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American Journal of Pathology

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https://www.readbyqxmd.com/read/28646640/this-month-in-ajp
#1
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The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
June 21, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28641077/inhibition-of-early-growth-response-1-in-the-hippocampus-alleviates-neuropathology-and-improves-cognition-in-an-alzheimer-model-with-plaques-and-tangles
#2
Xike Qin, Yunling Wang, Hemant K Paudel
A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, amyloid-β (Aβ) pathology, and improves cognition in the 3xTg-AD mouse model...
June 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28641076/elevated-cd26-expression-by-skin-fibroblasts-distinguishes-a-profibrotic-phenotype-involved-in-scar-formation-compared-to-gingival-fibroblasts
#3
Wesley Mah, Guoqiao Jiang, Dylan Olver, Corrie Gallant-Behm, Colin Wiebe, David A Hart, Leeni Koivisto, Hannu Larjava, Lari Häkkinen
Compared to skin, wound healing in oral mucosa is faster and produces less scarring, but the mechanisms involved are incompletely understood. Studies in mice have linked high expression of CD26 to a profibrotic fibroblast phenotype, but this has not been tested in models more relevant for humans. We hypothesized that CD26 is highly expressed by human skin fibroblasts (SFBLs), and this associates with a profibrotic phenotype distinct from gingival fibroblasts (GFBLs). We compared CD26 expression in human gingiva and skin and in gingival and hypertrophic-like scar-forming skin wound healing in a pig model, and used three-dimensional cultures of human GFBLs and SFBLs...
June 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28633009/rna-interference-reveals-the-coregulatory-effects-of-cylindromatosis-on-apoptosis-and-necroptosis-of-photoreceptor-cells-in-experimental-retinal-detachment
#4
Kai Dong, Linfeng Han, Jingwen Liu, Fenghua Wang, Xiaodong Sun
Inhibiting only cell apoptosis or necroptosis in photoreceptor cells does not protect them against death after traumatic retinal detachment. This study was designed to evaluate the coregulatory effects of the deubiquitinating enzyme cylindromatosis on the apoptosis and necroptosis of photoreceptor cells in experimental retinal detachment. Lentivirus Cyld shRNA was generated and used to suppress cylindromatosis expression in Sprague-Dawley rats. Three weeks after injection of lentivirus Cyld shRNA, retinal detachment surgery was performed...
June 17, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28628761/loss-of-function-of-p2x7-receptor-scavenger-activity-in-aging-mice-a-novel-model-for-investigating-the-early-pathogenesis-of-age-related-macular-degeneration
#5
Kirstan A Vessey, Ben J Gu, Andrew I Jobling, Joanna A Phipps, Ursula Greferath, Mai X Tran, Michael A Dixon, Paul N Baird, Robyn H Guymer, James S Wiley, Erica L Fletcher
Age-related macular degeneration (AMD) is a leading cause of irreversible, severe vision loss in Western countries. Recently, we identified a novel pathway involving P2X7 receptor scavenger function expressed on ocular immune cells as a risk factor for advanced AMD. 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...
June 16, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28624505/deficiency-in-ep4-receptor-associated-protein-ameliorates-abnormal-anxiety-like-behavior-and-brain-inflammation-in-a-mouse-model-of-alzheimer-disease
#6
Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Kosuke Hayashi, Masayuki Yokode, Manabu Minami
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...
June 15, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28623674/cathepsin-k-in-lymphangioleiomyomatosis-lam-cell-fibroblast-interactions-enhance-protease-activity-by-extracellular-acidification
#7
Arundhati Dongre, Debbie Clements, Andrew J Fisher, Simon R Johnson
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...
June 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28627414/role-of-akt-hyperactivation-and-the-potential-of-akt-targeted-therapy-in-diffuse-large-b-cell-lymphoma
#8
Jinfen Wang, Zijun Y Xu-Monette, Kausar J Jabbar, Qi Shen, Ganiraju C Manyam, Alexandar Tzankov, Carlo Visco, Jing Wang, Santiago Montes-Moreno, Karen Dybkær, Wayne Tam, Govind Bhagat, Eric D Hsi, J Han van Krieken, Maurilio Ponzoni, Andrés J M Ferreri, Shi Wang, Michael B Møller, Miguel A Piris, L Jeffrey Medeiros, Yong Li, Lan V Pham, Ken H Young
AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor...
