This Month in AJP.
PMID: 32946838 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - September 15, 2020 Category: Pathology Authors: Chauhan C Tags: Am J Pathol Source Type: research

Somatic mutations in LRRK2 identify a subset of invasive mammary carcinomas associated with high mutation burden.
The objective of this study was to evaluate the occurrence of LRRK2 somatic mutations in breast cancer and the clinicopathologic features associated with LRRK2-mutated tumors. Using The Cancer Genome Atlas (TCGA-BRCA), somatic LRRK2 DNA sequence information was obtained for 93 cases, of which 17 cases (18%) with 18 mutations were identified. LRRK2-mutated mammary carcinomas are enriched with stop-gain, truncating mutations predicted to result in loss-of-function; missense mutations frequently targeted the GTPase and kinase domains. Tumors displayed predominantly high-grade morphology with abundant granular eosinophilic cyt...
Source: The American Journal of Pathology - September 12, 2020 Category: Pathology Authors: Parrilla Castellar ER, Plichta JK, Davis R, Gonzalez-Hunt C, Sanders LH Tags: Am J Pathol Source Type: research

Inhibition of histone deacetylase 6 by Tubastatin A attenuates the progress of osteoarthritis via improving mitochondrial function.
Abstract As the only resident cell in articular cartilage, the steady state of chondrocytes is important for the maintenance of joint function. In various osteoarthritis (OA) diseases, chondrocytes undergo a series of pathophysiological changes, leading to the loss of chondrocytes and the degradation of extracellular matrix (ECM). Here, cytoplasmic localized histone deacetylase 6 (HDAC6) is found to be up-regulated on the articular surface in DMM-induced mouse OA model. Since HDAC6 is highly related to the acetylation of tubulin, and the function of the microtubule system is closely related to material transport, ...
Source: The American Journal of Pathology - September 11, 2020 Category: Pathology Authors: Zheng Y, Chen Y, Lu X, Weng Q, Dai G, Yu Y, Yu K, Gao W Tags: Am J Pathol Source Type: research

An Uromodulin mutation drives autoimmunity and kidney mononuclear phagocyte endoplasmic reticulum stress.
Abstract We identified a family with a UMOD gene mutation (C106F) resulting in glomerular inflammation and complement deposition. To determine if the observed phenotype is due to immune system activation by mutant uromodulin, we developed a mouse line with a homologous cysteine to phenylalanine mutation (C105F) in the UMOD gene using CRISPR-Cas9 gene editing and examined the effect of this mutation on mononuclear phagocytic cells. Mutant mice develop high levels of intracellular and secreted aggregated uromodulin resulting in anti-uromodulin antibodies and circulating uromodulin containing immune complexes with gl...
Source: The American Journal of Pathology - September 11, 2020 Category: Pathology Authors: Plotkin M, O'Brien CA, Goellner J, Williams J, Carter W, Sharma S, Stone A Tags: Am J Pathol Source Type: research

CDK5RAP3 Deficiency Restrains Liver Regeneration after Partial Hepatectomy Triggering Endoplasmic Reticulum Stress.
Abstract CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) plays a crucial role in mammalian liver development and hepatic function by controlling hepatocyte proliferation and differentiation, glucose and lipid metabolism, UFMylation, and endoplasmic reticulum (ER) homeostasis. However, the role of CDK5RAP3 in liver regeneration remains unknown. A liver-specific Cdk5rap3 knockout (CKO) mouse model was used to study the function of CDK5RAP3 during liver regeneration induced by standard two-thirds partial hepatectomy (PHx). Twenty-four hours after PHx, liver-to-body weight ratio (LW/BW) was markedly higher in ...
Source: The American Journal of Pathology - September 11, 2020 Category: Pathology Authors: Yang S, Yang R, Wang H, Huang Y, Jia Y Tags: Am J Pathol Source Type: research

High-fat diet-induced functional and pathological changes in lacrimal gland.
Abstract The lacrimal gland is critical for maintaining the homeostasis of the ocular surface microenvironment through secreting aqueous tears in mammals. Many systemic diseases such as Sjögren's syndrome, rheumatoid arthritis and diabetes can alter the lacrimal gland function, eventually resulting in aqueous tear deficient dry eye. Here, we used a high fat diet (HFD) experimental mouse model to clarify how hyperlipidemia affects lacrimal gland function. Aqueous tear secretion fell about 50% after 1 month on a HFD. Lipid droplets accumulated in the matrix and acinar cells of the lacrimal gland after this peri...
Source: The American Journal of Pathology - September 10, 2020 Category: Pathology Authors: He X, Zhao Z, Wang S, Kang J, Zhang M, Bu J, Cai X, Jia C, Li Y, Li K, Reinach PS, Quantock AJ, Liu Z, Li W Tags: Am J Pathol Source Type: research

