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系統識別號 U0007-0107201420030100
論文名稱(中文) 以機器學習演算法對糖尿病及糖尿病前期的預測
論文名稱(英文) Prediction of Diabetes Mellitus and Prediabetes Based on Machine Learning Algorithms
校院名稱 臺北醫學大學
系所名稱(中) 醫學資訊研究所
系所名稱(英) Graduate Institute of Biomedical Informatics
學年度 102
學期 2
出版年 103
研究生(中文) 陳冠堯
學號 G658101007
學位類別 碩士
語文別 中文
口試日期 2014-06-19
論文頁數 126頁
口試委員 委員-吳漢銘
委員-蔣以仁
指導教授-蘇家玉
關鍵字(中) 機器學習
糖尿病
糖尿病前期
決策樹
類神經網路
邏輯斯迴歸
支持向量機
關鍵字(英) machine learning
diabetes mellitus
prediabetes
decision trees
artificial neural network
logistic regression
support vector machines
學科別分類
中文摘要 全世界約有近3億6千萬的糖尿病人口,2009年的國際糖尿病聯盟的資料顯示,糖尿病未來盛行率至2030年為止,有可能達到5億5千萬人次。近年我國罹患糖尿病人口不斷上升,依衛生福利部2012年公告,糖尿病自1987年,高居台灣十大死因前5 位,死亡率約為26.5%,罹病人口數從2000年起,以7%的速度逐年增加。根據美國糖尿病協會 (American Diabetes Association) 2014年公佈,無症狀成年人若過重 (BMI≧24kg/m2) 且符合其公告之十項危險因子任一者,包括缺乏運動、高血脂、高血壓等,建議作糖尿病篩檢。國外也有利用機器演算法對糖尿病預測所做的研究。因此,本研究以台灣門診中常見的檢驗項目,透過各種機器學習演算法,包含類神網路與支持向量機等分類技術,比較各種分析方法對糖尿病預測的準確率。
研究樣本以台北某教學醫院之2012年1月至2013年12月之全院年滿20歲以上回診病患之檢驗資料,以SAS軟體9.3中的SAS Enterprise Guide 5.1 作資料前處理,排除檢驗報告有欠缺之個案後,共有339筆資料,內含86筆為糖尿病 (Diabetes Mellitus, DM) 、111筆為非糖尿病 (Non-DM) 及162筆為糖尿病前期 (Prediabetes, Pre-DM)。研究分為兩組為Group 1 (DM vs. Non-DM) 與Group 2 (Pre-DM vs. Non-DM)。研究的方法為利用SAS Enterprise Miner 12.1,將Group 1與Group 2資料中80%做為訓練資料集,10%做為驗證資料集,最後以10%做為測試資料集。並輔以決策樹、類神經網路、邏輯斯迴歸、支持向量機等內建模型,對該兩組資料作預測分析。

研究結果發現,我們的研究方法可以達到精確的預測力。在Group 1以邏輯斯迴歸可以達到最佳的準確率 (85.8%) 及AUC (0.898)。Group 2則以決策樹可達到最佳的準確率 (77.8%),AUC以支持向量機可達最佳結果 (1.000)。此外,本研究所納入的變數符合醫學臨床輔佐判斷糖尿病的項目。本研究的方法亦能找出和糖尿病與糖尿病前期的特徵相符的變數。
英文摘要 It has been estimated that approximately 360 million people have diabetes mellitus worldwide, and that this number may reach 552 million by the year 2030. In Taiwan, diabetes mellitus ranks fifth among ten leading causes of death with a 26.5% mortality rate, and the diabetic population has increased by 7% annually since 2000. The American Diabetes Association also suggests that screening and early detection of undiagnosed diabetes mellitus are crucial in preventive medicine, especially for overweight adults with other risk factors, include less Physical Activity, hyperlipidemia and hypertension etc. Several previous studies that incorporate machine learning algorithms for prediction of diabetes mellitus have been proposed, and the average accuracy is around 79.0%. In this study, we developed a novel prediction method, where discriminative features from physiology and blood biochemical data are incorporated in various machine learning algorithms.
The patient data have been collected from January 2012 to December 2013 in a medical center in northern Taiwan. In data preprocessing, we apply SAS Enterprise Guide version 5.1 to filter patients with missing values and only extract those whose age is greater or equal to 20. The final data set composed of 339 individuals (i.e., 86 confirmed diabetes, 111 non-diabetes, and 142 pre-diabetes patients) is used as input for SAS Enterprise Miner version 12.1. We organize the data set into two groups as Group 1 (DM vs. Non-DM) and Group 2 (Pre-DM vs. Non-DM). Each group is further divided into a training set (80%) for model construction, a validation set (10%) for parameter selection, and a test set (10%) for performance evaluation. We apply machine learning algorithms including decision trees (DT), artificial neural network, logistic regression, and support vector machines to construct predictive models.

