Deletion of Endothelial TGF- β Signaling Leads to Choroidal Neovascularization.
Deletion of Endothelial TGF-β Signaling Leads to Choroidal Neovascularization. Am J Pathol. 2017 Aug 17;: Authors: Schlecht A, Leimbeck SV, Jägle H, Feuchtinger A, Tamm ER, Braunger BM Abstract The molecular pathogenesis of choroidal neovascularization (CNV), an angiogenic process that critically contributes to vision loss in age-related macular degeneration (AMD) is unclear. Here we analyzed the role of transforming growth factor (TGF)-β signaling for CNV formation by generating a series of mutant mouse models with induced conditional deletion of TGF-β signaling in the entire eye,...
Source: The American Journal of Pathology - August 17, 2017 Category: Pathology Authors: Schlecht A, Leimbeck SV, Jägle H, Feuchtinger A, Tamm ER, Braunger BM Tags: Am J Pathol Source Type: research

Imaging of wound closure of small epithelial lesions in the mouse trachea.
l;nig P Abstract Integrity of the airway epithelium is essential for normal lung function. However, studies analyzing the repair process of small epithelial lesions in pseudostratified airway epithelium are missing. To follow airway-epithelial wound closure over time, we lesioned small areas of the mouse tracheal epithelium (1 to 12 cells) using a femtosecond laser and followed wound closure up to 6 h by autofluorescence multiphoton microscopy. Selected lesions were also examined by scanning and transmission electron microscopy and by staining of F-actin. Most lesions with a size up to 6 cells closed by elongation...
Source: The American Journal of Pathology - August 17, 2017 Category: Pathology Authors: Kretschmer S, Pieper M, Klinger A, Hüttmann G, König P Tags: Am J Pathol Source Type: research

Cysteine protease-dependent mucus disruptions and differential mucin gene expression in Giardia duodenalis infection.
This study reveals a complex interaction at the surface of epithelial cells, between G. duodenalis and the intestinal mucus layer. Here, we reveal mechanisms whereby G. duodenalis evades and disrupts the first line of host defense by degrading human mucin-2 (MUC2), depleting mucin stores and inducing differential gene expression in the mouse small and large intestines. Human colonic biopsies exposed to G. duodenalis were depleted of mucus and in vivo, mice infected with G. duodenalis had a thinner mucus layer and demonstrated differential Muc2 and Muc5ac mucin gene expression. Infection in Muc2(-/-) mice elevated trophozoi...
Source: The American Journal of Pathology - August 17, 2017 Category: Pathology Authors: Amat CB, Motta JP, Fekete E, Moreau F, Chadee K, Buret AG Tags: Am J Pathol Source Type: research

Ggnbp2 Null Mutation in Mice Leads to Male Infertility Due to a Defect at the Spermiogenesis Stage.
Abstract Gametogenetin binding protein 2 (GGNBP2) is an evolutionarily conserved zinc finger protein. Although Ggnbp2 null embryos in the B6 background died due to a defective placenta, 6.8% of Ggnbp2 null mice in the B6/129 mixed background were viable and continued to adulthood. Adult Ggnbp2 null males were sterile with smaller testes and an azoospermic phenotype, while mutant females were fertile. Histopathological analysis of 2-month-old Ggnbp2 null testes revealed absence of mature spermatozoa in the seminiferous tubules and epididymides and reduction of the number of spermatids. Ultrastructural analysis indi...
Source: The American Journal of Pathology - August 17, 2017 Category: Pathology Authors: Liu L, He Y, Guo K, Zhou L, Li X, Tseng M, Cai L, Lan ZJ, Zhou J, Wang H, Lei Z Tags: Am J Pathol Source Type: research

Stromal expression of activated leukocyte cell adhesion molecule (ALCAM) promotes lung tumor growth and metastasis.
In this study, we made use of ALCAM-deficient (ALCAM(-/-)) mice to evaluate the role of ALCAM in lung tumor growth and metastasis. ALCAM(-/-) mice displayed an altered blood vascular network in the lung and the diaphragm, indicative of an angiogenesis defect. Absence of ALCAM expression by cells forming the stromal tumor microenvironment profoundly impacted lung tumor growth in three different intravenous metastasis models. In the case of Lewis lung carcinoma (LLC), an additional defect in tumor cell homing to the lungs and a resulting reduction in the number of lung tumor nodules was observed. Similarly, when LLC were sub...
Source: The American Journal of Pathology - August 16, 2017 Category: Pathology Authors: Willrodt AH, Beffinger M, Vranova M, Protsyuk D, Schuler K, Jadhav M, Heikenwalder M, van den Broek M, Borsig L, Winter CH Tags: Am J Pathol Source Type: research

Discerning Clinical Responses in Breast Cancer Based Upon Molecular Signatures.
Abstract Breast cancer represents a heterogeneous collection of diseases with disparate clinical behaviors, responses to treatment, and patient outcomes, despite common histopathological features at diagnosis. Examination of molecular signatures of breast cancer (based upon complex gene expression patterns) enabled identification of several intrinsic molecular subtypes: luminal A, luminal B, HER2-enriched, and basal-like. The intrinsic subtypes are associated with measures of clinical aggressiveness, but do not perfectly predict patient outcomes. Several molecular signatures have been developed for prediction and ...
Source: The American Journal of Pathology - August 16, 2017 Category: Pathology Authors: Coleman WB, Anders CK Tags: Am J Pathol Source Type: research

