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Unique Cellular Lineage Composition of the First Gland of the Mouse Gastric Corpus.
O'Neil A, Petersen CP, Choi E, Engevik AC, Goldenring JR
(2017) J Histochem Cytochem 65: 47-58
MeSH Terms: Animals, Clusterin, Gastric Mucosa, Male, Mice, Mice, Inbred C57BL, Mucin-4, Parietal Cells, Gastric, Plant Lectins, Protein-Serine-Threonine Kinases, Receptors, G-Protein-Coupled, SOXB1 Transcription Factors, Stem Cells, Stomach
Show Abstract · Added April 18, 2017
The glandular stomach has two major zones: the acid secreting corpus and the gastrin cell-containing antrum. Nevertheless, a single gland lies at the transition between the forestomach and corpus in the mouse stomach. We have sought to define the lineages that make up this gland unit at the squamocolumnar junction. The first gland in mice showed a notable absence of characteristic corpus lineages, including parietal cells and chief cells. In contrast, the gland showed strong staining of Griffonia simplicifolia-II (GSII)-lectin-positive mucous cells at the bases of glands, which were also positive for CD44 variant 9 and Clusterin. Prominent numbers of doublecortin-like kinase 1 (DCLK1) positive tuft cells were present in the first gland. The first gland contained Lgr5-expressing putative progenitor cells, and a large proportion of the cells were positive for Sox2. The cells of the first gland stained strongly for MUC4 and EpCAM, but both were absent in the normal corpus mucosa. The present studies indicate that the first gland in the corpus represents a unique anatomic entity. The presence of a concentration of progenitor cells and sensory tuft cells in this gland suggests that it may represent a source of reserve reparative cells for adapting to severe mucosal damage.
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2 Members
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14 MeSH Terms
Characterization of progressive metaplasia in the gastric corpus mucosa of Mongolian gerbils infected with Helicobacter pylori.
Shimizu T, Choi E, Petersen CP, Noto JM, Romero-Gallo J, Piazuelo MB, Washington MK, Peek RM, Goldenring JR
(2016) J Pathol 239: 399-410
MeSH Terms: Animals, Clusterin, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Inflammation, Male, Metaplasia, Mucin-4
Show Abstract · Added April 6, 2017
Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia are considered neoplastic precursors of gastric adenocarcinoma in humans. Loss of parietal cells causes the development of SPEM in the gastric corpus and then chronic inflammation drives SPEM toward a more proliferative lineage. Mongolian gerbils infected with Helicobacter pylori develop chronic gastritis and metaplasia, mimicking aspects of human gastritis with H. pylori infection. We therefore examined metaplastic lineages in the gastric corpus mucosa of gerbils infected by H. pylori strain 7.13, which produces rapid onset of severe inflammation. Six weeks following H. pylori infection, Griffonia simplicifolia lectin II (GSII)-positive SPEM developed in the base of oxyntic glands in association with parietal cell loss and inflammation. In association with severe inflammation, SPEM glands evolved into aberrant phenotypes, including branched lesions, dilated lesions, and penetrating invasive glands. Mucin 4 (MUC4) was up-regulated in SPEM and progressive SPEM. Clusterin was expressed in the tips of branched and dilated lesions and throughout regions of invasive glands. Intriguingly, clusterin-positive regions in these lesions expressed Ki67 and matrix metalloproteinase 7 (MMP-7). These same regions were also positive for expression of phospho-IkBα, suggestive of activated NFkB signalling. These findings suggest that clusterin-positive regions in progressive phenotypes of SPEM have invasive characteristics. Thus, H. pylori infection in gerbils induces SPEM, which then can progress to further aberrant and invasive metaplastic phenotypes. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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4 Members
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10 MeSH Terms
Proteomic profiling of paraffin-embedded samples identifies metaplasia-specific and early-stage gastric cancer biomarkers.
