-
Clinical Proteomics
From Diagnosis to Therapy
Edited by
Jennifer E. Van Eyk and Michael J. Dunn
InnodataFile Attachment9783527622160.jpg
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Clinical Proteomics
Edited by
Jennifer E. Van Eyk and
Michael J. Dunn
-
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Clinical Proteomics
From Diagnosis to Therapy
Edited by
Jennifer E. Van Eyk and Michael J. Dunn
-
The Editors
Dr. Jennifer van Eyk
Johns Hopkins University
Bayview Medical Campus
5200 Eastern Ave.
Baltimore, MD 21224
USA
Prof. Dr. Michael J. Dunn
Proteome Research Centre
UCD Conway Institute
Belfield
Dublin 4
Ireland
Cover
The front cover picture is based on a 2-D-DIGE
comparing a cell lysate preparation and secretome
preparations, both derived from SW620 cells. It was
published by Schwarte-Waldhoff et al. in Proteomics
Clin. Appl. 2007, 1, 47-61. Lysate proteins are shown
in red and secretome proteins in green.
Reproduced with kindly permission of the Medical
Proteome-Center, University of Bochum, Germany.
The background protein image has been reproduced
with the kind permission of Professor Alfredo Ricci,
Dpto. di Chimica Organica, Universita di Bologna,
Italy.
All books published by Wiley-VCH are carefully
produced. Nevertheless, authors, editors, and
publisher do not warrant the information contained
in these books, including this book, to be free of
errors. Readers are advised to keep in mind that
statements, data, illustrations, procedural details or
other items may inadvertently be inaccurate.
Library of Congress Card No.:
applied for
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the
British Library.
Bibliographic information published by
the Deutsche Nationalbibliothek
Die Deutsche Nationalbibliothek lists this
publication in the Deutsche Nationalbibliografie;
detailed bibliographic data are available on the
Internet at .
# 2008 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
All rights reserved (including those of translation into
other languages). No part of this book may be repro-
duced in any form - by photoprinting, microfilm, or
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as such, are not to be considered unprotected by law.
Composition Thomson Digital, Noida, India
Printing betz-druck GmbH, Darmstadt
Bookbinding Litges & Dopf GmbH, Heppenheim
Cover Design Anne Kessler, Karlsruhe
Printed in the Federal Republic of Germany
Printed on acid-free paper
ISBN 978-3-527-31637-3
-
Contents
Editor’s Overview XIX
List of Contributors XXI
I Technologies 1
1 Preanalytical Issues in Clinical Proteomic Studies 3Roisean E. Ferguson, Rosamonde E. Banks
1.1 Introduction 31.2 Preanalytical Factors 31.2.1 Biological Variation 41.2.1.1 Intrinic Influences/Factors 41.2.1.2 Extrinsic Influences/Factors 51.2.2 Technical Variables 51.2.2.1 Specimen/Sample Collection Mode 51.2.2.2 Type of Sample Container 61.2.2.3 Sample Processing and Handling Conditions 71.2.2.4 Sample Storage 71.3 Summary and Concluding Remarks 8
2 Protein Separation by Two-Dimensional Electrophoresis 13Pamela M. Donoghue, Miroslava Stastna, Michael J. Dunn
2.1 Introduction 132.2 2DE: Protein Solubilization and Sample Preparation 142.3 2DE: Protein Separation 152.3.1 Focusing in the First Dimension 152.3.2 Advances in IEF 162.4 Improving Proteomic Coverage by Subcellular Fractionation 212.5 Protein Detection and Image Analysis 242.6 The Future of 2DE 25
V
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3 Protein Separation: Liquid Chromatography 31Miroslava Stastna, Jennifer Van Eyk
3.1 Introduction 313.2 Liquid Chromatography 323.2.1 HPLC Separation Principles 323.2.2 Reversed-Phase LC (RPLC, 1DLC) 343.2.3 Affinity Chromatography 373.2.4 Size-Exclusion Chromatography 383.2.5 Ion-Exchange Chromatography 393.2.6 Two-Dimensional LC 403.2.6.1 Chromatofocusing to Reversed Phase 403.2.6.2 Ion-Exchange Reversed-Phase Liquid Chromatography 413.2.7 Three-Dimensional Liquid Chromatography 413.2.8 LC Image Analysis Requirement 423.2.9 Mass Spectrometry for LC 423.2.9.1 MALDI-TOF MS 433.2.9.2 ESI-MS/MS 433.3 Conclusions 46
4 HPLC in Protein Discovery 53Timothy J. Barder
4.1 Introduction 534.2 LC-Based Approaches in Peptide Mass Mapping 544.3 LC-Based Approaches in Protein Mapping 544.4 Orthogonal 2D HPLC Separations 564.5 Conclusion 57
5 IEF Analysis of Peptides for Biomarkers Discovery 61Ali R. Vaezzadeh, Catherine G. Zimmermann-Ivol, Jacques Deshusses,
Alexander Scherl, Denis F. Hochstrasser
5.1 Introduction 615.2 Background 625.2.1 Isoelectric Focusing 625.2.2 Shotgun Proteomics 625.2.3 Shotgun IEF 635.3 Shotgun IEF Workflow 645.4 Applications 665.5 Discussion and Outlook 66
6 Capillary Electrophoretic Separations for Clinical Proteomics 73Brian M. Balgley, Weijie Wang, Xueping Fang, Don L. DeVoe, Cheng S. Lee
6.1 Introduction 736.2 (Single-Dimension) Capillary Electophoretic Separation 746.3 Capillary Electrophoresis-Based Multidimensional Separations 746.3.1 Capillary Liquid Chromatography–Capillary Electrophoresis 75
VI Contents
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6.3.2 Capillary Electrophoresis–Capillary Electrophoresis 756.3.3 Capillary Electrophoresis–Liquid Chromatography 766.3.3.1 Characterization of Human Saliva Proteome 776.3.3.2 Targeted Tissue Proteomics 796.4 Conclusions 85