Next Generation Breast Cancer Omics.
PMID: 28822804 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - August 16, 2017 Category: Pathology Authors: Coleman WB 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: 28822232 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - August 16, 2017 Category: Pathology Tags: Am J Pathol Source Type: research

Thyroid hormone receptor-beta agonist GC-1 inhibits Met- β-catenin driven hepatocellular cancer.
CONCLUSION: GC-1 exerts a notable antitumoral effect on hMet-S45Y-β-catenin HCC, by inactivating Met signaling. GC-1 does not promote β-catenin activation in HCC. Thus GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency. PMID: 28807594 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - August 11, 2017 Category: Pathology Authors: Puliga E, Min Q, Tao J, Zhang R, Pradhan-Sundd T, Poddar M, Singh S, Columbano A, Yu J, Monga SP Tags: Am J Pathol Source Type: research

Sphingosine kinase-2 deficiency ameliorates kidney fibrosis by up-regulating Smad7 in a mouse model of unilateral ureteral obstruction.
In this study, we investigated the role of sphingosine kinase-2 (SPHK2) on the progression of tubular fibrosis by utilizing a mouse unilateral ureteral obstruction (UUO) model. We found that SPHK2 protein and activity are up-regulated in fibrotic renal tissue. Functionally, Sphk2 deficient (Sphk2(-/-)) mice showed an attenuated fibrotic response to UUO compared to wild-type mice as demonstrated by reduced collagen abundance and decreased expression of fibronectin-1, collagen I, α-smooth muscle actin, connective tissue growth factor (CTGF), and plasminogen activator inhibitor (PAI-1). Importantly, these changes were a...
Source: The American Journal of Pathology - August 11, 2017 Category: Pathology Authors: Schwalm S, Beyer S, Frey H, Haceni R, Grammatikos G, Thomas D, Geisslinger G, Schaefer L, Huwiler A, Pfeilschifter J Tags: Am J Pathol Source Type: research

The role of angiotensin II in parietal epithelial cell proliferation and crescent formation in glomerular diseases.
Abstract Crescentic glomerulonephritis (GN) is a devastating disease with rapidly progressive deterioration in kidney function, which, histologically, manifests as crescent formation in most glomeruli. We previously found that crescents derive from the aberrant proliferation and migration of parietal epithelial cells (PECs)/progenitor cells, and that the angiotensin (ang) II/ang II type-1 (AT1) receptor pathway may participate, together with the stromal cell-derived factor-1 (SDF-1)/CXCR4 axis, in the development of those lesions. Here, we elucidated sequential events and cellular and molecular interactions occurr...
Source: The American Journal of Pathology - August 11, 2017 Category: Pathology Authors: Rizzo P, Novelli R, Rota C, Gagliardini E, Ruggiero B, Rottoli D, Benigni A, Remuzzi G Tags: Am J Pathol Source Type: research

Linking Sex Differences in Non-Alcoholic Fatty Liver Disease to Bile Acid Signaling, Gut Microbiota, and High Fat Diet.
Abstract This commentary highlights the article by Jena et al that studied the complex interplay between diet, bile acids, sex, and dysbiosis in hepatic steatosis and inflammation. PMID: 28728746 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - July 23, 2017 Category: Pathology Authors: Chiang JYL Tags: Am J Pathol Source Type: research

Endothelial-to-Mesenchymal Transition in Bone Marrow and Spleen of Primary Myelofibrosis.
Abstract Primary myelofibrosis is characterized by the development of fibrosis in the bone marrow that contributes to ineffective hematopoiesis. Bone marrow fibrosis is the result of a complex and not yet fully understood interaction among megakaryocytes, myeloid cells, fibroblasts, and endothelial cells. Here, we report that>30% of the endothelial cells in the small vessels of the bone marrow and spleen of patients with primary myelofibrosis have a mesenchymal phenotype, which is suggestive of the process known as endothelial-to-mesenchymal transition (EndMT). EndMT can be reproduced in vitro by incubatio...
Source: The American Journal of Pathology - July 23, 2017 Category: Pathology Authors: Erba BG, Gruppi C, Corada M, Pisati F, Rosti V, Bartalucci N, Villeval JL, Vannucchi AM, Barosi G, Balduini A, Dejana E 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: 28727986 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - July 17, 2017 Category: Pathology Tags: Am J Pathol Source Type: research

