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Probing the Virtual Proteome to Identify Novel Disease Biomarkers.
Mosley JD, Benson MD, Smith JG, Melander O, Ngo D, Shaffer CM, Ferguson JF, Herzig MS, McCarty CA, Chute CG, Jarvik GP, Gordon AS, Palmer MR, Crosslin DR, Larson EB, Carrell DS, Kullo IJ, Pacheco JA, Peissig PL, Brilliant MH, Kitchner TE, Linneman JG, Namjou B, Williams MS, Ritchie MD, Borthwick KM, Kiryluk K, Mentch FD, Sleiman PM, Karlson EW, Verma SS, Zhu Y, Vasan RS, Yang Q, Denny JC, Roden DM, Gerszten RE, Wang TJ
(2018) Circulation 138: 2469-2481
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Carotid Artery Diseases, Female, Genome-Wide Association Study, Genotype, Humans, Lectins, C-Type, Male, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Proteome, Proteomics, Receptor, Platelet-Derived Growth Factor beta
Show Abstract · Added April 2, 2019
BACKGROUND - Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals.
METHODS - We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651).
RESULTS - In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-β.
CONCLUSIONS - We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.
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18 MeSH Terms
IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ.
Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, Sherwood ER
(2015) J Immunol 195: 2353-64
MeSH Terms: Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Body Temperature, CD8-Positive T-Lymphocytes, Cell Proliferation, Cytotoxicity, Immunologic, Dose-Response Relationship, Drug, Female, Flow Cytometry, Granzymes, Humans, Interferon-gamma, Interleukin-15, Interleukin-15 Receptor alpha Subunit, Killer Cells, Natural, Lectins, C-Type, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes, Perforin
Show Abstract · Added October 18, 2015
IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.
Copyright © 2015 by The American Association of Immunologists, Inc.
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22 MeSH Terms
Cell cycle and apoptosis regulatory proteins, proliferative markers, cell signaling molecules, CD209, and decorin immunoreactivity in low-grade myxofibrosarcoma and myxoma.
Cates JM, Memoli VA, Gonzalez RS
(2015) Virchows Arch 467: 211-6
MeSH Terms: Adult, Aged, Apoptosis Regulatory Proteins, Biomarkers, Tumor, Cell Adhesion Molecules, Cell Cycle Proteins, Decorin, Diagnosis, Differential, Female, Fibrosarcoma, Humans, Immunohistochemistry, Lectins, C-Type, Male, Middle Aged, Myxoma, Neoplasm Grading, Receptors, Cell Surface
Show Abstract · Added February 15, 2016
The histologic differential diagnosis between intramuscular myxoma and low-grade myxofibrosarcoma can be quite difficult in some cases. To identify a diagnostic immunohistochemical marker, we compared the staining profiles of 19 different antigens, including cell cycle proteins, apoptosis proteins, and proliferative markers, and selected other signaling and structural proteins in these two tumors. Ten cases each of intramuscular myxoma and low-grade myxofibrosarcoma were stained with antibodies directed against apoptosis regulatory proteins (Bcl2, activated caspase-3, phospho-H2A.X, and cleaved PARP), cell cycle regulatory proteins (Rb1, Cyclin-A, CDKN1B, and Cdt1), proliferative markers (KI67, MCM2, phospho-histone H3, and geminin), cell signalling molecules (c-Myc, EGF, EGFR, PLA2G4A, and HSP90), a dendritic cell marker (CD209), and the extracellular matrix proteoglycan decorin. Staining patterns of myxoma and myxofibrosarcoma were compared using Fisher's exact test and the Mann-Whitney test. For each potential diagnostic marker studied, the proportions of cases scored as positive on both dichotomous or ordinal scales were not significantly different between myxoma and myxofibrosarcoma. Myxoma and myxofibrosarcoma share a common immunophenotype for each of the markers studied. Distinction between these tumors is still predominantly based on morphologic criteria.
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18 MeSH Terms
Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation.
