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Cancer continues to be a leading cause of death worldwide despite the increasing research advances into novel treatments. Thermal ablation of tumors is a relatively established method for the destruction of many tumor types, despite inherent shortcomings including incomplete tumor treatment and non-specific treatment. Novel therapies are currently studied including nanoparticle-based therapies to overcome these limitations. One field of research is focused on utilizing non-lethal hyperthermia to enhance carried chemotherapeutic drugs. Additionally a novel field of non-thermal ablations termed Irreversible Electroporation has recently been developed to treat tumors by irreversibly destroying cell membrane function through short electrical pulses. The goal of the present study is to research two novel potential treatments for cancer that do not require thermal destruction of tissue. Firstly, we developed and tested novel ways to load the antineoplastic agent Cisplatin into SWNHs to test the ability to thermally enhance carried drugs with non-lethal, mild hyperthermia. We attached the imaging agent Quantum Dots (QDs) to the particles to understand how hyperthermia affects cellular uptake, minimizing thermal enhancement. Results of this study highlight the need for better biomimetic in vitro models of the tumors to study how hyperthermia affects tissue level transport of nanoparticles. In the second aim we utilized a perfusable 3D collagen in vitro model of the tumor microenvironment, previously developed by our group to study tumor angiogenesis, to study nanoparticle transport. We demonstrated the ability of this model to study key mass transport obstacles nanoparticles face in the tumor including extravasation from a leaky, pro-angiogenic vasculature, diffusion in the extracellular matrix, and cellular uptake in a 3D environment. This model was then utilized in the third aim to study how mild hyperthermia affects transport of SWNHs. Results from this aim were valuable in showing the utility of the 3D in vitro model to controllably test the effects of external stimuli on transport of particles and shows how mild hyperthermia can selectively allow increased permeability of SWNHs in the tumor, increasing selectivity of nanoparticle transport to the targeted tissue. Lastly, we tested the non-thermal ablation, high-frequency irreversible electroporation (H-FIRE) in a 3D tumor platform and in an in vivo swine model to better understand the ability of H-FIRE to produce repeatable destruction of hepatocellular carcinoma, a disease state growing in incidence rate. We then used H-FIRE in an outpatient treatment for infiltrative skin tumors in equines, showcasing the ability to deliver high voltage, short duration pulses in a clinical setting without muscle contractions. Ultimately, the results of this study the engineering studies that must occur to optimize novel treatments utilizing non-lethal hyperthermia, or non-thermal death mechanism to treat cancer. The studies show the usefulness of more complex 3D in vitro models of tumors for early development of novel therapies and the utility of in vivo models to validate studies. / Ph. D.

O mastocitoma é a neoplasia cutânea mais comum em cães. Acredita-se que as células inflamatórias associadas ao tumor desempenham papéis importantes no comportamento biológico do mastocitoma. Este estudo teve como objetivo verificar a presença de macrófagos associados ao tumor (TAMs) e eosinófilos na região intratumoral e comparar à graduação histopatológica e à evolução clínica dos casos para avaliar se são marcadores prognósticos para MCTs cutâneos caninos. Foram avaliados 38 MCTs provenientes de 30 animais submetidos à cirurgia, sem nenhuma outra terapia complementar. Os tumores foram submetidos à análise imuno-histoquímica para detecção de CD68 e à contagem de eosinófilos em lâminas coradas por hematoxilina e eosina. Os resultados foram comparados à classificação histopatológica segundo os critérios de Patnaik et a. (1984) e Kiupel et al. (2011) e à sobrevida e mortalidade em função do tumor. O número de TAM detectado pela imunomarcação de CD68 não apresentou diferenças significativas entre os graus histopatológicos, assim como não foi um indicador de mortalidade em função do tumor, nem para sobrevida, o mesmo sendo observado para a contagem de eosinófilos. Os números de TAMs e eosinófilos não apresentaram correlação. Nossos resultados sugerem que a presença de TAM e eosinófilos em MCTs cutâneos caninos não são bons indicadores prognósticos para esta doença. / Mast cell tumors are the most common skin cancer in dogs. It is believed that tumor-associated inflammatory cells play important roles in biological behavior of this neoplasm. This study aimed to verify the presence of the tumor associated macrophages (TAMs) and eosinophils in the intratumoral region in comparison with the histopathologic grading and clinical evolution of cases in order to assess their prognostic value for canine cutaneous MCTs. Thirty-eight MCTs from 30 dogs treated by surgery with no complementary therapy were investigated. The tumors were submitted to immunohistochemical analysis for CD68 detection and eosinophil count on HE-stained slides. The results were compared with histopathological classification, according to the criteria of Patnaik et al. (1984) and Kiupel et al. (2011), and with survival and mortality due to the disease. The number of TAMs and eosinophils showed no significant differences between the histopathologic grades, as well as it was not a predictor of disease-related mortality or survival. The number of TAMs and eosinophil count showed no correlation. Our results suggest that the presence of TAMs and eosinophils in cutaneous canine MCTs are not good prognostic indicators for this disease.

