Handbook of Biomarkers (eBook)

Preface 6
Contents 8
List of Abbreviations 20
1 Introduction 22
Definitions 22
Historical Aspects of Biomarkers 23
Classification of Biomarkers 24
Biological Marker as Response to Therapeutic Intervention 24
Pharmacokinetic/Pharmacodynamics Biomarkers 25
Predictive Biomarkers 25
Valid Biomarkers 26
Types of Biomarkers 26
Genes as Biomarkers 27
Proteins as Biomarkers 27
Proteomics 28
DNA Biomarkers 28
Mitochondrial DNA 28
Mitochondrial Mutations 29
RNA Biomarkers 29
Transcriptomics 30
MicroRNAs 31
Metabolomics 31
Glycomics 32
Single-Nucleotide Polymorphisms 33
Haplotyping 33
Cell Biomarkers of Disease 34
Stem Cell Biomarkers 34
Cancer Stem Cell Biomarkers 35
Endoglin as a Functional Biomarker of Stem Cells 35
p75NTR as a Biomarker to Isolate Adipose Tissue-Derived Stem Cells 36
Protein Expression Profile as Biomarker of Stem Cells 36
STEMPRO EZChekTM for Analysis of Biomarkers of hESCs 36
SSEA-4 as Biomarker of MSCs 37
Autoantibodies as Biomarkers of Autoimmune Diseases 37
The Ideal Biomarker 38
Biomarkers and Systems Biology 39
Systems Biology Approach to Biomarker Identification 40
Relation of Biomarkers to Other Technologies and Health care 41
Biomarkers and Translational Medicine 41
Limitations of Use of Biomarkers in Health Care 41
2 Technologies for Discovery of Biomarkers 43
Introduction 43
Detection of Biomarkers in Tissues and Body Fluids 43
Disease Biomarkers in Breath 43
Portable Breath Test for Volatile Organic Compounds 44
Detection of Breath Biomarkers by Sensation Technology 44
Detection of Breath Biomarkers Optical Frequency Comb Spectroscopy 45
Genomic Technologies 45
Gene Expression 45
Whole-Genome Expression Array 46
Gene Expression Profiling on Whole Blood Samples 47
Profiling Gene Expression Patterns of White Blood Cells 47
Tissue Microarrays for Study of Biomarkers 48
Epigenomic Technologies 48
Discovery of Methylation Biomarkers 49
Proteomic Technologies 50
2D GE 51
Isotope-Coded Affinity Tags 52
Mass Spectrometry 53
MALDI Mass Spectrometry for Biomarker Discovery 53
2D PAGE and Mass Spectrometry 54
Quantitative Tandem MS 55
Single-Molecule Mass Spectrometry Using a Nanopore 55
Imaging Mass Spectrometry 56
Requirements for MS-Based Proteomic Biomarker Development 57
Liquid Chromatography--MS Combination 57
Protein Tomography 57
Protein Biochips/Microarrays and Biomarkers 58
Detection of Biomarkers Using Peptide Array Technology 58
Protein Nanobiochip 59
Antibody-Based Biomarker Discovery 59
Real-Time PCR for Quantification of Protein Biomarkers 59
Magnetic Beads for Protein Biomarker Discovery 60
CellCarta® Proteomics Platform 60
MASStermindTM 61
Search for Biomarkers in Body Fluids 61
Challenges and Strategies for Discovery of Protein Biomarkers in Plasma 61
3D Structure of CD38 as a Biomarker 63
BDTM Free Flow Electrophoresis System 63
Isotope Tags for Relative and Absolute Quantification 64
Plasma Protein Microparticles as Biomarkers 64
Proteome Partitioning 65
Stable Isotope Tagging Methods 65
Technology to Measure Both the Identity and the Size of The Biomarker 66
Biomarkers in the Urinary Proteome 67
Peptides in Body Fluids and Tissues as Biomarkers of Disease 67
Analysis of Peptides in Bodily Fluids 68
Serum Peptidome Patterns 68
SISCAPA Method for Quantitating Proteins and Peptides in Plasma 69
Verification for Interlaboratory Reproducibility of Protein Biomarkers 69
Significance of Similar Protein Biomarkers in Different Tissues 70
Glycomic Technologies 70
Metabolomic Technologies 71
Mass Spectrometry-Based Kits for Discovery of Metabolic Biomarkers in Plasma 72
Urinary Profiling by Capillary Electrophoresis 72
Lipid Profiling 73
Role of Metabolomics in Biomarker Identification and Pattern Recognition 73
Validation of Biomarkers in Large-Scale Human Metabolomics Studies 74
Lipidomics 74
Fluorescent Indicators for Biomarkers 75
Molecular Imaging Technologies 76
Computer Tomography 76
Magnetic Resonance Imaging 77
Positron Emission Tomography 77
Advantages of Imaging Biomarkers 78
Monitoring In Vivo Gene Expression by Molecular Imaging 78
Molecular Imaging In Vivo as a Biomarker 79
Challenges and Future Prospects of Molecular Imaging 79
Basic Research in Molecular Imaging 79
Imaging Intracellular NADH as a Biomarker of Disease 79
Devices for Molecular Imaging 80
Imaging Biomarkers in Clinical Trials 80
Molecular Imaging in Clinical Practice 80
Nuclear Magnetic Resonance 81
Chemical Derivatization to Enhance Biomarker Detection by NMR 81
Fluxomics by Using NMR 82
Nanobiotechnology 82
Nanomaterials for Biolabeling 83
Quantum Dot Molecular Labels 84
