The American Journal of Pathology
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Farnesoid X Receptor Critically Determines the Fibrotic Response in Mice but Is Expressed to a Low Extent in Human Hepatic Stellate Cells and Periductal Myofibroblasts.
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The nuclear bile acid receptor, farnesoid X receptor (FXR), may play a pivotal role in liver fibrosis. We tested the impact of genetic FXR ablation in four different mouse models. Hepatic fibrosis was induced in wild-type and FXR knock-out mice (FXR(-/-)) by CCl4 intoxication, 3,5-diethoxycarbonyl-1,4-dihydrocollidine feeding, common bile duct ligation, or Schistosoma mansoni (S.m.) -infection. In addition, we determined nuclear receptor expression levels (FXR, pregnane X receptor (PXR), vitamin D receptor, constitutive androstane receptor (CAR), small heterodimer partner (SHP)) in mouse hepatic stellate cells (HSCs), ...
Source: The American Journal of Pathology - November 12, 2009 Category: Pathology Authors: Fickert P, Fuchsbichler A, Moustafa T, Wagner M, Zollner G, Halilbasic E, Stöger U, Arrese M, Pizarro M, Solís N, Carrasco G, Caligiuri A, Sombetzki M, Reisinger E, Tsybrovskyy O, Zatloukal K, Denk H, Jaeschke H, Pinzani M, Trauner M Tags: Am J Pathol Source Type: journals
Conjunctival Interleukin-13 Expression in Mucous Membrane Pemphigoid and Functional Effects of Interleukin-13 on Conjunctival Fibroblasts in Vitro.
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Interleukin-13 (IL-13) is the dominant effector cytokine of fibrosis in pulmonary and liver disease. Excessive conjunctival fibrosis in the immunobullous disease ocular mucous membrane pemphigoid (MMP) causes blindness; the pathogenesis of scarring in this disease is incompletely understood. To determine whether IL-13 is involved in conjunctival fibrosis in MMP, we studied the expression of IL-13 in ocular MMP patients before and after systemic immunosuppression and examined the effects of IL-13 on normal human conjunctival fibroblasts. We found high stromal cell expression of IL-13 in active ocular MMP by immunohistoc...
Source: The American Journal of Pathology - November 12, 2009 Category: Pathology Authors: Saw VP, Offiah I, Dart RJ, Galatowicz G, Dart JK, Daniels JT, Calder VL Tags: Am J Pathol Source Type: journals
Atrial Natriuretic Peptide Reduces Vascular Leakage and Choroidal Neovascularization.
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Atrial natriuretic peptide (ANP) is a hormone with diuretic, natriuretic, and vasodilatory properties. ANP blocks vascular endothelial growth factor (VEGF) production and signaling in vitro; however, its role in vascular leakage and angiogenesis is unknown. In vitro, retinal barrier permeability (transepithelial electrical resistance (TEER)) was measured in cultured retinal endothelial (HuREC) and retinal epithelial (ARPE-19) cells with VEGF (10 ng/ml), ANP (1 pM to 1 mumol/L), and/or isatin, an ANP receptor antagonist. In vivo, blood-retinal barrier (BRB) leakage was studied using the Evans Blue dye technique in rats ...
Source: The American Journal of Pathology - November 12, 2009 Category: Pathology Authors: Lara-Castillo N, Zandi S, Nakao S, Ito Y, Noda K, She H, Ahmed M, Frimmel S, Ablonczy Z, Hafezi-Moghadam A Tags: Am J Pathol Source Type: journals
Thy1-Positive Cells have Bipotential Ability to Differentiate into Hepatocytes and Biliary Epithelial Cells in Galactosamine-induced Rat Liver Regeneration.
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In galactosamine (GalN)-induced rat liver injury, hepatic stem/progenitor cells, small hepatocytes (SHs) and oval cells, transiently appear in the initial period of liver regeneration. To clarify the relationship between SHs and oval cells, CD44(+) and Thy1(+) cells were sorted from GalN-treated livers and used as candidates for SHs and oval cells, respectively. Some Thy1(+) cells isolated 3 days after GalN-treatment (GalN-D3) formed CD44(+) cell colonies, but those from GalN-D2 could form few. GeneChip (Affymetrix, Inc, Santa Clara, CA) analysis of the sorted cells and cultured Thy1(+) cells suggested that hepatocytic...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Kon J, Ichinohe N, Ooe H, Chen Q, Sasaki K, Mitaka T Tags: Am J Pathol Source Type: journals
Activation of the Wnt Pathway Plays a Pathogenic Role in Diabetic Retinopathy in Humans and Animal Models.
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Although Wnt signaling is known to mediate multiple biological and pathological processes, its association with diabetic retinopathy (DR) has not been established. Here we show that retinal levels and nuclear translocation of beta-catenin, a key effector in the canonical Wnt pathway, were increased in humans with DR and in three DR models. Retinal levels of low-density lipoprotein receptor-related proteins 5 and 6, coreceptors of Wnts, were also elevated in the DR models. The high glucose-induced activation of beta-catenin was attenuated by aminoguanidine, suggesting that oxidative stress is a direct cause for the Wnt ...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Chen Y, Hu Y, Zhou T, Zhou KK, Mott R, Wu M, Boulton M, Lyons TJ, Gao G, Ma JX Tags: Am J Pathol Source Type: journals
Signal Regulatory Protein-{beta}1: A Microglial Modulator of Phagocytosis in Alzheimer's Disease.