Experiment results show that our method achieve accurate predictive performance. First, we apply LR for prediction of diabetes in Group 1 and attain a high accuracy and area under the curve (AUC) of 85.8% and 0.898, respectively. In addition, for prediction of prediabetes in Group 2, our approach selects DT to obtain accuracy of 77.8% and SVM for AUC of 1.000, respectively. Moreover, the proposed biomedical features in our method also correspond well with medical domain knowledge. This demonstrates that our approach is able to generate discriminative features to identify diabetes and prediabetes patients.
論文目次 標題 i
審定書 iii
臺北醫學大學博碩士論文授權書 iv
電子暨紙本學位論文書目同意公開申請書 v
學位考試保密同意書暨簽到表 vi
誌 謝 vii
目錄 viii
表目錄 xi
圖目錄 xiii
論 文 摘 要 xv
Abstract xvii
第一章 緒論 1
1.1 前言 1
1.2 研究動機 1
1.3 研究目的 2
第二章 文獻探討 3
2.1 糖尿病簡介 3
2.1.1糖尿病的定義與分類 4
2.1.2糖尿病前期定義 8
2.1.3糖尿病與糖尿病前期相關危險因子與篩檢 8
2.1.4糖尿病的流行病學 11
2.1.5糖尿病的預防 12
2.1.6糖尿病的治療與照護 13
2.1.7糖尿病的合併症 15
2.1.8糖尿病合併症的預防治療 16
2.2 機器學習 17
2.2.1 支持向量機 18
2.2.2 決策樹 19
2.2.3 邏輯斯迴歸 20
2.2.4 類神經網路 20
2.3 利用資料探勘預測糖尿病及糖尿病前期相關研究 24
2.3.1 國外研究文獻 24
2.3.2 國內研究文獻 29
第三章 研究材料與方法 32
3.1 研究架構 32
3.2 研究材料和資料來源 33
3.2.1 資料前處理 33
3.3研究工具 35
3.4使用分類器參數選擇 37
3.5 驗證與評估與方法比較 39
3.5.1 驗證方法 39
3.5.2 模型績效評估方法 40
第四章 分析與結果 43
4.1 研究樣本 43
4.2初步分析 58
4.3 研究成果 60
4.3.1 各分類器預測表現之比較 60
4.3.2決策樹 63
4.3.3邏輯斯迴歸 66
4.3.4支持向量機 66
4.3.5類神經網路 66
4.4 研究結果提要 67
第五章 討論 69
5.1預測模型設定與比較 69
5.1.1 決策樹 69
5.1.2 邏輯斯迴歸 82
5.1.3 支持向量機 86
5.1.4 類神經網路 92
5.2與其他研究方法比較和討論 96
5.2.1與國內糖尿病研究比較 96
5.2.2與國外糖尿病研究比較 97
5.2.3 與國外糖尿病前期研究比較 98
5.2.4 與國內糖尿病前期研究比較 98
5.3特徵選取討論 99
第六章 結論與建議 101
6.1 結論 101
6.2 研究限制 102
6.3 未來發展與建議 102
參考資料 104
1.英文文獻 104
2.中文文獻 107
參考文獻 1.英文文獻

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(17) Lee, D. H., Steffes, M. W., & Jacobs, D. R., Jr. (2008) . Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes? Diabetologia, 51 (3) , 402-407. doi: 10.1007/s00125-007-0896-5
(18) Meng, X. H., Huang, Y. X., Rao, D. P., Zhang, Q., & Liu, Q. (2013) . Comparison of three data mining models for predicting diabetes or prediabetes by risk factors. Kaohsiung J Med Sci, 29 (2) , 93-99. doi: 10.1016/j.kjms.2012.08.016
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(25) Tapak, L., Mahjub, H., Hamidi, O., & Poorolajal, J. (2013) . Real-data comparison of data mining methods in prediction of diabetes in iran. Healthc Inform Res, 19 (3) , 177-185. doi: 10.4258/hir.2013.19.3.177
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2.中文文獻