Bioconjugated QDs for Multiplexed Profiling of Biomarkers 84
Magnetic Nanotags for Multipley Detection of Biomarkers 85
Nanoproteomics and Biomarkers 85
High-Field Asymmetric Waveform Ion Mobility Mass Spectrometry 86
Nanoparticles for Molecular Imaging 86
Nanoparticles for Discovering Biomarkers 87
Nucleoprotein Nanodevices for Detection of Cancer Biomarkers 87
Future Prospects of Application of Nanobiotechnology for Biomarkers 87
Bioinformatics 88
Biomarker Workflow Guide 88
Analysis of Microarray Data for Selecting Useful Biomarkers 88
Role of Bioinformatics in Discovery of Proteomic Biomarkers 89
Role of Bioinformatics in Detection of Cancer Biomarkers 90
Biomarker Databases 90
Gene Networks as Biomarkers 91
Pitfalls in the Discovery and Development of Biomarkers 91
3 Biomarkers and Molecular Diagnostics 93
Introduction 93
Molecular Diagnostic Technologies 93
Polymerase Chain Reaction 93
Real-Time PCR Systems 94
Combined PCR--ELISA 95
Non-PCR Methods 96
Linked Linear Amplification 96
Transcription-Mediated Amplification 97
Rapid Analysis of Gene Expression 97
WAVE Nucleic Acid Fragment Analysis System 97
DNA Probes with Conjugated Minor Groove Binder 98
Rolling-Circle Amplification Technology 99
Gene-Based Diagnostics Through RCAT 99
RCAT Immunodiagnostics 100
RCAT Biochips 100
RCAT Pharmacogenomics 101
Circle-to-Circle Amplification 101
Biochips and Microarrays 101
Applications of Biochips/Microarrays 102
Role of Biochip/Microarrays in Discovery of Biomarkers 102
Detection and Expression Profiling of miRNA 103
Real-Time PCR for Expression Profiling of miRNAs 103
Use of LNA to Explore miRNA 104
Microarrays for Analysis of miRNA Gene Expression 104
4 Biomarkers for Drug Discovery and Development 106
Introduction 106
Biomarker Technologies for Drug Discovery 107
Proteomics-Based Biomarkers for Drug Discovery 107
Chemoproteomics 108
Transcriptomics for Drug Discovery 108
Metabolomics for Drug Discovery 109
Biomarkers and Drug Safety 110
Biomarkers of Adverse Drug Reactions 110
Applications of Biomarkers in Drug Safety Studies 110
Genomic Technologies for Toxicology Biomarkers 111
Proteomic Technologies for Toxicology Biomarkers 112
Metabonomic Technologies for Toxicology Biomarkers 112
Integration of Genomic and Metabonomic Data to Develop Toxicity Biomarkers 113
Toxicology Studies Based on Biomarkers 113
Biomarkers of Hepatotoxicity 114
Biomarkers of Nephrotoxicity 115
Cardiotoxicity 117
Neurotoxicity 117
Applications of Biomarkers for Drug Development 118
Application of Metabonomics/Metabolomics for Drug Development 118
Role of Pharmacokinetic/Pharmacodynamic Biomarkers in Drug Development 119
Molecular Imaging as a Biomarker in Drug Development 120
Molecular Imaging in Preclinical Studies 121
Molecular Imaging in Clinical Trials 122
Prospects of Molecular Imaging in Drug Discovery and Development 123
Biomarkers in Clinical Trials 124
NIH Recommendations on the Use of Biomarkers in Clinical Trials 124
Advantages of Biomarkers for Drug Development 126
Limitations and Problems with Use of Biomarkers in Clinical Trials 126
Application of Biomarkers by the Pharmaceutical Companies 127
Use of Biomarkers in Relation to Stage of Drug Discovery and Development 127
Drug Development in Cardiovascular Disorders 128
Drug Development in Neurological Disorders 128
Future Prospects of Biomarker-Based Drug Development 129
The Biomarker Alliance 129
Molecular Libraries and Imaging Roadmap of NIH 130
Biomarkers Consortium 131
5 Role of Biomarkers in Health Care 133
Introduction 133
Biomarkers of Inflammation 134
Biomarkers of Oxidative Stress 134
Oxidative DNA Damage 134
Proteins as Biomarkers of Oxidative Stress in Diseases 135
1,4-Dihydroxynonane Mercapturic Acid 135
Biomarkers in Metabolic Disorders 135
Biomarkers of Acute Intermittent Porphyria 135
Liver X Receptors 136
Biomarkers of Diabetes Mellitus 136
Biomarkers of Hyperglycemia 137
Biomarkers of Diabetes-Associated Oxidative Stress 138
Biomarkers of Inflammation Associated with Diabetes 138
Biomarkers of Renal Complications in Diabetes Mellitus Type 2 138
Biomarkers of Diabesity 139
Glycosylated Hemoglobin in Diabetes Mellitus 139
Lack of C-Peptide as Biomarker of Complications of Diabetes Type 1 139
Serum Retinol Binding Protein-4 as Biomarker of Insulin Resistance 140
Biomarkers of Metabolic Syndrome 140
Adiponectin 140
Biomarkers in Immune Disorders 141
Biomarkers of Failure of Transplanted Organs 141
Immunological Biomarkers of Graft Versus Host Disease 142
Biomarkers of Renal Allograft Failure 143
Biomarkers of Lung Transplant Rejection 144
Systemic Lupus Erythematosus 144
