by Cheung Yuen-Nei. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 194-208). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / 摘要 --- p.iv / Contents --- p.vi / List of Figures --- p.xii / List of Tables --- p.xv / Abbreviations --- p.xvi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1 --- Introduction --- p.2 / Chapter 1.1 --- Characteristic of Saponins --- p.3 / Chapter 1.1.1 --- Occurrence of Saponins --- p.3 / Chapter 1.1.2 --- General Properties of Saponins --- p.3 / Chapter 1.1.2.1 --- Emulsifying Agents --- p.3 / Chapter 1.2.2.2 --- Forming Complex with Cholesterol --- p.4 / Chapter 1.1.2.3 --- Hemolytic Property --- p.4 / Chapter 1.1.3 --- Structure of Saponins --- p.5 / Chapter 1.1.3.1 --- Categories of Saponins --- p.5 / Chapter 1.1.3.1.1 --- Triterpene Saponins --- p.5 / Chapter 1.1.3.1.2 --- Steroid Saponins --- p.5 / Chapter 1.1.3.2 --- Monodesmosidic and Bidesmosidic Saponins --- p.7 / Chapter 1.1.4 --- Biological and Pharmacological Properties of Saponins --- p.9 / Chapter 1.1.4.1 --- Anti-microbial Activity --- p.9 / Chapter 1.1.4.1.1 --- Anti-fungal Activities --- p.9 / Chapter 1.1.4.1.2 --- Anti-bacterial Activities --- p.10 / Chapter 1.1.4.1.3 --- Anti-viral Activities --- p.10 / Chapter 1.1.4.2 --- Insecticidal Activity --- p.10 / Chapter 1.1.4.3 --- Molluscicidal Activity --- p.10 / Chapter 1.1.4.4 --- Hypocholesterolemic Activity --- p.11 / Chapter 1.1.4.5 --- Anti-ulcer Activity --- p.11 / Chapter 1.1.4.6 --- Contraceptive Activity --- p.12 / Chapter 1.1.4.7 --- Immunomodulatory Activities --- p.12 / Chapter 1.1.4.7.1 --- Direct Immunostimulation --- p.12 / Chapter 1.1.4.7.2 --- Acting as Immuno-adjuvants --- p.13 / Chapter 1.1.4.8 --- Anti-tumor Activity --- p.14 / Chapter 1.1.4.8.1 --- Anti-carcinogenesis --- p.15 / Chapter 1.1.4.8.2 --- Suppression of Tumor Growth --- p.16 / Chapter 1.1.5 --- Anti-tumor Activity of Steroid Saponins --- p.18 / Chapter 1.1.5.1 --- Diosgenin Steroid Saponin --- p.18 / Chapter 1.1.5.2 --- Hong Kong Compounds --- p.18 / Chapter 1.1.5.3 --- Hong Kong18 --- p.21 / Chapter 1.2 --- Human Hepatocellular Carcinoma (HCC) --- p.24 / Chapter 1.2.1 --- The Incidence of Liver Cancer --- p.24 / Chapter 1.2.2 --- Classification of Liver Cancer --- p.24 / Chapter 1.2.3 --- Human Hepatocellular Carcinoma Cell Lines --- p.25 / Chapter 1.2.3.1 --- Human Hepatocellular Carcinoma Cell Line HepG2 --- p.25 / Chapter 1.2.3.2 --- Multidrug Resistant Human Hepatocellular Carcinoma Cell Line R-HepG2 --- p.27 / Chapter 1.2.3.2.1 --- Mechanisms of Multidrug Resistance --- p.28 / Chapter 1.2.3.2.2 --- Structure and Characteristics of P-glycoprotein --- p.29 / Chapter 1.2.3.2.3 --- Methods in Dealing with P-glycoprotein Over-expressed MDR Cells --- p.31 / Chapter 1.3 --- Objectives of the Project --- p.32 / Chapter 1.3.1 --- Study of the Anti-tumor Activities of Hong Kong 18 on Human Hepatocellular Carcinoma Cell Line HepG2 and Unravel the Underlying Mechanisms --- p.32 / Chapter 1.3.2 --- Study of the Anti-tumor Activities of Hong Kong 18on Multidrug Resistant Human Hepatocellular Carcinoma Cell Line R-HepG2 and Unravel the Underlying Mechanisms --- p.32 / Chapter Chapter 2 --- Materials and Methods --- p.33 / Chapter 2.1 --- Materials --- p.34 / Chapter 2.1.1 --- Cell Culture --- p.34 / Chapter 2.1.1.1 --- Cell Lines --- p.34 / Chapter 2.1.1.2 --- Culture Media --- p.35 / Chapter 2.1.2 --- Reagents and Buffers --- p.36 / Chapter 2.1.2.1 --- Phosphate Buffered Saline (PBS) --- p.36 / Chapter 2.1.2.2 --- Reagents and Buffers for DNA Fragmentation --- p.36 / Chapter 2.1.2.3 --- Reagents and Buffers for Western Analysis --- p.37 / Chapter 2.1.2.4 --- Reagents and Buffer for Caspases Activities --- p.39 / Chapter 2.1.2.5 --- Fluorescent Dyes used for Flow Cytometry --- p.39 / Chapter 2.1.3 --- Chemicals --- p.39 / Chapter 2.2 --- Methods --- p.46 / Chapter 2.2.1 --- MTT Assay --- p.46 / Chapter 2.2.2 --- Determination of Cell Viability --- p.46 / Chapter 2.2.3 --- Purification of Macrophages from balb/c Mice --- p.47 / Chapter 2.2.4 --- Hemolysis Assay --- p.47 / Chapter 2.2.5 --- In vivo Studies of the Toxicity of HK18 --- p.48 / Chapter 2.2.6 --- DNA Fragmentation Assay --- p.50 / Chapter 2.2.7 --- Detection of Apoptotic and Necrotic / Late Apoptotic Cells Death by Flow Cytometry with Annexin V-FITC / PI --- p.51 / Chapter 2.2.8 --- Detection of Mitochondrial Membrane Potential by JC-1 Fluorescent Dye --- p.52 / Chapter 2.2.9 --- Detection of Intracellular Ca Level by Flow Cytometry with Fluo-3 Fluorescent Dye --- p.52 / Chapter 2.2.10 --- Detection of Intracellular Hydrogen Peroxide Level by Flow Cytometry with DCF Fluorescence Dye --- p.53 / Chapter 2.2.11 --- Simultaneous Detection of Mitochondrial Membrane Potential and Intracellular Ca2+ or Mitochondrial Membrane Potential and Intracellular Hydrogen Peroxide --- p.54 / Chapter 2.2.12 --- Western Analysis --- p.55 / Chapter 2.2.12.1 --- Total Protein Extraction --- p.55 / Chapter 2.2.12.2 --- Extraction of Cytosolic Proteins --- p.59 / Chapter 2.2.13 --- Determination of Caspases Enzymatic Activity --- p.63 / Chapter 2.2.14 --- Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) --- p.67 / Chapter 2.2.14.1 --- RNA Extraction by TRIzol Reagent --- p.67 / Chapter 2.2.14.2 --- Reverse Transcription --- p.68 / Chapter 2.2.14.3 --- Polymerase Chain Reaction --- p.68 / Chapter 2.3 --- Statistic Analysis --- p.71 / Chapter Chapter 3 --- Cytotoxicity of HK18 --- p.72 / Chapter 3.1 --- Cytotoxicity of HK18 on HepG2 Cells --- p.73 / Chapter 3.1.1 --- Study of the Cytotoxic Activity of HK18 on HepG2 Cells by MTT Assay --- p.73 / Chapter 3.1.2 --- Study of the Cytotoxic Activity of HK18 on HepG2 Cells by Tryphan Blue Exclusion Assay --- p.76 / Chapter 3.2 --- Cytotoxicity of HK18 on R-HepG2 Cells --- p.78 / Chapter 3.2.1 --- Study of the Cytotoxic Activity of HK18 on R-HepG2 Cells by MTT Assay --- p.78 / Chapter 3.2.2 --- Study of the Cytotoxic Activity of HK18 on R-HepG2 Cells by Tryphan Blue Exclusion Assay --- p.81 / Chapter 3.3 --- Cytotoxicity of HK18 on Macrophages --- p.83 / Chapter 3.4 --- Hemolytic Activity of HK18 --- p.85 / Chapter 3.5 --- In vivo Study of the Toxicity of HK18 --- p.87 / Chapter Chapter 4 --- Mechanistic Study of HK18 on HepG2 Cells --- p.90 / Chapter 4.1 --- Hallmarks of Apoptosis Induced by HK18 on HepG2 Cells --- p.91 / Chapter 4.1.1 --- Induction of Phosphatidylserine Externalization by HK18 on HepG2 Cells --- p.91 / Chapter 4.1.2 --- Induction of DNA Fragmentation by HK18 of HepG2 Cells --- p.97 / Chapter 4.2 --- Study of the Underlying Mechanisms of HK18 Induced Apoptosis in HepG2 Cells --- p.99 / Chapter 4.2.1 --- The Role of Mitochondria in HK18 Induced Apoptosis of HepG2 Cells --- p.99 / Chapter 4.2.1.1 --- HK18 Induced Mitochondrial Membrane Depolarization in HepG2 Cells --- p.101 / Chapter 4.2.1.2 --- Addition of Bongkrekic Acid Reduced HK18 Cytotoxicity on HepG2 Cells --- p.105 / Chapter 4.2.1.3 --- Elevation of Intracellular Hydrogen Peroxide Level in HK18 Treated HepG2 Cells --- p.108 / Chapter 4.2.1.4 --- Elevation of Intracellular Ca2+ Level in HK18 Treated HepG2 Cells --- p.114 / Chapter 4.2.1.5 --- HK18 Induced Cytochrome c and AIF Released from Mitochondria of HepG2 Cells --- p.120 / Chapter 4.3 --- Downstream Biochemical Changes Induced by HK18 on HepG2 Cells --- p.123 / Chapter 4.3.1 --- Activation of Caspase 3 of HepG2 Cells by HK18 as Demonstrated by Western Blot --- p.123 / Chapter 4.3.2 --- Induction of Caspases Activities of HepG2 Cells by HK18 as Demonstrated by Enzymatic Activity Assays --- p.125 / Chapter 4.4 --- Down-regulation of Anti-apoptotic Bcl-2 Family Members of HepG2 Cells by HK18 --- p.129 / Chapter Chapter 5 --- Mechanistic Study of HK18 on R-HepG2 Cells --- p.133 / Chapter 5.1 --- Hallmarks of Apoptosis Induced by HK18 on R-HepG2 Cells --- p.134 / Chapter 5.1.1 --- Induction of Phosphatidylserine Externalization by HK18 on R-HepG2 Cells --- p.134 / Chapter 5.1.2 --- Induction of DNA Fragmentation by HK18 of R-HepG2 Cells --- p.137 / Chapter 5.2 --- Study of the Underlying Mechanisms of HK18 Induced Apoptosis in R-HepG2 Cells --- p.139 / Chapter 5.2.1 --- The Role of Mitochondria in HK18 Induced Apoptosis of R-HepG2 Cells --- p.139 / Chapter 5.2.1.1 --- HK18 Induced Mitochondrial Membrane Depolarization in R-HepG2 Cells --- p.139 / Chapter 5.2.1.2 --- Addition of Bongkrekic Acid Reduced HK18 Cytotoxicity on R-HepG2 Cells --- p.142 / Chapter 5.2.1.3 --- Elevation of Intracellular Hydrogen Peroxide Level in HK18 Treated R-HepG2 Cells --- p.144 / Chapter 5.2.1.4 --- Elevation of Intracellular Ca2+ Level in HK18 Treated R-HepG2 Cells --- p.146 / Chapter 5.3 --- Downstream Biochemical Changes Induced by HK18 on R-HepG2 Cells --- p.148 / Chapter 5.3.1 --- Activation of Caspase 3 of R-HepG2 Cells by HK18 as Demonstrated by Western Blot --- p.148 / Chapter 5.3.2 --- Induction of Caspases Activation of R-HepG2 Cells by HK18 as Demonstrated by Enzymatic Activity Assays --- p.150 / Chapter 5.4 --- Down-regulation of the Anti-apoptotic Bcl-2 Protein of R-HepG2 Cells by HK18 --- p.154 / Chapter 5.5 --- HK18 was Not a Substrate of P-glycoprotein Contents --- p.156 / Chapter Chapter 6 --- Discussion --- p.158 / Chapter 6.1 --- Cytotoxicity of HK18 --- p.159 / Chapter 6.1.1 --- HK18 was Cytotoxic to the Human Hepatocellular Carcinoma Cell Line HepG2 and Multidrug Resistant Human Hepatocellular Carcinoma Cell Line R-HepG2 --- p.159 / Chapter 6.1.2 --- Study of the Toxicity of HK18 --- p.160 / Chapter 6.2 --- Mechanistic Studies of the Cytotoxic Effects of HK18 on HepG2 Cells --- p.161 / Chapter 6.2.1 --- Apoptotic Cell Death Induction of HK18 on HepG2 Cells --- p.161 / Chapter 6.2.2 --- Studies of the Underlying Mechanisms of HK18 Induced Apoptosis of HepG2 Cells --- p.162 / Chapter 6.3 --- Mechanistic Studies of the Cytotoxic Effects of HK18 on R-HepG2 Cells --- p.181 / Chapter 6.3.1 --- Apoptotic Cell Death Induction of HK18 on R-HepG2 Cells --- p.181 / Chapter 6.3.2 --- Studies of the Underlying Mechanisms of HK18 Induced Apoptosis of HepG2 Cells --- p.181 / Chapter Chapter 7 --- Future Perspectives --- p.190 / Chapter Chapter 8 --- References --- p.193

by Lam Kai Yi. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 156-165). / Abstract also in Chinese. / Chapter Chapter One: --- Introduction --- p.1 / Chapter 1.1 --- Tumor Necrosis Factor-α in Cancer Treatment --- p.1 / Chapter 1.1.1 --- Historical Background --- p.1 / Chapter 1.1.2 --- Mechanisms of Action --- p.2 / Chapter 1.1.2.1 --- Production of Reactive oxidative Species / Chapter 1.1.2.2 --- Increase of Intracellular Free Calcium Concentration / Chapter 1.1.2.3 --- Activation of Ca2+/Mg2+-dependent Endonuclease / Chapter 1.1.2.4 --- Decrease of glucose uptake and Protein Synthesis / Chapter 1.1.2.5 --- Formation of Ion-permeable Channel / Chapter 1.1.2.6 --- Activation of Phospholipase / Chapter 1.1.2.7 --- Increase of S-phase Cells / Chapter 1.1.2.8 --- Immunomodulatory Effects / Chapter 1.1.3 --- Resistance of Cells to TNF-α --- p.7 / Chapter 1.1.4 --- Clinical Studies --- p.11 / Chapter 1.1.5 --- Side Effects --- p.12 / Chapter 1.2 --- Hyperthermia and Cancer Treatment --- p.14 / Chapter 1.2.1 --- Hyperthermic Agents --- p.15 / Chapter 1.2.2 --- Intrinsic Heat Sensitivity --- p.15 / Chapter 1.2.3 --- Mechanisms of Action --- p.17 / Chapter 1.2.3.1 --- Depolarization of Membrane Potential / Chapter 1.2.3.2 --- "Reduction of glucose transport and DNA, mRNA and Protein Synthesis" / Chapter 1.2.3.3 --- Decrease of Intracellular pH / Chapter 1.2.3.4 --- Calcium Imbalance / Chapter 1.2.3.5 --- Effect on Nucleolar Protein / Chapter 1.2.3.6 --- Apoptosis / Chapter 1.2.3.7 --- Induction of Autologous Tumor Killing / Chapter 1.2.3.8 --- "Blood Flow, Tumor Oxygenation and Vascular Damage" / Chapter 1.2.4 --- Clinical Studies --- p.20 / Chapter 1.3 --- Combined Treatment --- p.21 / Chapter 1.3.1 --- Combined Treatment with TNF-α and Fixed-temperature Hyperthermia --- p.22 / Chapter 1.3.2 --- Combined Treatment with TNF + Step-down Hyperthermia --- p.22 / Chapter 1.3.3 --- In Vivo Study --- p.23 / Chapter 1.3.4 --- Sequence of Treatment --- p.24 / Chapter 1.3.5 --- Proposed Mechanism of Synergism --- p.24 / Chapter 1.4 --- Objective of Study --- p.26 / Chapter 1.4.1 --- Sequence of Treatments --- p.26 / Chapter 1.4.2 --- Comparison of Treatments' Effectiveness --- p.27 / Chapter 1.4.3 --- Effect on Normal Cell --- p.27 / Chapter 1.4.4 --- Effect on Distribution of Cells in Cell Cycle Phases --- p.28 / Chapter 1.4.5 --- In Vivo Study --- p.28 / Chapter Chapter Two: --- Materials and Methods --- p.30 / Chapter 2.1. --- Materials --- p.30 / Chapter 2.1.1 --- For Cell Culture --- p.30 / Chapter 2.1.2 --- In vitro Treatments --- p.31 / Chapter 2.1.3 --- DNA Electrophoresis --- p.31 / Chapter 2.1.4 --- Flow Cytometry --- p.32 / Chapter 2.2. --- Reagent Preparation --- p.33 / Chapter 2.2.1 --- Culture Media --- p.33 / Chapter 2.2.2 --- Human Recombinant Tumor Necrosis Factor alpha (rhTNF-α) --- p.33 / Chapter 2.2.3 --- Phosphate Buffered Saline (PBS) --- p.33 / Chapter 2.2.4 --- Lysis Buffer --- p.34 / Chapter 2.2.5 --- TE Buffer --- p.34 / Chapter 2.2.6 --- Proteinase K and Ribonuclease A (RNase A) --- p.34 / Chapter 2.2.7 --- 100 Base-Pair DNA Marker --- p.34 / Chapter 2.2.8 --- Propidium Iodide (PI) --- p.35 / Chapter 2.3 --- Methods --- p.35 / Chapter 2.3.1 --- Cell Culture --- p.35 / Chapter 2.3.1.1 --- Ehrlich Ascitic Tumor (EAT) and Human Leukemia (HL-60) / Chapter 2.3.1.2 --- Human Coronary Artery Endothelial Cells (HCAEC) / Chapter 2.3.2 --- In vitro Experiments --- p.36 / Chapter 2.3.3 --- Tumor Necrosis Factor