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The signal regulatory protein-beta1 (SIRPbeta1) is a DAP12-associated transmembrane receptor expressed in a subset of hematopoietic cells. Recently, it was shown that peritoneal macrophages express SIRPbeta1, which positively regulated phagocytosis. Here, we found that SIRPbeta1 was up-regulated and acted as a phagocytic receptor on microglia in amyloid precursor protein J20 (APP/J20) transgenic mice and in Alzheimer's disease (AD) patients. Interferon (IFN)-gamma and IFN-beta stimulated gene transcription of SIRPbeta1 in cultured microglia. Activation of SIRPbeta1 on cultured microglia by cross-linking antibodies indu...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Gaikwad S, Larionov S, Wang Y, Dannenberg H, Matozaki T, Monsonego A, Thal DR, Neumann H Tags: Am J Pathol Source Type: journals
Fluorescence In Situ Hybridization Markers for Prediction of Cervical Lymph Node Metastases.
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We examined single genetic markers and a composite marker, comprised of three fluorescence in situ hybridization (FISH) probes targeting the genes LAMP3, PROX1, and PRKAA1, in pretreatment cervical biopsies from 16 lymph node positive cases and 15 lymph node negative controls from women with stage IB and IIA cervical cancer. In addition, we determined clonal patterns by including CCND1 to compare the clonal constitution of primary tumors and associated lymph node metastases. The composite FISH marker allowed for classification of patients into those with and without lymph node metastases with a sensitivity and specificity ...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Wangsa D, Heselmeyer-Haddad K, Ried P, Eriksson E, Schäffer AA, Morrison LE, Luo J, Auer G, Munck-Wikland E, Ried T, Avall Lundqvist E Tags: Am J Pathol Source Type: journals
Phenolic Compounds Prevent Alzheimer's Pathology through Different Effects on the Amyloid-{beta} Aggregation Pathway.
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This study systematically investigated the effects of phenolic compounds on AD model transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin, ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in both the NDGA- and RA-treated groups, Abeta deposition was significantly decreased in the brain (P < 0.05). In the RA-treated group, the level of Tris-buffered saline (TBS)-soluble Abeta monomers was increased (P < 0.01), whereas that of oligomers, as probed with the A11 antibody (A11-positive oligomers), was de...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Hamaguchi T, Ono K, Murase A, Yamada M Tags: Am J Pathol Source Type: journals
Establishment of an Improved Mouse Model for Infantile Neuroaxonal Dystrophy That Shows Early Disease Onset and Bears a Point Mutation in Pla2g6.
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Calcium-independent group VIA phospholipase A2 (iPLA2beta), encoded by PLA2G6, has been shown to be involved in various physiological and pathological processes, including immunity, cell death, and cell membrane homeostasis. Mutations in the PLA2G6 gene have been recently identified in patients with infantile neuroaxonal dystrophy (INAD). Subsequently, it was reported that similar neurological impairment occurs in gene-targeted mice with a null mutation of iPLA2beta, whose disease onset became apparent approximately 1 to 2 years after birth. Here, we report the establishment of an improved mouse model for INAD that bea...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Wada H, Yasuda T, Miura I, Watabe K, Sawa C, Kamijuku H, Kojo S, Taniguchi M, Nishino I, Wakana S, Yoshida H, Seino KI Tags: Am J Pathol Source Type: journals
Pseudomonas aeruginosa Exotoxin Pyocyanin Causes Cystic Fibrosis Airway Pathogenesis.
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In this study, we demonstrate that PCN is critical for chronic infection in mouse airways and orchestrates adaptive immune responses that mediate lung damage. Wild-type FVBN mice chronically exposed to PCN developed goblet cell hyperplasia and metaplasia, airway fibrosis, and alveolar airspace destruction. Furthermore, after 12 weeks of exposure to PCN, mouse lungs down-regulated the expression of T helper (Th) type 1 cytokines and polarized toward a Th2 response. Cellular analyses indicated that chronic exposure to PCN profoundly increased the lung population of recruited macrophages, CD4(+) T cells, and neutrophils respo...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Caldwell CC, Chen Y, Goetzmann HS, Hao Y, Borchers MT, Hassett DJ, Young LR, Mavrodi D, Thomashow L, Lau GW Tags: Am J Pathol Source Type: journals
Trophoblastic Neoplasms Express Fatty Acid Synthase, Which May Be a Therapeutic Target via Its Inhibitor, C93.
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In this study, we analyzed the expression of FASN in normal and molar placentas, as well as gestational trophoblastic neoplasia, and assessed the effects of a new FASN inhibitor, C93, on cellular proliferation and apoptosis in choriocarcinoma cells. Using a FASN-specific monoclonal antibody, we found that FASN immunoreactivity was detected in the cytotrophoblast and intermediate (extravillous) trophoblast of normal and molar placentas, as well as in placental site nodules. All choriocarcinomas (n = 33), 90% of epithelioid trophoblastic tumors (n = 20), and 60% of placental site trophoblastic tumors (n = 10) exhibited FASN ...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Ueda SM, Mao TL, Kuhajda FP, Vasoontara C, Giuntoli RL, Bristow RE, Kurman RJ, Shih IM Tags: Am J Pathol Source Type: journals
Gla-Rich Protein Is a Novel Vitamin K-Dependent Protein Present in Serum That Accumulates at Sites of Pathological Calcifications.