Immunopathology of Hyperinflammation in COVID-19.
Abstract The rapid spread of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented public health crisis worldwide. Recent studies indicate that a hyperinflammatory syndrome induced by SARS-CoV-2 contributes to disease severity and mortality in COVID-19. In this Review, an overview of the pathophysiology underlying the hyperinflammatory syndrome in severe COVID-19 is provided. The current evidence suggests the hyperinflammatory syndrome results from a dysregulated host innate immune response. The gross and microscopic pathologic...
Source: The American Journal of Pathology - September 10, 2020 Category: Pathology Authors: Gustine JN, Jones D Tags: Am J Pathol Source Type: research

Kupffer cells: Inflammation pathways and cell-cell interactions in alcohol-associated liver disease.
Abstract Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma (HCC). Several cell types are involved in ALD progression including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. Additionally, KCs are involved in the production of reactive oxygen species (ROS). ROS are linked to the induction of oxidative stress and inf...
Source: The American Journal of Pathology - September 10, 2020 Category: Pathology Authors: Slevin E, Baiocchi L, Wu N, Ekser B, Sato K, Lin E, Ceci L, Chen L, Lorenzo SR, Xu W, Kyritsi K, Meadows V, Zhou T, Kundu D, Han Y, Kennedy L, Glaser S, Francis H, Alpini G, Meng F Tags: Am J Pathol Source Type: research

Transient Receptor Potential Ankyrin 1 (TRPA1) is Up-Regulated in Response to Lipopolysaccharide via P38/ Mitogen-Activated Protein Kinase (MAPK) in Dental Pulp Cells and Promotes Mineralization.
In conclusion, this study demonstrated that LPS stimulation induced TRPA1 via the NO-p38 MAPK signaling pathway and TRPA1 agonists promoted differentiation or mineralization of dental pulp cells. PMID: 32919979 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - September 10, 2020 Category: Pathology Authors: Tazawa K, Kawashima N, Kuramoto M, Noda S, Fujii M, Nara K, Hashimoto K, Okiji T Tags: Am J Pathol Source Type: research

Striated preferentially expressed protein kinase (SPEG)-deficient skeletal muscles display fewer satellite cells with reduced proliferation and delayed differentiation.
In this study, we examined the overall population, proliferation, and differentiation of myogenic cells obtained from striated-muscle specific Speg-KO mice and compared them with wild-type (WT) controls. SPEG-deficient skeletal muscles contained fewer myogenic cells, which on further study demonstrated reduced proliferation and delayed differentiation compared to those from WT. Regenerative response to skeletal muscle injury in Speg-KO was compared to that of WT, leading to the identification of similar abnormalities including fewer satellite cells, fewer dividing cells, and an increase in apoptotic cells in KO mice. Overa...
Source: The American Journal of Pathology - September 10, 2020 Category: Pathology Authors: Li Q, Lin J, Rosen SM, Zhang T, Kazerounian S, Luo S, Agrawal PB Tags: Am J Pathol Source Type: research

Pathology of idiopathic pulmonary fibrosis assessed by a combination of micro-computed tomography, histology, and immunohistochemistry.
This study examined associations between the histopathological features of UIP/IPF in explanted lungs and quantitative microCT measurements including alveolar surface density, total lung volume taken up by tissue (tissue%), and terminal bronchiolar number. Sixty frozen samples from 10 air-inflated explanted lungs with severe IPF and 36 samples from 6 donor control lungs were scanned with microCT and processed for histology. An experienced pathologist scored 3 major UIP criteria (patchy fibrosis, honeycomb, and fibroblastic foci), 5 additional pathological changes such as emphysema, and immunohistochemical staining for CD68...
Source: The American Journal of Pathology - September 10, 2020 Category: Pathology Authors: Tanabe N, McDonough JE, Vasilescu DM, Ikezoe K, Verleden SE, Xu F, Wuyts WA, Vanaudenaerde BM, Colby TV, Hogg JC Tags: Am J Pathol Source Type: research

The Surprising Story of IL-2: From Experimental Models to Clinical Application.
Abstract Equilibrium in the immune system is maintained by a balance between activation, which generates effector and memory cells, and suppression, which is mediated mainly by regulatory T cells. Understanding this balance and how to exploit it therapeutically is one of the dominant themes of modern immunology. The cytokine IL-2 was discovered as a growth factor for T cells and thus a key component of immune activation. It was initially used to boost immune responses in patients with cancer. Studies in experimental models and humans showed that the major function of IL-2 is to maintain functional regulatory T cel...
Source: The American Journal of Pathology - August 25, 2020 Category: Pathology Authors: Abbas AK Tags: Am J Pathol Source Type: research

