Protagonists of Medicine (eBook)

Contents 8
Part I Immunology and Pathology 13
1 Foreword 14
2 Paul Ehrlichs Doctoral Thesis: A Milestone in the Study of Mast Cells 18
3 The Contribution of Gianni Bonadonna to the History of Chemotherapy 23
3.1 Historical Background 23
3.2 The Cyclophosphamide, Methotrexate and Fluorouracil (CMF) Regimen in the Treatment of Breast Cancer 23
3.3 The Adriamycin, Bleomycin, Vinblastine and Dacarbazide (ABVD) Regimen in the Treatment of Hodgkins Disease 25
4 Sir Frank Macfarlane Burnet and the Clonal Selection Theory of Antibody Formation 28
4.1 Introduction 28
4.2 Biographical Profile 28
4.3 The Instructive Theories of Antibody Production 30
4.4 The Selective Theories of Antibody Production 31
4.5 The Clonal Selection Theory 32
4.6 Evidence Supporting the Theory 33
4.7 Concluding Remarks 34
5 The Contribution of Bruce Glick to the Definition of the Role Played by the Bursa of Fabricius in the Development of the B-Cell Lineage 36
5.1 Fabricius ab Aquapendente 36
5.2 The BF Plays a Major Role in the Development of Antibody-Mediated Immunity 37
5.3 BSX Do Not Abrogate the Antibody Response to Cellular Antigens 38
5.4 Immunoglobulin Synthesis Regulation 39
5.5 Delineation of the Thymic and Bursal Lymphoid Systems in the Chicken 39
5.6 BF Equivalent in Mammals and Other Vertebrates 40
6 Millers Seminal Studies on the Role of Thymus in Immunity 42
6.1 Introduction 42
6.2 The Thymus in Mouse Leukaemia 42
6.3 The Thymus Is Essential for Normal Development of the Immune System 43
6.4 If the Immune System Was Destroyed in the Adult, Would the Thymus Still Be Involved in Lymphopoiesis? 45
6.5 Cell Transfer Studies 45
6.6 The Functional Anatomy of the Thymus 46
6.7 Thymocyte Positive and Negative Selection 47
6.8 The Medulla and Central Tolerance 47
7 The Fundamental Contribution of Robert A. Good to the Discovery of the Crucial Role of Thymus in Mammalian Immunity 49
7.1 Idiopathic Acquired Agammaglobulinaemia Associated with Thymoma 49
7.2 The Role of Thymus in Immunity 50
7.3 The Effects of Neonatally Thymectomy 50
7.4 The Restorative Effect of Thymomas or Thymus Grafts on Thymic Function 52
7.5 Removal of Either the Thymus or Bursa of Fabricius 52
7.6 The Importance of a Functional Thymus in Human 53
8 The Fundamental Contribution of Jan C. Waldenstrm to the Discovery and Study of the So-Called Waldenstrm Macroglobulinaemia 55
8.1 Biographical Notes 55
8.2 Waldenstrm Involvement in the Discovery and Study of the Waldenstrm Macroglobulinaemia 56
Part II Vascular Biology and Angiogenesis 60
9 Foreword 61
10 Giulio Bizzozero and the Discovery of Platelets 65
10.1 Biographical Notes 65
10.2 The Discovery of Platelets 65
10.3 The Role of Platelets in Thrombosis and Blood Coagulation 66
11 A milestone in the Study of the Vascular System: Wilhelm Rouxs Doctoral Thesis on the Bifurcation of Blood Vessels 69
12 Stephen Paget and the Seed and Soil Theory of Metastatic Dissemination 71
12.1 Introduction 71
12.2 Pagets Theory 72
12.3 Ewings Viewpoint 73
12.4 The Contribution of Experimental Pathology to the Study of the Process of Metastasis 74
12.5 Metastasis Can Result from Survival of Only a Few Tumour Cells 74
12.6 Experimental Evidence of Metastatic Heterogeneity of Tumours 75
12.7 Studies of Experimental Brain Metastasis 76
12.8 Concluding Remarks 76
13 The Contribution of Roberto Montesano to the Study of Interactions Between Epithelial Sheetsand the Surrounding Extracellular Matrix 78
13.1 Introduction 78
13.2 Mechanisms Underlying Angiogenesis 79
13.3 Collagen Matrix Promotes the Organization of Endothelial Cells into Capillary-Like Tubules and the Induction of the Invasive Phenotype 80
13.4 Unbalanced Proteolysis Results in Aberrant Vascular Morphogenesis 81
13.5 Mechanisms Underlying Tubulogenesis 82
13.6 Fibroblast-Derived Soluble Factors Induce Morphogenesis of Branching Tubules by Kidney Epithelial Cells 82