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Mineralization of soft tissues is an abnormal process that occurs in any body tissue and can greatly increase morbidity and mortality. Vitamin K-dependent (VKD) proteins play a crucial role in these processes; matrix Gla protein is considered one of the most relevant physiological inhibitors of soft tissue calcification know to date. Several studies have suggested that other, still unknown, VKD proteins might also be involved in soft tissue calcification pathologies. We have recently identified in sturgeon a new VKD protein, Gla-rich protein (GRP), which contains the highest ratio between number of Gla residues and siz...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Viegas CS, Cavaco S, Neves PL, Ferreira A, João A, Williamson MK, Price PA, Cancela ML, Simes DC Tags: Am J Pathol Source Type: journals
Keratinocyte-/Fibroblast-Targeted Rescue of Col7a1-Disrupted Mice and Generation of an Exact Dystrophic Epidermolysis Bullosa Model Using a Human COL7A1 Mutation.
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Recessive dystrophic epidermolysis bullosa (RDEB) is a severe hereditary bullous disease caused by mutations in COL7A1, which encodes type VII collagen (COL7). Col7a1 knockout mice (COL7(m-/-)) exhibit a severe RDEB phenotype and die within a few days after birth. Toward developing novel approaches for treating patients with RDEB, we attempted to rescue COL7(m-/-) mice by introducing human COL7A1 cDNA. We first generated transgenic mice that express human COL7A1 cDNA specifically in either epidermal keratinocytes or dermal fibroblasts. We then performed transgenic rescue experiments by crossing these transgenic mice wi...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Ito K, Sawamura D, Goto M, Nakamura H, Nishie W, Sakai K, Natsuga K, Shinkuma S, Shibaki A, Uitto J, Denton CP, Nakajima O, Akiyama M, Shimizu H Tags: Am J Pathol Source Type: journals
Expression of Activated STAT5 in Neoplastic Mast Cells in Systemic Mastocytosis. Subcellular Distribution and Role of the Transforming Oncoprotein KIT D816V.
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We examined the expression of pSTAT5 in neoplastic mast cells in systemic mastocytosis and asked whether the disease-related oncoprotein KIT D816V is involved in STAT5 activation. As assessed by immunohistochemistry using the anti-pSTAT5 antibody AX1, neoplastic mast cells were found to display pSTAT5 in all SM patients examined (n = 40). Expression of pSTAT5 was also demonstrable in the KIT D816V-positive mast cell leukemia cell line HMC-1. Using various staining-protocols, pSTAT5 was found to be located in both the cytoplasmic and nuclear compartment of mast cells. To define the functional role of KIT D816V in STAT5-acti...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Baumgartner C, Cerny-Reiterer S, Sonneck K, Mayerhofer M, Gleixner KV, Fritz R, Kerenyi M, Boudot C, Gouilleux F, Kornfeld JW, Sillaber C, Moriggl R, Valent P Tags: Am J Pathol Source Type: journals
Treatment with a Novel Chemokine-Binding Protein or Eosinophil Lineage-Ablation Protects Mice from Experimental Colitis.
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In conclusion, the influx of eosinophils is critical for the induction of colitis by DSS. Treatment with a novel chemokine-binding protein decreased eosinophil influx and greatly ameliorated colitis, suggesting that strategies that interfere with the recruitment of eosinophils may be useful as therapy for colitis.
PMID: 19893035 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Vieira AT, Fagundes CT, Alessandri AL, Castor MG, Guabiraba R, Borges VO, Silveira KD, Vieira EL, Gonçalves JL, Silva TA, Deruaz M, Proudfoot AE, Sousa LP, Teixeira MM Tags: Am J Pathol Source Type: journals
Syk Tyrosine Kinase Acts as a Pancreatic Adenocarcinoma Tumor Suppressor by Regulating Cellular Growth and Invasion.
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This study demonstrates a prominent role for syk in regulating the differentiation state and invasive phenotype of PDAC cells.
PMID: 19893036 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Layton T, Stalens C, Gunderson F, Goodison S, Silletti S Tags: Am J Pathol Source Type: journals
Melanoma-Associated Antigen Expression in Lymphangioleiomyomatosis Renders Tumor Cells Susceptible to Cytotoxic T Cells.
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The antibody HMB45 is used to diagnose lymphangioleiomyomatosis, a hyperproliferative disorder of lung smooth muscle cells with mutations in both alleles of either TSC1 or TSC2. A subset of these tumor cells expresses the melanoma-associated antigens gp100 and melanoma antigen recognized by T cells (MART-1). To explore the feasibility of targeting tumors in lymphangioleiomyomatosis by melanoma immunotherapy, we therefore assessed melanoma target antigen expression and existing immune infiltration of affected tissue compared with normal lung and melanoma as well as the susceptibility of cultured lymphangioleiomyomatosis...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Klarquist J, Barfuss A, Kandala S, Reust MJ, Braun RK, Hu J, Dilling DF, McKee MD, Boissy RE, Love RB, Nishimura MI, Le Poole IC Tags: Am J Pathol Source Type: journals
Epithelial Mesenchymal Transition in Human Ocular Chronic Graft-Versus-Host Disease.