Associations of Autoimmunity, Immunodeficiency, Lymphomagenesis, and Gut Microbiota in Mice with Knockins for a Pathogenic Autoantibody.
Abstract A number of mouse strains transgenic for B-cell receptors specific for nucleic acids or other autoantigens have been generated to understand how autoreactive B cells are regulated in normal and autoimmune mice. Previous studies of nonautoimmune C57BL/6 mice heterozygous for both the IgH and IgL knockins of the polyreactive autoantibody, 564, produced high levels of autoantibodies in a largely Toll-like receptor 7-dependent manner. Herein, we describe studies of mice homozygous for the knockins that also expressed high levels of autoantibodies but, unlike the heterozygotes, exhibited a high incidence of ma...
Source: The American Journal of Pathology - July 17, 2017 Category: Pathology Authors: Jain S, Ward JM, Shin DM, Wang H, Naghashfar Z, Kovalchuk AL, Morse HC Tags: Am J Pathol Source Type: research

Stellate Cells Orchestrate Concanavalin A-Induced Acute Liver Damage.
Abstract Concanavalin A (ConA) causes immune cell-mediated liver damage, but the contribution of resident nonparenchymal cells is also evident. Hepatic stellate cells (HSCs) induce hepatic inflammation and immunological reactions; we therefore investigated their role in ConA-induced liver injury. ConA was administered i.v. to control or HSC-depleted mice; hepatic histopathology and cytokines/chemokines were determined after 6 hours. In vitro, the effects of ConA-conditioned HSC medium on hepatocytes were determined. ConA induced robust inflammation, sinusoidal congestion, and extensive midzonal hepatocyte dea...
Source: The American Journal of Pathology - July 12, 2017 Category: Pathology Authors: Rani R, Tandon A, Wang J, Kumar S, Gandhi CR Tags: Am J Pathol Source Type: research

M1 Macrophage-Induced Endothelial-to-Mesenchymal Transition Promotes Infantile Hemangioma Regression.
In conclusion, our findings indicate that EndMT induced by M1 macrophages promotes infantile hemangioma regression and may lead to novel therapeutic treatments for this vascular tumor. PMID: 28710904 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - July 12, 2017 Category: Pathology Authors: Wu KQ, Muratore CS, So EY, Sun C, Dubielecka PM, Reginato AM, Liang OD Tags: Am J Pathol Source Type: research

Western Diet-Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment.
Abstract Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin). Mice were subjected to morphological analysis as well as gut microbiota and bile acid profil...
Source: The American Journal of Pathology - July 11, 2017 Category: Pathology Authors: Jena PK, Sheng L, Liu HX, Kalanetra KM, Mirsoian A, Murphy WJ, French SW, Krishnan VV, Mills DA, Wan YY Tags: Am J Pathol Source Type: research

Short-Term Alcohol Abstinence Improves Antibacterial Defenses of Chronic Alcohol-Consuming Mice against Gut Bacteria-Associated Sepsis Caused by Enterococcus faecalis Oral Infection.
Abstract The effects of short-term alcohol abstinence on host antibacterial resistance against Enterococcus faecalis oral infection was investigated in chronic alcohol-consuming mice [mice with 0.1 g/day of 20% ethanol consumption for 12 or 16 weeks (CAC-mice)]. These mice were highly susceptible to the infection; however, after 7 days of alcohol abstinence (aaCAC-mice), their antibacterial resistances were completely restored to the normal mouse level. Normal mice inoculated with CAC-mouse hepatic macrophages were shown to be susceptible to the infection, whereas the same macrophage preparation from aaCAC-mice di...
Source: The American Journal of Pathology - July 11, 2017 Category: Pathology Authors: Kobayashi M, Asai A, Ito I, Suzuki S, Higuchi K, Suzuki F Tags: Am J Pathol Source Type: research

UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration Capabilities in Bone Marrow-Differentiated Dendritic Cells.
In this study, dendritic cells (DCs) differentiating from the bone marrow of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV-chimeric mice (ie, mice transplanted with bone marrow from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility. Compared with DCs from the bone marrow of nonirradiated mice, those from UV-irradiated mice produced more lactate, used greater amounts of glucose, and had greater glycolytic flux in...
Source: The American Journal of Pathology - July 11, 2017 Category: Pathology Authors: McGonigle TA, Keane KN, Ghaly S, Carter KW, Anderson D, Scott NM, Goodridge HS, Dwyer A, Greenland E, Pixley FJ, Newsholme P, Hart PH Tags: Am J Pathol Source Type: research

Regulator of Calcineurin 3 Ameliorates Autoimmune Arthritis by Suppressing Th17 Cell Differentiation.
Abstract Regulator of calcineurin 3 (RCAN3), an endogenous regulator of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, inhibits the phosphatase activity of calcineurin, the nuclear translocation of NFAT, and the NFAT downstream pathway. To investigate the effects of RCAN3 on T-cell regulatory function and the development and progression of inflammatory arthritis, we studied the effects of RCAN3 transfection on regulation of Th17 cell differentiation in a murine T-lymphoma cell line and primary splenic CD4(+) T cells. Overexpression of RCAN3 suppressed Th17 cell differentiation throug...
Source: The American Journal of Pathology - July 10, 2017 Category: Pathology Authors: Park JS, Jeong JH, Byun JK, Lim MA, Kim EK, Kim SM, Choi SY, Park SH, Min JK, Cho ML Tags: Am J Pathol Source Type: research