Treatment --- p.37 / Chapter 2.3.4 --- Hyperthermia Treatments --- p.37 / Chapter 2.3.5 --- Cell Counting --- p.38 / Chapter 2.3.5.1 --- Trypan Blue Exclusion Assay / Chapter 2.3.5.2 --- Neutral Red Assay / Chapter 2.3.6 --- Determination of Additive or Synergistic Effect --- p.39 / Chapter 2.3.7 --- DNA Electrophoresis --- p.40 / Chapter 2.3.8 --- Flow Cytometry --- p.42 / Chapter 2.3.7.1 --- Preparation of Samples / Chapter 2.3.7.2 --- Flow Cytometry Acquisition / Chapter 2.3.7.3 --- Analysis / Chapter 2.3.9 --- In vivo Experiments --- p.44 / Chapter 2.3.8.1 --- Animal Strain / Chapter 2.3.8.2 --- Cell Line / Chapter 2.3.8.3 --- Tumor Necrosis Factor Treatment / Chapter 2.3.8.4 --- Hyperthermia Treatments / Chapter 2.3.8.5 --- Test of Body Temperature / Chapter 2.3.8.6 --- Cell Harvesting / Chapter Chapter Three: --- Result --- p.50 / Chapter 3.1 --- Optimal Sequence of Treatments --- p.50 / Chapter 3.1.1 --- Optimal Sequence of Treatments on Murine Ehrlich Ascitic Tumor (EAT) cells --- p.50 / Chapter 3.1.1.1 --- TNF + Fixed-temperature Hyperthermia / Chapter 3.1.1.2 --- TNF + Step-down Hyperthermia2 / Chapter 3.1.1.3 --- TNF + Step-down Hyperthermia3 / Chapter 3.1.2 --- Optimal Sequence of Treatments on Human Leukemia cells HL-60 --- p.60 / Chapter 3.1.2.1 --- TNF + Fixed-temperature Hyperthermia / Chapter 3.1.2.2 --- TNF + Step-Down Hyperthermia2 / Chapter 3.1.2.3 --- TNF + Step-Down Hyperthermia3 / Chapter 3.2 --- Comparison of Effectiveness of Treatments --- p.72 / Chapter 3.2.1 --- Effectiveness of Various treatments on EAT cells --- p.72 / Chapter 3.2.2 --- Synergistic Effect between rhTNF-α and Hyperthermia on EAT cells --- p.74 / Chapter 3.2.3 --- Decrease of Relative Growth and Viability of EAT with Time --- p.79 / Chapter 3.2.3.1 --- TNF + Fixed-temperature Hyperthermia / Chapter 3.2.3.2 --- TNF + Step-down Hyperthermia2 / Chapter 3.2.3.3 --- TNF + Step-down Hyperthermia3 / Chapter 3.2.4 --- Comparison of Effectiveness of Various Treatments on HL-60 cells --- p.82 / Chapter 3.2.5 --- Synergistic Effect between rhTNF-α and Hyperthermia on HL-60 cells --- p.87 / Chapter 3.2.6 --- Change of Relative Growth and Viability of HL-60 with Time --- p.90 / Chapter 3.2.6.1 --- TNF + Fixed-temperature Hyperthermia / Chapter 3.2.6.2 --- TNF + Step-down Hyperthermia2 / Chapter 3.2.6.3 --- TNF + Step-down hyperthermia3 / Chapter 3.3 --- Cell Death Pathway --- p.96 / Chapter 3.3.1 --- Experiments on Ehrlich Ascitic Tumor (EAT) Cells --- p.96 / Chapter 3.3.2 --- Experiments on Human Leukemia (HL-60) Cells --- p.100 / Chapter 3.4 --- Experiment on Normal Cell --- p.104 / Chapter 3.5 --- Effect of TNF + Fixed-temperature Hyperthermia on the Cell Cycle Progression --- p.107 / Chapter 3.5.1 --- Different Times of TNF Administration and Distribution of EAT cells in Cell cycle --- p.107 / Chapter 3.5.2 --- Different Times of TNF Administration and Distribution of HL-60 cells in Cell Cycle --- p.114 / Chapter 3.5.3 --- Shift of Cells Cycle after TNF Treatment --- p.120 / Chapter 3.5.3.1 --- Response of Ehrlich Ascitic Tumor Cells / Chapter 3.5.3.2 --- Response of Human leukemia Cells / Chapter 3.6 --- Effectiveness of Treatments in vivo: --- p.129 / Chapter 3.6.1 --- Dose-dependent Response --- p.129 / Chapter 3.6.2 --- Change of Body Temperature During Hyperthermia --- p.131 / Chapter 3.6.3 --- Comparison of Effectiveness of Various Treatments in vivo --- p.133 / Chapter 3.6.4 --- Synergistic Effect Between rhTNF-α and Hyperthermia in vivo --- p.135 / Chapter Chapter Four: --- Discussion --- p.138 / Chapter 4.1 --- Optimal Sequence of Treatments --- p.139 / Chapter 4.2 --- Comparison of Various Treatments --- p.143 / Chapter 4.3 --- Distribution of Cells in Cell Cycle Phases --- p.149 / Chapter 4.4 --- In vivo Study --- p.153 / Chapter Chapter Five: --- References --- p.156

by Leung Wing Chung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 67-68). / Abstract also in Chinese. / Chapter 1 --- Background and Modelling --- p.5 / Chapter 1.1 --- Treatment of Cancer --- p.5 / Chapter 1.2 --- Tumour Growth Model ´ؤ Gompertz Model --- p.5 / Chapter 1.3 --- Drug Concentration and Drug Effects --- p.7 / Chapter 1.3.1 --- Drug Effects on Tumour Cells --- p.9 / Chapter 1.3.2 --- "Drug Effects with Different Values of λG,k, vth" --- p.9 / Chapter 1.4 --- Constraints on the Gompertz Model --- p.11 / Chapter 2 --- Minimization on the Gompertz Model --- p.12 / Chapter 2.1 --- Mathematical Modelling on the Gompertz Model --- p.12 / Chapter 2.1.1 --- Constraints Transformation --- p.13 / Chapter 2.2 --- Simplified Minimization Problem --- p.15 / Chapter 2.2.1 --- Avoiding Non-Minimal Stationary Points --- p.16 / Chapter 2.2.2 --- The Final Minimization Problem --- p.23 / Chapter 2.2.3 --- Existence of Optimal Solutions --- p.24 / Chapter 2.3 --- Gradients of the Objective Function and the Constraints --- p.25 / Chapter 2.3.1 --- First Derivatives --- p.25 / Chapter 2.3.2 --- Second Derivatives --- p.29 / Chapter 3 --- Numerical Methods for Minimization Problems --- p.31 / Chapter 3.1 --- Lagrangian Multiplier Method --- p.32 / Chapter 3.1.1 --- Kuhn-Tucker Condition --- p.33 / Chapter 3.1.2 --- Model Augmented Lagrangian Algorithm --- p.34 / Chapter 3.1.3 --- Armijo Algorithm --- p.36 / Chapter 3.1.4 --- Modified Augmented Lagrangian Algorithm --- p.40 / Chapter 3.2 --- Data on the Gompertz Model --- p.42 / Chapter 3.2.1 --- Optimality of Solutions --- p.42 / Chapter 3.3 --- Numerical Results --- p.45 / Chapter 3.4 --- Well-Conditioned Penalty Function Method for Constrained Optimization --- p.56 / Chapter 3.5 --- Discussion --- p.64 / Chapter 3.5.1 --- Model Augmented Lagrangian Algorithm and Modified Augmented Lagrangian Algorithm --- p.65 / Chapter 3.5.2 --- Modified Augmented Lagrangian Algorithm and Penalty Function Algorithm --- p.65 / Bibliography

