cell differentiation via Ascl2 regulation might contribute to the pathogenesis of autoimmunity. PMID: 31539517 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Otsuka K, Yamada A, Saito M, Ushio A, Sato M, Kisoda S, Shao W, Tsunematsu T, Kudo Y, Arakaki R, Ishimaru N Tags: Am J Pathol 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). These findings were subsequently validated in three independent RP cohorts (N=222, N=273, and N=387) and functional overexpression studies conducted in PC cells (PC3M). High miR-615-3p expression was significantly associated with BCR in four independent PC patient cohorts (P
Source: The American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Laursen EB, Fredsøe J, Schmidt L, Strand S, Kristensen H, Ildor Rasmussen AK, Daugaard TF, Mouritzen P, Høyer S, Kristensen G, Stroomberg HV, Brasso K, Røder MA, Borre M, Sørensen KD Tags: Am J Pathol Source Type: research

Klotho deficiency induces arteriolar hyalinosis in a trade-off with vascular calcification.
Abstract 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. Finally, spironolactone was used to inhibit calcification in kl/kl mice and vascular lesions we...
Source: The American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Mencke R, Umbach AT, Wiggenhauser LM, Voelkl J, Olauson H, Harms G, Bulthuis M, Krenning G, Quintanilla-Martinez L, van Goor H, Lang F, Hillebrands JL Tags: Am J Pathol 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 demonstrate that glycosylation of tubulin-β2 (TUBB2) and tubulin-β3 (TUBB3) in microtubules enhances sensitivity to TGF-β1 stimulation in human microvascular endothelial cells. We observed that the microtubules enriched in glycosylated TUBB2 and TUBB3 were necessary for caveolae-dependent TGF-β receptor internalization. Posttranslational modulation is critical for the generation of myofibroblasts through endothelial-mesenchymal transition during fibrosis development. We suggest that microtubule glycosylation may become the target of new effective therapies for patients with re...
Source: The American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Sobierajska K, Wawro ME, Ciszewski WM, Niewiarowska J Tags: Am J Pathol 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.
Abstract 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 (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 worsened glucose tolerance tests and caused increased adipocyte size; for mice on a HFD, SAP improved gl...
Source: The American Journal of Pathology - September 17, 2019 Category: Pathology Authors: Pilling D, Cox N, Thomson MA, Karhadkar TR, Gomer RH Tags: Am J Pathol Source Type: research

Bioactive lipids in shoulder tendon tears.
Abstract 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. PMID: 31526772 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - September 14, 2019 Category: Pathology Authors: Das UN Tags: Am J Pathol Source Type: research

This Month in AJP.
Abstract The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID: 31525359 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - September 13, 2019 Category: Pathology Authors: Chauhan C Tags: Am J Pathol Source Type: research

Lactoferrin CpG Island Hypermethylation and Decoupling of mRNA and Protein Expression in the Early Stages of Prostate Carcinogenesis.
We report that the LTF CpG island is frequently and densely methylated in high grade prostatic intraepithelial neoplasia, primary prostate carcinoma, and metastases. We further report a decoupling of lactoferrin mRNA and protein expression, including in lesions where LTF mRNA has presumably been silenced via CpG island methylation. We conclude that LTF mRNA expression is silenced in prostate tumorigenesis via hypermethylation, supporting a role for LTF as a prostate cancer tumor suppressor gene. Likewise, the frequency at which the LTF CpG island is methylated across samples suggests it is an important and conserved step i...
Source: The American Journal of Pathology - September 6, 2019 Category: Pathology Authors: Porter CM, Haffner MC, Kulac I, Maynard JP, Baena-Del Valle JA, Isaacs WB, Yegnasubramanian S, De Marzo AM, Sfanos KS Tags: Am J Pathol Source Type: research

Identification of Metabolic Changes in Ileum, Jejunum, Skeletal Muscle, Liver, and Lung in a Continuous I.V. Pseudomonas aeruginosa Model of Sepsis Using Nontargeted Metabolomics Analysis.
Abstract Sepsis is a multiorgan disease affecting the ileum and jejunum (small intestine), liver, skeletal muscle, and lung clinically. The specific metabolic changes in the ileum, jejunum, liver, skeletal muscle, and lung have not previously been investigated. Live Pseudomonas aeruginosa, isolated from a patient, was given via i.v. catheter to pigs to induce severe sepsis. Eighteen hours later, ileum, jejunum, medial gastrocnemius skeletal muscle, liver, and lung were analyzed by nontargeted metabolomics analysis using gas chromatography/mass spectrometry. The ileum and the liver demonstrated significant changes ...
Source: The American Journal of Pathology - August 25, 2019 Category: Pathology Authors: Ilaiwy A, Ten Have GAM, Bain JR, Muehlbauer MJ, O'Neal SK, Berthiaume JM, Parry TL, Deutz NE, Willis MS Tags: Am J Pathol Source Type: research