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In this study, we used immunohistochemistry and electron microscopy to investigate whether epithelial mesenchymal transition (EMT) contributed to the pathogenesis of ocular cGVHD. We detected down-regulation of E-cadherin and translocation of beta-catenin from the intercellular junction to the cytoplasm and nucleus of cGVHD conjunctival basal epithelia and lacrimal gland myoepithelia. Notable findings included expression of Snail, an inducer of EMT, in the nucleus of ocular cGVHD epithelia. The fibrosis markers heat shock protein 47, alpha-smooth muscle actin, and fibroblast specific protein-1 were overexpressed in ocular ...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Ogawa Y, Shimmura S, Kawakita T, Yoshida S, Kawakami Y, Tsubota K Tags: Am J Pathol Source Type: journals
Novel Biomarkers for Prostate Cancer Including Noncoding Transcripts.
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Levels of 27 transcripts were investigated as potential novel markers for prostate cancer, including genes encoding plasma membrane proteins (ADAM2, ELOVL5, MARCKSL1, RAMP1, TMEM30A, and TMEM66); secreted proteins (SPON2, TMEM30A, TMEM66, and truncated TMEFF2 (called POP4)); intracellular proteins (CAMK2N1, DHCR24, GLO1, NGFRAP1, PGK1, PSMA7, SBDS, and YWHAQ); and noncoding transcripts (POP1 (100 kb) from mRNA AK000023), POP2 (4 kb from mRNA AL832227), POP3 (50 kb from EST CFI40309), POP5 (intron of NCAM2, accession DO668384), POP6 (intron of FHIT), POP7 (intron of TNFAIP8), POP8 (intron of EFNA5), POP9 (intron of DSTN...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Romanuik TL, Ueda T, Le N, Haile S, Yong TM, Thomson T, Vessella RL, Sadar MD Tags: Am J Pathol Source Type: journals
Feasibility of Immunotherapy for Lymphangioleiomyomatosis.
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This Commentary discusses the feasibility of vaccines against melanoma-associated differentiation antigens for treatment of lymphangioleiomyomatosis.
PMID: 19893040 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Carbone M Tags: Am J Pathol Source Type: journals
Gene Expression Profiling of Pulmonary Fibrosis Identifies Twist1 as an Antiapoptotic Molecular "Rectifier" of Growth Factor Signaling.
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Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into IPF pathogenesis, we performed gene expression profiling of IPF lungs. Twist1, a basic helix-loop-helix protein, was found among the most consistently and highly up-regulated genes and was expressed in nuclei of type II epithelial cells, macrophages, and fibroblasts in IPF lungs. We studied the function of Twist1 in fibroblasts further, because they are the major effector cells in this disease and persist despite an ambient proapoptotic environment. Twist1 was induced by the profibrotic growth factors (GFs) basic...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Bridges RS, Kass D, Loh K, Glackin C, Borczuk AC, Greenberg S Tags: Am J Pathol Source Type: journals
TRAIL-Deficient Mice Exhibit Delayed Regression of Retinal Neovascularization.
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While it is well established that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various cell types, the role of TRAIL in regulation of retinal neovascularization (NV) has not been described. Here we determined the role of TRAIL in retinal NV during oxygen-induced retinopathy using TRAIL deficient ((-/-)) mice. TRAIL and its receptor, DR5, were expressed in wild-type retinas at all time points evaluated (postnatal days 12, 17, 21, 24) during oxygen-induced retinopathy and in age-matched room air control animals. Localization of TRAIL(+) cells within the neovascular tufts of hyperox...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Hubert KE, Davies MH, Stempel AJ, Griffith TS, Powers MR Tags: Am J Pathol Source Type: journals
High Expression of the PAX3-FKHR Oncoprotein Is Required to Promote Tumorigenesis of Human Myoblasts.
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PAX3-FKHR is a fusion oncoprotein generated by the 2;13 chromosomal translocation in alveolar rhabdomyosarcoma (ARMS), a cancer associated with the skeletal muscle lineage. Previous studies determined that high-level PAX3-FKHR expression is a consistent feature in ARMS tumors. To investigate the relationship between expression and phenotype in human myogenic cells, PAX3-FKHR was introduced into immortalized human myoblasts to produce a low overall PAX3-FKHR expression level. Although PAX3-FKHR alone failed to exert transforming activity, a combination of PAX3-FKHR and MYCN induced transforming activity in cell culture ...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Xia SJ, Holder DD, Pawel BR, Zhang C, Barr FG Tags: Am J Pathol Source Type: journals
Matrilysin (Matrix Metalloproteinase-7) Regulates Anti-Inflammatory and Antifibrotic Pulmonary Dendritic Cells That Express CD103 ({alpha}E{beta}7-Integrin).
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In conclusion, matrilysin regulates pulmonary localization of DC that express CD103, and E-cadherin cleavage may activate CD103(+) DC to limit inflammation and inhibit fibrosis.
PMID: 19893044 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Manicone AM, Huizar I, McGuire JK Tags: Am J Pathol Source Type: journals
Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease.