Yeung Chung Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 83-97). / Abstracts in English and Chinese. / Abstract --- p.i / Abstract (Chinese) --- p.iv / Acknowledgements --- p.vii / Table of contents --- p.ix / List of figures --- p.xii / List of tables --- p.xiv / List of abbreviations --- p.xv / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General Introduction --- p.1 / Chapter 1.2 --- Literature Review --- p.5 / Chapter 1.2.1 --- Cancer and melanoma --- p.5 / Chapter 1.2.2 --- Anticancer drugs from natural products --- p.6 / Chapter 1.2.3 --- Challenges in treatment of melanoma --- p.9 / Chapter 1.2.4 --- TCM - New source of natural products for cancer therapy --- p.10 / Chapter 1.2.6 --- The genus Schefflera --- p.11 / Chapter 1.2.7 --- Anticancer activities of triterpenoids --- p.16 / Chapter 1.2.8 --- Cancer and apoptosis --- p.17 / Chapter 1.2.8.1 --- The Apoptosis Pathways --- p.20 / Chapter 1.2.9 --- Studies of anticancer molecules against melanoma --- p.26 / Chapter 1.2.9.1 --- In vitro models for studying anticancer molecules --- p.26 / Chapter 1.2.9.2 --- In vivo models for studying anticancer molecules --- p.30 / Chapter Chapter 2 --- Materials and Methods --- p.34 / Chapter 2.1 --- Phytochemicals --- p.34 / Chapter 2.2 --- "Chemicals, Cell Lines and Culture Conditions" --- p.34 / Chapter 2.3 --- Determination of in vitro antiproliferative effects of HLDA and the ethyl acetate fraction from S. heptaphylla on human cancer cells --- p.36 / Chapter 2.3.1 --- MTT assay --- p.36 / Chapter 2.4 --- Determination of the in vitro antiproliferative mechanisms of HLDA and the ethyl acetate fraction from S. heptaphylla in human melanoma A375 cells --- p.37 / Chapter 2.4.1 --- Flow cytometric analysis --- p.37 / Chapter 2.4.2 --- Western blot analysis --- p.38 / Chapter 2.5 --- Determination of the in vivo anticancer effects of the ethyl acetate fraction from S. heptaphylla --- p.41 / Chapter 2.5.1 --- Determination of cancer chemopreventive effect of the ethyl acetate fraction with DMBA/TPA-induced skin carcinogenesis model --- p.41 / Chapter 2.5.2 --- Determination of cancer therapeutic effect of the ethyl acetate fraction with athymic BALB/c nude mice model --- p.42 / Chapter 2.6 --- Statistical Analysis --- p.44 / Chapter Chapter 3 --- Results --- p.45 / Chapter 3.1 --- Effects of HLDA and the ethyl acetate fraction on viability and proliferation of different cancer cell lines by MTT assay --- p.45 / Chapter 3.2 --- Effects of HLDA and the ethyl acetate fraction on cell cycle and apoptosis in A375 cells determined by DNA flow cytometry --- p.46 / Chapter 3.3 --- Effects of HLD A and the ethyl acetate fraction on apoptosis induction in A375 cells determined by Western blotting --- p.53 / Chapter 3.4 --- Effects of HLD A and ethyl acetate fraction on caspases in A375 cells --- p.55 / Chapter 3.5 --- Effects of caspase inhibitors on the HLDA- and the ethyl acetate fraction-induced apoptosis in A375 cells --- p.57 / Chapter 3.6 --- Effects of HLD A and the ethyl acetate fraction on the expression of Bcl-2 family proteins in A375 cells --- p.62 / Chapter 3.7 --- Chemopreventive effect of the ethyl acetate fraction from S. heptaphylla on the DMBA/TPA-induced skin carcinogenesis model --- p.65 / Chapter 3.8 --- Chemotherapeutic effect of the ethyl acetate fraction from S. heptaphylla on A375 xenograft in athymic nude mice --- p.70 / Chapter Chapter 4 --- Discussion --- p.73 / References --- p.83

Wong Yue Hang Albert. / Thesis submitted in: December 2005. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 108-119). / Abstracts in English and Chinese. / Abstract --- p.i / Acknowledgements --- p.v / List of Figures --- p.x / List of Tables --- p.xi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter Chapter 2 --- Literature Review --- p.4 / Chapter 2.1 --- Nasopharyngeal Carcinoma (NPC) --- p.4 / Chapter 2.1.1 --- Anatomy of Nasopharynx --- p.4 / Chapter 2.1.2 --- Histopathology of Nasopharyngeal Carcinoma --- p.5 / Chapter 2.1.3 --- Epidemiology and Etiology of Nasopharyngeal Carcinoma --- p.5 / Chapter 2.1.3.1 --- Endemic Regions of Nasopharyngeal Carcinoma --- p.5 / Chapter 2.1.3.2 --- Gender and Age Bias --- p.6 / Chapter 2.1.3.3 --- Nasopharyngeal Carcinoma in Hong Kong --- p.6 / Chapter 2.1.3.4 --- Environmental Factors and Diet --- p.7 / Chapter 2.1.3.5 --- HLA Haplotypes and Nasopharyngeal Carcinoma --- p.9 / Chapter 2.1.4 --- Epstein-Barr Virus (EBV) and Nasopharyngeal Carcinoma --- p.10 / Chapter 2.1.4.1 --- EBV and Human Cacners --- p.10 / Chapter 2.1.4.2 --- EBV Infection --- p.10 / Chapter 2.1.4.3 --- "Latent, Clonal EBV Infection" --- p.11 / Chapter 2.1.4.4 --- EBV Latency Form --- p.11 / Chapter 2.1.4.5 --- Reactivation of EBV --- p.12 / Chapter 2.1.5 --- Molecular Pathogenesis of Nasopharyngeal Carcinoma --- p.13 / Chapter 2.1.5.1 --- Genetic Changes --- p.13 / Chapter 2.1.5.2 --- Epigenetic Changes --- p.13 / Chapter 2.1.6 --- Therapy of Nasopharyngeal Carcinoma and its Deficiency --- p.14 / Chapter 2.1.6.1 --- Radiotherapy --- p.14 / Chapter 2.1.6.2 --- Concurrent Chemoradiotherapy --- p.16 / Chapter 2.1.6.3 --- Adjuvant and Neo-adjuvant Chemotherapy --- p.17 / Chapter 2.1.6.4 --- Chemotherapy in Metastatic Nasopharyngeal Carcinoma --- p.18 / Chapter 2.1.6.5 --- Novel Therapeutic Agents and Approach --- p.19 / Chapter 2.2 --- Histone Modification and Cancer --- p.20 / Chapter 2.2.1 --- Histone Modification and Transcription Regulation --- p.20 / Chapter 2.2.2 --- Carcinogenic Effect of Aberrant HAT and HDAC Activities --- p.21 / Chapter 2.2.3 --- Structural Classes of HDAC Inhibitors --- p.24 / Chapter 2.2.4 --- Anti-Cancer Mechanisms of HDAC Inhibitors --- p.25 / Chapter 2.3 --- Suberoylanilide Hydroxamic Acid (SAHA) --- p.27 / Chapter 2.3.1 --- Anti-tumor Effect of SAHA in Various Cancer Cell Lines --- p.27 / Chapter 2.3.2 --- SAHA Mediated Non-apoptotic Programmed Cell Death --- p.29 / Chapter 2.3.3 --- Anti-tumor and Preventive Effect of SAHA in Animal Model --- p.29 / Chapter 2.3.4 --- Clinical Trials of SAHA --- p.30 / Chapter 2.4 --- FK228 (Depsipeptide or FR901228) --- p.31 / Chapter 2.4.1 --- Anti-malignancy mechanism of FK228 --- p.31 / Chapter 2.4.2 --- Anti-angiogenesis --- p.32 / Chapter 2.4.3 --- Drug Resistance and FK228 --- p.33 / Chapter 2.4.4 --- Studies of FK228 on Animal Models --- p.33 / Chapter 2.4.5 --- Clinical Trials --- p.34 / Chapter 2.5 --- Histone Modification and Nasopharyngeal Carcinoma --- p.34 / Chapter Chapter 3 --- Materials and Methods --- p.36 / Chapter 3.1 --- Cell Lines --- p.36 / Chapter 3.2 --- EBER ish Hybridization (EBER ISH) --- p.37 / Chapter 3.3 --- HDAC Inhibitors --- p.38 / Chapter 3.4 --- Cellular Sensitivity of NPC Cell Lines to HDAC Inhibitors --- p.38 / Chapter 3.4.1 --- Drug Treatment --- p.38 / Chapter 3.4.2 --- Determining Relative Amount of Survival Cells (WST-1 Assay) --- p.39 / Chapter 3.5 --- Flow Cytometry Analysis --- p.40 / Chapter 3.5.1 --- Collecting Cells and Fixation --- p.40 / Chapter 3.5.2 --- Staining --- p.41 / Chapter 3.5.3 --- Flow Cytometry Analysis --- p.41 / Chapter 3.6 --- Protein Extraction --- p.41 / Chapter 3.6.1 --- Harvesting Samples --- p.41 / Chapter 3.6.2 --- Protein Extraction --- p.42 / Chapter 3.6.3 --- Protein Quantification --- p.42 / Chapter 3.7 --- Western Blotting --- p.43 / Chapter 3.7.1 --- SDS-Polyarcylamide Gel Electrophoresis (PAGE) (SDS-PAGE) --- p.43 / Chapter 3.7.2 --- Wet Transfer of Proteins --- p.43 / Chapter 3.7.3 --- Immunoblotting --- p.44 / Chapter 3.7.4 --- Signal Detection --- p.44 / Chapter 3.8 --- CodeLin´kёØ Oligonucleotide Microarray --- p.45 / Chapter 3.8.1 --- HDAC Inhibitor Treatment --- p.45 / Chapter 3.8.2 --- RNA Extraction --- p.45 / Chapter 3.8.3 --- Quality and Quantity Assessment of Total RNA Extracted --- p.46 / Chapter 