Sousa JF, Ham AJ, Whitwell C, Nam KT, Lee HJ, Yang HK, Kim WH, Zhang B, Li M, LaFleur B, Liebler DC, Goldenring JR
(2012) Am J Pathol 181: 1560-72
MeSH Terms: Biomarkers, Tumor, Calcium-Binding Proteins, Cell Lineage, Clusterin, DNA-Binding Proteins, Disease Progression, Gastric Mucosa, Humans, Intercellular Signaling Peptides and Proteins, Lactoferrin, Metaplasia, Models, Biological, Neoplasm Proteins, Neoplasm Staging, Paraffin Embedding, Peptides, Proteomics, Receptors, Cell Surface, Stomach, Stomach Neoplasms, Trefoil Factor-2, Tumor Suppressor Proteins, Up-Regulation
Show Abstract · Added October 7, 2013
Early diagnosis and curative resection are the predominant factors associated with increased survival in patients with gastric cancer. However, most gastric cancer cases are still diagnosed at later stages. Since most pathologic specimens are archived as FFPE samples, the ability to use them to generate expression profiles can greatly improve cancer biomarker discovery. We sought to uncover new biomarkers for stomach preneoplastic metaplasias and neoplastic lesions by generating proteome profiles using FFPE samples. We combined peptide isoelectric focusing and liquid chromatography-tandem mass spectrometry analysis to generate proteomic profiles from FFPE samples of intestinal-type gastric cancer, metaplasia, and normal mucosa. The expression patterns of selected proteins were analyzed by immunostaining first in single tissue sections from normal stomach, metaplasia, and gastric cancer and later in larger tissue array cohorts. We detected 60 proteins up-regulated and 87 proteins down-regulated during the progression from normal mucosa to metaplasia to gastric cancer. Two of the up-regulated proteins, LTF and DMBT1, were validated as specific markers for spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia, respectively. In cancers, significantly lower levels of DMBT1 or LTF correlated with more advanced disease and worse prognosis. Thus, proteomic profiling using FFPE samples has led to the identification of two novel markers for stomach metaplasias and gastric cancer prognosis.
Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
1 Communities
5 Members
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23 MeSH Terms
Heterogeneity in mouse spasmolytic polypeptide-expressing metaplasia lineages identifies markers of metaplastic progression.
Weis VG, Sousa JF, LaFleur BJ, Nam KT, Weis JA, Finke PE, Ameen NA, Fox JG, Goldenring JR
(2013) Gut 62: 1270-9
MeSH Terms: Animals, Azetidines, Biomarkers, Clusterin, Cystic Fibrosis Transmembrane Conductance Regulator, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Helicobacter Infections, Humans, Inflammation, Intercellular Signaling Peptides and Proteins, Intestines, Laser Capture Microdissection, Metaplasia, Mice, Mice, Inbred CFTR, Parietal Cells, Gastric, Peptides, Piperazines, Precancerous Conditions, Up-Regulation
Show Abstract · Added October 7, 2013
OBJECTIVES - Spasmolytic polypeptide-expressing metaplasia (SPEM) develops as a preneoplastic lesion in the stomachs of mice and humans after parietal cell loss. To identify the commonalities and differences between phenotypic SPEM lineages, SPEM were studied from three different mouse models of parietal cell loss: with chronic inflammation with Helicobacter felis infection; with acute inflammation with L635 treatment; and without inflammation following DMP-777 treatment.
DESIGN - RNA transcripts from laser capture microdissected normal chief cells and SPEM lineages were compared using gene microarray. Alterations in transcripts were validated by quantitative real-time PCR. Clusterin and cystic fibrosis transmembrane conductance regulator (CFTR) were selected for immunohistochemical analysis in all mouse models as well as in human SPEM, intestinal metaplasia and gastric cancer.
RESULTS - Transcript expression patterns demonstrated differences among the phenotypic SPEM models. Clusterin expression was significantly upregulated in all three mouse SPEM models as well as in human SPEM. The highest clusterin expression in human gastric cancers correlated with poor survival. Conversely, CFTR expression was upregulated only in SPEM with inflammation in mice. In humans, intestinal metaplasia, but not SPEM, expressed CFTR.