(1) 中華民國糖尿病學會. (2012) . 2012年糖尿病臨床照護指引.
(2) 台北榮民總醫院新陳代謝科.) . 台北榮總新陳代謝科糖尿病概論. from http://homepage.vghtpe.gov.tw/~meta/dm.htm#DM_epid1
(3) 行政院衛生署國民健康局, 宜蘭縣政府衛生局. (2004) . 糖尿病共同照護工作指引手冊. from http://www.hpa.gov.tw/BHPnet/Web/HealthTopic/TopicArticle.aspx?No=200712250075&parentid=200712250014
(4) 李俊宏, 古清仁. (2010) . 類神經網路與資料探勘技術在醫療診斷之應用研究. 工程科技與教育學刊, 7 (1) .
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(6) 張俊郎, 陳啟浩, 曾輝鈺. (2007) . 結合類神經網路與決策樹於糖尿病前期診斷之研究. Paper presented at the 全國品質管理研討會, Taiwan.
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(9) 陳敏麗, 黃松元. (2005) . 某社區民眾糖尿病篩檢中血糖值與糖尿病高危險因子及健康促進生活型態之探討. 衛生教育學報, 24.
(10) 黃國晉, 黃蘭菁; 李貫廷; 李育霖; 楊偉勛;. (2013) . 2013年美國糖尿病學會臨床治療指引摘要. 台北市醫師公會會刊, 57 (3) , 23-31.
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(13) 廖麗娜. (2010) . 第七章 羅吉斯迴歸 - 中國醫藥大學 生物統計中心. from http://www2.cmu.edu.tw/~biostat/online/teaching_corner_050-1.pdf
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系統識別號 U0007-0107201420390600
論文名稱(中文) 應用機器學習演算法預測台灣孩童與青少年的代謝症候群
論文名稱(英文) Applications of Machine Learning Algorithm to Predict Metabolic Syndrome in Taiwanese Children and Adolescents
校院名稱 臺北醫學大學
系所名稱(中) 醫學資訊研究所
系所名稱(英) Graduate Institute of Biomedical Informatics
學年度 102
學期 2
出版年 103
研究生(中文) 陳潔雯
學號 G658101009
學位類別 碩士
語文別 中文
口試日期 2014-06-19
論文頁數 85頁
口試委員 委員-王治元
委員-蔣以仁
指導教授-蘇家玉
關鍵字(中) 代謝症候群
兒童
青少年
機器學習
臺灣
關鍵字(英) Metabolic Syndrome
Children
Adolescences
Machine Learning
Taiwanese
學科別分類
中文摘要 代謝症候群是一種集合心血管與代謝疾病的危險因子的聚集,其診斷和治療仍在國際間受高度重視。在肥胖兒童的數量隨著不健康的飲食和生活習慣上升,國際糖尿病聯盟(Internal Diabetes Foundation, IDF)在2007年公佈兒童和青少年代謝症候群的診斷標準,然而此診斷標準未必適合評估臺灣地區的兒童和青少年的代謝症候群。此研究目的為運用機器學習演算法找出有效用以評估臺灣地區的兒童和青少年的代謝症候群的預測模型。

在2,362位10至16歲兒童及青少年的健康報告中,以IDF的兒童和青少年代謝症候群的診斷標準,合併臺灣地區依據身體質量指數的肥胖定義,共81位符合代謝症候群的診斷標準。另外,從不符合診斷的2,281位的健康報告中,以隨機取樣得到107位列為不符合代謝症候群的診斷標準。採用的分析參數包括血壓、血糖、血脂肪、甲狀腺功能及血球分析等。以WEKA3.6中的決策樹、隨機森林、支持向量機、多層感向器及邏輯斯迴歸,共五種機器學習演算法進行分析及建置預測模型。

結果發現以支持向量機建置臺灣地區10至16歲兒童和青少年代謝症候群的預測模型,其Area Under Curve (AUC) 達0.967 相較其他機器學習演算法為最高,而準確度以支持向量機和決策樹為最佳達90.9%。此外,針對臺灣地區的兒童及青少年的代謝症候群診斷,從決策分類樹的結果發現BMI、三酸甘油酯、空腹血糖、舒張壓及低密度脂蛋白可讓診斷準確率達90.9%。
英文摘要 Metabolic syndrome consists of a cluster of the dangerous risk factors of cardiovascular diseases and diabetes. Due to the increasing prevalence of obesity in children related to unhealthy diet and lifestyle, the International Diabetes Federation (IDF) published diagnosis criteria of metabolic syndrome in children and adolescents in 2007. Yet, the IDF also recognized that such diagnostic criteria may not be applicable among the various racial, gender and age differences in this unique population subjected to development of adult physical and sexual characteristics. The aim of this study is using machine learning Algorithms to predict metabolic syndrome in Taiwanese children and adolescents for early screening and diagnosis.