by Ko Samuel. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 209-227). / Abstract also in Chinese. / Acknowledgements --- p.i / Abbreviations --- p.ii / Abstract --- p.vii / Abstract in Chinese --- p.x / List of Figures --- p.xiii / List of Tables --- p.xx / Publication --- p.xxi / Contents --- p.xxii / Chapter Chapter 1. --- General Introduction --- p.1 / Chapter 1.1 --- Tumor Necrosis Factor --- p.2 / Chapter 1.1.1 --- History of Tumor Necrosis Factor --- p.2 / Chapter 1.1.2 --- TNF Subtypes and Their Purification --- p.3 / Chapter 1.1.3 --- Release of TNF --- p.9 / Chapter 1.1.4 --- Biological Actions of TNF --- p.9 / Chapter 1.2 --- Tumor Necrosis Factor Receptor --- p.11 / Chapter 1.2.1 --- Purification of TNF Receptor --- p.11 / Chapter 1.2.2 --- Regulation of TNF Receptor --- p.14 / Chapter 1.2.3 --- "Functions of TNF Receptor 1,Receptor 2 and Soluble TNF Receptors" --- p.15 / Chapter 1.3 --- Possible Signal Transductions of Tumor Necrosis Factor-Alpha --- p.17 / Chapter 1.3.1 --- Activation of Phospholipase A2 Cascade --- p.18 / Chapter 1.3.2 --- Activation of Phospho lipase C Pathway --- p.19 / Chapter 1.3.3 --- Activation of Sphingomyelin Pathway --- p.20 / Chapter 1.3.4 --- Activation of Protein Kinase --- p.22 / Chapter 1.3.5 --- Activation of the Cascade of Death Domain --- p.23 / Chapter 1.4 --- Induction of Both Necrosis and Apoptosis by Tumor Necrosis Factor-Alpha --- p.25 / Chapter 1.4.1 --- Apoptosis Versus Necrosis --- p.25 / Chapter 1.4.2 --- TNF Can Induce Both Apoptosis and Necrosis --- p.27 / Chapter 1.5 --- Possible Mechanisms of Tumor Necrosis Factor-Alpha- Mediated Cytotoxicity --- p.27 / Chapter 1.5.1 --- Release of Reactive Oxygen Species --- p.28 / Chapter 1.5.2 --- Release of Intracellular Calcium --- p.31 / Chapter 1.5.3 --- Miscellaneous Mechanisms --- p.36 / Chapter 1.6 --- Objective of Studies --- p.37 / Chapter Chapter 2. --- Materials and Methods --- p.39 / Chapter 2.1 --- Materials --- p.40 / Chapter 2.1.1 --- Buffer --- p.40 / Chapter 2.1.2 --- Culture Media --- p.45 / Chapter 2.1.3 --- Chemicals --- p.46 / Chapter 2.1.4 --- Culture of Cells --- p.49 / Chapter 2.1.4.1 --- "Tumor Necrosis Factor-Alpha-Sensitive Cell Line, L929" --- p.49 / Chapter 2.1.4.2 --- "Tumor Necrosis Factor-Alpha-Resistant Cell Line, rL929, rL929-l IE and rL929-4F" --- p.50 / Chapter 2.2 --- Methods --- p.50 / Chapter 2.2.1 --- Agarose Gel Electrophoresis --- p.50 / Chapter 2.2.2 --- Cytotoxicity Assay --- p.52 / Chapter 2.2.3 --- Confocal Laser Scanning Microscopy --- p.53 / Chapter 2.2.4 --- Flow Cytometry --- p.57 / Chapter Chapter 3. --- Results --- p.65 / Chapter 3.1 --- Induction of Apoptosis in Tumor Necrosis Factor-Alpha- Treated L929 Cell --- p.66 / Chapter 3.1.1 --- Introduction --- p.66 / Chapter 3.1.2 --- TNF Induced DNA Fragmentation in L929 Cells --- p.67 / Chapter 3.2 --- Effect of Tumor Necrosis Factor-Alpha on Cell Cycle --- p.73 / Chapter 3.2.1 --- Introduction --- p.73 / Chapter 3.2.2 --- Effect of TNF on Cell Cycle --- p.75 / Chapter 3.3 --- Release of Reactive Oxygen Species in Tumor Necrosis Factor-Alpha Treatment --- p.79 / Chapter 3.3.1 --- Introduction --- p.79 / Chapter 3.3.2 --- Release of Reactive Oxygen Species in TNF- Treated L929 Cells is Time Dependent --- p.81 / Chapter 3.3.3 --- Effect of