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Grant Details

Grant Number: 5R01CA135069-09 Interpret this number
Primary Investigator: Goldman, Radoslav
Organization: Georgetown University
Project Title: Glycans in Hepatocellular Carcinoma
Fiscal Year: 2018
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Abstract

? DESCRIPTION (provided by applicant): The goal of our study is to identify serologic markers that complement alpha fetoprotein (AFP) and its core- fucosylated analog (AFP-L3) in the detection of hepatocellular carcinoma (HCC) at a treatable stage. We and others have shown that major re-distribution of protein N-glycoforms occurs at the premalignant stage of liver cirrhosis. Our latest studies show that high mannose, core- and outer arm- fucosylated glycoforms of specific glycopeptides increase in HCC. These glycoforms are associated with liver secreted glycoproteins and are detectable in serum. In this study, we analyze liver secreted glycoproteins carrying these HCC specific N- glycan modifications by newly developed LC-MS-MRM targeted quantification methods. This is done because AFP and ultrasonography detect only approximately 60% of HCC cases and additional markers are needed to improve sensitivity of screening for this malignancy with continuously increasing incidence. Our data suggests that quantification of specific glycoforms of specific glycoprotein peptides offers the highest diagnostic accuracy. The optimized glycosidase assisted LC-MS-MRM methods allow, for the first time, targeted validation of the site specific glycopeptide marker candidates. Defining clinically applicable markers of HCC has potentially far-reaching consequences for disease management and patient health. Our study is expected to generate new hypotheses on the functional impact of protein glycosylation on the development of cancer and to stimulate new line of cancer detection research.

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Publications

Hydrophilic interaction liquid chromatography in the separation of glycopeptides and their isomers.
Authors: Kozlik P. , Goldman R. , Sanda M. .
Source: Analytical And Bioanalytical Chemistry, 2018-05-28 00:00:00.0; , .
EPub date: 2018-05-28 00:00:00.0.
PMID: 29806066
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Loss and gain of N-linked glycosylation sequons due to single-nucleotide variation in cancer.
Authors: Fan Y. , Hu Y. , Yan C. , Goldman R. , Pan Y. , Mazumder R. , Dingerdissen H.M. .
Source: Scientific Reports, 2018-03-12 00:00:00.0; 8(1), p. 4322.
EPub date: 2018-03-12 00:00:00.0.
PMID: 29531238
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Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC.
Authors: Wang M. , Sanda M. , Comunale M.A. , Herrera H. , Swindell C. , Kono Y. , Singal A.G. , Marrero J. , Block T. , Goldman R. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2017 May; 26(5), p. 795-803.
EPub date: 2017-02-21 00:00:00.0.
PMID: 28223431
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Study of structure-dependent chromatographic behavior of glycopeptides using reversed phase nanoLC.
Authors: Kozlik P. , Goldman R. , Sanda M. .
Source: Electrophoresis, 2017-04-26 00:00:00.0; , .
EPub date: 2017-04-26 00:00:00.0.
PMID: 28444931
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Changes in the expression of N- and O-glycopeptides in patients with colorectal cancer and hepatocellular carcinoma quantified by full-MS scan FT-ICR and multiple reaction monitoring.
Authors: Darebna P. , Novak P. , Kucera R. , Topolcan O. , Sanda M. , Goldman R. , Pompach P. .
Source: Journal Of Proteomics, 2017-02-05 00:00:00.0; 153, p. 44-52.
EPub date: 2016-09-16 00:00:00.0.
PMID: 27646713
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Site-specific Analysis Of Changes In The Glycosylation Of Proteins In Liver Cirrhosis Using Data-independent Workflow With Soft Fragmentation
Authors: Sanda M. , Zhang L. , Edwards N.J. , Goldman R. .
Source: Analytical And Bioanalytical Chemistry, 2017 Jan; 409(2), p. 619-627.
PMID: 27822650
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Data Independent Analysis of IgG Glycoforms in Samples of Unfractionated Human Plasma.
Authors: Sanda M. , Goldman R. .
Source: Analytical Chemistry, 2016-10-18 00:00:00.0; 88(20), p. 10118-10125.
EPub date: 2016-09-29 00:00:00.0.
PMID: 27649061
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Expression of the extracellular sulfatase SULF2 is associated with squamous cell carcinoma of the head and neck.
Authors: Flowers S.A. , Zhou X. , Wu J. , Wang Y. , Makambi K. , Kallakury B.V. , Singer M.S. , Rosen S.D. , Davidson B. , Goldman R. .
Source: Oncotarget, 2016-07-12 00:00:00.0; 7(28), p. 43177-43187.
PMID: 27223083
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Increased Sialylation Of Site Specific O-glycoforms Of Hemopexin In Liver Disease
Authors: Sanda M. , Benicky J. , Wu J. , Wang Y. , Makambi K. , Ahn J. , Smith C.I. , Zhao P. , Zhang L. , Goldman R. .