Total 2,362 medical health records of children and adolescents of 10 to 16 years of age from one health examination center are collected for this study, and there was 162 records enrolled for this analysis (81 records matched the diagnostic criteria of metabolic syndrome, another 107 records which did not matched the diagnostic criteria was extracted by using random sample selection. Five-fold cross-validation is used to evaluate our experiment results. The presence of metabolic syndrome is diagnosed based on criteria defined by the IDF and presence of obesity identified by body mass index (BMI) according to Taiwanese children and adolescent obesity definition published by the Ministry of Health and Welfare (Taiwan 2002).

The study extracted eighteen features obtained from physical measurements and biochemical blood tests for prediction. The features include the following: BMI, blood pressure, fasting serum glucose (FG), lipid profile, thyroid function, and hemogram. For model construction, we apply WEKA 3.6, in which classifiers including decision trees (DT), random forests (RF), support vector machines (SVM), multilayer perceptron (MLP) and logistic regression (LR), are adopted to predict metabolic syndrome. We evaluated accuracy, sensitivity, specificity, and area under receiver operator characteristic curve (AUC) to assess predictive performance. Five-fold cross-validation is used to evaluate our experiment results.

We conclude that applying support vector machine (LibSVM) to predict metabolic syndrome can serve as an effective method to assist in establishing a clinical decision making system with AUC with 0.967. Both SVM and decision trees can reached the highest accuracy rate with 90.9%. In addition, BMI, TG, FG, LDL and diastolic blood pressure are selected as the most effective features in the diagnosis of metabolic syndrome in children and adolescents between the ages of 10 and 16 years old in Taiwan.
論文目次 標題 i
審定書 iii
臺北醫學大學博碩士論文授權書 iv
電子暨紙本學位論文書目同意公開申請書 v
學位考試保密同意書暨簽到表 vi
誌 謝 vii
表目錄 xiii
圖目錄 xiv
論 文 摘 要 xv
Abstract xvii
第一章 緒論 1
1.1前言 1
1.2研究動機 1
1.3研究目的 2
1.4研究特色 2
第二章 文獻探討 4
2.1兒童及青少年肥胖症 4
2.1.1定義 4
2.1.2流行病學 6
2.1.3肥胖的原因 7
2.1.4相關併發症 8
2.1.5兒童肥胖預防及治療 11
2.1.6與肥胖預測相關的研究 12
2.1.6.1國外研究文獻 12
2.1.6.2國內研究文獻 14
2.1.7利用機器學習演算法預測肥胖症的相關研究 15
2.2 代謝症候群 16
2.2.1 定義 16
2.2.2 流行病學 19
2.2.3 國外研究預測兒童及青少年代謝症候群 21
2.2.4 國內研究預測兒童及青少年代謝症候群 21
2.2.5 以機器學習演算法預測代謝症候群的研究 21
2.3機器學習演算法 24
2.3.1各種機器學習演算法簡介 24
2.3.1.1 決策樹 24
2.3.1.2 支持向量機 26
2.3.1.3 隨機森林 27
2.3.1.4 多層次感知器 28
2.3.1.5 邏輯斯迴歸 29
2.3.2 機器學習演算法在醫學研究上的應用 29
第三章 研究材料與方法 31
3.1資料來源與對象 31
3.1.1資料來源 31
3.1.2研究對象 31
3.1.3研究樣本 32
3.1.3.1組別定義 32
3.1.3.2資料前處理 33
3.2預測特徵項設定 35
3.2.1預測特徵項篩選 35
3.2.2增加預測特徵項 36
3.3 統計檢定方法 37
3.4研究工具及架構 38
3.4.1研究工具 38
3.4.2 資料轉換與簡化及特徵項縮減 38
3.4.2.1 資料轉換 39
3.4.2.2 特徵項縮簡 39
3.4.3使用分類器的參數選擇 39
3.4.3.1 使用預設參數 39
3.4.3.2 使用篩選參數 40
3.4.4 驗證與評估 40
3.4.4.1驗證方法 41
3.4.4.2模型績效評估 41
3.4.5研究架構 43
第四章 分析與結果 44
4.1兒童及青少年肥胖程度與各生理及血液檢驗的分析 44
4.1.1 分析-檢定結果 44
4.2 各種機器學習演算法對預測代謝症候群的比較 45
4.2.1決策樹對預測代謝症候群的決策分類樹 50
第五章 討論 51
5.1符合代謝症候群的兒童及青少年的生理及血液檢驗統計檢定結果 51
5.2預測模型的比較 51
5.3國內外代謝症候群的診斷標準差異 55
5.3.1特徵項選擇 55
5.3.2特徵項設定值 56
5.3 BMI是否能取代腰圍作為肥胖評估的工具 57
第六章 結論與建議 59
6.1結論 59
6.2研究限制 60
6.3 建議 61
參考資料 62
1. 中文文獻 62
2. 英文文獻 63
3. 電子資源 69
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3. 電子資源