13.7 Hepatocyte Growth Factor Is a Paracrine Mediator of Morphogenetic EpithelialMesenchymal Interactions in MDCK Cells 83
13.8 The Role of the Transcription Factor Snail in Modulation of Permeability and Tight Junction Proteins in MDCK Cells 83
13.9 Epithelial Tubulogenesis Is Dependent on Extracellular Plasmin-Dependent Proteolysis 84
13.10 Paracrine EpithelialMesenchymal Interactions Induce Tubulogenesis in Other Types of Epithelial Cells 84
13.11 HGF and TGF-1 Play a Role in Mammary Gland Morphogenesis In Vivo 84
13.12 Retinoids Induce Lumen Formation, Whereas Tumour Necrosis Factor Alpha and Bone Morphogenetic Protein-4 Confer an Invasive and Transformed Phenotype to Cultured Mammary Epithelial Cells 85
13.13 Concluding Remarks 86
14 The Seminal Work of Werner Risau in the Studyof the Development of the Vascular System 88
14.1 Introduction 88
14.2 Changes in Extracellular Matrix During Embryonic Vasculogenesis and Angiogenesis 88
14.3 Characterization of Flk-1 89
14.4 Embryonic Brain Angiogenesis 90
14.5 The Role of Vascular Endothelial Growth Factor in Brain Angiogenesis 90
14.6 Characterization of the BloodBrain Barrier 92
14.7 Angiogenesis in Glioma 93
14.8 The Role of Platelet-Derived Growth Factor in Angiogenesis 94
14.9 Hypoxia and Angiogenesis 95
15 Judah Folkman, A Pioneer in the Study of Angiogenesis 97
15.1 Early Evidence of Tumour Cells Releasing Specific Growth Factor for Blood Vessels 97
15.2 Tumours in Isolated Perfused Organs: Absence of Angiogenesis 97
15.3 Hypothesis: Tumour Growth Is Angiogenesis Dependent 98
15.4 Evidence that Tumours Are Angiogenesis Dependent 98
15.5 Isolation of the First Angiogenic Tumour Factor 100
15.6 First Evidence of the Existence of the Avascular and Vascular Phases of Solid Tumour Growth 101
15.7 Dormancy of Micrometastases May Be Governed by Angiogenesis 102
15.8 Prognostic Significance of Tumour Vascularity 102
15.9 Antiangiogenesis 102
15.9.1 Interferon Alpha 104
15.9.2 Platelet Factor 4/Protamine 104
15.9.3 Angiostatic Steroids 104
15.9.4 Fumagillin 105
15.9.5 Angiostatin and Endostatin 105
15.9.6 Thalidomide 106
15.9.6.1 2-Methoxyoestradiol 107
15.9.7 Cleaved Antithrombin III 107
15.9.8 Caplostatin 107
15.9.9 Antiangiogenic Chemotherapy 107
15.10 Concluding Remarks 108
16 The Contribution of Harold F. Dvorak to the Studyof Tumour Angiogenesis and Stroma Generation Mechanisms 109
16.1 Biographical Notes 109
16.2 Tumour Blood Vessels Are Hyperpermeable to Plasma Proteins and to Other Circulating Macromolecules 110
16.3 Vascular Permeability Factor Activity Is Present in Tumour Culture Supernatants 110
16.4 The Discovery of Vascular Permeability Factor/Vascular Endothelial Growth Factor 111
16.5 Tumours: Wounds That Not Heal 112
16.6 Expression of VEGF-A-164 In Vivo 112
16.7 The New Blood Vessels Generated by VEGF-A-164 113
17 Napoleone Ferrara and the Saga of Vascular Endothelial Growth Factor 115
17.1 Introduction 115
17.2 The Isolation of VEGF 117
17.3 Role of VEGF in Embryonic Vasculogenesis and Angiogenesis 120
17.4 Endocrine Gland-Derived VEGF 120
17.5 VEGF Expression in the Development of Pancreas 122
17.6 VEGF Expression in Skeletal Growth and Endochondral Bone Formation 122
17.7 VEGF Expression in Ovary 122
17.8 Role of VEGF in Intracular Neovascular Syndromes 123
17.9 Towards the Discovery of Avastin 123
18 Pietro M. Gullino and Angiogenesis 126
18.1 Biographical Notes 126
18.2 Tumour Pathophysiology: Interstitial Pressure and Blood Dissemination 126
18.3 Angiogenesis as a Marker for Neoplastic Transformation 127
18.4 Neoplastic Cell Populations Release Molecules Able to Stimulate Angiogenesis into the Surroundings: The Role of Prostaglandin E-1 128
18.5 Microenvironment and Tumour Angiogenesis: The Role of Copper and Gangliosides 129
18.6 Concluding Remarks 130
References 131