Advances in Clinical Chemistry (eBook)

eBook Download: EPUB

2011 | 1. Auflage
248 Seiten
Elsevier Science (Verlag)
978-0-08-092116-7 (ISBN)

Infos

Volume forty-five of the Advances in Clinical Chemistry series contains review articles of wide interest to clinical laboratory scientists and diagnostic adventurers. Articles in this volume cover such topics as Inhibins as Diagnostic Markers in Human Reproduction, uPA and PAI-1 in Breast Cancer: Review of Their Clinical Utility and Current Validation in the Prospective NNBC-3 Trial, Advances in Multiple Analyte Profiling, Immune Monitoring of Clinical Trials with Biotherapies, Dietary Modification of Brain Function: Effects on Neuroendocrine and Psychological Determinants of Mental Health and Stress Related Disorders, Menopause, Estrogen and Gonadotropins in Alzheimer Disease, Immunosuppression Routed via the Kynurenine Pathway: A Biochemical and Pathophysiologic Approach, Pathophysiology of Tumor-associated Macrophages.

---

Volume 45 of the Advances in Clinical Chemistry series contains review articles of wide interest to clinical laboratory scientists and diagnostic adventurers. Articles in this volume cover such topics as Inhibins as Diagnostic Markers in Human Reproduction; uPA and PAI-1 in Breast Cancer: Review of Their Clinical Utility and Current Validation in the Prospective NNBC-3 Trial; Advances in Multiple Analyte Profiling; Immune Monitoring of Clinical Trials with Biotherapies; Dietary Modification of Brain Function: Effects on Neuroendocrine and Psychological Determinants of Mental Health and Stress Related Disorders; Menopause, Estrogen and Gonadotropins in Alzheimer's Disease; Immunosuppression Routed via the Kynurenine Pathway: A Biochemical and Pathophysiologic Approach; and Pathophysiology of Tumor-associated Macrophages.