Proresolving mediators LXB4 and RvE1 regulate inflammation in stromal cells from patients with shoulder tendon tears.
Abstract Tendon stromal cells isolated from patients with chronic shoulder rotator-cuff tendon tears show dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation; therefore, new therapeutic approaches targeting tendon stromal cells are required. We determined if two specialized pro-resolving mediators (SPM) LXB4 and RvE1, modulate the bioactive lipid mediator profiles of interleukin (IL)-1β-stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also determined if LXB4 or RvE1 treatme...
Source: The American Journal of Pathology - August 19, 2019 Category: Pathology Authors: Dakin SG, Colas RA, Wheway K, Watkins B, Appleton L, Rees J, Gwilym S, Little C, Dalli J, Carr AJ Tags: Am J Pathol Source Type: research

A new role for the spleen: aggravation of the systemic inflammatory response in rats with severe acute pancreatitis.
Abstract Little is known about the role of the spleen in mediating systemic inflammatory responses in severe acute pancreatitis (SAP). Here, we investigated the role played by the spleen in rats after SAP induction. Splenectomy was performed at designated time points after SAP induction. Pancreatic tissue and serum samples were collected and subjected to histological, immunohistochemical, and immunological analyses. Following SAP induction, the splenic immune response was enhanced during SAP progression, as shown by the increased diameter of the splenic periarterial lymphatic sheath and the thickness of the spleni...
Source: The American Journal of Pathology - August 17, 2019 Category: Pathology Authors: Zhou R, Zhang J, Bu W, Zhang W, Duan B, Wang X, Yao L, Li Z, Li J Tags: Am J Pathol Source Type: research

The Inability of the Choroid to Revascularize in Oxygen-Induced Retinopathy Results from Increased P53/mir-Let-7b Activity.
Abstract Retinopathy of prematurity (ROP) is characterized by an initial retinal avascularisation, followed by pathologic neovascularization. Recently, choroidal thinning has also been detected in children formerly diagnosed with ROP; a similar sustained choroidal thinning is observed in ROP models. But the mechanism underlying the lack of choroidal revascularization remains unclear, and was investigated in an oxygen-induced retinopathy (OIR) model. In OIR, evidence of senescence was detected, preceded by oxidative stress in the choroid and the retinal pigment epithelium. This was associated with a global reductio...
Source: The American Journal of Pathology - August 17, 2019 Category: Pathology Authors: Zhou TE, Zhu T, Rivera JC, Omri S, Tahiri H, Lahaie I, Rouget R, Wirth M, Nattel S, Lodygensky G, Ferbeyre G, Nezhady M, Desjarlais M, Hamel P, Chemtob S Tags: Am J Pathol Source Type: research

N-acetylcysteine resolves placental inflammatory-vasculopathic changes in mice consuming a high fat diet.
Abstract The mechanism by which poor maternal nutrition can impact the long-term health of offspring is poorly understood. In mice, we previously demonstrated maternal high fat diet (HFD) exposure results in reduced fetal growth regardless of maternal genotype. Here, we test our hypothesis that maternal HFD-induced inflammation contributes to metabolic disease susceptibility of the offspring via alterations in the placenta. The effect of maternal genotype, diet, and treatment with the anti-inflammatory compound N-acetylcysteine (NAC) on placental morphology was investigated. Placentas from wild type (WT) dams main...
Source: The American Journal of Pathology - August 17, 2019 Category: Pathology Authors: Williams L, Burgos ES, Vuguin PM, Manuel CR, Pekson R, Munnangi S, Reznik SE, Charron MJ Tags: Am J Pathol Source Type: research

Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly Contribute to Lymphatic Metastasis in Clinical Breast Cancer.
Abstract Lymphatic metastasis is a high impact prognostic factor for mortality of breast cancer (BC) patients, and directly depends on tumor-associated lymphatic vessels. We previously reported that lipopolysaccharide-induced inflammatory lymphangiogenesis is strongly promoted by myeloid-derived lymphatic endothelial cell progenitors (M-LECP) derived from the bone marrow (BM). As BC recruit massive numbers of pro-vascular myeloid cells, we hypothesized that M-LECP, within this recruited population, are specifically programmed to promote tumor lymphatics that increase lymph node metastasis. In support of this hypot...
Source: The American Journal of Pathology - August 14, 2019 Category: Pathology Authors: Volk-Draper L, Patel R, Bhattarai N, Yang J, Wilber A, DeNardo D, Ran S Tags: Am J Pathol Source Type: research

Prostate Cancer- The Role of Inflammation and Chemokines.
Abstract Prostate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leucocyte subsets with pro-cancer and anti-cancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis and are instrumental/detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation and following subsequent ...
Source: The American Journal of Pathology - August 14, 2019 Category: Pathology Authors: Rani A, Dasgupta P, Murphy JJ Tags: Am J Pathol Source Type: research