Current Management and Need for Biomarkers 144
Role of Collaborative Efforts and Databases of SLE Biomarkers 145
C4d-Bearing Reticulocytes 145
Adiponectin 146
CB-CAPS 146
Genetic Loci of SLE 146
Epigenetic Biomarkers of SLE 147
Biomarkers of Musculoskeletal Disorders 147
Biomarkers of Rheumatoid Arthritis 147
Biomarkers of Spondylarthritis 148
Biomarkers of Osteoarthritis 149
Biomarkers of Osteoporosis 150
Dual X-Ray Absorptiometry 151
Bone Imaging with Quantitative CT and MRI 151
Assays for Detection of Biomarkers of Osteoporosis 152
Biomarkers of Infectious Diseases 152
Procalcitonin 153
Endotoxin 154
Chemokines as Biomarkers of Infection 155
Circulating CPS-1 as Biomarkers of Organ Damage in Sepsis 155
Application of Proteomics for Discovering Biomarkers of Infections 155
Systemic Inflammatory Response Syndrome 156
Tuberculosis 156
Conventional Diagnosis of Tuberculosis 157
Molecular Diagnostics for Tuberculosis 157
Biomarkers for Tuberculosis 158
Biomarkers of Pulmonary Tuberculosis in the Breath 158
Biomarkers of Viral Infections 159
Viral Hepatitis 159
Biomarkers of SARS 162
Biomarkers of HIV 162
Biomarkers in Parasitic Infections 163
Role of Biomarkers in Malaria 163
Identification of Biomarkers in Schistosomiasis Infections 164
Biomarkers of Liver Disease 165
Breath Biomarkers of Liver Disease 165
Biomarkers of Viral Hepatitis B and C 166
Biomarkers of Liver Injury 167
Biomarkers of Liver Cirrhosis 167
FibroMax 167
Biomarkers of Pancreatitis 168
Biomarkers of Renal Disease 168
Cystatin C as Biomarker of Glomerular Filtration Rate 169
Proteomic Biomarkers of Acute Kidney Injury 169
Biomarkers of Lupus Nephritis 170
Biomarkers of Diabetic Nephropathy 170
Biomarkers of Pulmonary Diseases 170
Biomarkers of Oxidative Stress in Lung Diseases 172
Biomarkers of Survival in Acute Respiratory Distress Syndrome 172
Urinary NO as Biomarker of ARDS 172
Plasma Biomarkers Related to Inflammation 172
Pulmonary Surfactant Proteins as Biomarkers for Lung Diseases 173
Cytokine/Chemokine Biomarkers of SARS 173
Biomarkers of Chronic Obstructive Pulmonary Disease 174
Increased Expression of PIGF as a Biomarker of COPD 174
Chromagranin A (CgA) as Biomarker of Airway Obstruction in Smokers 175
BNP as a Biomarker of Chronic Pulmonary Disease 175
Alpha1-Antitrypsin Gene Polymorphisms Predisposing to Emphysema 175
Biomarkers of Asthma 176
Comparison of Biomarkers of Asthma and COPD 176
Exhaled NO as a Biomarker of Asthma 176
Cytokines as Biomarkers of Asthma Severity 177
Biomarker for Rhinovirus-Induced Asthma Exacerbation 178
Biomarkers for Predicting Response to Corticosteroid Therapy 178
IgE as Guide to Dosing of Omalizumab for Asthma 179
Endothelin-1 in Exhaled Breath as Biomarker of Asthma 179
Biomarkers for Cystic Fibrosis 179
Biomarkers of Pulmonary Embolism 180
Biomarkers in Obstetrics and Gynecology 181
Biomarkers for Preeclampsia 181
Protein Biomarker of Preeclampsia in Urine 181
Protein Biomarkers of Preeclampsia in CSF 182
Protein HtrA1 as Biomarker for Preeclampsia 182
sFlt1 and Soluble Endoglin as Biomarkers of Preeclampsia 183
RNA Biomarkers 184
Biomarkers of Premature Birth 184
Biomarkers of Oxidative Stress in Complicated Pregnancies 185
Biomarkers of Premenstrual Dysphoric Disorder 185
Biomarkers of Endometriosis 186
Fetal Biomarkers in Maternal Blood 186
Biomarkers for Genetic Disorders 187
Biomarkers for Down's Syndrome 187
Biomarkers for Muscular Dystrophy 188
Biomarkers of Phenylketonuria 188
Biomarkers of Lysosomal Storage Disorders 189
Biomarkers of Aging 191
Study of Biomarkers of Aging in a Genetically Homogeneous Population 192
Genes as Biomarkers of Aging 192
Telomere Attrition as Aging Biomarker 193
Mitochondrial Mutations as Biomarkers of Aging 193
Role of Bioinformatics in Search for Biomarkers of Aging 194
Effect of Calorie Restriction on Biomarkers of Longevity 194
Biomarkers of Miscellaneous Disorders 194
Biomarkers of Inflammatory Bowel Disease 194
Biomarkers of Erectile Dysfunction 195
Biomarkers of Heat Stroke 196
Biomarkers of Pain 197
Biomarkers of Neuropathic Pain 197
Brain Insular Glutamate as Biomarker of Fibromyalgia 197
Biomarkers of Visceral Pain 198
Nasal Nitric Oxide as a Biomarker of Response to Rhinosinusitis Therapy 198
Biomarkers Common to Multiple Diseases 199
Biomarkers and Nutrition 200
Biomarkers in Nutritional Epidemiology 200
Biomarkers of Nutritional Status 200
Biomarkers of Branched-Chain Amino Acid Status 201
Biomarkers of Caloric Restriction 201
Biomarkers of Malnutrition 202
Proteomic Biomarkers and Nutrition 202
Biomarkers of GeneEnvironmental Interactions in Human Disease 202
Future Role of Biomarkers in Health Care 203