CONCLUSIONS - While markers such as clusterin are expressed in all phenotypic SPEM lineages, distinct patterns of upregulated genes including CFTR are present in murine metaplasia associated with inflammation, indicative of progression of metaplasia towards a more intestinalised metaplastic phenotype.
2 Communities
2 Members
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22 MeSH Terms
CRM1 protein-mediated regulation of nuclear clusterin (nCLU), an ionizing radiation-stimulated, Bax-dependent pro-death factor.
Leskov KS, Araki S, Lavik JP, Gomez JA, Gama V, Gonos ES, Trougakos IP, Matsuyama S, Boothman DA
(2011) J Biol Chem 286: 40083-90
MeSH Terms: Active Transport, Cell Nucleus, Animals, Antibiotics, Antineoplastic, Apoptosis, Cell Nucleus, Clusterin, Fatty Acids, Unsaturated, Gamma Rays, Humans, Karyopherins, Mice, Mice, Knockout, Protein Isoforms, Radiation Tolerance, Receptors, Cytoplasmic and Nuclear, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
Expression of the clusterin (CLU) gene results in the synthesis of a conventional secretory isoform set (pre- and mature secretory clusterin proteins, psCLU/sCLU), as well as another set of intracellular isoforms, appearing in the cytoplasm (pre-nuclear CLU, pnCLU) and in the nucleus as an ∼55-kDa mature nuclear clusterin (nCLU) form. These two isoform sets have opposing cell functions: pro-survival and pro-death, respectively. Although much is known about the regulation and function of sCLU as a pro-survival factor, the regulation and function of endogenous nCLU in cell death are relatively unexplored. Here, we show that depletion of endogenous nCLU protein using siRNA specific to its truncated mRNA increased clonogenic survival of ionizing radiation (IR)-exposed cells. nCLU-mediated apoptosis was Bax-dependent, and lethality correlated with accumulation of mature nCLU protein. nCLU accumulation was regulated by CRM1 because binding between CRM1 and nCLU proteins was significantly diminished by leptomycin B (LMB), and nuclear levels of nCLU protein were significantly enhanced by LMB and IR co-treatment. Moreover, LMB treatment significantly enhanced IR-induced nCLU-mediated cell death responses. Importantly, bax(-/-) and bax(-/-)/bak(-/-) double knock-out cells were resistant to nCLU-mediated cell death, whereas bak(-/-) or wild-type bax(+/+)/bak(+/+) cells were hypersensitive. The regulation of nCLU by CRM1 nuclear export/import may explain recent clinical results showing that highly malignant tumors have lost the ability to accumulate nCLU levels, thereby avoiding growth inhibition and cell death.
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17 MeSH Terms
Cytoplasmic clusterin expression is associated with longer survival in patients with resected non small cell lung cancer.
Albert JM, Gonzalez A, Massion PP, Chen H, Olson SJ, Shyr Y, Diaz R, Lambright ES, Sandler A, Carbone DP, Putnam JB, Johnson DH, Lu B
(2007) Cancer Epidemiol Biomarkers Prev 16: 1845-51
MeSH Terms: Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Clusterin, Cytoplasm, Female, Humans, Immunohistochemistry, Lung Neoplasms, Male, Microarray Analysis, Neoplasm Staging, Survival Analysis
Show Abstract · Added March 5, 2014
BACKGROUND - Clusterin is a glycoprotein that has been implicated in many processes, including apoptosis, cell cycle regulation, and DNA repair. Previous studies have examined the prognostic value of clusterin expression in various malignancies. In the present study, we examined clusterin staining in tumors resected from patients with non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS - Tumor specimens were obtained for 113 patients with completely resected NSCLC from paraffin-embedded tissue microarrays and stained with an antibody specific for clusterin. Staining patterns were observed and graded based on intensity and then correlated with clinical data.