Antioxidants on TNF-Mediated Cytotoxicity --- p.93 / Chapter 3.3.4 --- Effect of Mitochondrial Inhibitors on TNF-Mediated Cytotoxicity --- p.96 / Chapter 3.4 --- The Role of Calcium in Tumor Necrosis Factor-Alpha Treatment --- p.112 / Chapter 3.4.1 --- Introduction --- p.112 / Chapter 3.4.2 --- Release of Intracellular Calcium in TNF-Treated L929 Cells --- p.113 / Chapter 3.4.3 --- Effect of Calcium-Inducing Agents on TNF-Treated L929Cells --- p.127 / Chapter 3.5 --- Relationship between Reactive Oxygen Species and Calcium in Tumor Necrosis Factor-Alpha-Mediated Cytotoxicity --- p.133 / Chapter 3.5.1 --- Introduction --- p.133 / Chapter 3.5.2 --- Effect of Intracellular Calcium Chelator on TNF- Mediated ROS Release and Cytotoxicity --- p.133 / Chapter 3.5.3 --- Effect of Mitochondrial Calcium on TNF-Mediated ROS Release and Cytotoxicity --- p.147 / Chapter 3.6 --- Effect of Tumor Necrosis Factor-Alpha on pH --- p.162 / Chapter 3.6.1 --- Introduction --- p.162 / Chapter 3.6.2 --- Effect of TNF on pH --- p.162 / Chapter 3.7 --- Effect of Tumor Necrosis Factor-Alpha on Mitochondrial Membrane Potential --- p.165 / Chapter 3.7.1 --- Introduction --- p.165 / Chapter 3.7.2 --- Effect of TNF and Some Drugs on Mitochondrial Membrane Potential --- p.165 / Chapter 3.8 --- "Comparison of Effects of Tumor Necrosis Factor-Alpha on Susceptible Cell Line, L929 and Resistant Cell Line, rL929, rL929-11E and rL929-4F" --- p.169 / Chapter 3.8.1 --- Introduction --- p.169 / Chapter 3.8.2 --- Effect of TNF on the Cytotoxicity of Resistant Cell Lines --- p.170 / Chapter 3.8.3 --- Effect of TNF on the Release of ROS in Resistant Cell Lines --- p.170 / Chapter 3.8.4 --- Effect of TNF on the Release of Calcium in Resistant Cell Lines --- p.178 / Chapter 3.8.5 --- Effect of TNF on Cell Cycle in Resistant Cell Lines --- p.185 / Chapter Chapter 4. --- General Discussion --- p.187 / Chapter 4.1 --- Tumor Necrosis Factor Induced Apoptosis in L929 Cells --- p.188 / Chapter 4.2 --- Tumor Necrosis Factor Increased the Release of Reactive Oxygen Species in L929 Cells --- p.189 / Chapter 4.3 --- Tumor Necrosis Factor Increased the Release of Calcium in L929 Cells --- p.194 / Chapter 4.4 --- Calcium Induced Reactive Oxygen Species Release in TNF- Treated L929 Cells --- p.197 / Chapter 4.5 --- Tumor Necrosis Factor Did Not Change the pH and Mitochondrial Membrane Potential in TNF-Treated L929 Cells --- p.198 / Chapter 4.6 --- Tumor Necrosis Factor Did Not Increase the Release of Reactive Oxygen Species or Calcium in Resistant Cell Lines --- p.201 / Chapter Chapter 5. --- Future Perspective --- p.204 / Chapter 5.1 --- The Relationship Between Tumor Necrosis Factor and Cytochrome c --- p.205 / Chapter 5.2 --- The Relationship Between Tumor Necrosis Factor and Mitochondrial DNA Damage --- p.206 / Chapter 5.3 --- Clinical studies with Tumor Necrosis Factor --- p.206 / References --- p.208