Applications of Biomarkers Beyond Health Care 204
Combating Bioterrorism 204
Biomarkers for Monitoring Human Exposure to Environmental Toxins 204
Application of Biomarkers in Animal Health 205
6 Biomarkers of Cancer 207
Introduction 207
The Ideal Biomarker for Cancer 207
Single Versus Multiple Biomarkers of Cancer 208
Types of Cancer Biomarkers 209
miRNAs as Biomarkers in Cancer 210
Location of miRNAs 210
Circulating miRNAs for Cancer Detection 212
Diagnostic Value of miRNA in Cancer 213
Biomarkers of Epigenetic Gene Silencing in Cancer 213
Immunologic Biomarkers of Cancer 214
Molecular Diagnostic Techniques for Cancer 214
Technologies for Detection of Cancer Biomarkers 215
Genomic Technologies for Cancer Biomarkers 215
Cold-PCR 215
Genome Analysis at the Molecular Level 216
Sequencing-Based Approaches for Detection of Cancer Biomarkers 216
Early Detection of Tumor Suppressor Gene Mutations 217
Biomarkers of PTEN Tumor Suppressor Gene Status 217
HAAH as a Biomarker for Cancer 218
Telomerase as a Biomarker of Cancer 218
Digital Karyotyping for Cancer Biomarkers 219
LigAmp for Detection of Gene Mutations in Cancer 219
Mitochondrial DNA as a Cancer Biomarker 220
Tissue Microarrays for Study of Cancer Biomarkers 220
Molecular Fingerprinting of Cancer 221
Biomarkers of Inflammation in Cancer 222
Proteomic Technologies for Detecting Biomarkers of Cancer 223
2D PAGE 223
Antibody-Based Detection of Protein Biomarkers 224
Aptamer-Based Molecular Probes for Cancer Biomarker Discovery 225
Cancer Immunomics to Identify Autoantibody Signatures 226
Desorption Electrospray Ionization for Detection of Cancer Biomarkers 226
Detection of Circulating Nucleosomes in Serum of Cancer Patients 226
Detection of Tumor Markers with ProteinChip Technology 227
eTag Assay System for Cancer Biomarkers 227
Glycoprotein Biomarkers of Cancer 228
HER-2/neu Oncoprotein as Biomarkers for Cancer 229
Humoral Proteomics 229
Laser Capture Microdissection 230
Phage Display Technology 230
Proteomic Analysis of Cancer Cell Mitochondria 231
Proteomic Technologies for Detection of Autoimmune Biomarkers 231
SELDI-TOF MS 232
Serum Proteome Analysis for Early Detection of Cancer 232
Tissue Proteomics for Discovery of Cancer Biomarkers 232
Metabolomic Biomarkers of Cancer 233
Choline Phospholipid Biomarkers of Cancer 233
Hypoxia-Inducible Factor-1 234
Detection of Drug Resistance in Cancer by Metabolic Profiling 234
Epitomics for the Early Detection of Cancer 235
Detection of Biomarkers of DNA Methylation 235
Epigenomics Marker Machine for DNA Methylation Biomarkers 237
Methods Using Bisulfite for Detecting DNA Methylation Biomarkers 237
Non-bisulfite Methods for Detecting Methylation Biomarkers 239
Sequenom's Integrated Genetic Analysis Platform 239
Histone Deacetylase 239
Mucins as Epigenetic Biomarkers in Epithelial Cancers 240
Nanobiotechnology for Early Detection of Cancer to Improve Treatment 240
Selective Expression of Biomarkers by Cancer Compared with Normal Tissues 241
Ultrasound Radiation to Enhance Release of a Tumor Biomarker 241
In Vivo Imaging of Cancer Biomarkers 242
Computer Tomography 242
Positron Emission Tomography 242
Xenon-Enhanced Magnetic Resonance Imaging 243
Optical Systems for In Vivo Molecular Imaging of Cancer 243
Kallikrein Gene Family and Cancer Biomarkers 244
Circulating Cancer Cells in Blood as Biomarkers of Cancer 244
Applications of Cancer Biomarkers 245
Use of Biomarkers for Cancer Classification 246
Use of Biomarkers for Early Detection of Cancer 246
Application of Biomarkers for Cancer Diagnosis 247
Methylated DNA Sequences as Cancer Biomarkers 247
MicroRNA Expression Profiling for Diagnosis of Human Cancers 248
MUC4 as a Diagnostic Biomarker in Cancer 248
Applications of Biomarkers for Cancer Diagnosis Plus Therapy 249
Asparagine Synthetase as Biomarker for Therapy with L-Asparaginase 249
Peptide-Based Agents for Targeting Cancer Biomarkers 250
Biomarkers for Assessment of Efficacy of Cancer Therapy 250
ERCC1-XPF Expression as a Biomarker of Response to Chemotherapy 250
GRP78 as a Predictor for Chemoresponsiveness of Breast Cancer 251
HtrA1 as a Biomarker of Response to Chemotherapy in Ovarian Cancer 251
P53 Expression Level as Biomarker of Efficacy of Cancer Gene Therapy 251
Biomarkers of Angiogenesis for Developing Antiangiogenic Therapy 252
Tumor Endothelial Markers 252
Circulating Endothelial Cells as Targets for Antiangiogenic Drugs 253
Biomarkers of Response to Antiangiogenic Agent Brivanib Alaninate 253
DCE-MRI Biomarkers for Evaluation of Antiangiogenic Agents 254
Combination of Soluble Biomarkers of Angiogenesis with Imaging 254