(1) 臺灣營養健康狀況變遷調查 http://nahsit.nhri.org.tw/
(2) Random Forest (圖) http://kazoo04.hatenablog.com/entry/2013/12/04/175402
(3) 預防代謝症候群學習手冊
http://www.hpa.gov.tw/BHPNet/web/Books/manual_content15.aspx
(4) 成人 (20歲以上) 代謝症候群的判定標準
http://www.hpa.gov.tw/BHPNet/Web/Healthtopic/TopicArticle.aspx?No=200712250123&parentid=200712250023
(5) 高密度酯蛋白/低密度酯蛋白比值所代表的心血管疾病的威脅程度
http://www.fatfreekitchen.com/cholesterol/cholesterol-ldl-hdl-ratio.html

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系統識別號 U0007-1307201421032000
論文名稱(中文) 以機器學習技術預測台灣血液透析患者之存活
論文名稱(英文) Using Machine Learning Techniques to Predict the Survival of Maintenance Hemodialysis Patients in Taiwan
校院名稱 臺北醫學大學
系所名稱(中) 醫學資訊研究所
系所名稱(英) Graduate Institute of Biomedical Informatics
學年度 102
學期 2
出版年 103
研究生(中文) 許文定
學號 G658101004
學位類別 碩士
語文別 英文
口試日期 2014-06-26
論文頁數 41頁
口試委員 指導教授-李友專
委員-蘇家玉
委員-姜至剛
關鍵字(中) 血液透析
存活
機器學習
關鍵字(英) Hemodialysis (HD)
Survival
Machine Learning
學科別分類
中文摘要 背景:在台灣,以2010年而言,使用血液透析方式的末期腎臟病患,占百分之八十九點六。多重併發症會影響血液透析患者之存活,如何能準確預測其存活是相當重要的課題,因為關係到醫師的決策、國家的財政負擔與病患的抉擇。台灣全民健保資料庫於2000年釋出並廣泛用在相當多的研究上。Weka是一資料探勘運用的開放軟體,它提供了目前普遍運用的機器學習之流程,使用者可輕易將資料輸入分析。而我們的這個研究,利用從健保資料庫得到血液透析病人的資料,利用Weka中機器學習的技術,欲建立一個理想的預測其存活率的模型。
方法:我們從西元1997到2008年,百萬人健保資料庫中擷取資料。我們選擇年紀大於20歲,血液透析至少90天,沒有換腎紀錄,也沒有接受過腹膜透析紀錄,我們收集這些患者的年紀、性別、存活時間與併發症,包含糖尿病、心衰竭、腦中風、慢性阻塞性肺病、C型肝炎感染、癌症、心律不整、焦慮、動脈硬化性心臟病、骨折、腸胃道出血、肝硬化、B型肝炎感染與副甲狀腺切除病史。依預測存活時間長短分為三組,依次為2年、6年與10年。每組在分為兩小組,一小組為小於預測時間,另一小組為大於預測時間。再將這些資料利用Weka中的單純貝氏分類、支持向量機、多層次感知、邏輯式迴歸與隨機森林法做預測模型分析,決定預測值之好壞取決於接收者操作特徵曲線下區域之大小。
結果:共有2591名血液透析患者進入本研究。第一組有2114人,第二組有1348人,第三組有998人。活得較長的那幾小組,年紀都比較輕且有統計上的意義。女性在活得較長的那幾小組占多數。糖尿病、心衰竭、腦中風與慢性阻塞性肺病,在活得較短的那幾小組占多數且有統計上的意義。副甲狀腺切除術紀錄,在活得較長的那幾小組占多數。C型肝炎感染在第一組與第二組中,反而在活的較長那些小組有高比例。動脈硬化性心臟病、骨折、腸胃道出血、肝硬化有高比例在活得較短的小組,但在統計上僅第二和第三組有意義。癌症比例除第三組外,在第一和第二組中,活的較短的那小組有較高比例。經過變數選擇,我們在三組中,每組可得到一組對預測模型貢獻的排序,年紀與糖尿病在三組中均分居一、二名,而接收者操作特徵曲線下區域之大小表現上,我們發現單用年紀此變數,就足以表示出整個模型的預測度,其他變數影響並不大。
結論:年紀本身在預測台灣血液透析患者的存活上,是一個很強的預測因子,而機器學習技術能廣泛運用在醫學領域上。
英文摘要 Background: End-stage renal disease was highly prevalent in Taiwan and the prevalence of hemodialysis modality in end-stage renal disease patients was 89.6% in 2010. Multiple comorbidities can influence the survival of hemodialysis patients. How to predict the patients’ survival is an important issue because it is concerned with the doctors’ decision making, the national financial burden and the patients’ choices. The National Health Insurance Research Dataset (NHIRD) of Taiwan was released in 2000 and it be widely used in lots of studies. Weka is open source software for data mining task. It provides some popular machine learning algorithms that you can easily apply to your dataset. In this study, we want to utilize the hemodialysis patients’ data from NHIRD to construct an ideal prediction model for their survival with machine learning techniques in Weka.