Yuen, Ka Chun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 160-185). / Abstracts in English and Chinese. / ABSTRACT --- p.I / 摘要 --- p.IV / ACKNOWLEDGEMENTS --- p.VI / LIST OF ABBREVIATIONS --- p.VII / TABLE OF CONTENTS --- p.VIII / LIST OF TABLES --- p.XII / LIST OF FIGURES --- p.XIII / Chapter SECTION I: --- BACKGROUND --- p.1 / Chapter CHAPTER 1: --- Pseudomalignant nature of the placenta --- p.2 / Chapter 1.1 --- Overview --- p.2 / Chapter 1.2 --- "Proliferation, migration and invasion behaviour" --- p.3 / Chapter 1.3 --- Gene expression --- p.4 / Chapter 1.3.1 --- Angiogenic factors --- p.5 / Chapter 1.3.2 --- Growth factors --- p.5 / Chapter 1.3.3 --- Proto-oncogenes --- p.6 / Chapter 1.3.4 --- Tumour suppressor genes --- p.8 / Chapter CHAPTER 2: --- Epigenetics --- p.10 / Chapter 2.1 --- Overview --- p.10 / Chapter 2.2 --- DNA methylation in mammals --- p.11 / Chapter 2.3 --- Regulation of DNA methylation machinery --- p.12 / Chapter 2.4 --- Role of DNA methylation --- p.13 / Chapter 2.5 --- Aberrant DNA methylation --- p.16 / Chapter 2.6 --- DNA methylation in normal cells --- p.17 / Chapter 2.6.1 --- X-chromosome inactivation --- p.17 / Chapter 2.6.2 --- Genomic imprinting --- p.18 / Chapter 2.6.3 --- Cell-type-specific methylation --- p.19 / Chapter 2.6.4 --- Placental-specific methylation --- p.20 / Chapter 2.7 --- Aim of Thesis --- p.21 / Chapter SECTION II: --- MATERIALS AND METHODOLOGY --- p.23 / Chapter CHAPTER 3: --- Materials and methods --- p.24 / Chapter 3.1 --- Preparation of samples --- p.24 / Chapter 3.1.1 --- Collection of placental tissues --- p.24 / Chapter 3.1.2 --- Preparation of blood cells --- p.25 / Chapter 3.1.3 --- Preparation of cell lines --- p.25 / Chapter 3.1.4 --- Treatment of JAR and JEG3 with 5-aza-2'-deoxycytidine (5-aza-CdR) and Trichostatin A (TSA) --- p.26 / Chapter 3.2 --- Nucleic acid extraction --- p.26 / Chapter 3.2.1 --- DNA extraction from tissue samples --- p.26 / Chapter 3.2.2 --- DNA extraction from blood cells --- p.29 / Chapter 3.2.3 --- RNA extraction from cell lines --- p.30 / Chapter 3.3 --- Methylation analysis --- p.31 / Chapter 3.3.1 --- Principles of bisulfite modification --- p.31 / Chapter 3.3.2 --- Bisulfite Conversion --- p.32 / Chapter 3.3.3 --- Primer design for methylation-specific polymerase chain reaction / Chapter 3.3.4 --- Methylation-specific polymerase chain reaction (MSP) --- p.33 / Chapter 3.3.5 --- Primer design for bisulfite sequencing --- p.34 / Chapter 3.3.6 --- Cloning and bisulfite genomic sequencing --- p.35 / Chapter 3.4 --- Quantitative measurements of nucleic acids --- p.39 / Chapter 3.4.1 --- Principles of real-time quantitative PCR --- p.39 / Chapter 3.4.2 --- Real-time quantitative MSP --- p.42 / Chapter 3.4.3 --- Real-time reverse transcriptase (RT)-PCR --- p.42 / Chapter 3.5 --- MALDI-TOF mass spectrometry (MS) --- p.43 / Chapter 3.5.1 --- Principle of homogeneous MassEXTEND assay and MALDI-TOF MS --- p.43 / Chapter 3.5.2 --- Methylation-sensitive restriction enzyme digestion and homogeneous MassEXTEND assay for APC and H19 --- p.46 / Chapter SECTION III: --- A SEARCH FOR HYPERMETHYLATED TUMOUR SUPPRESSOR GENES IN THE HUMAN PLACENTA --- p.48 / Chapter CHAPTER 4: --- Screening on TSGs and non TSGs --- p.49 / Chapter 4.1 --- Introduction --- p.49 / Chapter 4.2 --- Materials and methods --- p.50 / Chapter 4.2.1 --- Sample collection --- p.50 / Chapter 4.2.2 --- Sample processing and DNA extraction --- p.50 / Chapter 4.2.3 --- Experimental Design --- p.51 / Chapter 4.3 --- Results --- p.63 / Chapter 4.3.1 --- Identification of hypermethylated TSGs by methylation-specific PCR screening --- p.63 / Chapter 4.3.2 --- Validation of hypermethylated