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Pro-nerve growth factor (pro-NGF) is expressed at increased levels in Alzheimer's disease (AD)-affected brains and is able to induce cell death in cultures; however, the reasons for these phenomena remain elusive. Here we show that pro-NGF in human AD-affected hippocampus and entorhinal cortex is modified by advanced glycation and lipoxidation end-products in a stage-dependent manner. These modifications block pro-NGF processing to mature NGF, thus making the proneurotrophin especially effective in inducing apoptosis of PC12 cells in culture through the p75 neurotrophin receptor. The processing of advanced glycation an...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Kichev A, Ilieva EV, Piñol-Ripoll G, Podlesniy P, Ferrer I, Portero-Otín M, Pamplona R, Espinet C Tags: Am J Pathol Source Type: journals
Down-Regulation of FXYD3 Expression in Human Lung Cancers. Its Mechanism and Potential Role in Carcinogenesis.
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FXYD3 is a FXYD-containing Na,K-ATPase ion channel regulator first identified as a protein overexpressed in murine breast tumors initiated by oncogenic ras or neu. However, our preliminary study revealed that FXYD3 expression was down-regulated in oncogenic KRAS-transduced airway epithelial cells. This contradiction led us to investigate the role of FXYD3 in carcinogenesis of the lung. FXYD3 mRNA and protein levels were lower in most of the lung cancer cell lines than in either the noncancerous lung tissue or airway epithelial cells. Protein levels were also lower in a considerable proportion of primary lung cancers th...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Okudela K, Yazawa T, Ishii J, Woo T, Mitsui H, Bunai T, Sakaeda M, Shimoyamada H, Sato H, Tajiri M, Ogawa N, Masuda M, Sugimura H, Kitamura H Tags: Am J Pathol Source Type: journals
Discoidin Domain Receptor-1 Deficiency Attenuates Atherosclerotic Calcification and Smooth Muscle Cell-Mediated Mineralization.
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Intimal calcification is a feature of advanced atherosclerotic disease that predicts a two- to eightfold increase in the risk of coronary events. Type I collagen promotes vascular smooth muscle cell-mediated calcification, although the mechanism by which this occurs is unknown. The discoidin domain receptor 1 (DDR1) is a collagen receptor that is emerging as a critical mediator of atherosclerosis. To determine whether DDR1 is involved in intimal calcification, we fed male Ddr1(-/-);Ldlr(-/-) and Ddr1(+/+);Ldlr(-/-) mice an atherogenic diet for 6, 12, or 24 weeks. DDR1 deficiency significantly reduced the calcium conten...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Ahmad PJ, Trcka D, Xue S, Franco C, Speer MY, Giachelli CM, Bendeck MP Tags: Am J Pathol Source Type: journals
Expression of the Brain Transcription Factor OTX1 Occurs in a Subset of Normal Germinal-Center B Cells and in Aggressive Non-Hodgkin Lymphoma.
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This study identifies OTX1 as a molecular marker for high-grade GC-derived NHL and suggests an involvement of this transcription factor in B-cell lymphomagenesis. Furthermore, OTX1 expression in a subset of normal GC B cells carrying plasma cell markers suggests its possible contribution to terminal B-cell differentiation.
PMID: 19893048 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Omodei D, Acampora D, Russo F, De Filippi R, Severino V, Di Francia R, Frigeri F, Mancuso P, De Chiara A, Pinto A, Casola S, Simeone A Tags: Am J Pathol Source Type: journals
Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice.
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In this study, we evaluated the role of lysosomal enzymes, cathepsins B and D, in determining neuronal vulnerability in NPC1-deficient (Npc1(-/-)) mouse brains. Our results showed that Npc1(-/-) mice exhibit an age-dependent degeneration of neurons in the cerebellum but not in the hippocampus. The cellular level/expression and activity of cathepsins B and D are increased more predominantly in the cerebellum than in the hippocampus of Npc1(-/-) mice. In addition, the cytosolic levels of cathepsins, cytochrome c, and Bax2 are higher in the cerebellum than in the hippocampus of Npc1(-/-) mice, suggesting a role for these enzy...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Amritraj A, Peake K, Kodam A, Salio C, Merighi A, Vance JE, Kar S Tags: Am J Pathol Source Type: journals
Robust Th1 and Th17 Immunity Supports Pulmonary Clearance but Cannot Prevent Systemic Dissemination of Highly Virulent Cryptococcus neoformans H99.
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The present study dissected the role of a Th2 bias in pathogenesis of Cryptococcus neoformans H99 infection by comparing inhalational H99 infections in wild-type BALB/c and IL-4/IL-13 double knockout mice. H99-infected wild-type mice showed all major hallmarks of Th2 but not Th1/Th17 immunity in the lungs and lung-associated lymph nodes. In contrast, the IL-4/13(-/-) mice developed robust hallmarks of Th1 and Th17 but not Th2 polarization. The IL-4/IL-13 deletion prevented pulmonary eosinophilia, goblet cell metaplasia in the airways and resulted in elevated serum IgE, and a switch from alternative to classical activat...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Zhang Y, Wang F, Tompkins KC, McNamara A, Jain AV, Moore BB, Toews GB, Huffnagle GB, Olszewski MA Tags: Am J Pathol Source Type: journals
Brain-Specific Deletion of Extracellular Signal-Regulated Kinase 2 Mitogen-Activated Protein Kinase Leads to Aberrant Cortical Collagen Deposition.