RESULTS - Positive cytoplasmic clusterin staining was observed in 44 patients, and weak/negative staining was observed in 62 patients. Patients who had tumors that stained positive for cytoplasmic clusterin had significantly longer survival in multivariate analysis (hazard ratio 0.487, 95% confidence interval 0.27-0.89). A correlation was also observed for recurrence-free survival, which approached statistical significance (hazard ratio 0.345, 95% confidence interval 0.12-1.02). In univariate analysis, patients with clusterin-positive tumors had a 63% 3-year survival, whereas patients with clusterin-negative tumors had a 42% 3-year survival (P = 0.0108); clusterin-positive tumors also had significantly less recurrence (P = 0.0231).
CONCLUSIONS - Cytoplasmic clusterin staining is present in a substantial number of NSCLC tumors and may be a biomarker for longer survival in patients with surgically resected NSCLC.
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2 Members
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12 MeSH Terms
Clusterin as a therapeutic target for radiation sensitization in a lung cancer model.
Cao C, Shinohara ET, Li H, Niermann KJ, Kim KW, Sekhar KR, Gleave M, Freeman M, Lu B
(2005) Int J Radiat Oncol Biol Phys 63: 1228-36
MeSH Terms: Animals, Apoptosis, Cell Line, Tumor, Clusterin, Female, Humans, Lung Neoplasms, Mice, Mice, Nude, Neoplasm Proteins, Oligonucleotides, Antisense, Thionucleotides, Transfection, Transplantation, Heterologous
Show Abstract · Added March 5, 2014
PURPOSE - Clusterin plays important roles in cell survival and death. Inactivation of clusterin enhances the therapeutic efficacy of chemotherapy in lung cancer models. The purpose of this study was to determine whether inhibition of clusterin by an antisense-based investigative drug enhances radiation sensitization in a lung cancer model.
METHODS AND MATERIALS - Cells were transfected with an antisense oligonucleotide (ASO) against clusterin (OGX-011). Apoptosis was determined by 7-aminoactinomycin D staining. Cell survival was examined by 3-(4, 5-methylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and clonogenic assay. Xenograft model was used to demonstrate tumor growth and tumor blood flow.
RESULTS - OGX-011 specifically attenuated the expression of secreted clusterin (prosurvival), with no apparent effect on the expression of nuclear clusterin (proapoptotic). Apoptosis was significantly increased when H460 lung cancer cells were treated with OGX-011 plus radiation. Inhibition of clusterin followed by radiation greatly decreased cell survival. H460 xenografts that were treated with OGX-011 plus radiotherapy demonstrated growth delay beyond 17 days. Doppler studies showed that tumor blood flow was compromised when mice bearing H460 xenografts were treated with OGX-011 and radiation.
CONCLUSION - A combination of radiotherapy and OGX-011 improved control of tumor growth and vascular regression in the H460 lung cancer model.
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1 Members
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14 MeSH Terms
Chronic pulmonary histoplasmosis following the excavation of a bird roost.
Latham RH, Kaiser AB, Dupont WD, Dan BB
(1980) Am J Med 68: 504-8
MeSH Terms: Animals, Birds, Chronic Disease, Disease Outbreaks, Disease Reservoirs, Histoplasmosis, Humans, Kentucky, Lung Diseases, Fungal, Male, Middle Aged, Space-Time Clustering, Spores, Fungal
Show Abstract · Added March 21, 2014
The clinical and epidemiologic characteristics of chronic pulmonary histoplasmosis, as compared with the more familiar acute pulmonary histoplasmosis, are relatively unknown. Opinions vary as to the pathogenesis, and only the severe forms of the disease are readily recognized. Over a 22 month period following the excavation of blackbird roost, an unusual outbreak of chronic pulmonary histoplasmosis occurred in a town in southern Kentucky. Thirteen of the cases developed over a span of only four months. An associated outbreak of acute pulmonary histoplasmosis did not occur. During the course of the ensuing investigation, the residential addresses of the affected persons were noted to be clustered about the previously excavated blackbird roost. A case-control study was initiated; the median distance of the residential addresses of the affected persons was found to be 1.0 miles from the roost, compared with 3.2 miles for the control subjects (P less than 0.001). It was concluded that (1) the excavated blackbird roost had served as the common source of the epidemic; (2) the inhalation of exogenous spores accounted for the infections; (3) the spectrum of clinical illness ranged from asymptomatic and mild illness to cavitary disease with considerable morbidity; and (4) following excavation, blackbird roosts may remain an infection hazard for an indefinite period of time.