7 Quantitative Proteomics Using Nano-LC with High Accuracy
Mass Spectrometry 89Ljiljana Paša-Tolić, Jon M. Jacobs, Wei-Jun Qian, Richard D. Smith
7.1 Introduction 897.2 Fundamentals of a High Mass Accuracy-Based LC–MS
Approach 907.3 Nano-LC–MS for Enhanced Sensitivity and Dynamic
Range Coverage 927.4 Further Developments for Increasing Proteomic Throughput 947.5 Obtaining More Robust Quantitative Proteomic Measurements 947.6 Summary and Perspective 96
8 Antibody Microarrays for Protein and Glycan Detection 101Songming Chen, Brian B. Haab
8.1 Introduction 1018.2 Antibody Preparation and Microarray Production 1028.3 Sandwich Assays with Fluorescence Detection 1048.4 Antibody Microarrays with Lectin Detection 1068.5 Conclusion 1068.6 Detailed Protocols 107
9 Biomarker Identification: The Role of Experimental Design,
Statistics, and Data Sharing 113Marc R.Wilkins
9.1 Introduction 1139.2 Experimental Designs for Biomarker Discovery 1149.3 Identification of Biomarker Proteins 1169.4 Biomarker Validation and the Issue of Data Sharing 1189.5 Conclusions 119
II Cancer 121
10 Applications of Stable Isotope Tagging Based Quantitative
Proteomics in Cancer Research 123Ru Chen, Teresa A. Brentnall, Ruedi Aebersold
10.1 Introduction 12310.2 Stable Isotope Tagging Methods 12410.2.1 Chemical Labeling of Stable Isotope Tags 125
Contents VII
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10.2.2 Biological Incorporation of Stable Isotope Tags 12710.3 Applications in Studies of Tissue Samples 12810.3.1 Whole Tumor Tissue Labeled with ICAT 12810.3.2 Whole Tumor Tissue Labeled with ICAT and iTRAQ 13010.3.3 Isolated Tumor Cells Labeled with ICAT 13110.3.4 Isolated Tumor Cells Labeled with 16O/18O 13110.4 Applications in Studies of Bodily Fluids 13210.4.1 Pancreatic Juice Labeled with ICAT 13310.4.2 Nipple Aspirate Fluid Labeled with ICAT 13310.4.3 CSF 13410.5 Applications in Studies of Cell Lines 13510.5.1 Ovarian Cancer Cell Lines Labeled with ICAT 13510.5.2 Breast Cancer Cell Lines Labeled with 18O Labeling 13510.5.3 Prostate Cancer Cell Lines Labeled with SILAC 13610.5.4 Secretome by Pancreatic Cancer Cell Line Labeled with SILAC 13610.6 Applications in Studies of Protein Interaction 13710.7 Applications in Studies of Posttranslational Modifications (PTM) 13810.8 Summary 139
11 Two-Dimensional Liquid Separations, Protein Microarrays,
and Mass Spectrometry in Comprehensive Analysis of
Posttranslational Modifications and Biomarker
Discovery in Cancers 145Tasneem H. Patwa, Jia Zhao, David E. Misek, David M. Lubman
11.1 Challenges in Biomarker Discovery: The Emerging Role of
Posttranslational Modifications 14511.2 Proteomics in Disease Research 14611.3 The Problem of Identifying and Characterizing Posttranslational
Modifications: Current Efforts 14711.4 Microarrays in Proteomic Investigations 14811.5 A Comprehensive Method Combining Liquid Separations,
Microarrays, and Mass Spectrometry 14811.6 2D Liquid-Based Separations and Mass Mapping 15011.7 Posttranslational Modification (PTM) Analysis 15211.8 Phosphorylation 15311.9 Glycosylation 15411.10 Autoimmune (Humoral) Response Studies 15611.11 Future of a 2DLC, Microarray Methodologies in Discovery and
Diagnostics 158
12 Development and Use of Reversed-Phase Protein Microarrays
for Clinical Applications 165Virginia Espina, Julia Wulfkuhle, Valerie S. Calvert,
Kirsten H. Edmiston, Lance A. Liotta, Emanuel F. Petricoin III
12.1 Introduction 165
VIII Contents
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12.2 The Growing Role of Protein Arrays in Molecular Diagnostics 16712.3 Reversed-Phase Arrays: Enabling Technology for Patient-Tailored
Therapeutics 16712.4 Use of Reversed-Phase Arrays for Signal Pathway Profiling
of Human Cancer 16912.5 Use of Reversed-Phase Arrays: A View to the Future 171
13 Cyclin-Dependent Kinase Inhibitors and Cancer: Usefulness
of Proteomic Approaches in Assessment of the Molecular
Mechanisms and Efficacy of Novel Therapeutics 177Marian Hajduch, Helena Skalnikova, Petr Halada, David Vydra,
Petr Dzubak, Marta Dziechciarkova, Miroslav Strnad,
Danuta Radioch, Suresh Jivan Gadher, Hana Kovarova
13.1 Introduction 17713.2 Proteomic Analysis of Cancer Cells Responding to the
Synthetic CDKI 18213.3 Two-Dimensional Protein Maps of Cancer Cells Treated by CDKI 18413.3.1 Model of Hematological Malignancy: CEM T-Lymphoblastic
Leukemia 18413.3.2 Solid Tumor Model: A549 Lung Adenocarcinoma Cells 18713.4 Evaluation of the Protein Maps: Possible Pathways Relevant to
Anticancer Effects of CDK Inhibition 18913.4.1 Candidate Biomarkers Identified Using the Hematological
Malignancy Model 18913.4.2 Candidate Biomarkers Identified Using the Solid Tumor Model 19213.5 Biomarker Validation Studies Focused on the crkl Protein 19413.6 Conclusions 195
III Cardiac Disease 203
14 Diagnostic Markers for Monitoring Heart Transplant Rejection 205Ciara A. McManus, Marlene L. Rose, Michael J. Dunn
14.1 Introduction 20514.2 Acute Rejection 20614.3 Chronic Rejection 20814.4 Cardiopulmonary Bypass 21214.5 Conclusions 213
15 The Study of Microheterogeneity in Human Plasma Proteins:
Application to Acute Myocardial Infarction 217Randall W. Nelson, Urban A. Kiernan, Dobrin Nedelkov,
Kemmons A. Tubbs, Eric E. Niederkofler