Laminin-Dependent Interaction between Astrocytes and Microglia: A Role in Retinal Angiogenesis.
Abstract Retinal vascular diseases are among the leading causes of acquired blindness. In recent years, retinal microglia have been shown to influence vascular branching density and endothelial cell proliferation. However, how microglial recruitment and activation are regulated during development remains unclear. We hypothesized that microglial recruitment, activation, and down-stream signaling are modulated by components of the mural basement membrane. We used a reverse genetic approach to disrupt laminin expression in the vascular basement membrane and demonstrate that microglia respond to the mural basement mem...
Source: The American Journal of Pathology - July 8, 2017 Category: Pathology Authors: Biswas S, Bachay G, Chu J, Hunter DD, Brunken WJ Tags: Am J Pathol Source Type: research

HIV-Associated Cardiovascular Disease: Role of Connexin 43.
Abstract Chronic HIV infection due to effective antiretroviral treatment has resulted in a broad range of clinical complications, including accelerated heart disease. Individuals with HIV infection have a 1.5 to 2 times higher incidence of cardiovascular diseases than their uninfected counterparts; however, the underlying mechanisms are poorly understood. To explore the link between HIV infection and cardiovascular diseases, we used postmortem human heart tissues obtained from HIV-infected and control uninfected individuals to examine connexin 43 (Cx43) expression and distribution and HIV-associated inflammation. ...
Source: The American Journal of Pathology - July 5, 2017 Category: Pathology Authors: Prevedel L, Morocho C, Bennett MVL, Eugenin EA Tags: Am J Pathol Source Type: research

Characterization of Brown Adipose-Like Tissue in  Trauma-Induced Heterotopic Ossification in Humans.
In this study, we evaluated the presence of brown fat within human HO lesions. Most of the excised tissue samples displayed histological characteristics of bone, fibroproliferative cells, blood vessels, and adipose tissue. Immunohistochemical analysis revealed extensive expression of uncoupling protein 1 (UCP1), a definitive marker of brown adipocytes, within HO-containing tissues but not normal tissues. As seen in the brown adipocytes observed during HO in the mouse, these UCP1(+) cells also expressed the peroxisome proliferator-activated receptor γ coactivator 1α. However, further characterization showed thes...
Source: The American Journal of Pathology - July 4, 2017 Category: Pathology Authors: Salisbury EA, Dickerson AR, Davis TA, Forsberg JA, Davis AR, Olmsted-Davis EA Tags: Am J Pathol Source Type: research

Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations.
ld DM Abstract Chylous pleural effusion (chylothorax) frequently accompanies lymphatic vessel malformations and other conditions with lymphatic defects. Although retrograde flow of chyle from the thoracic duct is considered a potential mechanism underlying chylothorax in patients and mouse models, the path chyle takes to reach the thoracic cavity is unclear. Herein, we use a novel transgenic mouse model, where doxycycline-induced overexpression of vascular endothelial growth factor (VEGF)-C was driven by the adipocyte-specific promoter adiponectin (ADN), to determine how chylothorax forms. Surprisingly, 100% of ad...
Source: The American Journal of Pathology - July 3, 2017 Category: Pathology Authors: Nitschké M, Bell A, Karaman S, Amouzgar M, Rutkowski JM, Scherer PE, Alitalo K, McDonald DM Tags: Am J Pathol Source Type: research

Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders.
Abstract Multicentric carpal-tarsal osteolysis; multicentric osteolysis, nodulosis, and arthropathy; and Winchester syndromes, skeletal dysplasias characterized by carpal/tarsal and epiphyseal abnormalities, are caused by mutations in v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B (MAFB), matrix metalloproteinase 2 (MMP2), and MMP14, respectively; however, the underlying pathophysiology is unclear. Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution. We hypothesized that MAFB, MMP-2, and MMP-14 have integral roles in carpal/tarsal and ep...
Source: The American Journal of Pathology - July 1, 2017 Category: Pathology Authors: Lazarus S, Tseng HW, Lawrence F, Woodruff MA, Duncan EL, Pettit AR Tags: Am J Pathol Source Type: research

Semaphorin 3E Alleviates Hallmarks of House Dust Mite-Induced Allergic Airway Disease.
Abstract Semaphorins are an essential family of guidance cues ubiquitously expressed in various organs, which play diverse developmental, homeostatic, and pathological roles. Semaphorin 3E (Sema3E), initially identified as a neuronal chemorepellent, is involved in the regulation of cell migration, proliferation, and angiogenesis. However, expression and function of Sema3E in allergic asthma has not been extensively investigated. We determined the expression of Sema3E in the airways and its effect on airway inflammation, hyperresponsiveness, and remodeling as pathological features of allergic asthma provoked by hou...
Source: The American Journal of Pathology - June 23, 2017 Category: Pathology Authors: Movassagh H, Shan L, Duke-Cohan JS, Halayko AJ, Uzonna JE, Gounni AS Tags: Am J Pathol Source Type: research