Source: Clinical Proteomics, 2016; 13, p. 24.
PMID: 27688741
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Quantitative Analysis Of Immunoglobulin Subclasses And Subclass Specific Glycosylation By Lc-ms-mrm In Liver Disease
Authors: Yuan W. , Sanda M. , Wu J. , Koomen J. , Goldman R. .
Source: Journal Of Proteomics, 2015-02-26 00:00:00.0; 116, p. 24-33.
PMID: 25582524
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Sulf2, A Heparan Sulfate Endosulfatase, Is Present In The Blood Of Healthy Individuals And Increases In Cirrhosis
Authors: Singer M.S. , Phillips J.J. , Lemjabbar-Alaoui H. , Wang Y.Q. , Wu J. , Goldman R. , Rosen S.D. .
Source: Clinica Chimica Acta; International Journal Of Clinical Chemistry, 2015-02-02 00:00:00.0; 440, p. 72-8.
PMID: 25444749
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Targeted Methods For Quantitative Analysis Of Protein Glycosylation
Authors: Goldman R. , Sanda M. .
Source: Proteomics. Clinical Applications, 2015 Feb; 9(1-2), p. 17-32.
PMID: 25522218
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Structure-function Analysis Of Hepatitis C Virus Envelope Glycoproteins E1 And E2
Authors: Nayak A. , Pattabiraman N. , Fadra N. , Goldman R. , Kosakovsky Pond S.L. , Mazumder R. .
Source: Journal Of Biomolecular Structure & Dynamics, 2015; 33(8), p. 1682-94.
PMID: 25245635
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Protein And Site Specificity Of Fucosylation In Liver-secreted Glycoproteins
Authors: Pompach P. , Ashline D.J. , Brnakova Z. , Benicky J. , Sanda M. , Goldman R. .
Source: Journal Of Proteome Research, 2014-12-05 00:00:00.0; 13(12), p. 5561-9.
PMID: 25265424
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Quantification Of Fucosylated Hemopexin And Complement Factor H In Plasma Of Patients With Liver Disease
Authors: Benicky J. , Sanda M. , Pompach P. , Wu J. , Goldman R. .
Source: Analytical Chemistry, 2014-11-04 00:00:00.0; 86(21), p. 10716-23.
PMID: 25302577
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Site-specific Glycan Microheterogeneity Of Inter-alpha-trypsin Inhibitor Heavy Chain H4
Authors: Chandler K.B. , Brnakova Z. , Sanda M. , Wang S. , Stalnaker S.H. , Bridger R. , Zhao P. , Wells L. , Edwards N.J. , Goldman R. .
Source: Journal Of Proteome Research, 2014-07-03 00:00:00.0; 13(7), p. 3314-29.
PMID: 24884609
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Sex hormone pathway gene polymorphisms are associated with risk of advanced hepatitis C-related liver disease in males.
Authors: White D.L. , Liu Y. , Garcia J. , El-Serag H.B. , Jiao L. , Tsavachidis S. , Franco L.M. , Lee J.S. , Tavakoli-Tabasi S. , Moore D. , et al. .
Source: International Journal Of Molecular Epidemiology And Genetics, 2014; 5(3), p. 164-76.
EPub date: 2014-10-22 00:00:00.0.
PMID: 25379136
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A Click Chemistry Approach to Identify Protein Targets of Cancer Chemopreventive Phenethyl Isothiocyanate.
Authors: Fu Y. , Mi L. , Sanda M. , Silverstein S. , Aggarwal M. , Wang D. , Gupta P. , Goldman R. , Appella D.H. , Chung F.L. .
Source: Rsc Advances, 2014; 4(8), p. 3920-3923.
PMID: 28725420
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Exploring Site-specific N-glycosylation Microheterogeneity Of Haptoglobin Using Glycopeptide Cid Tandem Mass Spectra And Glycan Database Search
Authors: Chandler K.B. , Pompach P. , Goldman R. , Edwards N. .
Source: Journal Of Proteome Research, 2013-08-02 00:00:00.0; 12(8), p. 3652-66.
PMID: 23829323
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Lc-ms3 Quantification Of O-glycopeptides In Human Serum
Authors: Sanda M. , Pompach P. , Benicky J. , Goldman R. .
Source: Electrophoresis, 2013 Aug; 34(16), p. 2342-9.
PMID: 23765987
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Quantitative Liquid Chromatography-mass Spectrometry-multiple Reaction Monitoring (lc-ms-mrm) Analysis Of Site-specific Glycoforms Of Haptoglobin In Liver Disease
Authors: Sanda M. , Pompach P. , Brnakova Z. , Wu J. , Makambi K. , Goldman R. .
Source: Molecular & Cellular Proteomics : Mcp, 2013 May; 12(5), p. 1294-305.