15.1 Background 21715.2 Technical Approach 218
Contents IX
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15.3 Programmatic Study of Disease: Population Proteomics
Versus Myocardial Infarction 21915.3.1 Preliminary Screening, (Putative) Biomarker Discovery and
Identification 22215.3.2 Verification 22315.3.3 Knowledge Assembly and Next-Generation Assay Design 22315.3.4 Data Generation 22515.3.5 Data Analysis 22515.3.6 Blind and Randomized Challenge of Final Assay 22715.4 Summary 228
16 Discovery of Biomarkers for Cardiovascular Diseases 231Anthony O. Gramolini, Andrew Emili
16.1 Current Proteomic Technologies Available for CVD Biomarker
Searches 23216.2 Challenging Issues for Proteomic Profiling 23316.3 Screening Blood for Biomarkers 23416.4 Tissue Surveys 23516.5 The Value of Animal Models 23616.6 After Technology Platform and Sample Selection:
What Makes a Good Biomarker? 23716.7 Ongoing Considerations 23816.8 Outlook 238
17 Development of Biomarker Development Pipeline:
Search for Myocardial Ischemia Biomarkers 241Qin Fu, Shijun Sheng, Jennifer E. Van Eyk
17.1 Introduction 24117.2 Myocardial Ischemia and Infarction 24217.3 Lessons Learned from Cardiac Troponin 24517.4 Building a Biomarker Development Platform I-Discovery 24617.4.1 High-Abundant Protein Partitioning 24817.4.2 Utilizing Multiple Protein Separation Methods to Maximize
Proteome Coverage: A Synergistic Approach 25017.5 Validation 25417.5.1 Technologies in Validation 25617.5.2 Cohorts for the Validation 25617.6 Summary 257
18 The Albuminome as a Tool for Biomarker Discovery 263Rebekah L. Gundry, Robert J. Cotter
18.1 Protein–Protein Interactions and Protein-Centric
Approaches in Proteomics 263
X Contents
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18.2 Defining the Albuminome 26518.3 The Albuminome as a Tool in Biomarker Discovery 27018.4 Role of the Albuminome in Cardiovascular Proteomics 27518.5 Other Plasma Subproteomes 27618.6 Conclusion 277
19 Application of Metabolomics to Cardiovascular
Biomarker and Pathway Discovery 279Gregory D. Lewis, Robert E. Gerszten
19.1 Introduction 27919.2 The Birth of Metabolomics 27919.3 Technologies to Define the Human Metabolome 28119.4 The Diagnostic Utility of Metabolic Peak Patterns:
A Call for Unambiguous Identification 28219.5 Pathway Analysis of Metabolomic Data 28319.6 Rationale for Metabolomic Approaches to Study Atherosclerosis
and its Complications: The Role of Proinflammatory Lipid
Metabolites 28519.7 Unanticipated Roles of ‘‘Intracellular’’ Metabolites 28619.8 Clinical Rationale for Applying Metabolomics to Coronary
Heart Disease 28619.9 Impediments to Human Applications 28719.10 Application of Metabolomics to Unique Human Cardiovascular
Disease Models 28719.11 Conclusion 290
IV Vascular Disease: Pulmonary, Diabetes and Brain 295
20 Urinary Biomarkers in Diabetic Nephropathy and Other
Glomerular Diseases 297John M. Arthur, T. Brian Powell
20.1 Urine as a Source of Protein Biomarkers 30020.2 Size Selectivity of Urine Proteins as a Marker 30120.3 Charge Specificity of Urine Proteins as a Marker 30220.4 Markers in Diabetic Nephropathy 30320.5 Markers for Other Glomerular Diseases 30420.6 Urine Proteomics 30420.7 Proteomics and Glomerular Disease Markers 30520.8 Diabetic Nephropathy 30820.9 Lupus Nephritis 31120.10 Other Glomerular Diseases 31220.11 Summary 315
Contents XI
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21 Pulmonary Proteomics 323Jan Hirsch, Lorraine B. Ware, Michael A. Matthay
21.1 Introduction 32321.2 The Proteome of Bronchoalveolar Lavage Fluid 32321.3 BAL Studies in Animals 32521.4 Plasma and Serum Measurements 32621.5 Induced Sputum 32721.6 Pulmonary Edema Fluid 32821.7 Nasal Lavage Fluid 32921.8 Exhaled Breath Condensates 33021.9 Cell Analysis 33021.10 Frozen Tissue Slices 33521.11 Pleural Effusions 33721.12 Other Samples 33821.13 Summary 338
22 Proteomics Providing Insights into Major Psychiatric Disorders 349Melanie Föcking, Kyla Pennington, Jane English, Michael Dunn,
David Cotter
22.1 Introduction 34922.1.1 Schizophrenia and Affective Disorders: Definitions and
Epidemiology 35022.1.2 Schizophrenia and Affective Disorders: Brain Changes 35122.1.3 Effects of Psychiatric Drug Treatments on the Brain 35222.1.4 Application of Microarrays to Psychiatric Disorders 35222.1.5 The Value of Proteomic Approaches in Investigating the
Pathophysiology of Major Psychiatric Disorders 35322.1.6 Gel-Based Proteomic Methods 35422.1.7 Non-Gel-Based Methods 35522.1.8 Creating a Subproteome 35822.2 The Importance of Validation 35922.2.1 What Samples can be Used? 35922.3 Drug Discovery 36022.3.1 Pharmacoproteomic Investigations of the Brain 36022.4 Studies from Our Group 36122.4.1 Dorsolateral Prefrontal Cortex 36122.4.2 White Matter 36222.4.3 Anterior Cingulate Cortex 36322.4.4 Insular Cortex 36622.4.5 Hippocampus 36722.4.6 Studies of Effects of Psychotropic Medication 36822.4.7 Confounding Factors Influencing Human Postmortem Brain
Proteomic Studies 36922.4.8 Final Conclusions 369
XII Contents
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V Toxicity, Bacterial and Viral Infections 379
23 Redox Proteomics Analysis of Oxidative Modified Brain
Proteins in Alzheimer’s Disease and Mild Cognitive Impairment:
Insights into the Progression of This Dementing Disorder 381Rukhsana Sultana, D. Allan Butterfield
23.1 Introduction 38123.1.1 Proteomics 38123.1.2 Mass Spectrometry and Database Searching 38423.1.3 Oxidative Stress in AD 38523.1.4 Oxidative Stress in MCI 38623.2 Redox Proteomics in AD and MCI 38723.2.1 Oxidized Proteins in AD and MCI Identified Using Redox
Proteomics 38823.2.1.1 Energy Dysfunction 38823.2.1.2 Proteasome-Related Proteins 38923.2.1.3 Cholinergic System 39023.2.1.4 Structural Proteins 39023.2.1.5 Cell Cycle, Phosphorylated Tau, and Ab Production 39123.2.1.6 pH Regulation Protein 39123.2.1.7 Neurotransmitter-Related Proteins 39123.3 Conclusion 392
24 Toxicoproteomics: Correlating Tissue and Serum Proteomics
in Liver Injury 403B. Alex Merrick
24.1 The Field of Toxicoproteomics 40324.2 Toxicoproteomics and Pharmaceutical Development 40424.3 Disciplines and Platforms for Toxicoproteomic Research 40624.4 Correlating Tissue and Serum Analysis 40824.5 Toxicoproteomic Studies in Liver Injury 41024.6 Acetaminophen 41124.7 Carbon Tetrachloride 41724.8 Bromobenzene 41824.9 Wyeth 14643 41824.10 Hydrazine 41924.11 Thioacetamide 42024.12 New Blood Biomarkers in Liver Injury 42124.13 Expectations and Reality 42324.14 Future Trends and Tools in Toxicoproteomics 42424.15 Summary 425
25 Biomarkers for Renal Disease and Uremic Toxins 435Eric Schiffer, Harald Mischak, Raymond C. Vanholder
25.1 Introduction 435
Contents XIII
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25.2 Proteome Analysis 43625.3 Technical Aspect of CE–MS 43825.3.1 Ionization and Choice of Mass Spectrometers 43825.3.2 CE–MS Coupling 43925.3.3 Coating 44025.3.4 Sample Preparation 44025.3.5 Data Evaluation 44125.3.6 Identification of Biomarkers 44125.4 Application of Proteomic Techniques to Uremic Toxicity 44425.5 Conclusion 447
26 HIV and Other Viral Screens 453David R. Graham
26.1 Introduction 45326.2 Current State of Clinical Virology 45326.2.1 Diagnosis 45526.2.2 Treatment 45926.3 Predicting Pathogenicity: A Need for Clinical Viral
Proteomics 45926.4 Concepts in Virology as They Relate to Proteomics: The Problem
of Mutation 46026.5 Understanding the Biological Limitations of the Pathogen to
Succeed in a Proteomic Approach 46126.5.1 Culture 46126.5.2 Purity – Enveloped/Nonenveloped 46326.6 The Requirements and Approaches to Proteomic Research 46426.6.1 Decision Tree 46426.6.2 Broad-Based Approaches 46526.6.2.1 Protein Identifications or Posttranslational Modifications 46526.6.3 Liquid Chromatography-Based Approaches 46626.6.3.1 Reverse-Phase HPLC (rp-HPLC) – Separation Based on
Hydrophobicity 46726.6.3.2 Two-Dimensional HPLC 46826.7 Pushing the Envelope of Detection 46926.7.1 Protein Interactions 47026.7.1.1 Affinity Capture Based 47026.7.2 Protein Identification 47126.7.2.1 Antibody Based 47126.7.2.2 Mass Spectrometry Based 47126.8 Bioinformatics (Host Proteins Versus Viral Proteins) 47226.8.1 Are Molecular Approaches Sufficient? 47226.8.1.1 Laying the groundwork 47326.8.1.2 Virus sequencing 475
XIV Contents
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26.8.2 Toward the Real World – Emerging Clinical Applications 47526.8.2.1 Protein Arrays 47526.8.2.2 The Evolution of Protein Arrays – Multiplex Assays 47626.8.3 Assessing Immune Responses Using Arrays and Multiplex
Assays 47626.8.3.1 Proper Data Analysis 47826.8.3.2 The Development of Clinical Cohorts for Validation 478
VI Autoimmune Disease and Autoantibodies 481
27 Application of Fungal Cyclic Peptides and Metabolites 483Jan Nedvěd, Miroslav Sulc, Alexandr Jegorov,
Anastassios Giannakopulos, Vladimir Havlicek
27.1 Introduction 48327.2 Role of Mass Spectrometry in Fungal Diagnostics 48427.3 The Importance of Secondary Fungal Metabolites: Mycotoxins and
Peptides 48627.4 Biological Activities of Cyclic Peptides 48927.5 Mass Spectrometry of Cyclic Peptides 49027.6 Concluding Remarks 496
28 Microarray Approaches to Autoantibody Profiling 511John M. Astle, Thomas Kodadek
28.1 Introduction 51128.2 Native Antigen Microarrays 51328.2.1 Protein Microarrays 51428.2.2 Peptide Microarrays 51628.2.3 Glycan Microarrays 51828.2.4 Lipid Microarrays 51828.2.5 Reverse-Phase Microarrays 51928.2.6 Antibody Microarrays 52128.3 Antigen Mimic Microarrays 52328.4 Antibody Microarrays in the Clinic 527
29 Identification of Tumor Antigen Directed Autoantibodies 533Sandra Faca, Sam Hanash
29.1 Introduction 53329.2 Proteomic Approaches for the Identification of Tumor Antigen
Directed Autoantibodies 53429.2.1 Some of the Potential Diagnostic Tumor Antigens Directed
Autoantibodies Identified by 2D western blot 53529.2.1.1 PGP 9.5 535
Contents XV
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29.2.1.2 Annexins 1 and 2 53729.2.1.3 Calreticulin 53829.2.1.4 Other Potential Diagnostic Antigens Identified 53929.3 Development of a High-Throughput Microarray Approach
to Screen for Diagnostic Cancer Antigens 54029.3.1 Identification of UCH-L3 as a Potential Diagnostic Marker
for Colon Cancer Based on Screening Using Natural Protein
Microarray-Based Approach 54429.4 Conclusion 546
30 Antibody and Reverse Capture Protein Microarrays
for Clinical Proteomics 549Harvey B. Pollard, Ofer Eidelman, Meera Srivastava, Catherine Joswik,
Stephen Rothwell, Gregory P. Mueller, David M. Jacobowitz,