3.8.4 --- CodeLinkIM Expression Bioarray System --- p.46 / Chapter 3.8.5 --- Data Analysis --- p.48 / Chapter 3.9 --- Real-time Reverse Transcription PCR (Real-time RT-PCR) --- p.48 / Chapter Chapter 4 --- Results --- p.50 / Chapter 4.1 --- Presence of EBV --- p.50 / Chapter 4.2 --- Anti-prolirative Effect of HDAC Inhibitors --- p.52 / Chapter 4.3 --- Histone Acetylation --- p.56 / Chapter 4.4 --- Induction of p21 Expression in NPC Cell Lines --- p.58 / Chapter 4.5 --- HDAC Inhibitors Induced Cell Cycle Arrest and Polyploidy Formation --- p.60 / Chapter 4.5.1 --- Trichostatin A Induced G2/M Arrest --- p.60 / Chapter 4.5.2 --- Suberoylanilide Hydroxamic Acid Induced G1 Arrest --- p.62 / Chapter 4.5.3 --- FK228 Mediated G2/M Arrest --- p.64 / Chapter 4.6 --- HDAC Inhibitors Altered the Expression of Cell Cycle Regulatory Proteins --- p.66 / Chapter 4.6.1 --- TSA Down-regulated Cyclin A and B --- p.66 / Chapter 4.6.2 --- Suppressed Expression of Cyclin D1 and B by SAHA --- p.69 / Chapter 4.6.3 --- Effect of FK228 on Expression of Different Cyclins in NPC Cell Lines --- p.71 / Chapter 4.7 --- Effect of HDAC Inhibitors on EBV Proteins --- p.73 / Chapter 4.8 --- HDAC Inhibitors Modulated Gene Expression Profile --- p.76 / Chapter 4.8.1 --- SAHA and FK228-Induced Gene Expression Profile --- p.76 / Chapter 4.8.2 --- Validation of Expression Profile of Selected Genes by Real-time RT-PCR --- p.83 / Chapter Chapter 5 --- Discussion --- p.87 / Chapter 5.1 --- Anti-proliferative Effect of SAHA and FK228 on NPC Cell Lines --- p.88 / Chapter 5.2 --- Resistance of SAHA or FK228 in NPC --- p.93 / Chapter 5.3 --- Growth Inhibitory Mechanism of SAHA and FK228 in NPC Cells --- p.94 / Chapter 5.4 --- Induction of Polyploidy Cells in NPC Cell Lines --- p.98 / Chapter 5.5 --- Does EBV play a Role in HDAC Inhibiotrs Induced Growth Arrest in NPC Cell Lines? --- p.99 / Chapter 5.6 --- Transcriptional Signature of SAHA and FK228 in NPC Cell Lines --- p.100 / Chapter 5.7 --- Combining SAHA or FK228 with other Anti-tumor Agents --- p.104 / Chapter 5.8 --- Future Prospectus --- p.105 / Chapter Chapter 6 --- Summary --- p.106 / References --- p.108 / Appendix 1 --- p.120 / Appendix 2 --- p.121

Os medicamentos devem ser monitorados devido ao seu potencial de causar lesões e danos ao paciente se prescritos ou administrados de maneira incorreta, podendo aumentar o tempo de internação e diminuir a qualidade de vida do indivíduo no período de recuperação. Estudos de utilização de medicamento têm como objetivo conhecer e avaliar de que forma os medicamentos estão sendo utilizados para possibilitar medidas de intervenção adequadas e apropriadas para o serviço, bem como o planejamento de ações dentro da unidade estudada, buscando beneficiar o paciente e a melhoria da qualidade do serviço prestado. A prescrição de medicamentos em pediatria segue os mesmos critérios da adotada para adultos, embora a complexidade do paciente seja maior, por particularidades do metabolismo neonatal e infantil. A necessidade de uma dose ajustada ao peso e alterações nos parâmetros farmacocinéticos faz com que a população pediátrica seja mais suscetível a erros de medicação. Este estudo teve como objetivo analisar o perfil de utilização de medicamentos no período perioperatório de cirurgias pediátricas realizadas em um hospital. Trata-se de um estudo transversal, retrospectivo, conduzido em um hospital do Sul do Brasil. Foi realizado estudo piloto com 30 pacientes, o qual identificou que o procedimento mais realizado foi a hernioplastia. A classe terapêutica mais prescrita durante a cirurgia foi a de anestésicos e no período pós cirúrgico, analgésicos. Para analisar o perfil de utilização de medicamentos no período perioperatório, foram incluídos pacientes entre 0 e 18 anos submetidos à hernioplastia. Os medicamentos mais prescritos na pré-anestesia foram midazolam e cetamina. Durante o procedimento cirúrgico, sevoflurano, fentanil e propofol foram os anestésicos mais utilizados. O antimicrobiano predominantemente utilizado na profilaxia cirúrgica foi a cefazolina. No pós operatório 100% dos pacientes tiveram prescrição de pelo menos um medicamento analgésico, sendo o mais prescrito a dipirona. A metoclopramida foi o fármaco de escolha para tratar náuseas e vômitos. As prescrições estavam de acordo com a literatura e os protocolos assistenciais do hospital. Alguns dados não puderam ser analisados devido ao subregistro encontrados nos prontuários físicos. Estudos de utilização de medicamentos na área devem ser continuados, para obtenção de maior conhecimento sobre a prescrição e utilização de medicamentos na pediatria, possibilitando uma melhor assistência à saúde dos pacientes. / Anesthetic drugs should be monitored due to their potential to cause injury and damage to the patient if prescribed or administered incorrectly, with the possibility of increasing the length of stay and reducing the quality of life of individuals in the recovery period. Drug utilization studies aim to understand and evaluate how drugs are being used to enable intervention measures that are adequate and appropriate for the service, as well as action planning within the unit studied, with the aim of benefiting the patient and improving quality of service. The prescription of drugs in pediatrics follows the same criteria as those adopted for adults, although the patient complexity is greater, due to peculiarities of neonatal and child metabolism. The need for a weight-adjusted dose and alterations in pharmacokinetic parameters causes the pediatric population to be more susceptible to medication errors. This study aimed to analyze the drug use profile in the perioperative period of pediatric surgery performed in a hospital. It is a cross-sectional, retrospective study conducted in a hospital in the South region of Brazil, including patients aged 0-18 years. A pilot study was conducted with 30 patients, which found that the procedure performed was hernioplasty. The most prescribed therapeutic classes were anesthetics during surgery and painkillers during the postsurgical period. To analyze the drug use profile in the perioperative period, we included patients aged 0-18 years undergoing hernioplasty. The drugs most commonly prescribed in the pre-anesthesia period were midazolam and ketamine. During the surgical procedure, sevoflurane, fentanyl and propofol were the most used anesthetics. The antimicrobial that was predominantly used in surgical prophylaxis was cefazolin. In the postoperative period, 100% of the patients were prescribed at least one painkiller, the most common being dipyrone. Metoclopramide is the drug of choice to treat nausea and vomiting. The prescriptions were in accordance with the literature and the hospital’s care protocols. The use of metoclopramide may be controversial due to the extrapyramidal effects that may be caused by the drug, in particular in children. Some data could not be analyzed due to an undercount found in the physical records. Drug use studies in the area should be continued to provide greater knowledge of the prescription and use of drugs in pediatrics, enabling better care for patients.