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The mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and 2 are essential intracellular mediators of numerous transmembrane signals. To investigate neural-specific functions of ERK2 in the brain, we used a Cre/lox strategy using Nestin:Cre to drive recombination in neural precursor cells. Nestin:Cre;ERK2(fl/fl) conditional knockout (cKO) mice have architecturally normal brains and no gross behavioral deficits. However, all cKO mice developed early-onset (postnatal day 35 to 40) frontal cortical astrogliosis, without evidence of neuronal degeneration. Frontoparietal cortical gray matter, but...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Heffron DS, Landreth GE, Samuels IS, Mandell JW Tags: Am J Pathol Source Type: journals
Septoclast Deficiency Accompanies Postnatal Growth Plate Chondrodysplasia in the Toothless (tl) Osteopetrotic, Colony-Stimulating Factor-1 (CSF-1)-Deficient Rat and Is Partially Responsive to CSF-1 Injections.
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The septoclast is a specialized, cathepsin B-rich, perivascular cell type that accompanies invading capillaries on the metaphyseal side of the growth plate during endochondral bone growth. The putative role of septoclasts is to break down the terminal transverse septum of growth plate cartilage and permit capillaries to bud into the lower hypertrophic zone. This process fails in osteoclast-deficient, osteopetrotic animal models, resulting in a progressive growth plate dysplasia. The toothless rat is severely osteopetrotic because of a frameshift mutation in the colony-stimulating factor-1 (CSF-1) gene (Csf1(tl)). Where...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Gartland A, Mason-Savas A, Yang M, Mackay CA, Birnbaum MJ, Odgren PR Tags: Am J Pathol Source Type: journals
Chemokine CXCL16 Regulates Neutrophil and Macrophage Infiltration into Injured Muscle, Promoting Muscle Regeneration.
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Only a few specific chemokines that mediate interactions between inflammatory and satellite cells in muscle regeneration have been identified. The chemokine CXCL16 differs from other chemokines because it has both a transmembrane region and active, soluble chemokine forms. Indeed, we found increased expression of CXCL16 and its receptor, CXCR6, in regenerating myofibers. Muscle regeneration in CXCL16-deficient (CXCL16KO) mice was severely impaired compared with regeneration in wild-type mice. In addition, there was decreased MyoD and myogenin expression in regenerating muscle in CXCL16KO mice, indicating impaired satel...
Source: The American Journal of Pathology - November 5, 2009 Category: Pathology Authors: Zhang L, Ran L, Garcia GE, Wang XH, Han S, Du J, Mitch WE Tags: Am J Pathol Source Type: journals
Detection of genomic amplification of the human telomerase gene TERC, a potential marker for triage of women with HPV-positive, abnormal pap smears.
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The vast majority of invasive cervical carcinomas harbor additional copies of the chromosome arm 3q, resulting in genomic amplification of the human telomerase gene TERC. Here, we evaluated TERC amplification in routinely collected liquid based cytology (LBC) samples with histologically confirmed diagnoses. A set of 78 LBC samples from a Swedish patient cohort were analyzed with a four-color fluorescence in situ hybridization probe panel that included TERC. Clinical follow-up included additional histological evaluation and Pap smears. Human papillomavirus status was available for all cases. The correlation of cytology,...
Source: The American Journal of Pathology - November 1, 2009 Category: Pathology Authors: Andersson S, Sowjanya P, Wangsa D, Hjerpe A, Johansson B, Auer G, Gravitt PE, Larsson C, Wallin KL, Ried T, Heselmeyer-Haddad K Tags: Am J Pathol Source Type: journals
Cytogenetic Abnormalities of Tumor-Associated Endothelial Cells in Human Malignant Tumors.
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Tumor blood vessels are thought to contain genetically normal and stable endothelial cells (ECs), unlike tumor cells, which typically display genetic instability. Yet, chromosomal aberration in human tumor-associated ECs (hTECs) in carcinoma has not yet been investigated. Here we isolated TECs from 20 human renal cell carcinomas and analyzed their cytogenetic abnormalities. The degree of aneuploidy was analyzed by fluorescence in situ hybridization using chromosome 7 and chromosome 8 DNA probes in isolated hTECs. In human renal cell carcinomas, 22-58% (median, 33%) of uncultured hTECs were aneuploid, whereas normal ECs...
Source: The American Journal of Pathology - October 29, 2009 Category: Pathology Authors: Akino T, Hida K, Hida Y, Tsuchiya K, Freedman D, Muraki C, Ohga N, Matsuda K, Akiyama K, Harabayashi T, Shinohara N, Nonomura K, Klagsbrun M, Shindoh M Tags: Am J Pathol Source Type: journals
Regulating the T-Cell Immune Response Toward the H99 Strain of Cryptococcus neoformans.
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C. neoformans infection induces a Th1 immune reaction resulting in an cellular inflammatory reaction toward the organism; however infection with virulent C. neoformans strains such as H99 results in a paucicellular Th2 response in mice. H99 infected mice develop fatal meningoencephalitis weeks following pulmonary infection. Switch from a Th2 to a Th1 immune response, results in a protective effect in the lung of H99 infected mice but does not prevent organism dissemination and subsequent development of meningoencephalitis. Further studies are required to explain what immune mediators are needed to prevent dissemination...
Source: The American Journal of Pathology - October 29, 2009 Category: Pathology Authors: Montone KT Tags: Am J Pathol Source Type: journals
Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B.
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In this study, we examined a mouse model of dysferlinopathy using light and electron microscopy as well as echocardiography and conscious electrocardiography. We determined that dysferlin is normally localized to the intercalated disk and sarcoplasm of the cardiomyocytes. In the absence of dysferlin, cardiomyocyte membrane damage occurs and is localized to the intercalated disk and sarcoplasm. This damage results in transient functional deficits at 10 months of age, but, unlike in skeletal muscle, the cell injury is sublethal and causes only mild cardiomyopathy even at advanced ages.