William B. Guggino, Jerry Wright, Pamela L. Zeitlin,
Cloud P. Paweletz
30.1 Introduction 54930.2 Antibody Microarrays 55030.2.1 A Technique in Development for Many Years 55030.2.2 Analysis of Patient Sera 55030.2.3 A Million Different Proteins in the Human Proteome 55230.2.4 Novel Expression Patterns for Hundreds of Known
Proteins 55230.3 Reverse Capture/Reversed-Phase Protein Microarrays 55330.3.1 A Massively Parallel Platform for Clinical Applications 55330.3.2 Discovery Platform for Signaling Pathway Analysis 55330.3.3 Peptide Arrays for Discovery of Autoantibodies 55530.4 Bioinformatics for Microarray Platforms 55630.4.1 Antibody Microarrays 55630.4.1.1 Overview 55630.4.1.2 Surfaces and Printers 55630.4.1.3 Detection Strategies 55730.4.1.4 Antibody Validation 55830.4.1.5 Normalization and Quantitation 55830.4.1.6 Interpretation 56330.4.2 Reverse Capture/Phase Protein Microarrays 56330.4.2.1 Overview 56330.4.2.2 Substratum Selection 56430.4.2.3 Detection Strategies 56430.4.2.4 Antibody Validation 56430.4.2.5 Normalization and Quantitation 56530.4.2.6 Interpretation 56530.5 Conclusions 566
XVI Contents
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31 Use of Antibody Microarrays in the Analysis of Inflammation,
Autoimmunity, Viral Infection, and Cancer Metastases 571Rodney Lui, Angus Brown, Bosco Wu, Ming-Wei Lin, John Thompson,
Filip Braet, Wayne Dyer, JoDee Lattimore, Peter Macdonald,
Stephen Adelstein, Cristobal G. dos Remedios
31.1 Introduction 57131.1.1 Extracellular Proteins 57231.1.2 How the Antibody Array Works 57231.1.3 Numerical Analyses 57431.1.4 Comparison of Antibody Arrays with Flow Cytometry 57531.2 Inflammation 57531.2.1 Ischemic Heart Disease 57531.3 Autoimmune Disease 58231.3.1 Background to Systemic Lupus Eythematosus (SLE) 58231.3.2 Features of SLE 58231.4 Melanoma Cancer 58331.4.1 The Diagnostic Question 58331.4.2 Outlier Patients 58331.4.3 Hierarchical Clustering 58431.5 Vaccine Inflammation 58431.5.1 Smallpox Vaccination 58431.5.2 DotScan Data 58631.6 Concluding Remarks 588
VII Translation: Discovery to the Clinic 593
32 The Future: Translation from Discovery to the Clinic – Roles
of HUPO and Industry in Biomarker Discovery 595Gilbert S. Omenn, Peipei Ping
32.1 Introduction 59532.2 Brief Introduction of HUPO Initiatives 59632.3 General Lessons Illustrated with the Human Plasma Proteome
Project (HPPP) 59732.4 Brief Descriptions of Other HUPO Initiatives 60232.4.1 The Human Liver Proteome Project (HLPP) 60232.4.2 The HUPO Brain Proteome Project (HBPP) 60332.4.3 The HUPO Cardiovascular Initiative (HCVI) 60332.4.4 The Human Disease Glycomics/Proteome Initiative (HGPI) 60432.4.5 The HUPO Proteomic Standards Initiative (PSI) 60432.4.6 The HUPO Antibody Initiative (HAI) 60532.4.7 The Umbrella HUPO Biomarker Initiative has Several
Components 60532.4.7.1 The Human Kidney-Urine Proteome Project (HKUPP) 60532.4.7.2 The HUPO Cancer Biomarker Initiative 605
Contents XVII
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32.4.7.3 HUPO Biomarkers Bioinformatics (BioBio) Initiative 60632.4.8 The HUPO/Invitrogen Test Sample Project 60632.5 General Strategies for the Use of Plasma or Serum for
Protein Biomarkers 60732.6 Pitfalls in Biomarker Discovery and Validation Studies 60832.7 Concluding Remarks 609
33 Requirements of a Good Biomarker: Translation
into the Clinical Laboratory 615Mario Plebani, Martina Zaninotto, Monica Maria Mion
33.1 Introduction 61533.2 Translational Research 61533.3 Biomarker: What Does It Mean? 61533.3.1 Biomarkers and Drug Development/Evaluation 61733.3.2 Biomarkers in Laboratory Medicine 61833.4 Development of Biomarkers: From Discovery to
Clinical Application 62133.5 Discovery 62233.5.1 Goal (Targeted)-Dependent Options 62333.5.2 Technologies 62333.6 Validation 62433.7 Standardization 62533.8 Clinical Association and Clinical Benefit 62633.9 Conclusions 628
34 Translation of Protein Biomarkers for Clinical Development 633Ian McCaffery, V. Dan Fitzpatrick, Shen Wu Wang, John M. Rossi,
Haifeng Bao, Sid V. Suggs, John Ferbas, Scott D. Patterson
34.1 Introduction 63334.2 Development of Biomarkers for Early Drug Development 63434.3 Marker of Biochemical Coverage – Development of an Assay of
Phospho S6 Protein as a PD Biomarker for Rapamycin Inhibition
of the mTOR Pathway 63834.3.1 PI3K/Akt/mTOR Pathway Background 63834.3.2 Therapeutics Directed at Inhibition of the mTOR Pathway 64034.3.3 Existing PBMC-Based PD Biomarker Assay of mTOR Inhibition 64034.3.4 Development of a Flow Cytometry Based PD Biomarker Assay and
Comparison of PBMC and Whole Blood Results 64134.3.5 Summary of Comparison of PD Biomarker Assays 64634.4 Discussion 64734.5 Summary 650
Index 653
XVIII Contents
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Editor’s Overview
Clinical proteomic is an emerging discipline within proteomics that is exclusively
focused on its application to biomedicine. This book focuses on biomarker discovery
and validation and the pipeline required to increase the probability of success from the
view point of proteomics. It is hoped that sophisticated proteomic techniques and a
better understanding of basic pathophysiologies and protein chemistries will enhance
early disease detection, prognosis, risk stratification and therapeutic monitoring.