Speck O, Tang W, Morgan DR, Kuan PF, Meyers MO, Dominguez RL, Martinez E, Gulley ML
(2015) Appl Immunohistochem Mol Morphol 23: 633-45
MeSH Terms: Adenocarcinoma, Carcinoma, Neuroendocrine, Cell Differentiation, Chromogranin A, Epithelial Cells, Epstein-Barr Virus Infections, Gastric Mucosa, Gastrins, Gene Expression, Genetic Heterogeneity, Herpesvirus 4, Human, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Lectins, C-Type, Pancreatitis-Associated Proteins, Prognosis, Stomach, Stomach Neoplasms
Show Abstract · Added May 18, 2016
Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.
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19 MeSH Terms
Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent.
Palmer ND, Musani SK, Yerges-Armstrong LM, Feitosa MF, Bielak LF, Hernaez R, Kahali B, Carr JJ, Harris TB, Jhun MA, Kardia SL, Langefeld CD, Mosley TH, Norris JM, Smith AV, Taylor HA, Wagenknecht LE, Liu J, Borecki IB, Peyser PA, Speliotes EK
(2013) Hepatology 58: 966-75
MeSH Terms: Adaptor Proteins, Signal Transducing, Adult, African Continental Ancestry Group, Aged, Chondroitin Sulfate Proteoglycans, Cohort Studies, European Continental Ancestry Group, Fatty Liver, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Hispanic Americans, Humans, Lectins, C-Type, Lipase, Lysophospholipase, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Non-alcoholic Fatty Liver Disease, Phosphoprotein Phosphatases
Show Abstract · Added February 28, 2014
UNLABELLED - Nonalcoholic fatty liver disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African- and/or Hispanic-Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age(2) , gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m(2) , respectively. Hepatic steatosis was 0.20-0.34 heritable in African- and Hispanic-American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1.
CONCLUSION - Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African- and Hispanic-Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries.
© 2013 by the American Association for the Study of Liver Diseases.
1 Communities
1 Members
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23 MeSH Terms
Interaction of members of the heat shock protein-70 family with the macrophage mannose receptor.
Yang S, Vigerust DJ, Shepherd VL
(2013) J Leukoc Biol 93: 529-36
MeSH Terms: Amino Acid Sequence, Binding Sites, Blotting, Western, Catechin, Gene Expression, HEK293 Cells, HSP70 Heat-Shock Proteins, HeLa Cells, Humans, Immunoprecipitation, Lectins, C-Type, Macrophages, Mannose-Binding Lectins, Mass Spectrometry, Microscopy, Confocal, Molecular Sequence Data, Plasmids, Protein Binding, Protein Interaction Domains and Motifs, Protein Transport, Receptors, Cell Surface, Transfection
Show Abstract · Added March 22, 2016
The macrophage MR has been the subject of investigation for over 20 years, and several important physiological functions have been described. However, the molecular mechanisms that regulate MR signaling and trafficking during these processes still remain elusive. The focus of the current paper was to identify potential cellular MR-interacting proteins. An initial screen of binding proteins in MR-expressing cells was performed using coimmunoprecipitation, followed by identification of matching peptide sequences using proteomics and MS. The major class of binding proteins identified belonged to the heat shock family of proteins. The specific interaction of the MR with HSP70 family members was validated by Western blot analysis, ligand binding assays, and intracellular colocalization using confocal microscopy. Additional studies indicated that inhibition of the HSP BiP by treatment of cells with EGCG reduced BiP interaction with and surface expression of the MR. Studies of possible motifs within the cytoplasmic tail of the receptor suggested that a juxtamembrane dibasic sequence may contribute to the interaction with BiP. These findings suggest that the molecular association of the MR with HSP70 family members via the receptor cytoplasmic tail may contribute to MR trafficking in macrophages.
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22 MeSH Terms
Macrophage-specific RNA interference targeting via "click", mannosylated polymeric micelles.