Universal precautions provide appropriate protection during autopsies of patients with infectious diseases.
Abstract The current COVID-19 pandemic has raised concerns about the safety of laboratory personnel who handle tissue samples that harbor pathogens, including performing autopsies. While pathologists have performed autopsies on infected patients for centuries, universal precaution protocols to limit exposure to pathogens were not developed until the 20th century. This paper reviews the history and effectiveness of universal precautions, with an emphasis on performing autopsies on COVID-19 patients. PMID: 32827462 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - August 19, 2020 Category: Pathology Authors: Kritselis M, Remick D Tags: Am J Pathol Source Type: research

Correction.
Authors: PMID: 32827463 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - August 19, 2020 Category: Pathology Tags: Am J Pathol Source Type: research

Kidney tertiary lymphoid structures in Lupus Nephritis develop into large interconnected networks and resemble lymph nodes in gene signature.
on KA Abstract Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within kidneys of systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). We characterized renal TLS in lupus-prone (NZBxNZW) F1 mice with respect to cell composition and vessel formation. Ribonucleic acid (RNA) sequencing was performed on transcriptomes isolated from lymph nodes (LyN), macro-dissected TLS from kidneys, and total kidneys of mice at different disease stages by using Ion Torrent Personal Genome Machine (Ion PGM) and RNAseq from Illumina. Formation of TLS was found in anti-dsDNA antibody posit...
Source: The American Journal of Pathology - August 17, 2020 Category: Pathology Authors: Dorraji ES, Kanapathippillai P, Karlssen Hovd AM, Stenersrød MR, Horvei KD, Ursvik A, Figenschau SL, Thiyagarajan D, Fenton CG, Pedersen HL, Fenton KA Tags: Am J Pathol Source Type: research

This Month in AJP (TMIA).
Authors: PMID: 32810470 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - August 15, 2020 Category: Pathology Tags: Am J Pathol Source Type: research

S100A4/non-muscle myosin IIA/p53 axis contributes to aggressive features in ovarian high-grade serous carcinoma.
Abstract S100A4 is a small calcium-binding protein that exerts its biological functions by interacting with non-muscle myosin IIA (NMIIA) and p53. Although S100A4 promotes metastasis in several tumors, little is known about its involvement in the progression of ovarian high-grade serous carcinomas (HGSC). Herein, we focused on functional roles of the S100A4/NMIIA/p53 axis in these tumors. In HGSC cell lines harboring mutant p53 (p53mt), knockdown (KD) of S100A4 reduced the expression of several epithelial-mesenchymal transition (EMT) /cancer stem cell (CSC) markers and the ALDH1high population, consistent with an ...
Source: The American Journal of Pathology - August 14, 2020 Category: Pathology Authors: Hiruta A, Oguri Y, Yokoi A, Matsumoto T, Oda Y, Tomohiro M, Hashimura M, Jiang Z, Tochimoto M, Nakagawa M, Saegusa M Tags: Am J Pathol Source Type: research

Pik3cg is a potential therapeutic target in androgen receptor-indifferent metastatic prostate cancer.
In this report a mouse model for metastatic prostate cancer was generated through deletion of the tumor suppressor gene Trp53 in conjunction with oncogenic activation of the proto-oncogene Kras. These mice developed early onset metastatic prostate cancer with complete penetrance. Tumors from these mice are poorly differentiated adenocarcinoma, characterized by extensive epithelial-mesenchymal transition (EMT). With no or very low level of AR expression, the tumor cells are resistant to AR inhibition. Pik3cg, encoding the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit γ, is highly expressed in these...
Source: The American Journal of Pathology - August 14, 2020 Category: Pathology Authors: Chung WC, Zhou X, Atfi A, Xu K Tags: Am J Pathol Source Type: research

Pyruvate kinase M2 (PKM2) tetramerization protects against hepatic stellate cell activation and liver fibrosis.
We examined PKM2 expression and location in liver tissues and primary hepatic cells. The in vitro and in vivo effects of a PKM2 antagonist (shikonin) and its allosteric agent (TEPP-46) on liver fibrosis were investigated in HSCs and liver fibrosis mouse model. Chromatin immunoprecipitation sequencing (ChIP) and immunoprecipitation were performed to identify the relevant molecular mechanisms. We found that PKM2 expression was significantly upregulated in both mouse and human fibrotic livers compared to normal livers, and mainly detected in activated, rather than quiescent HSCs. PKM2 knockdown markedly inhibited the activati...
Source: The American Journal of Pathology - August 14, 2020 Category: Pathology Authors: Zheng D, Jiang Y, Qu C, Yuan H, Hu K, He L, Chen P, Li J, Tu M, Lin L, Chen H, Lin Z, Lin W, Fan J, Cheng G, Hong J Tags: Am J Pathol Source Type: research