Biomarkers of Drug Resistance in Cancer 255
A Systems Approach to Biomarkers of Innate Drug Resistance 255
Epithelial Membrane Protein-1 as a Biomarker of Gefitinib Resistance 255
Methylation Biomarkers of Drug Resistance in Cancer 256
Biomarkers of Radiation Exposure 256
Role of Biomarkers in Drug Development in Oncology 257
Molecular Imaging of Tumor as a Guide to Drug Development 257
Use of PET to Assess Response to Anticancer Drugs 258
Use of MRI to Assess Response to Anticancer Drugs 258
Biomarkers in Plucked Hair for Assessing Cancer Therapy 259
Molecular Targets of Anticancer Drugs as Biomarkers 259
Safety Biomarkers in Oncology Studies 260
Role of Biomarkers in Phase I Clinical Trials of Anticancer Drugs 260
Biomarkers According to Location/Type of Cancer 261
Bladder Cancer Biomarkers 261
Urinary Telomerase as Biomarker for Detection of Bladder Cancer 261
Brain Cancer Biomarkers 262
Biomarkers to Predict Response to EGFR Inhibitors 262
CD133 as Biomarker of Resistance to Radiotherapy 263
Circulating Microvesicles as Biomarkers 263
CSF Protein Profiling 264
CSF Attractin as a Biomarker of Malignant Astrocytoma 264
Methylation Profiling of Brain Tumors 265
Metabolite Biomarkers of Brain Tumors 266
miRNA Biomarker of Brain Tumors 266
MRI Biomarker for Response of Brain Tumor to Therapy 266
Neuroimaging Biomarkers Combined with DNA Microarray Analysis 267
Receptor Protein Tyrosine Phosphatase as Biomarker of Gliomas 267
Serum Protein Fingerprinting 267
Breast Cancer Biomarkers 268
Biomarkers of Breast Cancer in Breath 268
Biomarkers for Breast Cancer in Nipple Aspiration Fluid 270
Decreased Breast Density as a Biomarker of Response to Tamoxifen 270
Flow Cytometry for Quantification of Biomarker Expression Patterns 270
Plasma Proteomics for Biomarkers of Breast Cancer 270
Quantitative Real-time PCR Assays for Biomarker Validation 271
Cdk6 as a Biomarker of Breast Cancer 272
Centromere Protein-F 272
Carbonic Anhydrase IX 273
COX-2 as a Biomarker of Breast Cancer 273
Glycomic Biomarkers of Breast Cancer 274
HER-2/neu Oncoprotein 274
High Mobility Group Protein A2 275
Lipocalin 2 as Biomarker of Breast Cancer Progression 276
Mammaglobin 276
p27 Expression as Biomarker for Survival After Chemotherapy 277
Podocalyxin 277
Progranulin as a Biomarker of Breast Cancer 278
Proliferating Cell Nuclear Antigen 278
Protein Kinase C as a Predictive Biomarker of Metastatic Breast Cancer 278
Retinoblastoma Tumor Suppressor Gene as a Biomarker 279
Riboflavin Carrier Protein 279
Serum CA-15-3 as Biomarker of Prognosis in Advanced Breast Cancer 280
Suppressor of Deltex Protein 280
Tumor Microenvironment as Biomarker of Metastasis in Breast Cancer 281
Type III TGF- Receptor as Regulator of Cancer Progression 281
Diagnostic Tests Based on Breast Cancer Genes 282
Prognostic Role of Breast Cancer Genes 283
Protein Biomarkers for Breast Cancer Prevention 284
Biomarkers to Evaluate Efficacy of Chemoprevention 285
Biomarker Prognosis of Breast Cancer Treated with Doxorubicin 285
Cervical Cancer Biomarkers 286
Gastrointestinal Cancer Biomarkers 287
Colorectal Cancer Biomarkers 287
Gastric Cancer Biomarkers 292
Head and Neck Cancer 293
Leukemia Biomarkers 294
Chromosome Translocations in Leukemias 294
DNA Methylation Biomarkers in Leukemia 295
Gene Mutations as Biomarkers in Leukemia 295
Molecular Diagnostic Techniques for Leukemia 296
Proteomic Technologies for Discovering Biomarkers of Leukemia 297
Biomarkers of Chronic Lymphocytic Leukemia 297
Biomarkers of Chronic Myeloid Leukemia 298
Biomarkers of Drug Resistance in Leukemia 298
Biomarkers of Myelodysplastic Syndromes 299
Liver Cancer Biomarkers 299
Lung Cancer Biomarkers 300
Autoantibodies as Biomarkers in Lung Cancer 300
Biomarkers Associated with Neuroendocrine Differentiation in NSCLC 302
Biomarkers of Chronic Inflammation in Lung Cancer 302
Biomarkers for Predicting Sensitivity to Chemotherapy in Lung Cancer 303
Biomarkers for Prediction of Sensitivity to EGFR Inhibitors 303
Circulating Tumor Cells as Biomarkers 305
Gene Expression Profiling for Biomarkers of Lung Cancer 305
Methylation Biomarkers of Lung Cancer 306
miRNA Biomarkers in Lung Cancer 306
Proteomic Biomarkers in Exhaled Breath Condensate 307
Serum Protein Biomarkers of Lung Cancer 307
tNOX as Biomarker of Lung Cancer 308
Tumor-Derived DNA and RNA Biomarkers in Blood 308
Volatile Organic Compounds in the Exhaled Breath 309
Malignant Pleural Mesothelioma 309
Melanoma Biomarkers 310
Nasopharyngeal Carcinoma Biomarkers 312
Proteomic Biomarkers of Nasopharyngeal Cancer 312
miRNA Biomarkers of Nasopharyngeal Carcinoma 313