Method: We extracted approximately one million patients’ data from NHIRD of Taiwan from 1997 to 2008. We recruited the patients who were on hemodialysis more than 90 days and older than 20 years old. The patients who had been renal transplanted and had undergone peritoneal dialysis were excluded. Their gender, age, survival-length and comorbidities such as diabetes mellitus, congestive heart failure, cerebrovascular accident, chronic obstructive pulmonary disease, hepatitis C virus infection, cancer, arrhythmia, anxiety, atherosclerotic heart disease, bone fracture, gastrointestinal bleeding, liver cirrhosis and hepatitis B infection and parathyoidectomy history were recorded. Three groups were created by the prediction of survival-length. Group 1 was divided two subgroups according the patients’ survival-length were longer than 2 years or not. Group 2 and 3 were also individually separated to two subgroups according to the patients’ survival-length were longer than 6 and 10 years or not respectively. The data was inputted to the machine learning tools including Naive Bayes, support vector machines, multilayer perception, logistic regression and Random Forests in Weka. We identified an ideal prediction model according to the values of area under the receiver operating characteristic curve (AUROC).
Result: A total of 2591 hemodialysis patients were included in this study. There were 2114, 1384 and 998 patients in Group 1, Group 2 and Group 3. Young age patients were statistical significance in the longer survival-length subgroups in three groups. Female patient ratio was higher in all longer survival-length subgroups. The comorbidities such as congestive heart failure, cerebrovascular accident, chronic obstructive pulmonary disease and diabetes mellitus were higher patient ratio in the short survival-length subgroups and all statistical significances in three groups. The history of parathyroidectomy was obvious in long survival-length subgroups and there were all statistical significances in three groups. The long survival-length subgroups owned more hepatitis C virus infected patient ratio than the short survival-length subgroups and were statistical significances in Group 1 (p=0.043) and Group 2 (p=0.014). The comorbidities including atherosclerotic heart disease, bone fracture, gastrointestinal bleeding and liver cirrhosis were higher patient ratio in short survival-length subgroups but only were statistical significances in Group 2 and Group 3. Cancer patient ratio was higher in short survival-length subgroups in Group 1 and Group 2 except in Group 3. After machine learning with attributes selection, we got the attributes rank for prediction model contribution. Age was top 1 attribute and diabetes mellitus was top 2 in all groups. The AUROC was 0.708 by 1-attribute prediction model with age and was 0.715 (the highest AUROC) by 8-attribute prediction model with top1 to top 8 attributes in logistic regression model in Group 1. The AUROC was 0.752 by 1-attribute prediction model with age and was 0.778 (the highest AUROC) by 12-attribute prediction model with top1 to top 12 attributes in logistic regression model in Group 2. The AUROC was 0.809 by 1-attribute prediction model with age and was 0.858 (the highest AUROC) by 3-attribute prediction model with top1 to top 3 attributes in logistic regression model in Group 3. According to this finding, age played an important role in the survival prediction of hemodialysis patients in Taiwan.
Conclusion: Age per se is the strongest attribute in the prediction model for the survival of maintenance hemodialysis patients in Taiwan. Machine learning techniques can be widely utilized in the medical fields.
論文目次 Table of Contents