A Quimioterapia antineoplásica (QtA) adjuvante para câncer colorretal (CCR) traz consequências fisiológicas e psicossociais como os eventos adversos (EA) gastrintestinais e dermatológicos, que podem trazer dificuldades na utilização de equipamentos para os pacientes com estomia intestinal. Este estudo teve por objetivos analisar a produção científica nacional e internacional sobre os EA gastrintestinais e dermatológicos para pacientes com CCR em QtA adjuvante; e estabelecer as recomendações em relação à indicação de equipamentos coletores e adjuvantes para os pacientes com estomia intestinal por CCR, assim como para os cuidados com a estomia intestinal e o manejo destes equipamentos durante a QtA, com base nas evidências científicas. Trata-se de uma Revisão Integrativa, fundamentada na Prática Baseada em Evidências, cuja pergunta formulada foi: Quais os EA gastrintestinal e dermatológico decorrentes da quimioterapia adjuvante em pacientes com câncer colorretal? Os descritores utilizados para as buscas foram Neoplasias Colorretais, Quimioterapia, Toxicidade, Efeitos adversos, nas bases de indexação eletrônica PubMed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Cumulative Index to Nursing and Allied Health (CINAHL), e Excerpta Médica (EMBASE), mediante os critérios de inclusão: estudos que abordassem a ocorrência e o tratamento de EA gastrintestinais ou dermatológicos em pacientes com CCR em QtA adjuvante; e estudos publicados em inglês, português ou espanhol, sem corte temporal de publicação; obtidos na íntegra via Biblioteca Central do Campus de Ribeirão Preto da Universidade de São Paulo; e os critérios de exclusão que foram estudos em modelo animal e modelo in vitro; estudos sobre metástases associadas ao tumor primário colorretal. Do total de 4.021 artigos científicos, resultantes das buscas, foram selecionados mediante os critérios de inclusão e exclusão, 20 estudos que constituíram a amostra final, sendo que todos foram publicados em inglês, com níveis de evidência pouco fortes em 65% (IV e VI) e cujos aspectos abordados foram categorizados em quatro temáticas: Diarreia e demais EA gastrintestinais; Diarreia e EA Gastrodermatológicos; EA Gastrintestinais; e EA Dermatológicos. No tema Diarreia e demais EA gastrintestinais evidenciou-se diarreia, náusea, perda de apetite e constipação, vinculados à QtA adjuvante com 5-FU, capecitabina e irinotecano. No tema Diarreia e EA Gastrodermatológicos evidenciou-se síndrome palmar-plantar, outras afecções cutâneas (eritema, úlcera, descamação, prurido, eritema, bolha), estomatite, edema das mãos/face/boca, e hipersensibilidade por capecitabina e oxaliplatina. No tema EA Gastrintestinais verificamos que náusea e vômito foram mais frequentes e relacionados à oxaliplatina. No tema EA Dermatológicos, evidenciou-se rash cutâneo, rubor, prurido, reações alérgicas, síndrome palmar-plantar nos esquemas com 5-FU, capecitabina, oxaliplatina e irinotecano. Considerando estas evidências e a necessidade de utilização de equipamentos coletores do paciente com estomia intestinal por CCR em QtA adjuvante, a assistência de enfermagem especializada deve assegurar a demarcação de estoma, ensino do autocuidado sobre EA e seu manejo, indicação e fornecimento de equipamentos coletores e adjuvantes, que atendam as suas necessidades, assim como o desenvolvimento de protocolos para avaliação dos EA gastrintestinais e dermatológicos durante a QtA adjuvante / The antineoplastic chemotherapy for adjuvant colorectal cancer (ACC) brings physiological and psychosocial consequences such as gastrointestinal and dermatologic adverse events (AE), which can cause difficulties in using equipment for patients with ostomy. This study aimed to analyze the national and international scientific literature on the gastrointestinal and dermatological EA for patients with CRC in adjuvant chemotherapy; and establish recommendations regarding the indication of equipment supplies and also aid for patients with ostomy by CRC, as well as for ostomy care and management of this equipment during the chemotherapy, based on scientific evidence. This is an integrative review, based on the evidence-based practice, whose question was: What are the gastrointestinal and dermatological EA resulting from adjuvant chemotherapy in patients with colorectal cancer? The descriptors used for the search were Colorectal neoplasms, Drug therapy, Toxicity, and Adverse effects, in electronics PubMed indexing bases, Latin American and Caribbean Health Sciences (LILACS), Cumulative Index to Nursing and Allied Health (CINAHL) and Excerpta Medical (EMBASE) by the inclusion criteria: studies that addressed the occurrence and treatment of gastrointestinal or dermatological EA in patients with CRC in adjuvant chemotherapy; and studies published in English, Portuguese or Spanish, without temporal cutting time publication; obtained in entirety at Ribeirão Preto Campus Central Library of the University of São Paulo; and the exclusion criteria were studies in animal models and in vitro model; studies on colorectal metastases associated with primary tumor. Of the total of 4,021 scientific articles resulting from the searches, they were selected by the inclusion and exclusion criteria, 20 studies which formed the final sample, all of which have been published in English, with little strong evidence levels 65% (IV and VI) and whose addressed aspects were categorized into four themes: Diarrhea and other gastrointestinal EA; Diarrhea and gastrointestinal and dermatologic EA; Gastrointestinal EA; Dermatologic EA. In the subject Diarrhea and other gastrointestinal EA became evident diarrhea, nausea, loss of appetite and constipation linked with adjuvant 5-FU, capecitabine, and irinotecan. On the topic diarrhea and Gastrointestinal and dermatologic EA showed up hand-foot syndrome, other skin disorders (erythema, ulcers, peeling, itching, erythema, and bubble), and stomatitis, swelling of the hands / face / mouth, and hypersensitivity oxaliplatin and capecitabine. On the topic Gastrointestinal EA were found that nausea and vomiting were more frequent and related to oxaliplatin. On the topic of Dermatological EA, evidence of skin rash, redness, itching, allergic reactions and palmar-plantar syndrome in the schemes with 5-FU, capecitabine, oxaliplatin and irinotecan. Considering this evidence and the need for equipment supplies in patients with ostomy by CRC in chemotherapy, specialized nursing care to ensure the demarcation of stoma, self-care education on EA and its management, display and supply collectors equipment and adjuvants that meet their needs, as well as the development of protocols for evaluation of gastrointestinal and dermatological EA during adjuvant chemotherapy.