PMID: 19875504 [PubMed - as supplie...
Source: The American Journal of Pathology - October 29, 2009 Category: Pathology Authors: Chase TH, Cox GA, Burzenski L, Foreman O, Shultz LD Tags: Am J Pathol Source Type: journals
Identification of EpCAM as a Molecular Target of Prostate Cancer Stroma.
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To delineate the molecular changes that occur in the tumor microenvironment, we previously performed global transcript analysis of human prostate cancer specimens using tissue microdissection and expression microarrays. Epithelial and stromal compartments were individually studied in both tumor and normal fields. Tumor-associated stroma showed a distinctly different expression pattern compared with normal stroma, having 44 differentially expressed transcripts, the majority of which were up-regulated. In the present study, one of the up-regulated transcripts, epithelial cell adhesion activating molecule, was further eva...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Mukherjee S, Richardson AM, Rodriguez-Canales J, Ylaya K, Erickson HS, Player A, Kawasaki ES, Pinto PA, Choyke PL, Merino MJ, Albert PS, Chuaqui RF, Emmert-Buck MR Tags: Am J Pathol Source Type: journals
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types.
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Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans, parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes ...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Wemheuer WM, Benestad SL, Wrede A, Schulze-Sturm U, Wemheuer WE, Hahmann U, Gawinecka J, Schütz E, Zerr I, Brenig B, Bratberg B, Andréoletti O, Schulz-Schaeffer WJ Tags: Am J Pathol Source Type: journals
Hyperoxia-Induced Lung Injury in Gamma-Glutamyl Transferase Deficiency Is Associated with Alterations in Nitrosative and Nitrative Stress.
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gamma-Glutamyl transferase (GGT) regulates glutathione metabolism and cysteine supply. GGT inactivation in GGT(enu1) mice limits cysteine availability causing cellular glutathione deficiency. In lung, the resultant oxidant burden is associated with increased nitric oxide (NO) production, yet GGT(enu1) mice still exhibit higher mortality in hyperoxia. We hypothesized that NO metabolism is altered under severe oxidant stress and contributes to lung cellular injury and death. We compared lung injury, NO synthase (NOS) expression, nitrate/nitrite production, nitroso product formation, peroxynitrite accumulation, and cell d...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Klings ES, Lowry MH, Li G, Jean JC, Fernandez BO, Garcia-Saura MF, Feelisch M, Joyce-Brady M Tags: Am J Pathol Source Type: journals
Selective and Specific Macrophage Ablation Is Detrimental to Wound Healing in Mice.
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Macrophages are thought to play important roles during wound healing, but definition of these roles has been hampered by our technical inability to specifically eliminate macrophages during wound repair. The purpose of this study was to test the hypothesis that specific depletion of macrophages after excisional skin wounding would detrimentally affect healing by reducing the production of growth factors important in the repair process. We used transgenic mice that express the human diphtheria toxin (DT) receptor under the control of the CD11b promoter (DTR mice) to specifically ablate macrophages during wound healing. ...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Mirza R, Dipietro LA, Koh TJ Tags: Am J Pathol Source Type: journals
Viral RNA Induces Type I Interferon-Dependent Cytokine Release and Cell Death in Mesangial Cells via Melanoma-Differentiation-Associated Gene-5. Implications for Viral Infection-Associated Glomerulonephritis.
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Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanoma-differentiation-associated gene (MDA)-5 and retinod-inducible gene (RIG)-I in the cytosol or via Toll-like receptors (TLRs) in intracellular endosomes. We hypothesized that viral RNA would also activate glomerular mesangial cells to produce type I interferon (IFN) via TLR-dependent and TLR-independent pathways. To test this hypothesis, we examined Toll/Interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial ...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Flür K, Allam R, Zecher D, Kulkarni OP, Lichtnekert J, Schwarz M, Beutler B, Vielhauer V, Anders HJ Tags: Am J Pathol Source Type: journals
Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity.
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Recent reports suggest that commensal bacteria may play a down-regulatory role in autoimmune disease. In the present studies, we demonstrate that phosphorylated dihydroceramides, uniquely structured lipids derived from the common human oral bacterium Porphyromonas gingivalis and from bacteria commonly found in the gastrointestinal tract and other organs, are capable of enhancing autoimmunity. We have previously reported that these lipids have proinflammatory effects on human fibroblasts in vitro and, in preliminary studies, have recovered these lipids from surgically removed human carotid atheroma, suggesting that they...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Nichols FC, Housley WJ, O'Conor CA, Manning T, Wu S, Clark RB Tags: Am J Pathol Source Type: journals
Neuroprotective Effect of Oligodendrocyte Precursor Cell-Transplantation in a Long-Term Model of Periventricular Leukomalacia.
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Perinatal white matter injury, or periventricular leukomalacia (PVL), is the most common cause of brain injury in premature infants and is the leading cause of cerebral palsy. Despite increasing numbers of surviving extreme premature infants and associated long-term neurological morbidity, our understanding and treatment of PVL remains incomplete. Inflammation- or ischemia/hypoxia-based rodent models, although immensely valuable, are largely restricted to reproducing short-term features of up to 3 weeks after injury. Given the long-term sequelae of PVL, there is a need for subchronic models that will enable testing of ...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Webber DJ, Van Blitterswijk M, Chandran S Tags: Am J Pathol Source Type: journals
Suppression of PLC{beta}2 by Endotoxin Plays a Role in the Adenosine A2A Receptor-Mediated Switch of Macrophages from an Inflammatory to an Angiogenic Phenotype.