Page
標題: 以機器學習技術預測台灣血液透析患者之存活 i
臺北醫學大學碩士學位考試委員審定書 ii
臺北醫學大學電子暨紙本學位論文書目公開同意申請書 iii
臺北醫學大學學位考試保密同意書暨簽到表 iv
誌 謝 v
Table of Contents vi
List of Tables viii
List of Figures ix
論 文 摘 要 x
Abstract xiii
Chapter 1 Introduction 1
1.1 Background 1
1.2 Motivations 2
1.3 Research Objectives 3
Chapter 2 Literature Review 3
2.1 The Mortalities and Comorbidities in the patient of End-Stage Renal Disease on Hemodialysis 3
2.2 The National Health Insurance Research Dataset of Taiwan 5
2.3 Data Mining and Machine Learning 5
2.4 WEKA 7
2.5 Machine Learning Techniques in Hemodialysis Studies 7
Chapter 3 Materials and Methods 9
3.1 Study Population 9
3.2 Comorbidities Selection 9
3.3 Survival-Length 10
3.4 Statistical Analyses 11
3.4 Data Mining 11
Chapter 4 Results 12
4.1 Participants Selection 12
4.2 Baseline Demographic Characteristics and Comorbidities in different groups 15
4.3 Attributes Selection and Prediction Models Construction with Machine Learning 16
Chapter 5 Discussion 28
Chapter 6 Conclusion and Recommendation 33
References 34
Appendices 40
Charlson Comorbidity Index 40
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系統識別號 U0007-1507201402565900
論文名稱(中文) 運用機器學習演算法對脂肪肝預測研究
論文名稱(英文) Clinical Application of Machine Learning Algorithms to Predict Fatty Liver Disease
校院名稱 臺北醫學大學
系所名稱(中) 醫學資訊研究所
系所名稱(英) Graduate Institute of Biomedical Informatics
學年度 102
學期 2
出版年 103
研究生(中文) 吳杰成
學號 G658101005
學位類別 碩士
語文別 中文
口試日期 2014-06-20
論文頁數 114頁
口試委員 指導教授-李友專
委員-邱泓文
委員-謝忠和
關鍵字(中) 脂肪肝
隨機森林
支持向量機
類神經網路
邏輯迴歸
腹部超音波
肝生化異常
關鍵字(英) Fatty liver disease
Random Forest
Support Vector Machine
Artificial Neural Network
Abdominal Ultrasonography
Abnormal Liver Biochemistry
學科別分類
中文摘要 近年由於醫療系統電腦化,資料量亦快速增加,資料探勘技術逐漸被應用於醫療診斷系統,從複雜的醫療檢驗紀錄中,選取有相關因子作為變數,並運用資料探勘中之機器學習法之分類技術如多層感知類神經網路、隨機森林、支持向量機及邏輯斯迴歸等,分類出疾病發生之可能性,在作儀器檢查和侵入性治療 (例如切片) 之前,提供醫師作為診斷決策參考。

並嚐試縮減過多之屬性,刪除非必要之特徵,及錯誤或遺失資料的處理及對機器學習法中之各參數作適當的選擇,使達到最適當執行效率。從而比對出輔助臨床醫學診斷最好的機器學習分類方法。藉由不同疾病資料不同之屬性調整不同之驗證與評估方法之應用了解何種模型較適合於使用在醫療診斷上之用途,如此將對醫療之診斷治療及預後預測是有相當助益的。

本研究採用使用WEKA 3.7統計分析中數個具有代表性的主要分類器如多層感知類神經網路 (MLP) 及支撐向量機 (SVM/SMO) 、隨機森林 (RF) 、邏輯斯迴歸分析等資料探勘技術,來對 10 種醫療診斷資料作分類預測與結果的比較分析。所選用的變數包括年齡、性別、腹圍、三酸甘油脂、空腹血糖、血清麩氨基酸草醋酸轉氨基酵素、血清麩丙酮酸轉氨基酵素、高密度脂蛋白膽固醇、收縮壓、舒張壓。探討引響模型預測分析脂肪肝與肝生化異常的相關性,有、無脂肪肝參數差異,同時採用腹部超音波作為診斷有無脂肪肝之依據,作分類預測與結果的比較分析,進行預測評估罹患脂肪肝。

本研究使用準確度、靈敏度、特異度以及接收者操作特徵曲線下面積 (AUROC) 等指標評估該預測模型效能,藉以比對並驗證隨機森林、支持向量機、類神經網路和邏輯迴歸中結果較佳者為預測脂肪肝決策支援工具。