Leptin, resistin, and pcsk9 - the role of stat3.
LEPTIN, RESISTIN, AND PCSK9 - THE ROLE OF STAT3. Am J Pathol. 2020 Aug 13;: Authors: Macchi C, Greco MF, Botta M, Sperandeo P, Dongiovanni P, Valenti L, Cicero AFG, Borghi C, Lupo MG, Romeo S, Corsini A, Magni P, Ferri N, Ruscica M Abstract In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokines levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtil...
Source: The American Journal of Pathology - August 13, 2020 Category: Pathology Authors: Macchi C, Greco MF, Botta M, Sperandeo P, Dongiovanni P, Valenti L, Cicero AFG, Borghi C, Lupo MG, Romeo S, Corsini A, Magni P, Ferri N, Ruscica M Tags: Am J Pathol Source Type: research

Treatment of COVID-19 Patients with Convalescent Plasma Reveals a Signal of Significantly Decreased Mortality.
We present here the results of an interim analysis of 316 patients (n=316) enrolled at Houston Methodist hospitals from March 28 to July 6, 2020. Of the 316 transfused patients, 136 met a 28-day outcome and were matched to 251 non-transfused control COVID-19 patients. Matching criteria included age, sex, BMI, comorbidities, and baseline ventilation requirement 48 h from admission, and in a second matching analysis, ventilation status at Day 0. Variability in the timing of transfusion relative to admission and titer of antibodies of plasma transfused allowed for analysis in specific matched cohorts. The analysis showed a si...
Source: The American Journal of Pathology - August 11, 2020 Category: Pathology Authors: Salazar E, Christensen PA, Graviss EA, Nguyen DT, Castillo B, Chen J, Lopez BV, Eagar TN, Yi X, Zhao P, Rogers J, Shehabeldin A, Joseph D, Leveque C, Olsen RJ, Bernard DW, Gollihar J, Musser JM Tags: Am J Pathol Source Type: research

Medical treatment can unintentionally alter the Treg compartment in patients with widespread pathophysiologic conditions.
Abstract Regulatory T cells (Tregs) are non-redundant mediators of immune tolerance, critical to prevent autoimmune disease and promote an anti-inflammatory tissue environment. Many individuals experience diseases of a chronic nature and physiological changes associated with aging requiring long-term medication. Unfortunately, side-affects accompany every pharmacologic intervention and may impact overall outcomes. Here we focus on medications typically prescribed during the treatment of prevalent chronic diseases/disorders including cardiovascular disease, autoimmune disease, and menopausal symptoms affecting>2...
Source: The American Journal of Pathology - July 31, 2020 Category: Pathology Authors: Copsel SN, Malek TR, Levy RB Tags: Am J Pathol Source Type: research

Heparanase level and procoagulant activity are increased in thalassemia and attenuated by JAK-2 inhibition.
Abstract Patients with thalassemia demonstrate an increased risk of thrombotic events that is augmented following splenectomy. Heparanase protein, aside from enhancing cancer progression, angiogenesis and inflammation, is shown to activate the coagulation system through direct interaction with tissue factor (TF). Additionally, erythropoietin, elevated in anemic patients, is found to upregulate heparanase expression via the JAK-2 pathway. The study aim was to explore the heparanase profile in thalassemia. Coagulation factors were analyzed using immunostaining, enzyme-linked immunosorbent assay, and heparanase proco...
Source: The American Journal of Pathology - July 31, 2020 Category: Pathology Authors: Ghoti H, Ackerman S, Rivella S, Casu C, Nadir Y Tags: Am J Pathol Source Type: research

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

"Retinoid-related orphan receptor ROR γt in CD4+T cell-mediated intestinal homeostasis and inflammation."
"Retinoid-related orphan receptor RORγt in CD4+T cell-mediated intestinal homeostasis and inflammation." Am J Pathol. 2020 Jul 28;: Authors: Mickael ME, Bhaumik S, Basu R Abstract RORγt, a retinoid orphan nuclear receptor and the master transcription factor of the Th17 subset of CD4+T helper cells, is one of the most promising targets to treat a host of autoimmune diseases. This includes the inflammatory bowel diseases (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-caused by untoward reactivity of the immune system to the components of the intestinal microbiome. The mamma...
Source: The American Journal of Pathology - July 28, 2020 Category: Pathology Authors: Mickael ME, Bhaumik S, Basu R Tags: Am J Pathol Source Type: research