June 13, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28627413/modeling-esophagitis-using-human-three-dimensional-organotypic-culture-system
#9
Dorottya Laczkó, Fang Wang, F Bradley Johnson, Nirag Jhala, András Rosztóczy, Gregory G Ginsberg, Gary W Falk, Anil K Rustgi, John P Lynch
Esophagitis, whether caused by acid reflux, allergic responses, graft-versus-host disease, drugs, or infections, is a common condition of the gastrointestinal tract affecting nearly 20% of the US population. The instigating agent typically triggers an inflammatory response. The resulting inflammation is a risk factor for the development of esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Research into the pathophysiology of these conditions has been limited by the availability of animal and human model systems...
June 13, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28627412/macrophages-regulate-unilateral-ureteral-obstruction-induced-renal-lymphangiogenesis-through-c-c-motif-chemokine-receptor-2-dependent-phosphatidylinositol-3-kinase-akt-mechanistic-target-of%C3%A2-rapamycin-signaling-and-hypoxia-inducible-factor-1%C3%AE-vascular-endothelial
#10
Yan-Chao Guo, Meng Zhang, Fa-Xi Wang, Guang-Chang Pei, Fei Sun, Ying Zhang, Xiaoyu He, Yi Wang, Jia Song, Feng-Ming Zhu, Nuruliarizki S Pandupuspitasari, Jing Liu, Kun Huang, Ping Yang, Fei Xiong, Shu Zhang, Qilin Yu, Ying Yao, Cong-Yi Wang
Lymphangiogenesis occurs during renal fibrosis in patients with chronic kidney diseases and vascular endothelial growth factor (VEGF)-C is required for the formation of lymphatic vessels; however, the underlying mechanisms remain unclear. We demonstrate that macrophages can regulate unilateral ureteral obstruction (UUO)-induced renal lymphangiogenesis by expressing high levels of VEGF-C by C-C motif chemokine receptor 2 (CCR2)-mediated signaling. Mice deficient in Ccr2 manifested repressed lymphangiogenesis along with attenuated renal injury and fibrosis after UUO induction...
June 13, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28618256/cigarette-smoke-regulates-calcium-independent-phospholipase-a2-metabolic-pathways-in-breast-cancer
#11
Shannon Kispert, Theresa Schwartz, Jane McHowat
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)...
June 12, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28618255/osteocyte-regulation-of-receptor-activator-of-nf-%C3%AE%C2%BAb-ligand-osteoprotegerin-in-a-sheep-model-of-osteoporosis
#12
Thaqif El Khassawna, Felix Merboth, Deeksha Malhan, Wolfgang Böcker, Diaa E S Daghma, Sabine Stoetzel, Stefanie Kern, Fathi Hassan, Dirk Rosenbaum, Judith Langenstein, Natali Bauer, Anja Schlagenhauf, Angela Rösen-Wolff, Felix Schulze, Markus Rupp, Dirk Hose, Anja Secklinger, Anita Ignatius, Hans-Joachim Wilke, Katrin S Lips, Christian Heiss
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 of osteocytes has been frequently addressed, with focus on their role in osteoclastogenesis. However, the quantification of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) signaling in osteocytes was not studied in sheep. The current study reproduced the sheep model of osteoporosis to study the RANKL/OPG ratio correlation to the method of osteoporosis induction...
June 12, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28618254/platelet-derived-growth-factor-bb-influences-muscle-regeneration-in-duchenne-muscle-dystrophy
#13
Patricia Piñol-Jurado, Eduard Gallardo, Noemi de Luna, Xavier Suárez-Calvet, Carles Sánchez-Riera, Esther Fernández-Simón, Clara Gomis, Isabel Illa, Jordi Díaz-Manera
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...