Inhalt

Front Cover 1
Advances in Clinical Chemistry 4
Copyright Page 5
Contents 6
Contributors 10
Preface 14
Chapter 1: Inhibins as Diagnostic Markers in Human Reproduction 15
1. Abstract 15
2. History and Background 16
3. Inhibins in Women's Reproductive Function 20
3.1. Effects of Inhibin on Pituitary FSH Secretion 20
3.2. Inhibin During the Menstrual Cycle 21
3.3. Control of Inhibin B by FSH in Gnrh-Deficient Women 22
3.4. Inhibins and Activin A in Ovulation Induction 22
3.5. Premature Ovarian Failure 23
3.6. Inhibin and Activin in Polycystic Ovary Syndrome 24
3.7. Reproductive Aging 25
4. Pregnancy 26
4.1. Inhibin in Abnormal Pregnancy 27
4.2. Pre-eclampsia 28
4.3. Down's Syndrome 30
5. Inhibins in Men's Reproductive Function 31
6. Conclusion 33
References 33
Chapter 2: UPA and PAI-1 In Breast Cancer: Review of Their Clinical Utility and Current Validation in the Prospective NNBC-3 Trial 45
1. Abstract 45
2. The UPA/PAI-1 System 46
3. Clinical Relevance of UPA and PAI-1 in Breast Cancer 47
3.1. Prognostic Impact of UPA and PAI-1 48
3.2. Predictive Impact of UPA and PAI-1 49
4. Methods for Determination of UPA and PAI-1 51
5. Clinical NNBC-3 Trial 51
6. Current Use of UPA/PAI-1 in Clinical Decision Making 54
References 56
Chapter 3: Advances in Multiple Analyte Profiling 61
1. Abstract 61
2. Introduction 62
3. Multiple Analyte Profiling Platforms 63
3.1. Planar Arrays and Hybrid Bead-Based Systems 63
3.2. High-Content Cellular Imaging 66
3.3. Suspension Arrays/Flow Cytometry 67
4. Fluorescence Technology 70
4.1. Fluorescence-Based Assays 70
4.2. Fluorescent Labels 72
5. Flow-Cytometry High-Content Profiling Applications 73
5.1. Principles of Multiplexing for Suspension Arrays 73
5.2. Multiplexed Nucleic Acid Endpoint Assays 75
5.3. Multiplexed Protein Endpoint Assays 76
5.4. Multiplex Assays of Molecular Assemblies 78
5.5. Throughput 80
6. Future Directions 81
Acknowledgments 82
References 82
Chapter 4: Immune Monitoring of Clinical Trials with Biotherapies 89
1. Abstract 89
2. Introduction 90
3. Rationale for Immune Monitoring 92
3.1. Requirements 93
3.2. Significance 94
4. Selection of Assays for Immune Monitoring 94
4.1. Use of Cryopreserved vs. Freshly Harvested Specimens 96
4.2. Single-Cell Assays: Tetramers, CFC, ELISPOT 96
4.3. Elispot as a Monitoring Assay 98
4.4. Attributes of Selected Assays 98
5. Profiling of in Immune Biomarkers 99
5.1. Multiplexing for Cytokines 99
5.2. Genomics and Proteomics 100
5.3. Polychromatic Flow Cytometry 102
6. The QA/QC Program and Assay Quality 103
6.1. QA/QC in Practice 104
6.2. Assay Standardization 104
6.3. Assay Validation 105
7. Interpretation of Immune Monitoring Assays 105
7.1. Statistical Analysis 106
7.2. Interpretation Discrepancies 107
8. Conclusions 108
Acknowledgment 109
References 110
Chapter 5: Dietary Modification of Brain Function: Effects on Neuroendocrine and Psychological Determinants of Mental Health-and Stress-Related Disorders 113
1. Abstract 113
2. Introduction 114
3. Meal Composition 115
3.1. Carbohydrate 116
3.2. Fat 117
3.3. Protein 120
3.4. Antioxidant 121
3.5. Phytochemicals 122
3.6. Vitamins 122
3.7. Minerals and Trace Elements 125
4. Meal Frequency 127
5. Meal Size 127
6. Appetite 128
7. Emotion 128
8. Metabolic Acidosis 129
9. Glucocorticoids 130
10. Monoamine 132
11. Stress 133
12. Conclusion 135
References 136
Chapter 6: Menopause, Estrogen, and Gonadotropins in Alzheimer's Disease 153
1. Abstract 153
2. Introduction 154
3. Hypothesized Pathogenic Mechanisms of AD 155
4. Gender Dichotomy in AD: Role of Sex Steroids 156
5. A Gonadotropin Evidence-Based Hypothesis for AD: High Gonadotropin vs Low Estrogen 158
6. Conclusion 161
References 162
Chapter 7: Immunosuppression Routed via the Kynurenine Pathway: A Biochemical and Pathophysiologic Approach 169
Abbreviations 170
1. Abstract 170
2. Introduction 171
3. Trp-Kynurenine Degradation Pathway 171
3.1. Comparison Between IDO and TDO 173
3.2. Distribution of the Kynurenine Pathway Enzymes 173
4. Biochemistry of IDO 174
4.1. Molecular Biology of the Indo Gene 174
4.2. Catalytic Properties of IDO 175
4.3. Posttranslational Regulation of the IDO Activity 175
5. IDO Induction 176
5.1. Induction of IDO by IFNS 176
5.2. Induction of IDO by Cytolytic T-Lymphocyte-Associated Antigen 4-Immunoglobulin Fusion Prote 176
5.3. Induction of IDO by Unmethylated Cytidyl Guanosyl Oligodeoxynucleotides 177
5.4. Induction of IDO by 4-1BB 177
5.5. Signaling Pathways Involved in IDO Induction 178
6. Measurement of Kynurenines in Human Biological Fluids 178
7. Nitric Oxide and the Kynurenine Pathway 180
8. Role of IDO in the Defense Against Infectious Pathogens 181
9. IDO as an Immunosuppressive Molecule 181
9.1. IDO-Mediated Suppression by Innate Immunity 182
9.2. IDO-Mediated Suppression by Adaptive Immunity 183
9.3. Mechanism of Suppression 185
10. Protective Role of IDO in Rejection of the Fetus During Pregnancy 188
11. Clinical Implications of the Immunosuppression Provoked by the Kynurenine Pathway 190
11.1. Cancer Immune Evasion by IDO Expression 190
11.2. Autoimmune Diseases 193
11.3. Transplantation 194
11.4. HIV Immunoescape by Inducing Kynurenine Pathway 195
11.5. Cardiovascular Diseases 196
11.6. Neurological and Psychiatric Diseases 197
12. Conclusions 198
References 200
Chapter 8: Pathophysiology of Tumor-Associated Macrophages 213
1. Abstract 213
2. Introduction 214
3. Association Between TAM Density and Patient Prognosis 215
4. Antitumor Activity of TAMs and the Association Between High TAM Density and a Good Prognosis 219
5. Polarization of TAM into M1 and M2 Phenotype Macrophage in Tumor Microenvironment 222
6. Effect of TAMs on Cancer Cells 223
7. Possible Regulatory Mechanism of Gene Expression in TAMs or Cancer Cells After the TAM-Cancer Cell Interaction 225
8. Effect of TAMs on Stromal Cells in the Tumor Microenvironment 227
9. A Global View on Changes in Gene Expression in Cancer Cells After Interaction with TAMs 227
10. Implication of TAMs in Immunotherapy of Human Cancers 228
11. Concluding Remarks 230
References 230
Index 239