Knockout of the tachykinin receptor 1 in the Mdr2-/- mouse model of primary sclerosing cholangitis reduces biliary damage and liver fibrosis.
Abstract Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated (BDL) and Mdr2-/- mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for microRNA (miR)-31 in TGF-β1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2-/- and NK1R to further address the role of the SP/NK1R axis du...
Source: The American Journal of Pathology - July 23, 2020 Category: Pathology Authors: Ceci L, Francis H, Zhou T, Giang T, Yang Z, Meng F, Wu N, Kennedy L, Kyritsi K, Meadows V, Wu C, Liangpunsakul S, Franchitto A, Sybenga A, Ekser B, Mancinelli R, Onori P, Gaudio E, Glaser S, Alpini G Tags: Am J Pathol Source Type: research

Association of neutrophil extracellular traps with the development of idiopathic osteonecrosis of the femoral head.
Abstract Idiopathic osteonecrosis of the femoral head (ONFH) is defined as necrosis of osteocytes due to a non-traumatic ischemia of the femoral head. Iatrogenic glucocorticoid administration and habitual alcohol intake are regarded as risk factors. It has been suggested that glucocorticoid-induced activation of platelets contribute to the local blood flow disturbance of the femoral head. Both activated platelets and alcohol can induce neutrophil extracellular traps (NETs). To determine the association of NETs with the development of idiopathic ONFH, surgically resected femoral heads of patients with idiopathic ON...
Source: The American Journal of Pathology - July 20, 2020 Category: Pathology Authors: Nonokawa M, Shimizu T, Yoshinari M, Hashimoto Y, Nakamura Y, Takahashi D, Asano T, Nishibata Y, Masuda S, Nakazawa D, Tanaka S, Tomaru U, Iwasaki N, Ishizu A Tags: Am J Pathol Source Type: research

Glaucoma after ocular surgery or trauma: the role of infiltrating monocytes and their response to cytokine inhibitors.
Abstract Glaucoma is a frequent and devastating long-term complication following ocular trauma, including corneal surgery, open globe injury, chemical burn, infection, etc. Post-event inflammation and neuroglial remodeling plays a key role in subsequent ganglion cell apoptosis and glaucoma. To this end, this study was designed to investigate the amplifying role of monocyte infiltration into the retina. By using 3 different ocular injury mouse models (corneal suture, penetrating keratoplasty, and globe injury) and monocyte fate mapping techniques we show that ocular trauma or surgery can cause robust infiltration o...
Source: The American Journal of Pathology - July 18, 2020 Category: Pathology Authors: Chen X, Lei F, Zhou C, Chodosh J, Wang L, Huang Y, Dohlman CH, Paschalis EI Tags: Am J Pathol Source Type: research

The guanine nucleotide exchange factor, LARG, and RhoC play a role in glioblastoma cell invasion and resistance.
Abstract Glioblastoma (GBM) is the most common primary malignant brain cancer in adults. A hallmark of GBM is aggressive invasion of tumor cells into the surrounding normal brain. The current standard of care therapy, as well as targeted therapies, have largely failed to specifically address this issue. Therefore, identifying key regulators of GBM cell migration and invasion is of particular interest. The leukemia-associated RhoGEF (LARG) has previously been implicated in cell invasion in other tumor types; however, the role of LARG in GBM pathobiology remains undefined. Here, we report that the expression level o...
Source: The American Journal of Pathology - July 18, 2020 Category: Pathology Authors: Ding Z, Dong Z, Yang Y, Fortin Ensign SP, Sabit H, Nakada M, Ruggieri R, Kloss JM, Symons M, Tran NL, Loftus JC Tags: Am J Pathol Source Type: research

This Month in AJP (TMIA).
PMID: 32687797 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - July 17, 2020 Category: Pathology Authors: Chauhan C Tags: Am J Pathol Source Type: research

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

Lacrimal Gland Myoepithelial Cells Are Altered in a Mouse Model of Dry Eye Disease.
tt DA Abstract The purpose of this study was to determine the pathogenic changes that occur in myoepithelial cells (MECs) from lacrimal glands of a mouse model of Sjogren's syndrome. MECs were cultured from lacrimal glands of C57BL/6J (wild type, WT), and thrombospondin 1 null (TSP1-/-) mice, and from mice expressing smooth muscle actin-GFP (SMA-GFP) that labels MECs. MECs were stimulated with cholinergic and α1-adrenergic agonists, vasoactive intestinal peptide (VIP), and the purinergic (P)2 agonists, ATP and UTP. Then, intracellular [Ca2+] ([Ca2+]i) was measured using fura 2 and contraction was observed us...
Source: The American Journal of Pathology - July 14, 2020 Category: Pathology Authors: García-Posadas L, Hodges RR, Utheim TP, Olstad OK, Delcroix V, Makarenkova H, Dartt DA Tags: Am J Pathol Source Type: research