Testosterone Differentially Affects T Cells and Neurons in Murine and Human Models of Neuroinflammation and Neurodegeneration.
a A Abstract The high female-to-male sex ratio of multiple sclerosis (MS) prevalence has continuously confounded researchers, especially in light of male patients' accelerated disease course at later stages of MS. Although multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormone treatment on the acute inflammatory and chr...
Source: The American Journal of Pathology - June 23, 2017 Category: Pathology Authors: Massa MG, David C, Jörg S, Berg J, Gisevius B, Hirschberg S, Linker RA, Gold R, Haghikia A Tags: Am J Pathol Source Type: research

Gene Expression Differences between Ductal Carcinoma in Situ with and without Progression to Invasive Breast Cancer.
Abstract To understand the molecular alterations driving the progression of ductal carcinoma in situ (DCIS), we compared patients with pure DCIS and patients with DCIS and synchronous invasive breast cancer (IBC). Twelve patients with extensive pure DCIS were included as a representation of indolent lesions with limited invasive capacity. These cases were matched with 12 patients with a limited DCIS component and IBC, representing lesions with a high invasive potential. Matching included age and surrogate DCIS subtypes. Gene expression profiling was performed on DCIS cells to identify transcriptional differences b...
Source: The American Journal of Pathology - June 23, 2017 Category: Pathology Authors: Doebar SC, Sieuwerts AM, de Weerd V, Stoop H, Martens JWM, van Deurzen CHM Tags: Am J Pathol Source Type: research

Loss of Function of P2X7 Receptor Scavenger Activity in Aging Mice: A Novel Model for Investigating the Early Pathogenesis of Age-Related Macular Degeneration.
In this study, we investigate the effect of loss of P2X7 receptor function on retinal structure and function during aging. P2X7-null and wild-type C57bl6J mice were investigated at 4, 12, and 18 months of age for macrophage phagocytosis activity, ocular histological changes, and retinal function. Phagocytosis activity of blood-borne macrophages decreased with age at 18 months in the wild-type mouse. Lack of P2X7 receptor function reduced phagocytosis at all ages compared to wild-type mice. At 12 months of age, P2X7-null mice had thickening of Bruch membrane and retinal pigment epithelium dysfunction. By 18 months of age, P...
Source: The American Journal of Pathology - June 16, 2017 Category: Pathology Authors: Vessey KA, Gu BJ, Jobling AI, Phipps JA, Greferath U, Tran MX, Dixon MA, Baird PN, Guymer RH, Wiley JS, Fletcher EL Tags: Am J Pathol Source Type: research

Deficiency in EP4 Receptor-Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease.
Abstract Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2 type 4 receptor-associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20(+/-) onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20(+/-)EPRAP(+/+) and J20(+/-)EPRAP(-/-) mice. EPR...
Source: The American Journal of Pathology - June 15, 2017 Category: Pathology Authors: Fujikawa R, Higuchi S, Nakatsuji M, Yasui M, Ikedo T, Nagata M, Hayashi K, Yokode M, Minami M Tags: Am J Pathol Source Type: research

Cathepsin K in Lymphangioleiomyomatosis: LAM Cell-Fibroblast Interactions Enhance Protease Activity by Extracellular Acidification.
Abstract Lymphangioleiomyomatosis (LAM) is a rare disease in which clonal LAM cells infiltrate the lungs and lymphatics. In association with recruited fibroblasts, LAM cells form nodules adjacent to lung cysts. It is hypothesized that LAM nodule-derived proteases lead to cyst formation. On protease gene-expression profiling in whole-lung tissue, cathepsin K was 40-fold overexpressed in LAM compared with control lungs (P ≤ 0.0001). Immunohistochemistry confirmed cathepsin K protein in LAM nodules but not in control lungs. Cathepsin K gene expression and protein and protease activity were detected in LA...
Source: The American Journal of Pathology - June 14, 2017 Category: Pathology Authors: Dongre A, Clements D, Fisher AJ, Johnson SR Tags: Am J Pathol Source Type: research

Hypoxia-Inducible Factor 1 α Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury.
Hypoxia-Inducible Factor 1α Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury. Am J Pathol. 2017 Jun 12;: Authors: McClendon J, Jansing NL, Redente EF, Gandjeva A, Ito Y, Colgan SP, Ahmad A, Riches DWH, Chapman HA, Mason RJ, Tuder RM, Zemans RL Abstract During acute respiratory distress syndrome, epithelial cells, primarily alveolar type (AT) I cells, die and slough off the basement membrane, resulting in enhanced permeability. ATII cells proliferate and spread onto the denuded basement membrane to reseal the barrier. Repair of the alveolar epithelium is critical for c...
Source: The American Journal of Pathology - June 12, 2017 Category: Pathology Authors: McClendon J, Jansing NL, Redente EF, Gandjeva A, Ito Y, Colgan SP, Ahmad A, Riches DWH, Chapman HA, Mason RJ, Tuder RM, Zemans RL Tags: Am J Pathol Source Type: research