Yu SS, Lau CM, Barham WJ, Onishko HM, Nelson CE, Li H, Smith CA, Yull FE, Duvall CL, Giorgio TD
(2013) Mol Pharm 10: 975-87
MeSH Terms: Animals, Cells, Cultured, Click Chemistry, Dendritic Cells, Flow Cytometry, Humans, Lectins, C-Type, Macrophages, Mannose-Binding Lectins, Micelles, Microscopy, Confocal, Nanoparticles, Polymers, RNA Interference, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Receptors, Cell Surface
Show Abstract · Added August 29, 2013
Macrophages represent an important therapeutic target, because their activity has been implicated in the progression of debilitating diseases such as cancer and atherosclerosis. In this work, we designed and characterized pH-responsive polymeric micelles that were mannosylated using "click" chemistry to achieve CD206 (mannose receptor)-targeted siRNA delivery. CD206 is primarily expressed on macrophages and dendritic cells and upregulated in tumor-associated macrophages, a potentially useful target for cancer therapy. The mannosylated nanoparticles improved the delivery of siRNA into primary macrophages by 4-fold relative to the delivery of a nontargeted version of the same carrier (p < 0.01). Further, treatment for 24 h with the mannose-targeted siRNA carriers achieved 87 ± 10% knockdown of a model gene in primary macrophages, a cell type that is typically difficult to transfect. Finally, these nanoparticles were also avidly recognized and internalized by human macrophages and facilitated the delivery of 13-fold more siRNA into these cells than into model breast cancer cell lines. We anticipate that these mannose receptor-targeted, endosomolytic siRNA delivery nanoparticles will become an enabling technology for targeting macrophage activity in various diseases, especially those in which CD206 is upregulated in macrophages present within the pathologic site. This work also establishes a generalizable platform that could be applied for "click" functionalization with other targeting ligands to direct siRNA delivery.
2 Communities
4 Members
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17 MeSH Terms
Characterization of functional mannose receptor in a continuous hybridoma cell line.
Vigerust DJ, Vick S, Shepherd VL
(2012) BMC Immunol 13: 51
MeSH Terms: Animals, Candida albicans, Cell Line, Cell Membrane, Flow Cytometry, Green Fluorescent Proteins, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Hybridomas, Immunoblotting, Lectins, C-Type, Ligands, Macrophages, Mannose-Binding Lectins, Phagocytosis, Protein Binding, Rats, Rats, Sprague-Dawley, Receptors, Cell Surface, Reverse Transcriptase Polymerase Chain Reaction, Staphylococcus aureus, Transfection
Show Abstract · Added December 5, 2013
BACKGROUND - The mannose receptor is the best described member of the type I transmembrane C-type lectins; however much remains unanswered about the biology of the receptor. One difficulty has been the inability to consistently express high levels of a functional full length mannose receptor cDNA in mammalian cells. Another difficulty has been the lack of a human macrophage cell line expressing a fully functional receptor. Commonly used human macrophage cell lines such as U937, THP-1, Mono-Mac and HL60 do not express the mannose receptor. We have developed a macrophage hybridoma cell line (43MR cells) created by fusion of U937 cells with primary human monocyte-derived macrophages, resulting in a non-adherent cell line expressing several properties of primary macrophages. The purpose of this study was to identify and select mannose receptor-expressing cells using fluorescence-activated cell sorting and to characterize the expression and function of the receptor.
RESULTS - In the current study we show that the mannose receptor found on this novel cell has endocytic characteristics consistent with and similar to the mannose receptor found on the surface of monocyte-derived human macrophages and rat bone marrow-derived macrophages. In addition, we demonstrate that these cells engage and internalize pathogen particles such as S. aureus and C. albicans. We further establish the transfectability of these cells via the introduction of a plasmid expressing influenza A hemagglutinin.
CONCLUSIONS - The 43MR cell line represents the first naturally expressed MR-positive cell line derived from a human macrophage background. This cell line provides an important cell model for other researchers for the study of human MR biology and host-pathogen interactions.
1 Communities
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22 MeSH Terms
Macrophage dectin-1 expression is controlled by leukotriene B4 via a GM-CSF/PU.1 axis.