Decidual Vasculopathy Identification in Whole Slide Images Using Multi-Resolution Hierarchical Convolutional Neural Networks.
Abstract After a child is born, the examination of the placenta by a pathologist for abnormalities such as infection or maternal vascular malperfusion can provide important information about the immediate and long-term health of the infant. Detection of the pathologic placental blood vessel lesion decidual vasculopathy (DV) has been shown to predict adverse pregnancy outcomes such as pre-eclampsia, which can lead to mother and neonatal morbidity in subsequent pregnancies. However, due to the high volume of deliveries at large hospitals and limited resources, currently a large proportion of delivered placentas are ...
Source: The American Journal of Pathology - July 14, 2020 Category: Pathology Authors: Clymer D, Kostadinov S, Catov J, Skvarca L, Pantanowitz L, Cagan J, LeDuc P Tags: Am J Pathol Source Type: research

Expression of DNA methyltransferase 1 is a hallmark of melanoma, correlates with response to BRAF and MEK inhibition and with proliferation in melanocytic tumors.
ouml;cken M Abstract Aberrant DNA methylation is an epigenetic hallmark of melanoma and hypomethylating drugs with immunomodulatory activity are currently investigated in clinical trials. DNA methyltransferase 1 (DNMT1) is the major maintenance methyltransferase but its expression in melanocytic tumors is unknown. We analyzed DNMT1 expression in primary melanocytes, melanoma cell lines and 83 melanocytic tumors and explored its association with proliferation, mutational status and response to BRAF and MEK inhibition. We found that DNMT1 expression increased incrementally from nevi (mean fluorescence intensity (MFI...
Source: The American Journal of Pathology - July 14, 2020 Category: Pathology Authors: Gassenmaier M, Rentschler M, Fehrenbacher B, Eigentler TK, Ikenberg K, Kosnopfel C, Sinnberg T, Niessner H, Bösmüller H, Wagner NB, Schaller M, Garbe C, Röcken M Tags: Am J Pathol Source Type: research

The common microRNA signatures associated with mitochondrial dysfunction in different muscular dystrophies.
In this study, we aimed to identify the common miRNA signatures that are associated with mitochondrial damage in different muscular dystrophies (MDs) [Duchenne Muscular Dystrophy (DMD), Megaconial Congenital Muscular Dystrophy (CMD), Ullrich CMD (UCMD), and alpha-dystroglycanopathy (αDGpathy)]. We analyzed the miRnome profiles of skeletal muscle biopsies acquired from four different MD groups and control individuals by miRNA microarray. We identified 17 common upregulated miRNAs in all the tested MD groups. A specific bioinformatics approach identified 10 of these miRNAs to be specifically related to the mitochondria...
Source: The American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Aksu-Menges E, Akkaya-Ulum YZ, Dayangac-Erden D, Balci-Peynircioglu B, Yuzbasioglu A, Topaloglu H, Talim B, Balci-Hayta B Tags: Am J Pathol Source Type: research

ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITH OUTCOME AND SYMPTOMS.
Abstract The dynamics of viral load (VL) of the 2019 novel coronavirus (SARS-CoV-2) and its association with different clinical parameters remain poorly characterized in the United States patient population. Herein we investigate associations between VL and parameters such as severity of symptoms, disposition (admission vs direct discharge), length of hospitalization, and admission to the intensive care unit, length of need for oxygen support and overall survival in a cohort of 205 patients from a tertiary care center in New York City. VL was determined using q-PCR and Log10 transformed for normalization. Univaria...
Source: The American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Argyropoulos KV, Serrano A, Hu J, Black M, Feng X, Shen G, Call M, Kim MJ, Lytle A, Belovarac B, Vougiouklakis T, Lin LH, Moran U, Heguy A, Troxel A, Snuderl M, Osman I, Cotzia P, Jour G Tags: Am J Pathol Source Type: research