Oral Cancer Biomarkers 314
Ovarian Cancer Biomarkers 315
Gene Expression Studies 315
Mutation of Genes 316
Serum CA-125 as Biomarker of Ovarian Cancer Prognosis 317
Serum Albumin-Associated Peptides and Proteins 317
Multiplex Assays for Biomarkers of Ovarian Cancer 318
Epitomics Approach for Ovarian Cancer Biomarkers in Serum 319
Concluding Remarks on Biomarker-Based Tests of Ovarian Cancer 320
Pancreatic Cancer Biomarkers 320
Discovery and Validation of Pancreatic Cancer Biomarkers 321
Cancer Stem Cells as Biomarkers of Pancreatic Cancer 322
miRNA Biomarkers of Pancreatic Cancer 322
Proteomic Biomarkers of Pancreatic Cancer 323
Prostate Cancer 324
Adipose Tissue-Derived Biomarkers of Obesity-Related Prostate Cancer 325
B7-H3 as Biomarker of Prostate Cancer 325
Detection of Prostate Cancer Biomarkers in Urine 326
Detection of Prostatic Intraepithelial Neoplasia 327
Epigenetic Biomarkers of Prostate Cancer 328
Genetic Biomarkers of Prostate Cancer 328
Huntingtin Interacting Protein 1 Overexpression in Prostate Cancer 329
Id Proteins Expression in Prostate Cancer 329
Integrative Genomic and Proteomic Profiling of Prostate Cancer 329
LCM for Diagnosis of Prostate Cancer 330
Loss of p27 as Predictor of Recurrence of Prostate Cancer 331
Microarray for Diagnosis of Prostate Cancer 331
miRNA Biomarkers of Prostate Cancer 331
mRNA Biomarkers of Prostate Cancer 332
Prostate Cancer Biomarkers in Semen 332
PSA as Biomarker of Prostate Cancer 332
PSMA as Biomarker of Prostate Cancer 333
Serum HAAH as Biomarker of Prostate Cancer 333
Silenced CDH13 Gene as a Biomarker of Cancer 334
Serum Protein Fingerprinting 334
Tests for Prostate Cancer Based on Genetic Dislocations 334
Concluding Remarks on Biomarkers of Prostate Cancer 335
Renal Cancer Biomarkers 335
Gene Expression Profile of RCC for Biomarkers 335
Use of Proteomics for Detection of RCC Biomarkers 336
miRNA Biomarkers of Renal Cancer 336
Use of RCC Biomarkers for Prognosis and Therapy 337
Thyroid Cancer Biomarkers 338
Gene Expression Biomarkers of Thyroid Cancer 338
Multiple Endocrine Neoplasia Type 2B as Risk Factor for Thyroid Cancer 339
miRNA Biomarkers of Thyroid Cancer 339
Biochemical Markers of Thyroid Cancer 340
Role of the NCI in Biomarkers of Cancer 340
Cancer Genetic Markers of Susceptibility Project 340
Oncology Biomarker Qualification Initiative 340
Role of NCI in Cancer Biomarker Development and Validation 341
Future Prospects for Cancer Biomarkers 342
Cancer Biomarker Research at Academic Institutions 342
Future Prospects and Challenges in the Discovery of Cancer Biomarkers 343
7 Biomarkers of Disorders of the Nervous System 345
Introduction 345
Discovery of Biomarkers of Neurological Disorders 345
Biomarker Identification in the CSF Using Proteomics 346
Biomarker Identification in the CSF Using Lipidomics 347
Cerebral Microdialysis for the Study of Biomarkers of Cerebral Metabolism 347
Detection of Protein Biomarkers of CNS Disorders in the Blood 348
Brain Imaging for Detection of Biomarkers 348
Data Mining for Biomarkers of Neurological Disorders 348
Antibodies as Biomarkers in Disorders of the Nervous System 349
Biomarkers of Neural Regeneration 349
Biomarkers of Disruption of BloodBrain Barrier 350
Biomarkers of Neurotoxicity 351
Glial Fibrillary Acidic Protein as Biomarker of Neurotoxicity 351
Single-Stranded DNA as a Biomarker of Neuronal Apoptosis 352
Biomarkers of Neurodegenerative Disorders 352
Biomarkers of Alzheimer Disease 353
The Ideal Biomarker of AD 355
Protein Biomarkers of AD in CSF 356
Amyloid Precursor Protein 357
Tau Proteins in CSF 358
Tests for the Detection of A in CSF 358
Monitoring of Synthesis and Clearance Rates of A in the CSF 359
CSF Reelin as Biomarker of AD 360
Urine Tests for AD 360
Blood Tests for AD 361
Protein Kinase C in Red Blood Cells 361
Detection of Aggregated Misfolded Proteins in the Blood 362
Lymphocyte Proliferation Test 362
A Biomarker-Based Skin Test for AD 362
Radioiodinated Clioquinol as a Biomarker of A 363
Nanotechnology to Measure A -Derived Diffusible Ligands 363
Simultaneous Measurement of Several Biomarkers of AD 364
Use of Biomarkers to Predict AD in Patients with MCI 365
AddNeuroMed Study for Biomarkers of AD 365
Genetic Tests for AD 366
Gene Expression Patterns in AD 366
Magnetic Resonance Spectroscopy in AD 366
MRI for Biomarkers of AD 367
PET Scanning for Biomarkers of AD 369
Targeting of a Chemokine Receptor as Biomarker for Brain Imaging 370
Plasma Biomarkers of Drug Response in AD 371
Concluding Remarks About Biomarkers of AD 371
Biomarkers of Parkinson Disease 372
Biochemical Biomarkers of PD 373