TSGs by bisulfite sequencing --- p.69 / Chapter 4.4 --- Discussion --- p.77 / Chapter CHAPTER 5: --- Methylation status of TSGs in different tissues --- p.80 / Chapter 5.1 --- Introduction --- p.80 / Chapter 5.2 --- Materials and methods --- p.81 / Chapter 5.2.1 --- Sample collection --- p.81 / Chapter 5.2.2 --- Sample processing and DNA extraction --- p.81 / Chapter 5.2.3 --- Experimental design --- p.81 / Chapter 5.3 --- Results --- p.86 / Chapter 5.3.1 --- Methylation patterns of TSGs in non-placental fetal tissues --- p.86 / Chapter 5.4 --- Discussion --- p.90 / Chapter SECTION IV: --- FUNCTIONAL IMPLICATION OF HYPERMETHYLATED TUMOUR SUPPRESSOR GENES IN THE PLACENTA --- p.94 / Chapter CHAPTER 6: --- Imprinting checking --- p.95 / Chapter 6.1 --- Introduction --- p.95 / Chapter 6.2 --- Materials and methods --- p.96 / Chapter 6.2.1 --- Sample collection --- p.96 / Chapter 6.2.2 --- Sample processing and DNA extraction --- p.97 / Chapter 6.2.3 --- Experimental design --- p.97 / Chapter 6.3 --- Results --- p.100 / Chapter 6.3.1 --- Imprinting checking of H19 by enzyme digestion on placental tissues --- p.100 / Chapter 6.3.2 --- Imprinting checking of　APC by enzyme digestion on placental tissues --- p.101 / Chapter CHAPTER 7: --- CORRELATION OF HYPERMETHYLATION AND GENE EXPRESSION --- p.107 / Chapter 7.1 --- Introduction --- p.107 / Chapter 7.2 --- Materials and methods --- p.108 / Chapter 7.2.1 --- Sample preparation and processing --- p.108 / Chapter 7.2.2 --- DNA and RNA extraction from cell lines --- p.108 / Chapter 7.2.3 --- Experimental design --- p.108 / Chapter 7.3 --- Results --- p.111 / Chapter 7.3.1 --- Methylation status of APC in choriocarcinoma cell lines --- p.111 / Chapter 7.3.2 --- Demethylation of APC in choriocarcinoma cell lines --- p.114 / Chapter 7.4 --- Discussion --- p.115 / Chapter SECTION V: --- CONSERVATION OF METHYLATION IN PLACENTA ACROSS DIFFERENT SPECIES --- p.118 / Chapter CHAPTER 8: --- Methylation analysis of hypermethylated TSG homologues in the placentas of the mouse and rhesus monkey --- p.119 / Chapter 8.1 --- Introduction --- p.119 / Chapter 8.2 --- Materials and methods --- p.120 / Chapter 8.2.1 --- Sample collection --- p.120 / Chapter 8.2.2 --- Sample processing and DNA extraction --- p.120 / Chapter 8.2.3 --- Experimental design --- p.120 / Chapter 8.3 --- Results --- p.124 / Chapter 8.3.1 --- Methylation status of TSGs in rhesus monkey and murine placental tissues --- p.124 / Chapter 8.4 --- Discussion --- p.136 / Chapter SECTION VI: --- CONCLUDING REMARKS --- p.138 / Chapter CHAPTER 9: --- Conclusion and future perspectives --- p.139 / Chapter 9.1 --- Pseudomalignant nature of placenta at the epigenetic level --- p.139 / Chapter 9.2 --- Functional implication of TSG hypermethylation --- p.140 / Chapter 9.3 --- Significance of hypermethylated TSGs in the placental evolution --- p.142 / Chapter 9.4 --- Clinical implication of TSG hypermethylation --- p.143 / Chapter 9.5 --- Future perspectives --- p.145 / APPENDIX I COMPLETE BISULFITE SEQUENCING DATA FOR HYPERMETHYLATED TSGS --- p.147 / APPENDIX II BISULFITE SEQUENCING DATA FOR PTEN --- p.156 / APPENDIX III BISULFITE SEQUENCING DATA OF LOCI NOT SHOWING HYPERMETHYLATION --- p.158 / REFERENCES --- p.160