Platelet-Derived Growth Factor BB Influences Muscle Regeneration in Duchenne Muscle Dystrophy.
mis C, Illa I, Díaz-Manera J Abstract Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle fibers, and their substitution by fibrotic and adipose tissue. Many factors contribute to this process, but the molecular pathways related to regeneration and degeneration of muscle are not completely known. Platelet-derived growth factor (PDGF)-BB belongs to a family of growth factors that regulate proliferation, migration, and differentiation of mesenchymal cells. The role of PDGF-BB in muscle regeneration in humans has not been studied. We analyzed the expression of PDGF-BB in muscle b...
Source: The American Journal of Pathology - June 12, 2017 Category: Pathology Authors: Piñol-Jurado P, Gallardo E, de Luna N, Suárez-Calvet X, Sánchez-Riera C, Fernández-Simón E, Gomis C, Illa I, Díaz-Manera J Tags: Am J Pathol Source Type: research

Osteocyte Regulation of Receptor Activator of NF- κB Ligand/Osteoprotegerin in a Sheep Model of Osteoporosis.
Osteocyte Regulation of Receptor Activator of NF-κB Ligand/Osteoprotegerin in a Sheep Model of Osteoporosis. Am J Pathol. 2017 Jun 12;: Authors: El Khassawna T, Merboth F, Malhan D, Böcker W, Daghma DES, Stoetzel S, Kern S, Hassan F, Rosenbaum D, Langenstein J, Bauer N, Schlagenhauf A, Rösen-Wolff A, Schulze F, Rupp M, Hose D, Secklinger A, Ignatius A, Wilke HJ, Lips KS, Heiss C Abstract Osteoporosis induction in a sheep model by steroid administration combined with ovariectomy recapitulates decreased bone formation and substandard matrix mineralization in patients. Recently, the role ...
Source: The American Journal of Pathology - June 12, 2017 Category: Pathology Authors: El Khassawna T, Merboth F, Malhan D, Böcker W, Daghma DES, Stoetzel S, Kern S, Hassan F, Rosenbaum D, Langenstein J, Bauer N, Schlagenhauf A, Rösen-Wolff A, Schulze F, Rupp M, Hose D, Secklinger A, Ignatius A, Wilke HJ, Lips KS, Heiss C Tags: Am J Pathol Source Type: research

Cigarette Smoke Regulates Calcium-Independent Phospholipase A2 Metabolic Pathways in Breast Cancer.
Abstract Phospholipase A2 (PLA2)-dependent pathways are important in the regulation of cell proliferation, differentiation, motility, and immune responses, and can be dysregulated during tumor development and progression. We show herein, for the first time, that cigarette smoking leads to an increase in platelet-activating factor (PAF) content and PAF receptor expression in human breast cancer cells and tissue. PAF production could be abrogated in triple-negative breast cancer cells by inhibition of calcium-independent PLA2 (iPLA2). We also demonstrate that cigarette smoke induces the expression of cyclooxygenase-...
Source: The American Journal of Pathology - June 12, 2017 Category: Pathology Authors: Kispert S, Schwartz T, McHowat J Tags: Am J Pathol Source Type: research

Antifibrotic Actions of Peroxisome Proliferator-Activated Receptor γ Ligands in Corneal Fibroblasts Are Mediated by β-Catenin-Regulated Pathways.
Antifibrotic Actions of Peroxisome Proliferator-Activated Receptor γ Ligands in Corneal Fibroblasts Are Mediated by β-Catenin-Regulated Pathways. Am J Pathol. 2017 Jun 10;: Authors: Jeon KI, Phipps RP, Sime PJ, Huxlin KR Abstract Wound healing after corneal injury typically involves fibrosis, with transforming growth factor β1 (TGF-β1) as one of its strongest mediators. A class of small molecules-peroxisome proliferator-activated receptor γ (PPARγ) ligands-exert potent antifibrotic effects in the cornea by blocking phosphorylation of p38 mitogen-activated protein kinas...
Source: The American Journal of Pathology - June 10, 2017 Category: Pathology Authors: Jeon KI, Phipps RP, Sime PJ, Huxlin KR Tags: Am J Pathol Source Type: research

Tumor Necrosis Factor- α and IL-17A Activation Induces Pericyte-Mediated Basement Membrane Remodeling in Human Neutrophilic Dermatoses.
Tumor Necrosis Factor-α and IL-17A Activation Induces Pericyte-Mediated Basement Membrane Remodeling in Human Neutrophilic Dermatoses. Am J Pathol. 2017 Jun 10;: Authors: Lauridsen HM, Pellowe AS, Ramanathan A, Liu R, Miller-Jensen K, McNiff JM, Pober JS, Gonzalez AL Abstract Sweet syndrome is a prototypical neutrophilic dermatosis, a class of inflammatory diseases marked by elevated levels of tumor necrosis factor (TNF)-α and IL-17A, pathologic neutrophil recruitment, and microvascular remodeling. Histologic analyses of four matrix proteins-collagen I and IV, laminin, and fibronectin-in t...
Source: The American Journal of Pathology - June 10, 2017 Category: Pathology Authors: Lauridsen HM, Pellowe AS, Ramanathan A, Liu R, Miller-Jensen K, McNiff JM, Pober JS, Gonzalez AL Tags: Am J Pathol Source Type: research