Tenascin-C induces phenotypic changes in fibroblasts to myofibroblasts with high contractility through the integrin αvβ1/TGF-β/SMAD signaling axis in human breast cancer.
Tenascin-C induces phenotypic changes in fibroblasts to myofibroblasts with high contractility through the integrin αvβ1/TGF-β/SMAD signaling axis in human breast cancer. Am J Pathol. 2020 Jul 07;: Authors: Katoh D, Kozuka Y, Noro A, Ogawa T, Imanaka-Yoshida K, Yoshida T Abstract Tenascin-C (TNC) is strongly expressed by fibroblasts and cancer cells in breast cancer. To assess the effects of TNC on stromal formation, we examined phenotypic changes in human mammary fibroblasts (HMFs) treated with TNC. The addition of TNC significantly up-regulated α-smooth muscle actin (SMA) and c...
Source: The American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Katoh D, Kozuka Y, Noro A, Ogawa T, Imanaka-Yoshida K, Yoshida T Tags: Am J Pathol Source Type: research

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

Myogenic cell expression of intercellular adhesion molecule-1 (ICAM-1) contributes to muscle regeneration after injury.
Abstract We investigated intercellular adhesion molecule-1 (ICAM-1), a membrane protein that mediates cell-to-cell adhesion and communication, as a mechanism through which the inflammatory response facilitates muscle regeneration after injury. Toxin-induced muscle injury to tibialis anterior muscles of wild type mice caused ICAM-1 to be expressed by a population of satellite cells/myoblasts and myofibers. Myogenic cell expression of ICAM-1 contributed to the restoration of muscle structure after injury, as regenerating myofibers were more abundant and myofiber size was larger for wild type compared to ICAM-1-/- mi...
Source: The American Journal of Pathology - July 7, 2020 Category: Pathology Authors: Martin RA, Buckley KH, Mankowski DC, Riley BM, Sidwell AN, Douglas SL, Worth RG, Pizza FX Tags: Am J Pathol Source Type: research

ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITH OUTCOME AND SYMPTOMS.
Abstract The dynamics of viral load (VL) of the 2019 novel coronavirus (SARS-CoV-2) and its association with different clinical parameters remain poorly characterized in the United States patient population. Herein we investigate associations between VL and parameters such as severity of symptoms, disposition (admission vs direct discharge), length of hospitalization, and admission to the intensive care unit, length of need for oxygen support and overall survival in a cohort of 205 patients from a tertiary care center in New York City. VL was determined using q-PCR and Log10 transformed for normalization. Univaria...
Source: The American Journal of Pathology - July 3, 2020 Category: Pathology Authors: Argyropoulos KV, Serrano A, Hu J, Black M, Feng X, Shen G, Call M, Kim MJ, Lytle A, Belovarac B, Vougiouklakis T, Lin LH, Moran U, Heguy A, Troxel A, Snuderl M, Osman I, Cotzia P, Jour G Tags: Am J Pathol Source Type: research

Retraction notice to Plexin-B1 and Semaphorin 4D Cooperate to Promote Perineural Invasion in a RhoA/ROK-Dependent Manner Am J Pathol 180 (2012) 1232-1242.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article is being retracted following correspondence from the Office of Accountability and Compliance at the University of Maryland, Baltimore. An internal investigation into this manuscript by the University of Maryland, Baltimore, found evidence that there are errors with the presentation of the standard deviations and statistical significance shown in Figure 6 which are not supported by the original data, and that these inaccuracies warrant retraction to co...
Source: The American Journal of Pathology - June 25, 2020 Category: Pathology Authors: Binmadi NO, Yang YH, Zhou H, Proia P, Lin YL, De Paula AMB, Sena Guimarães AL, Poswar FO, Sundararajan D, Basile JR Tags: Am J Pathol Source Type: research

This Month in AJP.
Authors: PMID: 32574565 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - June 20, 2020 Category: Pathology Tags: Am J Pathol Source Type: research

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

Resolvin E1 Reduces Leukotriene B4-Induced Intracellular Calcium Increase and Mucin Secretion in Rat Conjunctival Goblet Cells.
Abstract Leukotriene B4 (LTB4) is a major proinflammatory mediator important in host defense whereas resolvins (Rvs) are produced during the resolution phase of inflammation. We determined the actions of both RvE1 and RvD1 on LTB4-induced responses of goblet cells cultured from rat conjunctiva. The responses measured were an increase in the intracellular [Ca2+] ([Ca2+]i) and high molecular weight glycoprotein secretion. Treatment with RvE1 or RvD1 for 30 min significantly blocked the LTB4-induced [Ca2+]i increase. The actions of RvE1 on LTB4-induced [Ca2+]i increase were reversed by siRNA for the RvE1 receptor and...
Source: The American Journal of Pathology - June 16, 2020 Category: Pathology Authors: Yang M, Bair JA, Hodges RR, Serhan CN, Dartt DA Tags: Am J Pathol Source Type: research