June 12, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28618253/hypoxia-inducible-factor-1%C3%AE-signaling-promotes-repair-of-the-alveolar-epithelium-after-acute-lung-injury
#14
Jazalle McClendon, Nicole L Jansing, Elizabeth F Redente, Aneta Gandjeva, Yoko Ito, Sean P Colgan, Aftab Ahmad, David W H Riches, Harold A Chapman, Robert J Mason, Rubin M Tuder, Rachel L Zemans
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 clinical recovery; however, the mechanisms underlying ATII cell proliferation and spreading are not well understood. We hypothesized that hypoxia-inducible factor (HIF)1α promotes proliferation and spreading of ATII cells during repair after lung injury...
June 12, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28609645/tumor-necrosis-factor-%C3%AE-and-il-17a-activation-induces-pericyte-mediated-basement-membrane-remodeling-in-human-neutrophilic-dermatoses
#15
Holly M Lauridsen, Amanda S Pellowe, Anand Ramanathan, Rebecca Liu, Kathryn Miller-Jensen, Jennifer M McNiff, Jordan S Pober, Anjelica L Gonzalez
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 the skin biopsies of patients with Sweet syndrome reveal that the basement membrane of dermal postcapillary venules undergoes changes in structure and composition. Increased neutrophil recruitment in vivo was associated with increases in collagen IV, decreases in laminin, and varied changes in fibronectin...
June 10, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28606794/antifibrotic-actions-of-peroxisome-proliferator-activated-receptor-%C3%AE-ligands-in-corneal-fibroblasts-are-mediated-by-%C3%AE-catenin-regulated-pathways
#16
Kye-Im Jeon, Richard P Phipps, Patricia J Sime, Krystel R Huxlin
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 kinase (MAPK). However, why this blocks fibrosis remains unknown. Herein, we show that PPARγ ligands (rosiglitazone, troglitazone, and 15-deoxy-Δ12,14-prostaglandin J2) decrease levels of β-catenin...
June 10, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28606795/endothelium-independent-primitive-myxoid-vascularization-creates-invertebrate-like-channels-to-maintain-blood-supply-in-optic-gliomas
#17
Matija Snuderl, Guoan Zhang, Pamela Wu, Tara S Jennings, Seema Shroff, Valerio Ortenzi, Rajan Jain, Benjamin Cohen, Jason J Reidy, Mitchell S Dushay, Jeffrey H Wisoff, David H Harter, Matthias A Karajannis, David Fenyo, Thomas A Neubert, David Zagzag
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 matrix...
June 9, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28411859/cd14-plays-a-protective-role-in-experimental-inflammatory-bowel-disease-by-enhancing-intestinal-barrier-function
#18
Stephanie Buchheister, Manuela Buettner, Marijana Basic, Andreas Noack, Gerhard Breves, Barbara Buchen, Lydia M Keubler, Christoph Becker, André Bleich
Intestinal homeostasis disturbance through intestinal barrier disruption presumably plays a key role in inflammatory bowel disease (IBD) development. Genetic and candidate gene analyses in an Il10-deficient IBD mouse model system identified Cd14 as a potentially protective candidate gene. The role of Cd14 in colitis development was determined using dextran sulfate sodium (DSS)-induced acute and an Il10-deficiency-induced chronic model of intestinal inflammation. Intestinal permeability was investigated by fluorescein isothiocyanate-dextran uptake assay, quantitative RT-PCR analysis of tight junction proteins, myosin light chain kinase, and proinflammatory cytokine expression...
April 5, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28634007/gene-expression-differences-between-ductal-carcinoma-in-situ-with-and-without-progression-to-invasive-breast-cancer
#19
Shusma C Doebar, Anieta M Sieuwerts, Vanja de Weerd, Hans Stoop, John W M Martens, Carolien H M van Deurzen
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...
July 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28634006/testosterone-differentially-affects-t-cells-and-neurons-in-murine-and-human-models-of-neuroinflammation-and-neurodegeneration
#20
Megan G Massa, Christina David, Stefanie Jörg, Johannes Berg, Barbara Gisevius, Sarah Hirschberg, Ralf A Linker, Ralf Gold, Aiden Haghikia
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 chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis...
July 2017: American Journal of Pathology
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