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Toll-like receptor (TLR) 2, 4, 7, and 9 agonists, together with adenosine A2A receptor (A2AR) agonists, switch macrophages from an inflammatory (M1) to an angiogenic (M2-like) phenotype. This switch involves induction of A2ARs by TLR agonists, down-regulation of tumor necrosis factor alpha (TNFalpha) and interleukin-12, and up-regulation of vascular endothelial growth factor (VEGF) and interleukin-10 expression. We show here that the TLR4 agonist lipopolysaccharide (LPS) induces rapid and specific post-transcriptional down-regulation of phospholipase C(PLC)beta1 and beta2 expression in macrophages by de-stabilizing the...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Grinberg S, Hasko G, Wu D, Leibovich SJ Tags: Am J Pathol Source Type: journals
The Expression of AIP-Related Molecules in Elucidation of Cellular Pathways in Pituitary Adenomas.
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Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene predispose to the development of pituitary adenomas. Here, we characterized AIP mutation positive (AIPmut+) and AIP mutation negative (AIPmut-) pituitary adenomas by immunohistochemistry. The expressions of the AIP-related proteins aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), cyclin-dependent kinase inhibitor 1B encoding p27(Kip1), and hypoxia-inducible factor 1-alpha were examined in 14 AIPmut+ and 53 AIPmut- pituitary adenomas to detect possible expression differences. In addition, the expression of CD34, an endoth...
Source: The American Journal of Pathology - October 21, 2009 Category: Pathology Authors: Heliövaara E, Raitila A, Launonen V, Paetau A, Arola J, Lehtonen H, Sane T, Weil RJ, Vierimaa O, Salmela P, Tuppurainen K, Mäkinen M, Aaltonen LA, Karhu A Tags: Am J Pathol Source Type: journals
The Metastasis-Associated Anterior Gradient 2 Protein Is Correlated with Poor Survival of Breast Cancer Patients.
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The secreted metastasis-inducing protein, human anterior gradient 2 (AGR2), has been independently reported to be associated with either a reduced or an increased survival of different groups of patients with breast cancer. We now aim to analyze the expression of AGR2 in a third completely independent group of patients using a specific AGR2 monoclonal antibody (mAb). Primary tumors from a group of 315 patients suffering from operable (stage I and II) breast cancer with 20-years follow-up were immunocytochemically stained with a specific mAb to AGR2 and associations with prognostic factors and patient survival were anal...
Source: The American Journal of Pathology - October 14, 2009 Category: Pathology Authors: Barraclough DL, Platt-Higgins A, de Silva Rudland S, Barraclough R, Winstanley J, West CR, Rudland PS Tags: Am J Pathol Source Type: journals
Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities.
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Mucopolysaccharidoses are a group of lysosomal storage diseases characterized by the build-up of glycosaminoglycans (GAGs) and severe skeletal abnormalities. As GAGs can regulate the collagenolytic activity of the major osteoclastic protease cathepsin K, we investigated the presence and activity of cathepsin K and its co-localization with GAGs in mucopolysaccharidosis (MPS) type I bone. The most dramatic difference between MPS I and wild-type mice was an increase in the amount of cartilage in the growth plates in MPS I bones. Though the number of cathepsin K-expressing osteoclasts was increased in MPS I mice, these mic...
Source: The American Journal of Pathology - October 14, 2009 Category: Pathology Authors: Wilson S, Hashamiyan S, Clarke L, Saftig P, Mort J, Dejica VM, Brömme D Tags: Am J Pathol Source Type: journals
Genetic Manipulation of Dysferlin Expression in Skeletal Muscle. Novel Insights into Muscular Dystrophy.
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Mutations in the gene DYSF, which codes for the protein dysferlin, underlie Miyoshi myopathy and limb-girdle muscular dystrophy 2B in humans and produce a slowly progressing skeletal muscle degenerative disease in mice. Dysferlin is a Ca(2+)-sensing, regulatory protein that is involved in membrane repair after injury. To assess the function of dysferlin in healthy and dystrophic skeletal muscle, we generated skeletal muscle-specific transgenic mice with threefold overexpression of this protein. These mice were phenotypically indistinguishable from wild-type, and more importantly, the transgene completely rescued the mu...
Source: The American Journal of Pathology - October 14, 2009 Category: Pathology Authors: Millay DP, Maillet M, Roche JA, Sargent MA, McNally EM, Bloch RJ, Molkentin JD Tags: Am J Pathol Source Type: journals
The Cellular Biology of Flexor Tendon Adhesion Formation--An Old Problem in a New Paradigm.
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In conclusion, adhesion formation occurs due to scarring between two damaged surfaces. The mouse model for flexor tendon injury represents a new platform to study adhesion formation that is genetically tractable.
PMID: 19834058 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - October 14, 2009 Category: Pathology Authors: Wong JK, Lui YH, Kapacee Z, Kadler KE, Ferguson MW, McGrouther DA Tags: Am J Pathol Source Type: journals