Textauszug

Inhibins as Diagnostic Markers in Human Reproduction

Anastasia Tsigkou*; Stefano Luisi*; Fernando M. Reis†; Felice Petraglia*,[e-mail]    * Chair of Obsterics and Gynecology, Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Policlinico, S. Maria alle Scotte Viale Bracci, 53100 Siena, Italy
† Department of Obstetrics and Gynecology, University of Minas Gerais, Belo Horizonte, Brazil
1 Corresponding author: Felice Petraglia

1 Abstract

Over the past 75 years, many publications have focused on measurement of inhibin concentration and/or activity in biological samples in order to understand its role in physiology and disease. This chapter highlights the accomplishments within this area of research over the past decade including development of specific inhibin assays. Inhibin A is a marker of dominant follicle and corpus luteum activity and decreases in polycystic ovary syndrome (PCOS). Inhibin A increases in gestational diseases such as pre-eclampsia and fetal Down's syndrome, and this increase in inhibin A improves early diagnosis of both conditions. The measurement of inhibin A in women with threatened abortion provides useful information about the likelihood of pregnancy loss. Inhibin B increases markedly in women with granulosa cell tumor and appears closely related to gametogenesis in men, that is, reflecting Sertoli cell activity. On the contrary, Inhibin B decreases in women with declining ovarian function and correlates with female response to ovulation induction. This review evaluates the biochemical significance of inhibins including their use in clinical practice.

2 History and Background

Inhibin is a gonadal hormone that exerts specific negative feedback on pituitary secretion of follicle stimulating hormone (FSH). The existence of inhibin was postulated in 1923 by Mottram and Cramer who observed hypertrophy of pituitary cells after irradiation of the testis of adult rats [1]. McCullagh [2] subsequently investigated this phenomenon by injecting a water-soluble extract from bovine testes and found that it could inhibit hypertrophy of the pituitary and thus named the active, water-soluble principle “inhibin” [2].

The concept of inhibin was refined after the discovery of two separate pituitary hormones, FSH and luteinizing hormone (LH), which together regulate the gonadal function. Klinefelter et al. [3] observed that serum levels of FSH were elevated in oligo- or azoospermic men. Heller and Nelson [4] suggested that the increased serum levels of FSH were caused by a lack of utilization of FSH by the defective seminiferous tubules. Some groups [5, 6] showed that the injection of water-soluble testicular extracts into rats could suppress peripheral FSH levels. de Jong and Sharpe [7] also found FSH-suppressing activity in ovarian follicular fluid. Little, however, was understood about the mechanism of action of inhibin on pituitary cells until Franchimont et al. [8] demonstrated that the addition of inhibin-containing preparations to pituitary cells caused an increase in the secretion of cGMP and a decrease in cAMP secretion. This finding was then followed by Jenner [9] who speculated that the decrease in cAMP in incubated hemipituitaries is followed by a decrease in the synthesis of FSH.