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1 Members
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13 MeSH Terms
Immunocytochemical localization and determination of hormone-induced synthesis of the sulfated oviductal glycoproteins.
Oliphant G, Reynolds AB, Smith PF, Ross PR, Marta JS
(1984) Biol Reprod 31: 165-74
MeSH Terms: Animals, Clusterin, Cytoplasmic Granules, Deer, Estrogens, Fallopian Tubes, Female, Glycoproteins, Histocytochemistry, Immunoenzyme Techniques, Molecular Chaperones, Sulfuric Acids
Show Abstract · Added March 28, 2014
Secretory products of the oviduct provide part of the milieu for the critical events of fertilization and embryo development. Past work from this laboratory has indicated that three large sulfated glycoproteins can be isolated from rabbit oviductal fluid and are synthesized by oviductal epithelium incubated in vitro. These three glycoproteins are antigenically similar. This paper presents evidence for their localization within the oviductal tissue and their hormonal control of synthesis. Utilizing goat antiserum to these oviductal glycoproteins and the immunoglobulin-horseradish peroxidase bridge method, these macromolecules have been localized in the ampulla and isthmus of the oviduct. Ten days after ovariectomy an oviduct was removed for immunolocalization. The does were then given estradiol for the next 4 days and the second oviduct was removed. Oviducts treated with estradiol showed immunostaining of virtually all of the secretory granules within the secretory cells of the isthmus. While light level immunocytochemistry suggested the possibility of two populations of secretory granules within the ampulla because some of the granules did not show immunocytochemical staining, the more sensitive immunocytochemistry at the electron microscopic level showed staining of all granules of the ampulla and isthmus. Absorption of the antiserum with pure antigen prevented all staining. After ovariectomy and hormone withdrawal, most of the immunostaining was lost in the isthmus and virtually no staining in the ampulla was observed. Oviductal cell suspensions were made to evaluate incorporation of [35S] sulfate and [3H] leucine as a function of hormonal priming of the tissue. Estrogen-primed oviductal cells incorporated the sulfate and leucine into these specific glycoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
1 Communities
1 Members
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12 MeSH Terms
Localization of clusterin in the epimembranous deposits of passive Heymann nephritis.
Eddy AA, Fritz IB
(1991) Kidney Int 39: 247-52
MeSH Terms: Animals, Blood Proteins, Clusterin, Complement Activation, Complement Membrane Attack Complex, Elapid Venoms, Female, Fluorescent Antibody Technique, Glomerulonephritis, Glycoproteins, Kidney Glomerulus, Molecular Chaperones, Rats, Rats, Inbred Lew
Show Abstract · Added February 3, 2012
The membrane attack complex of complement (MAC) plays an important role in the mediation of proteinuria in experimental membranous nephropathy induced by Heymann antiserum. SP-40,40 is a recently described serum protein which appears to inhibit the formation of cytolytic MAC in a manner analogous to S protein/vitronectin. SP-40,40 is homologous to proteins originally isolated from rat and ram seminal fluid (sulfated glycoprotein 2 and clusterin, respectively). By current convention, these proteins are considered clusterin homologues. The objective of this study was to examine the participation of rat clusterin in passive Heymann nephritis. Using an antibody to rat clusterin as an immunofluorescent probe, clusterin deposits were demonstrated along the glomerular capillary wall in an identical pattern to rat C3 and C5b-9. Decomplementation using cobra venom factor prevented proteinuria and intraglomerular MAC formation. The epimembranous clusterin were not detected in the complement-depleted animals. The role of clusterin in the mediation of glomerular injury remains unknown, but it is probably related to in situ formation of the terminal complement cascade where it may play a regulatory role.
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14 MeSH Terms