Biomarkers of PD Based on Gene Expression in Blood 373
Cardiac Denervation as a Biomarker of PD 374
Imaging Biomarkers of PD 374
Metabolic Brain Networks as Biomarkers 375
Metabonomic Biomarker Profile for Diagnosis and Monitoring of PD 375
Future Prospects of Biomarkers of PD 376
Biomarkers of Huntington Disease 376
Quantitative MRI Measurement of Brain Atrophy as Biomarker of HD 377
Biomarkers of Wilson Disease 378
Biomarkers of Amyotrophic Lateral Sclerosis 378
Biomarkers of Neuroinflammation in ALS 379
Detection of ALS Biomarkers in Blood Versus CSF 379
Ideal Biomarker of ALS 380
Imaging Biomarkers of ALS 380
Metabolomic Biomarkers of ALS 380
Proteomic Biomarkers of ALS 381
Future Prospects of Biomarkers of ALS 381
Biomarkers of Dementia in HIV-1-Infected Patients 382
Biomarkers of Prion Diseases 382
14-3-3 Protein and T-tau/P-Tau Ratio 382
Bioluminescence Imaging as a Surrogate Biomarker of Prion Infectivity 383
Biomarkers of Multiple Sclerosis 383
Antibodies in Multiple Sclerosis 384
Antibodies to Galactocerebroside 385
Antibodies to Myelin Oligodendrocyte Glycoprotein 385
Detecting Autoantibodies in Multiple Sclerosis 385
CSF Cystatin C as a Biomarker of Multiple Sclerosis 386
T Cells as Biomarkers of Multiple Sclerosis 386
Matrix Metalloproteinases as Biomarkers in Multiple Sclerosis 387
Gelsolin as a Biomarker of Multiple Sclerosis 387
Gene Expression Profiling of Biomarkers in Multiple Sclerosis 387
Serum Proteomic Pattern Analysis in Multiple Sclerosis 388
Biomarkers of Remyelination and Repair 388
Myelin Imaging by PET 388
Biomarkers of Response to Therapy of Multiple Sclerosis 389
Concluding Remarks and Future Perspective of Biomarkers of Multiple Sclerosis 389
Biomarkers of Stroke 390
Biomarkers of Intracerebral Hemorrhage 392
Biomarkers of Hypoxic Brain Damage 392
Brain Natriuretic Peptide as a Biomarker of Cardioembolic Stroke 393
Brain Lactate and N-Acetylaspartate as Biomarkers of Stroke 393
Intercellular Adhesion Molecule 1 as Biomarker of Ischemic Stroke 393
Lp-PLA2 and CRP as Biomarkers of Stroke 394
Neuroserpin Polymorphisms as a Biomarker of Stroke 394
NMDA Receptors as Biomarkers of Excitotoxicity in Stroke 394
Nucleosomes as Biomarkers of Stroke 395
PARK7 and Nucleoside Diphosphate Kinase A as Biomarkers of Stroke 395
Visinen-Like Protein 1 396
Gene Expression in Blood Following Ischemic Stroke 396
Future Prospects of Biomarkers of Stroke 397
Biomarkers of Traumatic Brain Injury 397
Technologies for Identification of Biomarkers of TBI 399
Proteomic Technologies for Biomarkers of TBI 399
Cerebral Microdialysis for Study of Biomarkers of TBI 400
Biomarkers of TBI 401
C-Tau as Biomarker of TBI 401
Hyperphosphorylated Axonal Neurofilament Protein 401
IL-6 and Nerve Growth Factor as Biomarkers of TBI 402
Serum S100B as Biomarker of TBI 402
Biomarkers of Inflicted TBI in Infants 402
Clinical Applications of Biomarkers of TBI 403
Biomarkers of CNS Infections 403
Biomarkers of CNS HIV Infection 404
Biomarkers of Bacterial Meningitis 404
Biomarkers of Epilepsy 405
Genetic Epilepsies 405
Biochemical Markers of Epilepsy 405
Imaging Biomarkers of Epilepsy 406
Biomarkers of Normal Pressure Hydrocephalus 406
Biomarkers of Retinal Disorders 407
Biomarkers of Age-Related Macular Degeneration 407
Biomarkers of Autism 408
Biomarkers of Sleep Disorders 409
Biomarker of Excessive Daytime Sleepiness 409
Biomarkers of Obstructive Sleep Apnea 410
Biomarkers of Restless Legs Syndrome 410
Biomarkers of Psychiatric Disorders 411
Biomarkers of Depression 411
Biomarkers of Psychosis 412
Biomarkers of Schizophrenia 412
Genetic Biomarkers of Schizophrenia 412
Gene Expression Analysis of Blood for Biomarkers of Schizophrenia 413
Proteomic Studies for Biomarkers of Schizophrenia 413
Metabolic Biomarkers of Schizophrenia 413
8 Biomarkers of Cardiovascular Disorders 415
Introduction 415
Epidemiology of Cardiovascular Disease 415
Biomarkers of Cardiovascular Diseases 416
Genetic Biomarkers of Cardiovascular Disorders 417
Methods for Identification of Cardiovascular Biomarkers 419
Application of Proteomics for Biomarkers of Cardiovascular Disease 419
Detection of Biomarkers of Myocardial Infarction in Saliva by a Nanobiochip 420
Metabolomic Technologies for Biomarkers of Myocardial Ischemia 420
Imaging Biomarkers of Cardiovascular Disease 421
Cardiovascular MRI 421
Annexin A5 as an Imaging Biomarker of Cardiovascular Disease 421
Applications of Biomarkers of Cardiovascular Disease 422
Biomarkers for Ischemic Heart Disease and Myocardial Infarction 422
Troponin 422
Natriuretic Peptide 424
Creatine Kinase Muscle Brain 425
Myoglobin 425