Lasting Retinal Injury in a Mouse Model of Blast-Induced Trauma.
Abstract Traumatic brain injury due to blast exposure is currently the most prevalent of war injuries. Although secondary ocular blast injuries due to flying debris are more common, primary ocular blast exposure resulting from blast wave pressure has been reported among survivors of explosions, but with limited understanding of the resulting retinal pathologies. Using a compressed air-driven shock tube system, adult male and female C57BL/6 mice were exposed to blast wave pressure of 300 kPa (43.5 psi) per day for 3 successive days, and euthanized 30 days after injury. We assessed retinal tissues using immunofluore...
Source: The American Journal of Pathology - June 9, 2017 Category: Pathology Authors: Mammadova N, Ghaisas S, Zenitsky G, Sakaguchi DS, Kanthasamy AG, Greenlee JJ, West Greenlee MH Tags: Am J Pathol Source Type: research

Endothelium-Independent Primitive Myxoid Vascularization Creates Invertebrate-Like Channels to Maintain Blood Supply in Optic Gliomas.
Abstract Optic gliomas are brain tumors characterized by slow growth, progressive loss of vision, and limited therapeutic options. Optic gliomas contain various amounts of myxoid matrix, which can represent most of the tumor mass. We sought to investigate biological function and protein structure of the myxoid matrix in optic gliomas to identify novel therapeutic targets. We reviewed histological features and clinical imaging properties, analyzed vasculature by immunohistochemistry and electron microscopy, and performed liquid chromatography-mass spectrometry on optic gliomas, which varied in the amount of myxoid ...
Source: The American Journal of Pathology - June 9, 2017 Category: Pathology Authors: Snuderl M, Zhang G, Wu P, Jennings TS, Shroff S, Ortenzi V, Jain R, Cohen B, Reidy JJ, Dushay MS, Wisoff JH, Harter DH, Karajannis MA, Fenyo D, Neubert TA, Zagzag D Tags: Am J Pathol Source Type: research

Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy.
Abstract Defective inflammation resolution is the underlying cause of prevalent chronic inflammatory diseases, such as arthritis, asthma, cancer, and neurodegenerative and cardiovascular diseases. Inflammation resolution is governed by several endogenous factors, including fatty acid-derived specialized proresolving mediators and proteins, such as annexin A1. Specifically, specialized proresolving mediators comprise a family of mediators that include arachidonic acid-derived lipoxins, omega-3 fatty acid eicosapentaenoic acid-derived resolvins, docosahexaenoic acid-derived resolvins, protectins, and maresins. Emerg...
Source: The American Journal of Pathology - May 22, 2017 Category: Pathology Authors: Fredman G, Tabas I Tags: Am J Pathol Source Type: research

CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis.
Abstract Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-prone Apoe(-/-) background developed increased aortic lipid-rich plaques compared to control Apoe(-/-) mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsib...
Source: The American Journal of Pathology - May 22, 2017 Category: Pathology Authors: Shi H, Zhang C, Pasupuleti V, Hu X, Prosdocimo DA, Wu W, Qing Y, Wu S, Mohammad H, Gerson SL, Perbal B, Klenotic PA, Dong N, Lin Z Tags: Am J Pathol Source Type: research

Correction.
Authors: PMID: 28527711 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - May 22, 2017 Category: Pathology Tags: Am J Pathol Source Type: research

Activation of Hypoxia Signaling in Stromal Progenitors Impairs Kidney Development.
In this study, we investigated the effects of HIF activation in the developing renal stroma, which also essentially modulates nephron development from the metanephric mesenchyme. HIF activation was achieved by conditional deletion of the von Hippel-Lindau tumor suppressor (VHL) protein in the forkhead box FOXD1 cell lineage, from which stromal progenitors arise. The resulting kidneys showed maturation defects associated with early postnatal death. In particular, nephron formation, tubular maturation, and the differentiation of smooth muscle, renin, and mesangial cells were impaired. Erythropoietin expression was stron...
Source: The American Journal of Pathology - May 17, 2017 Category: Pathology Authors: Gerl K, Steppan D, Fuchs M, Wagner C, Willam C, Kurtz A, Kurt B Tags: Am J Pathol Source Type: research

Cyst-Like Osteolytic Formations in Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) Augments Sheep Spinal Fusion.
In this report we show that, in addition to promoting lumbar spinal fusion through potent osteogenic effects, rhBMP-2 augmentation promotes local cyst-like osteolytic formations in sheep trabecular bones that have undergone anterior lumbar interbody fusion. Three months after operation, conventional computed tomography showed that the trabecular bones of the rhBMP-2 application groups could fuse, whereas no fusion was observed in the control group. Micro-computed tomography analysis revealed that the core implant area's bone volume fraction and bone mineral density increased proportionately with rhBMP-2 dose. Multiple cyst...
Source: The American Journal of Pathology - May 11, 2017 Category: Pathology Authors: Pan HC, Lee S, Ting K, Shen J, Wang C, Nguyen A, Berthiaume EA, Zara JN, Turner AS, Seim HB, Kwak JH, Zhang X, Soo C Tags: Am J Pathol Source Type: research