Clinical proteomics is a transdisciplinary field garnering aspects coming from
epidemiology, clinical chemistry, clinical medicine and proteomics. It is being built
on these disciplines, adapting experimental design, application, technologies and
knowledge to produce acceptable workflows. With respect to proteomics, success will
depend on the field developing and testing technologies and approaches for both
discovery and/or validation of biomarkers specifically in body fluids. The first section
of the book (Chapters 1–9) is composed of chapters dealing with the underlying
technologies which underpin proteomic applications – exploring the potential and
limitations of the various methods specifically for biomarker analysis. The subse-
quent sections highlight examples where proteomics is being applied in various
relevant clinical areas: cancer (Chapters 10–13); cardiovascular disease (Chapters 14–
19); vascular disease including stroke (Chapters 20–23); toxicity, bacterial and viral
assessment (Chapters 24–27); and autoantibody signatures (Chapters 28–31). In the
final section, three chapters deal with the broader context of clinical proteomics from
the perspective of clinical chemistry, academia and industry.
The dream of clinical proteomics is that patients’ lives are extended and the quality
of life can be improved by including proteomics in a clinicians’ diagnostic arsenal.
This book provides insight into the collective knowledge researchers have gained
over the last several years into a single resource book. It is aimed at addressing the
current issues surrounding the application of proteomics to the development of
biomarkers. There has been considerable hype around clinical proteomics and its
potential to change medicine. That potential remains. Nevertheless, there are many
challenges which need to be met.
Sincerely
The Editors
Michael Dunn and Jennifer Van Eyk
XIX
-
Short Summary
This is the first book to overview the emerging field of clinical proteomics with
sections focused on the latest technologies and summaries by leaders in the fields of
cancer, cardiovascular disease, toxicology, bacterial, viral and autoantibody assess-
ments. This book provides insight into the collective knowledge researchers have
gained over the last several years into a single resource book. It is aimed at
addressing the current issues surrounding the application of proteomics to the
development of biomarkers. There has been considerable excitement around clinical
proteomics and its potential to changemedicine. That potential remains but clinical,
technical and translational issues still need to be overcome.
Acknowledgements
The reasons for creating a book are numerous. The people to thanks are also
numerous. We thank the members of our labs who help to develop and create the
vision for biomarker discovery and our families, who provide the support to allow
those dream. Finally, we thank the authors who shared their insights and under-
standing.
XX Editor’s Overview
-
List of Contributors
Stephen Adelstein
Clinical Immunology
Royal Prince Alfred Hospital
Camperdown
Australia
Ruedi H. Aebersold
Institute of Molecular Systems
Biology,
ETH Zurich
and Faculty of Science
University of Zurich
Wolfgang-Pauli-Str. 16
8093 Zurich
Switzerland
N. Leigh Anderson
The Plasma Proteome Institute
Washington DC 20009-3450
USA
John M. Arthur
Medical University of
South Carolina
Division of Nephrology
PO Box 250623
Charleston, SC 29425-2220
USA
John M. Astle
Departments of Internal Medicine
and Molecular Biology
University of Texas Southwestern
Medical Center
5323 Harry Hines Blvd
Dallas, Texas 75390-9185
USA
Brian M. Bagley
Calibrant Biosystems,
910 Clopper Road,
Suite 220N,
Gaithersburg
MD 20878
USA
Rosamonde E. Banks
Cancer Research UK
Clinical Centre
St James’s University Hospital
Beckett Street
Leeds LS9 7TF
UK
Haifeng Bao
Amgen, Inc.