The serotype-specific role of RocA polymorphisms in the pathogenesis of invasive group A streptococcal infections.
Abstract This commentary highlights the article by Bernard et al that reports the role of rocA polymorphisms in the pathogenesis of Group A Streptococcus. PMID: 31421073 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - August 14, 2019 Category: Pathology Authors: Brouwer S, Walker MJ Tags: Am J Pathol Source Type: research

Localization and regulation of polymeric immunoglobulin receptor (PIgR) in healthy and diseased human kidney.
sson ME Abstract The polymeric immunoglobulin receptor (PIgR) constitutes an important part of the immune system by mediating transcytosis of dimeric IgA into mucosal fluids. Although well studied in organs such as the intestine, the regulation and localization of PIgR in human kidney are incompletely characterized. Here, using immunohistochemistry we show that in healthy human kidneys, PIgR is expressed by the progenitor-like tubular scattered cells of the proximal tubules and by parietal epithelial cells of glomeruli. We further show that proximal tubular expression of PIgR becomes widespread during kidney disea...
Source: The American Journal of Pathology - August 9, 2019 Category: Pathology Authors: Krawczyk KM, Nilsson H, Nyström J, Lindgren D, Leandersson K, Swärd K, Johansson ME Tags: Am J Pathol Source Type: research

KH-Type Splicing Regulatory Protein Controls Colorectal Cancer Cell Growth and Modulates the Tumor Microenvironment.
Abstract KH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination of in silico analysis of large datasets, ex vivo analysis of protein expression in patients, and mechanistic studies using in vitro models of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors. Ele...
Source: The American Journal of Pathology - August 9, 2019 Category: Pathology Authors: Caiazza F, Oficjalska K, Tosetto M, Phelan JJ, Noonan S, Martin P, Killick K, Breen L, O'Neill F, Nolan B, Furney S, Power R, Fennelly D, Craik CS, O'Sullivan J, Sheahan K, Doherty GA, Ryan EJ Tags: Am J Pathol Source Type: research

Integrated Molecular Analysis of Papillary Renal Cell Carcinoma and Precursor Lesions Unfolds Evolutionary Process from Kidney Progenitor-Like Cells.
Abstract Papillary renal cell carcinoma (PRCC) is the most common type of RCC in end-stage kidney disease (ESKD). Papillary adenoma (PA) is a small benign lesion morphologically similar to PRCC and is suggested by some to be its precursor. PA is also very prevalent in ESKD. The evolution of PAs to PRCCs and their relationship to ESKD is poorly understood. One-hundred and forty PAs, normal kidneys, ESKDs, and PRCCs were analyzed. Previously described markers of renal tubular progenitor cells were performed using immunohistochemistry and quantified with digital analysis (n=140). Progenitor cells were significantly increased in ESKD (P
Source: The American Journal of Pathology - August 2, 2019 Category: Pathology Authors: Saleeb RM, Farag M, Ding Q, Downes M, Bjarnason G, Brimo F, Plant P, Rotondo F, Lichner Z, Finelli A, Yousef GM Tags: Am J Pathol Source Type: research

Tumor-promoting activity of long non-coding RNA LINC00466 in lung adenocarcinoma via microRNA-144-regulated HOXA10 axis.
Abstract Previous investigations have implicated long non-coding RNAs (lncRNAs) in lung adenocarcinoma, which is an aggressive disease with poor prognosis and high mortality. Through the alteration of lung adenocarcinoma-related lncRNA and microRNA (miRNA) based on microarray analysis, our aim was to understand that the role of LINC00466 and miR-144 in lung adenocarcinoma progression. The relationship among LINC00466, miR-144, and HOXA10 was also verified. Moreover, to examine whether the LINC00466/miR-144/HOXA10 axis contributed to the cellular processes in lung adenocarcinoma, A549 and XWLC-05 cells were transdu...
Source: The American Journal of Pathology - August 2, 2019 Category: Pathology Authors: Ma T, Hu Y, Guo Y, Yan B Tags: Am J Pathol Source Type: research

Dichotomous Role of Plasmin in Regulation of Macrophage Function after Acetaminophen Overdose.
Abstract Kupffer cells and monocyte-derived macrophages are critical for liver repair after acetaminophen (APAP) overdose. These cells produce pro-mitogenic cytokines and growth factors, and phagocytose dead cell debris, a process that is critical for resolution of inflammation. The factors that regulate these dynamic functions of macrophages after APAP overdose, however, are not fully understood. We tested the hypothesis that the fibrinolytic enzyme, plasmin, is a key regulator of macrophage function after APAP-induced liver injury. In these studies, inhibition of plasmin in mice with tranexamic acid delayed up-r...
Source: The American Journal of Pathology - August 2, 2019 Category: Pathology Authors: Roth K, Strickland J, Joshi N, Deng M, Kennedy R, Rockwell CE, Luyendyk JP, Billiar TR, Copple BL Tags: Am J Pathol Source Type: research