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Made available in DSpace on 2015-07-22T20:49:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-12-31 / Objetivo: Avaliar o significado prognóstico do marcador tumoral c-met/HGF, através da técnica imuno-histoquímica, em doentes portadores de adenocarcinoma colorretal submetidos a tratamento cirúrgico. Métodos: Estudo retrospectivo de 286 doentes,portadores de adenocarcinoma colorretal, atendidos e operados no Hospital do Câncer de Barretos, de 1993 a 2002. A expressão tissular do marcador tumoral foi avaliada utilizando-se o anticorpo monoclonal antiproteína c-met/HGF, com a técnica da estreptavidina-biotina-peroxidase. A análise da positividade do marcador foi feita de maneira semiquantitativa e a leitura das lâminas, realizada por três patologistas, de forma independente e sem prévio conhecimento dos dados clínicos e histopatológicos dos doentes. Resultados: Do total de 286 doentes analisados, o marcador foi positivo em 236 (78,8%) e negativo em 50 (21,2%). Houve diferença, estatisticamente significante (p=0.004), entre os estádios l e lV, na sobrevida global (p=0.009) e no coeficiente de mortalidade por câncer (p=0.022), porém não se identificou associação do marcador com a ocorrência de recidivas (p=0.89) e o intervalo livre de doença (p=0.91). Conclusão: O marcador tumoral c-met/HGF demonstrou significância estatística, em relação à sua expressão, nos estádios l e lV da doença, na sobrevida global e no coeficiente de mortalidade por câncer, porém não se associou de forma significante com as outras variáveis prognósticas estudadas. / Objective: To evaluate the prognostic meaning of the c-met/HGF tumoral marker, through the immunohistochemical technique, in patients with colorectal adenocarcinoma who have been subjected to surgical treatment. Methods: A retrospective descriptive study of 286 patients with colorectal adenocarcinoma, who have been seen and operated at Barretos Cancer Hospital, from 1993 to 2002. The tissular expression of the tumoral marker was evaluated using the cmet/ HGF anti-protein monoclonal antibody through the estreptavidin-biotinperoxidase technique. The positivity analysis of the marker was semiquantitative, and plate reading was independently carried out by three pathologists with no previous knowledge on clinical and histopathological data of patients. Results: Out of a total of 286 patients, the marker was positive in 236 (78.8%) and negative in 50 (21.2%). It was found statistically significant difference (p=0.004) between stages l and lV, at global life span (p=0.009), and at cancer mortality rate (p=0.022); however, there was no association between the marker and recurrence (p=0.89) or the marker and disease-free period (p=0.91). Conclusion: c-met/HGF has shown significance as a tumoral marker in stages l and lV of the disease, at global life span, and at cancer mortality rate; however, there was no significant association with the remaining prognostic variables that have been studied. / TEDE / BV UNIFESP: Teses e dissertações

京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第24542号 / 人健博第113号 / 新制||人健||8(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 中尾 恵, 教授 杉本 直三, 教授 黒田 知宏 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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