Purkinje Cells Are More Vulnerable to the Specific Depletion of Cathepsin D Than to That of Atg7.
Abstract Neurologic phenotypes of cathepsin D (CTSD)-deficient mice, a murine model of neuronal ceroid lipofuscinoses, indicate the importance of CTSD for the maintenance of metabolism in central nervous system neurons. To further understand the role of CTSD in central nervous system neurons, we generated mice with a CTSD deficiency specifically in the Purkinje cells (PCs) (CTSD(Flox/Flox);GRID2-Cre) and compared their phenotypes with those of PC-selective Atg7-deficient (Atg7(Flox/Flox);GRID2-Cre) mice. In both strains of mice, PCs underwent degeneration, but the CTSD-deficient PCs disappeared more rapidly than t...
Source: The American Journal of Pathology - May 11, 2017 Category: Pathology Authors: Koike M, Shibata M, Sunabori T, Yamaguchi J, Sakimura K, Komatsu M, Tanaka K, Uchiyama Y Tags: Am J Pathol Source Type: research

Knockdown of Hepatic Gonadotropin-Releasing Hormone by Vivo-Morpholino Decreases Liver Fibrosis in Multidrug Resistance Gene 2 Knockout Mice by Down-Regulation of miR-200b.
Abstract Hepatic fibrosis occurs during the progression of primary sclerosing cholangitis (PSC) and is characterized by accumulation of extracellular matrix proteins. Proliferating cholangiocytes and activated hepatic stellate cells (HSCs) participate in the promotion of liver fibrosis during cholestasis. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone synthesized by hypothalamic neurons and the biliary epithelium and exerts its biological effects on cholangiocytes by interaction with the receptor subtype (GnRHR1) expressed by cholangiocytes and HSCs. Previously, we demonstrated that administrat...
Source: The American Journal of Pathology - May 11, 2017 Category: Pathology Authors: Kyritsi K, Meng F, Zhou T, Wu N, Venter J, Francis H, Kennedy L, Onori P, Franchitto A, Bernuzzi F, Invernizzi P, McDaniel K, Mancinelli R, Alvaro D, Gaudio E, Alpini G, Glaser S Tags: Am J Pathol Source Type: research

The Cellular Retinoic Acid Binding Protein 2 Promotes Survival of Malignant Peripheral Nerve Sheath Tumor Cells.
Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms that commonly occur in patients with neurofibromatosis type 1 (NF1). Effective chemotherapy is not available. To characterize a therapeutic target for treatment, we investigated the role of cellular retinoic acid binding protein 2 (CRABP2) in MPNST in vitro. CRABP2 is a transcriptional co-activator of retinoic acid signaling. Although overexpression of CRABP2 is described in several cancers, it has not yet been studied in MPNSTs. We investigated CRABP2 expression in cultured Schwann cells and formalin-fixed, paraffin-embedded ...
Source: The American Journal of Pathology - May 11, 2017 Category: Pathology Authors: Fischer-Huchzermeyer S, Dombrowski A, Hagel C, Mautner VF, Schittenhelm J, Harder A Tags: Am J Pathol Source Type: research

Megakaryocytes in Myeloproliferative Neoplasms Have Unique Somatic Mutations.
In this study we examined the megakaryocyte genome in 12 patients with MPNs to determine whether there are somatic variants and whether there is any association with marrow fibrosis. We performed targeted next-generation sequencing for 120 genes associated with myeloid neoplasms on megakaryocytes isolated from aspirated bone marrow. Eleven of the 12 patients had genomic defects in megakaryocytes that were not present in nonmegakaryocytic hemopoietic marrow cells from the same patient. The greatest allelic burden was in patients with increased reticulin deposition. The megakaryocyte-unique mutations were predominantly in ge...
Source: The American Journal of Pathology - May 11, 2017 Category: Pathology Authors: Guo BB, Nigel Allcock RJ, Mirzai B, Jacobus Malherbe JA, Choudry FA, Frontini M, Chuah H, Liang J, Kavanagh SE, Howman R, Ouwehand WH, Fuller KA, Erber WN Tags: Am J Pathol Source Type: research

Selective Activation of Estrogen Receptor α Activation Function-1 Is Sufficient to Prevent Obesity, Steatosis, and Insulin Resistance in Mouse.
Selective Activation of Estrogen Receptor α Activation Function-1 Is Sufficient to Prevent Obesity, Steatosis, and Insulin Resistance in Mouse. Am J Pathol. 2017 May 10;: Authors: Guillaume M, Handgraaf S, Fabre A, Raymond-Letron I, Riant E, Montagner A, Vinel A, Buscato M, Smirnova N, Fontaine C, Guillou H, Arnal JF, Gourdy P Abstract Estrogen receptor α (ERα) regulates gene transcription through two activation functions (ERα-AF1 and ERα-AF2). We recently found that the protection conferred by 17β-estradiol against obesity and insulin resistance requires ERα-A...
Source: The American Journal of Pathology - May 10, 2017 Category: Pathology Authors: Guillaume M, Handgraaf S, Fabre A, Raymond-Letron I, Riant E, Montagner A, Vinel A, Buscato M, Smirnova N, Fontaine C, Guillou H, Arnal JF, Gourdy P Tags: Am J Pathol Source Type: research