O câncer de mama é uma preocupação de saúde pública por sua grande incidência na população. A quimioterapia é a estratégia de tratamento mais empregada e dentre as formas de ser administrada, a mais comum é a intravenosa. A maioria das drogas citotóxicas é irritante ou vesicante, passível de promover trauma vascular. A pesquisa teve como objetivos: verificar a ocorrência de trauma vascular, oriundo do procedimento de punção venosa periférica, em pessoas submetidas à quimioterapia ambulatorial no tratamento do câncer de mama; identificar as manifestações clínicas de trauma vascular no local de punção venosa periférica para quimioterapia; verificar a existência de associação entre a ocorrência do trauma vascular e as variáveis estudadas; descrever a evolução temporal da ocorrência e continuidade do trauma vascular. Foram observadas 30 pacientes, durante 188 sessões. Quanto à caracterização da amostra, 93,3% das pacientes apresentaram o diagnóstico Carcinoma Ductal Invasivo, 3,3% Carcinoma Lobular Invasivo e 3,3% carcinoma metaplásico condróide; quanto ao estadiamento clínico os de maior porcentagem foram IIIA e IIIB com 26,7% cada um. Quanto ao programa de quimioterapia, 36,6% fizeram uso de Fluorouracil, Epirrubicina e Ciclofosfamida e 56,67% de uma combinação quatro Ciclos de Epirrubicina e Ciclofosfamida e quatro ciclos de Docetaxel associado ou não ao Trastuzumab. Outra característica, a presença de dor antes do inicio da quimioterapia, foi observada no ciclo 1 (10%), ciclo 2 (26,7%), ciclo 3 (36,7%), ciclo 4 (23,3%), ciclo 5 (26,67%), ciclo 6 (40%), ciclo 7 (14,3%) e ciclo 8 (14%); dentre as pacientes que apresentaram dor, os locais predominantes foram os membros superiores e inferiores. As características principais identificadas em relação aos acessos venosos foram visibilidade, em mais de 50% dos acessos escolhidos; palpabilidade, presente em 100% dos acessos; mobilidade, sendo que mais de 50% das veias eram fixas; alem de a maioria apresentar trajetória retilínea e com elasticidade preservada. Quanto ao local de inserção, predominou (>60%) o dorso da mão. Houve também um aumento de repetidas punções para se conseguir um acesso ao longo dos ciclos. Quanto ao material, identificou-se preferência pelos materiais flexíveis - vialon ou tefon - de calibre predominantemente 24G, fixados com adesivo micropore. Quanto ao sistema utilizado para infusão foi utilizado o frasco de plástico flexível e colabável, com equipo simples e com sistema extensor de duas vias. Nos 188 ciclos observados foram identificados como trauma vascular tardio: diminuição da elasticidade do vaso (63); hiperpigmentação (69); endurecimento (46); engurgitamento (10) e cordão venoso (30). Como manifestações imediatas: infiltração em 1,59% dos ciclos, flebite durante a infusão (35) e queixas de dor durante a infusão (9). Ao se comparar as médias de problemas (trauma vascular) apresentados pelas pacientes que fizeram uso de Fluorouracil, Epirrubicina e Ciclofosfamida e as que fizeram uso de Epirrubicina, Ciclofosfamida, e Docetaxel, foi identificado maior índice para as do primeiro grupo; a análise estatística Mann-whitney, (,062) aponta que a diferença entre os protocolos é significante. O trauma vascular, como eventual diagnóstico de enfermagem, possibilita ao enfermeiro, no âmbito de sua competência, intervir para minimizá-lo ou extingui-lo. / Breast cancer is a public health concern due to its high incidence in population. Chemotherapy is the most applied treatment strategy, and intravenous administration is the most common form. Most cytotoxic drugs are irritant or vesicant, and can cause vascular trauma. This research aimed to verify the occurrence of vascular trauma, caused by the peripheral venous puncture procedure, in patients subject to ambulatory chemotherapy in breast cancer treatment; to identify the clinical manifestations of vascular trauma in the site of peripheral venous puncture for chemotherapy; to verify the existence of association between the occurrence of vascular trauma and the studied variables; to describe the time evolution of the occurrence and the continuity of vascular trauma. In total, 30 patients were observed during 188 chemotherapy sessions. Regarding the characterization of the sample, 93.3% of the patients presented diagnosis of Invasive Ductal Carcinoma, 3.3% Invasive Lobular Carcinoma and 3.3% Carcinoma with Chondroid Metaplasia; as to the clinical staging, the ones with highest percentage where IIIA and IIIB with 26.7% each one. Regarding the chemotherapy program, 36.6% used Fluorouracil, Epirubicin and Cyclophosphamide and 56.67% used a combination of four cycles of Epirubicin and Cyclophosphamide and four cycles of Docetaxel associated or not to Trastuzumab. Presence of pain before the start of chemotherapy was observed at cycle 1 (10%), cycle 2 (26.7%), cycle 3 (36.7%), cycle 4 (23.3%), cycle 5 (26.67%), cycle 6 (40%), cycle 7 (14.3%) and cycle 8 (14%); among patients who presented pain, the main sites were lower and upper extremities. The main characteristics identified in relation to venous accesses were visibility, in more than 50% of the chosen accesses, palpability, present in 100% of the accesses, mobility, being more than 50% of the veins fixed, and most presented straight path and preserved elasticity. Regarding the insertion site, most (60%) were in the dorsum of the hand. There was also an increase in repetitive punctures to succeed in accessing throughout the cycles. Preference for flexible materials vialon or teflon - was identified, mainly with 24G gauge, fixed with Micropore tape. Plastic, flexible and collapsible flask was used for infusion, with simple gadget and two-ways extended system. In the 188 observed cycles, the following were identified as late vascular trauma: decrease in vascular elasticity (63); hyperpigmentation (69); hardening (46); ingurgitation (10) and venous cord (30). As immediate manifestations: infiltration in 1.59% of the cycles, phlebitis during infusion (35) and complaint of pain during the infusion (9). Comparing the average of problems (vascular trauma) presented by the patients who used Fluorouracil, Epirubicin and Cyclophosphamide and the ones who used Epirubicin, Cyclophosphamide and Docetaxel, higher rates were identified for the patients of the first group; Mann-Whitneys statistical analysis (.062) shows significant difference between the protocols. Vascular trauma, as an occasional nursing diagnosis, enables nurses, under their competencies, to intervene to minimize or extinguish it.