Serezani CH, Kane S, Collins L, Morato-Marques M, Osterholzer JJ, Peters-Golden M
(2012) J Immunol 189: 906-15
MeSH Terms: Animals, Candida albicans, Cells, Cultured, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Lectins, C-Type, Leukotriene B4, Macrophages, Alveolar, Macrophages, Peritoneal, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins, Receptors, Leukotriene B4, Trans-Activators, Transcription, Genetic
Show Abstract · Added May 4, 2017
Pattern recognition receptors for fungi include dectin-1 and mannose receptor, and these mediate phagocytosis, as well as production of cytokines, reactive oxygen species, and the lipid mediator leukotriene B(4) (LTB(4)). The influence of G protein-coupled receptor ligands such as LTB(4) on fungal pattern recognition receptor expression is unknown. In this study, we investigated the role of LTB(4) signaling in dectin-1 expression and responsiveness in macrophages. Genetic and pharmacologic approaches showed that LTB(4) production and signaling through its high-affinity G protein-coupled receptor leukotriene B(4) receptor 1 (BLT1) direct dectin-1-dependent binding, ingestion, and cytokine production both in vitro and in vivo. Impaired responses to fungal glucans correlated with lower dectin-1 expression in macrophages from leukotriene (LT)- and BLT1-deficent mice than their wild-type counterparts. LTB(4) increased the expression of the transcription factor responsible for dectin-1 expression, PU.1, and PU.1 small interfering RNA abolished LTB(4)-enhanced dectin-1 expression. GM-CSF controls PU.1 expression, and this cytokine was decreased in LT-deficient macrophages. Addition of GM-CSF to LT-deficient cells restored expression of dectin-1 and PU.1, as well as dectin-1 responsiveness. In addition, LTB(4) effects on dectin-1, PU.1, and cytokine production were blunted in GM-CSF(-/-) macrophages. Our results identify LTB(4)-BLT1 signaling as an unrecognized controller of dectin-1 transcription via GM-CSF and PU.1 that is required for fungi-protective host responses.
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17 MeSH Terms
The combined expression of metaplasia biomarkers predicts the prognosis of gastric cancer.
Suh YS, Lee HJ, Jung EJ, Kim MA, Nam KT, Goldenring JR, Yang HK, Kim WH
(2012) Ann Surg Oncol 19: 1240-9
MeSH Terms: Adenocarcinoma, Biomarkers, Tumor, Cadherins, Female, Galectin 4, Gene Expression Profiling, Granulocyte Colony-Stimulating Factor, Humans, Immunohistochemistry, Keratin-20, Lectins, C-Type, Male, Metaplasia, Middle Aged, Mucin 5AC, Mucins, Neoplasm Staging, Pancreatitis-Associated Proteins, Prognosis, Stomach Neoplasms
Show Abstract · Added September 3, 2013
BACKGROUND - Our previous study indicated that gene expression profiling of intestinal metaplasia (IM) or spasmolytic polypeptide-expressing metaplasia (SPEM) can identify useful prognostic markers of early-stage gastric cancer, and seven metaplasia biomarkers (MUC13, CDH17, OLFM4, KRT20, LGALS4, MUC5AC, and REG4) were selectively expressed in 17-50% of gastric cancer tissues. We investigated whether the combined expression of these metaplasia biomarkers could predict the prognosis of advanced stage gastric cancer.
METHODS - The expression of seven metaplasia biomarkers was evaluated immunohistochemically using tissue microarrays comprised of 450 gastric cancer patients. The clinicopathologic correlations and the prognostic impact were analyzed according to the expression of multiple biomarkers.
RESULTS - MUC13, CDH17, LGALS4, and REG4 were significant prognostic biomarkers in univariate analysis. No expression of four markers was found in 56 cases (14.2%); 1 marker was seen in 67 cases (17%), 2 in 106 cases (27%), 3 in 101 cases (25.7%), and 4 in 63 cases (16%). Patients in which two or fewer proteins were expressed (group B) showed younger age, undifferentiated or diffuse type cancer, larger tumor size, larger number of metastatic lymph nodes, and more advanced stage than those in which three or more proteins were expressed (group A). In undifferentiated or stage II/III gastric cancer, the prognosis of group B was significantly poorer than that of group A by multivariate analysis.
CONCLUSIONS - The combined loss of expression of multiple metaplasia biomarkers is considered an independent prognostic indicator in undifferentiated or stage II/III gastric cancer.
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20 MeSH Terms