Molecular Sciences
One Amgen Center Drive,
Mail Stop 1-1A
Thousand Oaks, CA 91320-1799
USA
XXI
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Timothy J. Barder
Eprogen, Inc.,
8205 S. Cass Ave. Ste. 106,
Darien, IL 60561
USA
Luca Bini
Department of Molecular Biology
University of Siena
Via Fiorentina
153100 Siena
Italy
Mary E. Bollard
Department of Biochemistry
University of Cambridge
Tennis Court Road
Cambridge
UK
Filip Braet
Australian Key Centre for
Microscopy and Microanalysis
The University of Sydney
Sydney 2006
Australia
Teresa A. Brentnall
Department of Medicine
University of Washington
1959 NE Pacific St
Seattle, WA 98195
USA
Angus Brown
Bosch Institute (F13)
The University of Sydney
Sydney 2006
Australia
D. Allan Butterfield
Center of Membrane Sciences
University of Kentucky
Lexington, KY 40506
USA
Valerie S. Calvert (12)
Center for Applied Proteomics and
Molecular Medicine
George Mason University
10900 University Blvd, MS 4E3
Manassas, VA 20110
USA
Richard M. Caprioli
Department of Biochemistry
Vanderbilt-Ingram Comprehensive
Cancer Center
9160 MRB III
Vanderbilt University
School of Medicine
Nashville, TN 37232-8575
USA
Julio E. Celis
Inst. Cancer Bio/Human
Genome Res
Danish Cancer Society
Strandboulevarden 49
2100 Copenhagen
Danmark
Daniel W. Chan
Biomarker Discovery Center
Johns Hopkins University
Baltimore, MD
USA
Ru Chen
Department of Medicine
University of Washington
1959 NE Pacific St
Seattle, WA 98195
USA
Songming Chen
The Van Andel Research Institute
333 Bostwick
Grand Rapids, MI 49503
USA
XXII List of Contributors
-
David E Clemmer
Department of Chemistry
Indiana University
800 E. Kirkwood Ave.
Bloomington, IN 47405
USA.
Garry L. Corthals
Biomedical Proteomics Research
Group
Geneva University Hospital/LCCC
24 rue Micheli-du-Crest
1211 Genève 14
Switzerland
David R. Cotter
Johns Hopkins University
School of Medicine
725 N. Wolfe St.
B7 Biophysics
Baltimore, MD 21205
USA
Robert J. Cotter
Johns Hopkins University
School of Medicine
725 N. Wolfe St.
B7 Biophysics
Baltimore, MD 21205
USA
Jacques Deshusses
Biomedical Proteomics Research
Group,
Department of Structural Biology
and Bioinformatics,
Geneva University,
1 Michel Servet,
1211 Geneva,
Switzerland
Don L. DeVoe
Department of Mechanical
Engineering and Bioengineering
Program
University of Maryland,
College Park, MD 20742
USA
Pamela M. Donoghue
Immune Regulation Research
Group
Trinity College
Dublin 2
Ireland
Cristobal G. dos Remedios
Bosch Institute (F13)
The University of Sydney
Sydney 2006
Australia
Michael J. Dunn
University College Dublin
Proteome Research Centre
UCD Conway Institute of
Biomolecular and Biomedical
Research
Dublin 4
Ireland
Wayne Dyer
Australian Red Cross Blood Service
Clarence Street
Sydney 2000
Australia
Marta Dziechciarkova
Palacky University and
University Hospital Olomouc
Faculty of Medicine and Dentistry
Puskinova 6
77520 Olomouc
Czech Republic
List of Contributors XXIII
-
Petr Dzubak
Faculty of Medicine and Dentistry
Palacky University and University
Hospital Olomouc
Puskinova 6
77520 Olomouc
Czech Republic
Kirsten H. Edmiston
Center for Applied Proteomics and
Molecular Medicine
George Mason University
10900 University Blvd, MS 4E3
Manassas, VA 20110
USA
Ofer Eidelman
Department of Anatomy,
Physiology and Genetics
USU School of Medicine (USUHS)
4301 Jones Bridge Road
Bethesda, MD 20814
USA
Andrew Emili
Banting and Besst Department of
Medical Research and Department
of Medical Genetics and
Microbiology
Donnelly Centre for Cellular and
Biomolecular Research
University of Toronto
Canada
Jane English
Royal College of Surgeons in
Ireland
Department of Psychiatry
Education and Research Centre
Beaumont Hospital
Dublin 9
Ireland
Virginia Espina
Center for Applied Proteomics and
Molecular Medicine
George Mason University
10900 University Blvd, MS 4E3
Manassas, VA 20110
USA
Sandra Faca
Fred Hutchinson Cancer Research
Center
1100 Fairview Avenue N., M5-C800
P.O. Box 19024
Seattle, WA 98109
USA
Xueping Fang
Department of Chemistry and
Biochemistry
University of Maryland,
College Park, MD 20742
USA
John Ferbas
Amgen, Inc.
Clinical Immunology
One Amgen Center Drive,Mail Stop
30E-3-C
Thousand Oaks, CA 91320-1799
USA
Roisean E. Ferguson
Cancer Research UK Clinical
Centre
St James’s University Hospital
Beckett Street
Leeds LS9 7TF
UK
XXIV List of Contributors
-
V. Dan Fitzpatrick
Amgen, Inc.
Molecular Sciences
One Amgen Center Drive, Mail
Stop 1-1A
Thousand Oaks, CA 91320-1799
USA
Melanie Föcking
Royal College of Surgeons in
Ireland
Department of Psychiatry
Education and Research Centre
Beaumont Hospital
Dublin 9
Ireland
Qin Fu
Department of Medicine
Johns Hopkins Bayview Proteomics
Center
Johns Hopkins University
Baltimore, MD 21224
USA
Suresh Jivan Gadher
Beckman Coulter International S.A.
22, rue Juste Olivier, Casa Postale
1059
1260 Nyon 1
Switzerland
Robert E. Gerszten, M.D.