The combination of an FSH radioimmunoassay (RIA) and an in vitro primary pituitary cell culture led to the purification of inhibin from bovine [10] and porcine [11–13] follicular fluids. Cloning established the protein sequence of inhibin as a 32-kDa dimeric glycosylated molecule consisting of an α and a β subunit. It soon became clear that there were two forms of inhibin. Each contains a common α subunit associated with either βA (inhibin A) or βB (inhibin B) subunits that also possess a high degree of homology (Table 1) [12]. Inhibin A and inhibin B were found to be equipotent in the rat pituitary cell bioassay [14], but in the sheep pituitary cell bioassay [10], inhibin A was much more potent than inhibin B. During the purification in bovine, it became clear that there was a large amount of free α chain inhibin that had no bioactivity [10] and could potentially interfere with quantitative assay unless the models were specifically configured to ignore its presence. Initially, inhibin was identifiable as a distinct entity only by bioassays [15–18]. These, of course, were of limited specificity, and generally unsuitable for use with complex body fluids. The development of highly specific and sensitive immunoassays proved essential in advancing the study of inhibin in physiologic as well as pathophysiologic conditions.

Table 1

Schematic Representation of Precursor and Mature Forms of Inhibin A and Inhibin B and Mature Forms of Activin

α-Subunit precursor

α Chain

pro + αN + αC

55

pro-αC

pro + αC

26

β-Subunit precursor

βA Chain

proβA + βA

58

βB Chain

proβB + βB

58

Mature forms

Inhibin A

α + βA

32

Inhibin B

α + βB

32

Activin A

βA + βA

28

Activin B

βB + βB

28

Activin AB

βA + βB

28

The original Monash RIA [19] was widely used in physiological studies before it was realized that it was detecting mostly free α subunits rather than dimeric bioactive inhibin forms in human body fluids [20]. The breakthrough in our understanding of the biology of inhibin came when Groome and collaborators established a specific immunoassay for the measurement of dimeric inhibin A in the menstrual cycle [21]. An assay for measurement of dimeric inhibin B was also subsequently developed by this group [22]. Both assays have been found to be useful for many clinical applications, some of which are detailed below.

During the purification of inhibin from porcine follicular fluid, two research groups isolated a protein that displayed FSH-releasing activity from the gonadotrophs in vitro [23–26]. This protein was termed “activin,” signifying its antagonistic effect to inhibin. The discovery of new genes related to the inhibin β subunit through the use of degenerate polymerase chain reaction (PCR) cloning methods further complicated the inhibinstory. There are now three known types of bioactive activins: activin A, activin AB, and activin B (Table 1). Three recently identified activins (C, D, and E) are not known to have any bioactivity and have a relatively restrictive tissue distribution. Activin has proven relevant to diverse research fields, including cell biology, developmental biology, and endocrinology. Activin bioassays have the same problems as inhibin, that is, a lack of specificity.

During purification of inhibin, another weak inhibitor of FSH secretion was identified, named follistatin, which was purified from both porcine [27] and bovine follicular fluid. It was soon realized that follistatin acted by binding to activin and thus neutralizing its actions. The protein is expressed abundantly in the granulosa cells of healthy antral follicles. Shimonaka et al. [27] demonstrated by double ligand blotting technique that activin A has two binding sites for follistatin, whereas inhibin A has one. From this, it can be shown that follistatin interacts with inhibin A and activin A through the common β subunit. Follistatin has the ability to neutralize activin-induced FSH release from pituitary cell cultures but this bioassay, like those for inhibins and activins, is susceptible to interference [28]. A number of immunoassays for total follistatin have now been established [29].

Another activin-binding protein of 70 amino acids (aa) has been identified as a follistatin-related gene (FLRG) product, based upon its primary sequence homology to follistatin and its modular architecture, which is remarkably similar to that of follistatin [30, 31]. Like follistatin, FLRG also interacts physically with activin A. This interaction prevents binding to activin receptors (ActRs) [31, 32], thus suggesting a regulatory role on activin-mediated cellular processes.

Both activin and inhibin have been classified as members of the transforming growth factor-β (TGF-β) superfamily [23,, 25,, 28,32–34]. They are synthesized as large precursors containing a signal sequence, a pro-domain of variable size, and a mature C-terminal segment that ranges from 110 to 140 aa in length. Within the mature segment, there are seven cysteine residues that are invariant across the...

Produkt-Details

• Erscheint lt. Verlag: 2.9.2011
• Mitarbeit: Herausgeber (Serie): Gregory S. Makowski
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Laboratoriumsmedizin
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Chemie ► Organische Chemie
• Themenwelt: Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik
• Themenwelt: Technik
• ISBN-10: 0-08-092116-7 / 0080921167
• ISBN-13: 978-0-08-092116-7 / 9780080921167