by Cheng Yuen Yee. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves [106]-113). / Abstracts in English and Chinese. / Abstract --- p.i / Acknowledgements --- p.iv / Research out puts --- p.v / Abbreviations --- p.vii / List of Figures --- p.viii / List of Tables --- p.xiii / Table of contents --- p.xiv / Chapter Chapter 1 --- Introduction & Hypothesis / Chapter 1.1. --- General Introduction --- p.1 / Chapter 1.2. --- Hypothesis --- p.4 / Chapter 1.3. --- Objectives --- p.4 / Chapter Chapter 2 --- An Overview of Giant Cell Tumour of Bone / Chapter 2.1. --- Introduction --- p.5 / Chapter 2.2. --- Pathobiological features of GCT --- p.6 / Chapter 2.2.1. --- Radiological appearances and clinical classifications of GCT --- p.7 / Chapter 2.2.2. --- Histological characteristics --- p.10 / Chapter 2.2.3. --- Metastatic GCT --- p.13 / Chapter 2.3. --- Histogenesis of GCT --- p.14 / Chapter 2.4. --- Treatment --- p.19 / Chapter 2.5. --- Summary --- p.22 / Chapter Chapter 3 --- Pharmacological aspect of bisphosphonates / Chapter 3.1. --- Introduction --- p.23 / Chapter 3.2. --- Chemical structures of bisphosphonates --- p.28 / Chapter 3.3. --- Mechanisms and actions --- p.28 / Chapter 3.3.1. --- Bisphosphonates induce osteoclast apoptosis --- p.30 / Chapter 3.3.2. --- Bisphosphonates induce cell apoptosis --- p.32 / Chapter 3.3.3. --- Apoptosis --- p.33 / Chapter 3.3.3.1. --- Morphological characteristic of apoptosis --- p.35 / Chapter 3.4. --- Clinical applications of bisphosphonates --- p.36 / Chapter 3.5. --- Bisphosphonates used in this study --- p.38 / Chapter 3.6. --- Summary --- p.43 / Chapter Chapter 4 --- Materials and methods / Chapter 4.1. --- Introduction --- p.44 / Chapter 4.2. --- Primary GCT cell culture and maintenance --- p.46 / Chapter 4.3. --- Drug preparation --- p.46 / Chapter 4.4. --- MTT assay --- p.47 / Chapter 4.5. --- Annexin-V-flous staining assay --- p.48 / Chapter 4.6. --- Haematoxyline and Eosin staining --- p.51 / Chapter 4.7. --- TUNEL assay (Terminal deoxynucleotidyltrasferase - mediated dUTP-biotin nick end labelling) --- p.52 / Chapter 4.8. --- TEM (Transmission Electron Microscopy) --- p.54 / Chapter 4.9. --- Statistical analysis --- p.54 / Chapter Chapter 5 --- Bisphosphonates induce apoptosis in giant cell tumour of bone -in vitro study / Chapter 5.1. --- Introduction --- p.56 / Chapter 5.2. --- Experimental design --- p.57 / Chapter 5.3. --- Results / Chapter 5.3.1. --- Bisphosphonates reduce cell viability of GCT stromal tumour cell --- p.59 / Chapter 5.3.2. --- Bisphosphonates induce morphological changesin GCT primary culture --- p.59 / Chapter 5.3.3. --- Bisphosphonate significantly induce apoptosis in GCT stromal cells in a dose dependent manner --- p.62 / Chapter 5.4. --- Discussions and Summary --- p.68 / Chapter Chapter 6 --- Bisphosphonates induce apoptosis in giant cell tumour of bone -in vivo study / Chapter 6.1. --- Introduction --- p.73 / Chapter 6.2. --- Experiment design --- p.74 / Chapter 6.3. --- Results / Chapter 6.3.1. --- H & E observations / Chapter 6.3.2. --- Pamidronate significantly induce apoptosis in both osteoclast-like giant cells and stromal tumour cells by TUNEL labelling assay --- p.79 / Chapter 6.3.3. --- Pamidronate induced cellular ultrastructural changes of GCT by TEM examination --- p.83 / Chapter 6.3.4. --- Pamidronate reduce the recurrent characteristic of GCT --- p.95 / Chapter 6.4. --- Discussions and Summary --- p.97 / Chapter Chapter 7 --- Summary and Future Study / Chapter 7.1. --- Summary --- p.101 / Chapter 7.2. --- Future directions --- p.103 / Chapter Chapter 8 --- Reference --- p.105 / Chapter Chapter 9 --- Appendix - solution preparation

Chan Tai-po. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 94-101). / Abstracts in English and Chinese. / Chapter 1 --- INTRODUCTION --- p.1 / Chapter 2 --- HYPOTHESIS --- p.3 / Chapter 3 --- OBJECTIVE --- p.4 / Chapter 4 --- CLINICAL IMPLICATIONS --- p.5 / Chapter 5 --- METHODOLOGY --- p.6 / Chapter 5.1 --- Materials --- p.8 / Chapter 5.2 --- Study method --- p.13 / Chapter 5.3 --- Venues of the research --- p.22 / Chapter 5.4 --- Data acquisition --- p.23 / Chapter 5.5 --- Data management and analysis --- p.24 / Chapter 5.6 --- Ethical considerations --- p.25 / Chapter 5.7 --- Participations of persons in the research --- p.28 / Chapter 6 --- RESULTS --- p.34 / Chapter 6.1 --- Problems and fate of rats in the model development group --- p.34 / Chapter 6.2 --- Morbidity and mortality after LEM administration --- p.38 / Chapter 6.3 --- Results of radiological findings --- p.39 / Chapter 6.4 --- Results of liver function tests --- p.48 / Chapter 6.5 --- Results of liver morphology --- p.52 / Chapter 6.6 --- Histological results --- p.53 / Chapter 7 --- DISCUSSION --- p.69 / Chapter 7.1 --- Problems encountered in the development group --- p.69 / Chapter 7.2 --- The pilot study group --- p.71 / Chapter 7.3 --- The need for the present study --- p.74 / Chapter 7.4 --- LEM in cirrhotic rat compared with the normal liver rat --- p.75 / Chapter 7.5 --- Liver function markers in cirrhotic liver --- p.76 / Chapter 7.6 --- Discussion on the assumptions of the research --- p.80 / Chapter 7.7 --- Assessment on measurement error --- p.82 / Chapter 7.8 --- Errors in the pilot study --- p.83 / Chapter 8 --- CONCLUSIONS --- p.84 / Chapter 9 --- Future experiments that may be performed using this model --- p.85 / Chapter 10 --- APPENDICES --- p.86 / Chapter 10.1 --- Appendix 1: Copy on the letter of ethics approval from the Animal Research Ethics Committee of the Chinese University of Hong Kong --- p.86 / Chapter 10.2 --- Appendix 2: Copy on the licences issued by the Department of Health of Hong Kong --- p.88 / Chapter 11 --- REFERENCES --- p.94