Cardiology Division and Center for
Immunology and Inflammatory
Diseases
Massachusetts General Hospital
East-8307
149 13th Street
Charlestown, MA 02129
USA
Anastassios Giannakopulos
Institute of Microbiology
Academy of Sciences of the
Czech Republic
Videnska 1083
142 20 Prague
Czech Republic
David R. Graham
Bayview NHLBI Proteomics Center
Johns Hopkins School of Medicine
Bayview Campus
5200 Eastern Avenue
Baltimore, MD 21224
USA
Anthony Gramolini
Department of Physiology and
Heart and Stroke/Richard Lewar
Center of Excellence
University of Toronto
112 College St, Rm 307
Toronto, Ontario
Canada
William B. Guggino
Department of Physiology,
Johns Hopkins University
School of Medicine,
JHMI,
Baltimore, MD 21205
USA
Rebekah L. Gundry (18)
Johns Hopkins University
School of Medicine
725 N. Wolfe St.
B7 Biophysics
Baltimore, MD 21205
USA
Brian B. Haab
The Van Andel Research Institute
333 Bostwick
Grand Rapids, MI 49503
USA
List of Contributors XXV
-
Marian Hajduch
Faculty of Medicine and Dentistry
Palacky University and University
Hospital Olomouc
Puskinova 6
77520 Olomouc
Czech Republic
Petr Halada
Institute of Microbiology
Czech Academy of Sciences
Videnska 1083
14220 Praha
Czech Republic
Samir M. Hanash
Fred Hutchinson Cancer Research
Center
1100 Fairview Avenue N., M5-C800
P.O. Box 19024
Seattle, WA 98109
USA
Gerald Hart
725 N Wolfe Street
Biochemistry Department
Baltimore, MD 21205
USA
Vladimir Havlicek
Institute of Microbiology
Academy of Sciences of the Czech
Republic
Videnska 1083
142 20 Prague
Czech Republic
Jan Hirsh
Department of Anesthesia and
Perioperative Medicine
University of California
505 Parnassus Ave. HSW 825
San Francisco, CA 94143-0130
USA
Denis F. Hochstrasser
Biomedical Proteomics Research
Group
Clinical Chemistry Laboratory
Geneva University Hospital
Geneva
Switzerland
Don Hunt
Chemistry Department
University of Virginia
Charlottesville, VA 22908
USA
David M. Jacobowitz
Laboratory of Clinical Science,
National Institute for Mental
Health,
Bethesda, MD 20892
USA
Jon M. Jacobs
Biological Sciences Division
Pacific Northwest National
Laboratory
P. O. Box 999
Richland, WA 99352
USA
Alexandr Jegorov
Institute of Microbiology
Academy of Sciences of the Czech
Republic
Videnska 1083
142 20 Prague
Czech Republic
XXVI List of Contributors
-
Robert L. Jesse
Department of Internal Medicine
Cardiology Division
Medical College of Virginia
Virginia Commonwealth University
Veterans Health Administration
12th and Marshall Streets
Richmond, VA 23298-0051
USA
Catherine Joswik
Department of Anatomy
Physiology and Genetics
USU School of Medicine (USUHS)
4301 Jones Bridge Road
Bethesda, MD 20814
USA
Urban A. Kiernan
Intrinsic Bioprobes, Inc.
2155 E. Conference Drive, Suite 104
Tempe, AZ 85284
USA
Thomas Kodadek
University of Texas
Southwestern Medical Center
Departments of Internal Medicine
and Molecular Biology
5323 Harry Hines Blvd
Dallas, TX 75390-9185
USA
Hana Kovarova
Czech Academy of Sciences
Institute of Animal Physiology and
Genetics
Rumburska 89
27721 Libechov
Czech Republic
JoDee Lattimore
Sydney Melanoma Unit
Royal Prince Alfred Hospital
Camperdown
Australia
Cheng S. Lee
Department of Chemistry and
Biochemistry
University of Maryland
College Park, MD 20742
USA
Gregory D. Lewis
Center for Immunology and
Inflammatory Diseases
Massachusetts General Hospital
Charlestown, MA and Harvard
Medical School
Boston, MA
USA
Daniel C. Liebler
Southwest Environmental Health
Sciences Center
College of Pharmacy
University of Arizona
Tucson, AZ 85721-0207
USA
Ming-Wei Lin
Clinical Immunology
Royal Prince Alfred Hospital
Camperdown
Australia
Lance A. Liotta
Center for Applied Proteomics and
Molecular Medicine
George Mason University
10900 University Blvd, MS 4E3
Manassas, VA 20110
USA
David M. Lubman
Department of Surgery
1150 West Medical Center Drive
Ann Arbor, MI 48109-1055
USA
List of Contributors XXVII
-
Rodney Lui
Bosch Institute (F13)
The University of Sydney
Sydney 2006
Australia
Peter MacDonald
Cardiopulmonary Transplant Unit
St. Vincent’s Hospital
Darlinghurst, 2010
Australia
Ian McCaffery
Amgen, Inc.
Molecular Sciences
One Amgen Center Drive,
Mail Stop 1-1A
Thousand Oaks, CA 91320-1799
USA
Dr. Ciara A. McManus
University College Dublin
Proteome Research Centre
UCD Conway Institute of
Biomolecular and Biomedical
Research
Dublin 4
Ireland
Michael A. Matthay
Department of Anesthesia and
Perioperative Medicine
University of California
505 Parnassus Ave. HSW 825
San Francisco, CA 94143-0130
USA
Bruce Alex Merrick
Proteomics Group
National Institute of Environmental
Health Sciences
P.O. Box 12233
Research Triangle Park, NC 27709
USA
Monica Maria Mion
Department of Laboratory Medicine
University-Hospital
Via Giustiniani 2
35128 Padova
Italy
Harald Mischak
Mosaiques-Diagnostics and
Therapeutics AG
Mellendorfer Str. 7-9
30173 Hannover
Germany
David E. Misek
University of Michigan
Department of Surgery
1150 West Medical Center Drive
Ann Arbor, MI 48109-1055
USA
Gregory P. Mueller
Department of Anatomy,
Physiology and Genetics
USU School of Medicine (USUHS)
4301 Jones Bridge Road
Bethesda, MD 20814
USA
Dobrin Nedelkov
Intrinsic Bioprobes, Inc.
2155 E. Conference Drive, Suite 104
Tempe, AZ 85284
USA
Jan Nedvěd
Institute of Microbiology
Academy of Sciences of the Czech
Republic
Videnska 1083
142 20 Prague
Czech Republic
XXVIII List of Contributors