Fatty Acid Binding Protein 425
Cripto-1 as a Biomarker of Myocardial Infarction 426
Cataract as a Biomarker of Ischemic Heart Disease 426
Plasma Fetuin-A Levels and the Risk of Myocardial Infarction 427
Biomarkers of Congestive Heart Failure 427
Angiogenesis Biomarkers 427
Beta-2a Protein as a Biomarker of Heart Failure 428
Galectin-3 as Biomarker of Acute Heart Failure 428
G protein-Coupled Receptor Kinase-2 as Biomarker of CHF 429
KIF6 Gene as Biomarker of CHF 429
NT-ProBNP as Biomarker of CHF 429
Oxidative Stress as Biomarker of Heart Failure 430
Future Prospects for Biomarkers of Heart Failure 430
Biomarkers for Atherosclerosis 431
Adipocyte Enhancer-Binding Protein 1 431
Ghrelin as a Biomarker of Atherosclerosis 431
Imaging Biomarkers of Hypercholesterolemia/Atherosclerosis 432
Inflammatory Biomarkers of Atherosclerosis 432
Lipid-Modified Proteins as Biomarkers of Atherosclerosis 432
Lp-PLA2 as Biomarker of Atherosclerotic Heart Disease 433
Nitric Oxide Impairment and Atherosclerosis 433
Oxygen Free Radicals as Biomarkers of Atherosclerosis 433
Proteomic Profiles of Serum Inflammatory Markers of Atherosclerosis 434
Biomarkers of Risk Factors for Coronary Heart Disease 434
Antibody to Oxidized-LDL 434
Apolipoproteins as Risk Factors for Coronary Heart Disease 435
CRP as Biomarker of Risk for Coronary Heart Disease 435
Impairment of EPCs by Oxidative Stress as a Biomarker of Disease 436
Biomarkers for Pulmonary Arterial Hypertension 437
Biomarkers of Abdominal Aortic Aneurysm 437
Genetic Biomarkers for Cardiovascular Disease 438
Genetic Biomarkers of Atherosclerosis 438
IL-1 Gene Polymorphism as Biomarker of Cardiovascular Disease 439
Polymorphisms of the eNOS Gene and Angina Pectoris 439
Polymorphisms in the Apolipoprotein E Gene 440
Mutations in the Low-Density Lipoprotein Receptor Gene 440
Mutations Within Several Genes That Code for Ion Channel 440
Polymorphism in the Angiotensinogen Gene 441
Kallikrein Gene Mutations in Cardiovascular Disease 441
Kallikrein Gene and Essential Hypertension 441
Gene Mutations in Pulmonary Arterial Hypertension 442
Genetic Biomarkers of Early-Onset Myocardial Infarction 442
Gene Variant as a Risk Factor for Sudden Cardiac Death 442
Multiple Biomarkers for Prediction of Death from Cardiovascular Disease 443
Role of Biomarkers in the Management of Cardiovascular Disease 443
Role of Biomarkers in the Diagnosis of Myocardial Infarction 444
Role of Biomarkers in the Prevention of Cardiovascular Disease 444
Molecular Signature Analysis in Management of Cardiovascular Diseases 445
C-Reactive Protein as Biomarker of Response to Statin Therapy 445
Role of Circulating Biomarkers and Mediators of Cardiovascular Dysfunction 446
Use of Biomarkers in the Management of Peripheral Arterial Disease 447
Use of Biomarkers in the Management of Hypertension 447
Use of Protein Biomarkers for Monitoring Acute Coronary Syndromes 447
Use of Multiple Biomarkers for Monitoring of Cardiovascular Disease 448
Future Prospects for Cardiovascular Biomarkers 449
Cardiovascular Biomarker Consortium 449
Systems Approach to Biomarker Research in Cardiovascular Disease 450
9 Biomarkers and Personalized Medicine 451
Introduction 451
Pharmacogenetics 452
Biomarkers and Pharmacogenetics 452
Pharmacogenomics 454
Pharmacoproteomics 454
Single-Cell Proteomics for Personalized Medicine 455
Role of Biomarkers in Development of Personalized Drugs 456
Use of Biomarkers for Developing MAb Therapy in Oncology 456
Biobanking, Biomarkers, and Personalized Medicine in EU 456
Expression Signatures as Diagnostic/Prognostic Tools 458
Biomarkers for Monitoring Response to Therapy 458
Drug Rescue by Biomarker-Based Personalized Medicine 459
Future Role of Biomarkers in Personalized Medicine 460
10 Regulatory Issues 461
Introduction 461
Biomarker Validation 461
FDA Criteria for a Valid Biomarker 462
Role of NIST in Validation of Cancer Biomarkers 463
Quality Specifications for BNP and NT-proBNP as Cardiac Biomarker Assays 464
FDA Perspective of Biomarkers in Clinical Trials 465
FDA and Predictive Medicine 467
Biomarkers and FDAs Voluntary Genomic Data Submission 467
Role of Imaging Biomarkers in Approval of Drugs 468
FDA Critical Path Initiative and Biomarker RD 469
FDA Consortium Linking Genetic Biomarkers to Serious Adverse Events 469
Oncology Biomarker Qualification Initiative 470
Critical Path Initiative 471
Predictive Safety Testing Consortium 472
From Validated Biomarker Assay to a Clinical Laboratory Diagnostic 474
Fast Path Programs 474
Need for a Single Federal Agency to Oversee Biomarker Field 475
References 476
Subject Index 504