PMID: 23389048
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Site-specific Glycoforms Of Haptoglobin In Liver Cirrhosis And Hepatocellular Carcinoma
Authors: Pompach P. , Brnakova Z. , Sanda M. , Wu J. , Edwards N. , Goldman R. .
Source: Molecular & Cellular Proteomics : Mcp, 2013 May; 12(5), p. 1281-93.
PMID: 23389049
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Glycoprotein Disease Markers And Single Protein-omics
Authors: Chandler K. , Goldman R. .
Source: Molecular & Cellular Proteomics : Mcp, 2013 Apr; 12(4), p. 836-45.
PMID: 23399550
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Structure-based Comparative Analysis And Prediction Of N-linked Glycosylation Sites In Evolutionarily Distant Eukaryotes
Authors: Lam P.V. , Goldman R. , Karagiannis K. , Narsule T. , Simonyan V. , Soika V. , Mazumder R. .
Source: Genomics, Proteomics & Bioinformatics, 2013 Apr; 11(2), p. 96-104.
PMID: 23459159
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Analysis Of Peptides By Denaturing Ultrafiltration And Lc-maldi-tof-ms
Authors: An Y. , Goldman R. .
Source: Methods In Molecular Biology (clifton, N.j.), 2013; 1023, p. 13-9.
PMID: 23765617
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Utilization Of Metabolomics To Identify Serum Biomarkers For Hepatocellular Carcinoma In Patients With Liver Cirrhosis
Authors: Ressom H.W. , Xiao J.F. , Tuli L. , Varghese R.S. , Zhou B. , Tsai T.H. , Ranjbar M.R. , Zhao Y. , Wang J. , Di Poto C. , et al. .
Source: Analytica Chimica Acta, 2012-09-19 00:00:00.0; 743, p. 90-100.
PMID: 22882828
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N-glycans In Liver-secreted And Immunoglogulin-derived Protein Fractions
Authors: Bekesova S. , Kosti O. , Chandler K.B. , Wu J. , Madej H.L. , Brown K.C. , Simonyan V. , Goldman R. .
Source: Journal Of Proteomics, 2012-04-03 00:00:00.0; 75(7), p. 2216-24.
PMID: 22326963
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Semi-automated Identification Of N-glycopeptides By Hydrophilic Interaction Chromatography, Nano-reverse-phase Lc-ms/ms, And Glycan Database Search
Authors: Pompach P. , Chandler K.B. , Lan R. , Edwards N. , Goldman R. .
Source: Journal Of Proteome Research, 2012-03-02 00:00:00.0; 11(3), p. 1728-40.
PMID: 22239659
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Delineating Diseases By Ims-ms Profiling Of Serum N-linked Glycans
Authors: Isailovic D. , Plasencia M.D. , Gaye M.M. , Stokes S.T. , Kurulugama R.T. , Pungpapong V. , Zhang M. , Kyselova Z. , Goldman R. , Mechref Y. , et al. .
Source: Journal Of Proteome Research, 2012-02-03 00:00:00.0; 11(2), p. 576-85.
PMID: 22148953
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Ms/ms Library Facilitated Mrm Quantification Of Native Peptides Prepared By Denaturing Ultrafiltration
Authors: Lenco J. , Lan R. , Edwards N. , Goldman R. .
Source: Proteome Science, 2012; 10(1), p. 7.
PMID: 22304756
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Proteome-wide Analysis Of Single-nucleotide Variations In The N-glycosylation Sequon Of Human Genes
Authors: Mazumder R. , Morampudi K.S. , Motwani M. , Vasudevan S. , Goldman R. .
Source: Plos One, 2012; 7(5), p. e36212.
PMID: 22586465
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Urinary Estrogen Metabolites And Prostate Cancer Risk: A Pilot Study
Authors: Kosti O. , Xu X. , Veenstra T.D. , Hsing A.W. , Chu L.W. , Goldman L. , Bebu I. , Collins S. , Dritschilo A. , Lynch J.H. , et al. .
Source: The Prostate, 2011 Apr; 71(5), p. 507-16.
PMID: 20886539
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Peptides In Low Molecular Weight Fraction Of Serum Associated With Hepatocellular Carcinoma
Authors: An Y. , Bekesova S. , Edwards N. , Goldman R. .
Source: Disease Markers, 2010; 29(1), p. 11-20.
PMID: 20826913
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Detection of hepatocellular carcinoma using glycomic analysis.
Authors: Goldman R. , Ressom H.W. , Varghese R.S. , Goldman L. , Bascug G. , Loffredo C.A. , Abdel-Hamid M. , Gouda I. , Ezzat S. , Kyselova Z. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2009-03-01 00:00:00.0; 15(5), p. 1808-13.
EPub date: 2009-03-01 00:00:00.0.
PMID: 19223512
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