Up-regulation of Matrix Metalloproteinase-2 by Scleral Monocyte-derived Macrophages Contributes to Myopia Development.
Abstract Myopia is a leading cause of visual impairment worldwide. This sight compromising condition is associated with scleral thinning, extracellular matrix (ECM) remodeling and inappropriate optical axial length elongation. Even though macrophages are present in the sclera, their involvement in this condition is unknown. By using a form-deprivation myopia (FDM) mouse model, we found that both the scleral macrophage density and their matrix metallopeptidase-2 (MMP-2) expression levels rose in myopic eyes. Partial scleral macrophage depletion by clodronate (CLOD) shifted the refraction towards hyperopia in both t...
Source: The American Journal of Pathology - June 15, 2020 Category: Pathology Authors: Zhao F, Wu H, Reinach PS, Wu Y, Zhai Y, Lei Y, Ma L, Su Y, Chen Y, Li F, Liu X, Srinivasalu N, Qu J, Zhou X Tags: Am J Pathol Source Type: research

Perivascular fibro-adipogenic progenitor tracing during post-traumatic osteoarthritis.
es AW Abstract Perivascular mural cells surround capillaries and microvessels, and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well known pathologic feature of osteoarthritis, yet transgenic animals to visualize perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreERT2 reporter mice were subjected to joint destabilization surgery in order to induce arthritic changes, and cell lineage traced over an 8 week period with a focus on the joint-associated fat pad. Results showed that at baseline inducible ...
Source: The American Journal of Pathology - June 10, 2020 Category: Pathology Authors: Sono T, Hsu CY, Wang Y, Xu J, Cherief M, Marini S, Huber AK, Miller S, Péault B, Levi B, James AW Tags: Am J Pathol Source Type: research

Lung and eye disease develop concurrently in supplemental oxygen-exposed neonatal mice.
Abstract Bronchopulmonary dysplasia and retinopathy of prematurity are two debilitating disorders that develop in preterm infants exposed to supplemental oxygen to prevent respiratory failure. Both can lead to lifelong disabilities such as chronic obstructive pulmonary disease and vision loss. Due to the lack of a standard experimental model of coincident disease, the underlying associations between BPD and ROP are not well characterized. To address this gap, the robust mouse model of oxygen-induced retinopathy was employed exposing C57BL/6 mice to 75% oxygen from postnatal day (PN) 7 to 12. The cardinal features ...
Source: The American Journal of Pathology - June 8, 2020 Category: Pathology Authors: Wickramasinghe LC, Lau M, Deliyanti D, Gottschalk TA, van Wijngaarden P, Talia D, Johnson C, Wilkinson-Berka JL, Tsantikos E, Hibbs ML Tags: Am J Pathol Source Type: research

The membrane protein sortilin can be targeted to inhibit pancreatic cancer cell invasion.
In this study, we found that sortilin expression was higher in pancreatic cell lines vs normal pancreatic ductal epithelial cells, as demonstrated by Western blot and mass spectrometry. The increased sortilin level in pancreatic cancer cells was confirmed by immunohistochemistry in a series of 99 human pancreatic adenocarcinomas vs 48 normal pancreatic tissues (p=0.0014). Sortilin inhibition by siRNA and the pharmacological inhibitor AF38469 strongly reduced the adhesion and invasion of pancreatic cancer cells without affecting cell survival and viability. Sortilin inhibition also decreased the phosphorylation of the focal...
Source: The American Journal of Pathology - June 8, 2020 Category: Pathology Authors: Gao F, Griffin N, Faulkner S, Li X, King SJ, Jobling P, Denham JW, Jiang CC, Hondermarck H Tags: Am J Pathol Source Type: research

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: 32513425 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - June 1, 2020 Category: Pathology Tags: Am J Pathol Source Type: research

M2 macrophages and phenotypic modulation of intestinal smooth muscle cells characterize Inflammatory stricture formation in the rat.
Abstract The progression of Crohn's disease to intestinal stricture formation is poorly controlled and the pathogenesis is unclear, although increased smooth muscle mass is present. Earlier, stricture formation was described in in the rat model of TNBS-induced colitis, now re-examined for early cellular features of stricture development. While inflammation of the mid-descending colon typically resolved, a subset showed characteristic stricturing by Day 16, with an inflammatory infiltrate in the neuromuscular layers that included eosinophils, CD3-positive T cells and CD68-positive macrophages. Closer study identifi...
Source: The American Journal of Pathology - May 29, 2020 Category: Pathology Authors: Lourenssen SR, Blennerhassett MG Tags: Am J Pathol Source Type: research