預期將其所獲得較佳結果之分類分析模型,應用在進行臨床初步篩檢分析脂肪肝,不需要全數仰賴腹部超音波當作第一線篩檢脂肪肝之唯一工具,如此將大大減輕健保醫療負擔,並且能準確輔助醫師判斷有無脂肪肝以及預防肝臟產生後續之病變,並可達到早期發現及早治療之目標。
英文摘要 In recent years, the capacity of healthcare computer data system has been increased rapidly. In addition, the technology of data mining is gradually being used in medical diagnostic systems. For instance, before making an abdominal ultrasound examination and/or invasive intervention (biopsy) to classify the clinical suspicious of fatty liver disease, a physician can first using medical data mining solution by first selecting the attributes of the medical examination laboratory data from complicated medical records and take useful and related factors as variables. By incorporating machine learning classification technology such as Multilayer Perceptron Neural Network, Random Forests, Support Vector Machines and Logistic Regress, the software can provide a highly reliable reference to help clinical physicians to make an accurate diagnosis.

For assisting a clinical diagnosis and medical treatment, we need to verify the best algorithm of machine learning by comparing their outcomes. Furthermore, based on the adjustment of different verifications, assessments and selected attributes, we also need to recognize which model of machine learning is more suitable for the clinical diagnosis purpose.

This study is using liver biochemistry data and utilizing WEKA 3.7 to analyze statistical parameters between fatty liver and non-fatty livers. The parameters used are Age, Abdominal girdle, Triglyceride, Glucose AC, SGOT-AST, SGPT_ALT systolic blood pressure and diastolic blood pressure.

Fatty liver was diagnosed based on the result of abdominal ultrasound and simultaneously applying fatty liver predictive model using techniques of Random forest, Support Vector Machine, Artificial Neural Network. The performances of the models will be evaluated according to parameters of accuracy, sensitivity, specificity and the area under receiver operating characteristic curve (AUROC).

The result of this study will prevent severe liver disease by early detection and treatment, and can also help physicians to give an appropriate and efficient medical advice to their patients.
論文目次 目錄

頁數
運用機器學習演算法對脂肪肝預測研究 i
臺北醫學大學碩士學位考試委員審定書 ii
臺北醫學大學電子暨紙本學位論文書目同意公開申請書 iii
臺北醫學大學學位考試保密同意書暨簽到表 iv
誌謝 v
目錄 vi
表目錄 ix
圖目錄 xii
論 文 摘 要 xiv
Abstract xvii
第一章 1
緒論 1
1.1 研究背景 1
1.2 研究動機與目的 2
第二章 5
文獻探討 5
2.1 脂肪肝簡介 5
2.1.1脂肪肝的定義 5
2.1.2脂肪肝成因 7
2.1.3脂肪肝的症狀 10
2.1.4重度脂肪肝症狀 11
2.1.5 脂肪肝併發症 12
2.1.6脂肪肝治療 13
2.2 機器學習 (Machine learning ) 13
2.2.1 類神經網路簡介 14
2.2.2 支持向量機 (Support Vector Machine, SVM) 19
2.2.3 隨機森林 (Random Forest) 22
2.2.4 邏輯斯迴歸 (Logistic Regression) 24
第三章 30
研究材料與方法 30
3.1 研究架構 30
3.2研究材料/資料來源 31
3.2.1 研究流程 33
3.3 研究工具與方法 37
3.3.1 資料轉換 38
3.3.2屬性縮簡 38
3.3.3資料簡化 39
3.4 使用分類器參數選擇 39
3.5 驗證與評估與方法比較 40
3.5.1 驗證方法 40
3.5.2 模型績效評估方法 40
3.6 特徵選取 45
第四章 47
研究結果 47
4.1第一組資料研究結果 47
4.1.1 類神經網路脂肪肝預測模型 47
4.1.2 隨機森林 50
4.1.3 支持向量機 52
4.1.3 類神經網路 54
4.1.4 邏輯斯迴歸 55
4.2第二組 研究結果 58
4.2.1 類神經網路脂肪肝預測模型 58
4.2.2 隨機森林 61
4.2.3 支持向量機 62
4.2.4 類神經網路 64
4.2.4 邏輯斯迴歸 65
4.3 資料結果分析比較 67
第五章 討論 83
5.1第一組資料 研究發現與討論 84
5.2第二組資料 研究發現與討論 85
第六章 結論與建議 88
6.1結論 88
6.2 研究限制 89
6.3未來發展與建議 90
參考資料 91
1.中文文獻 91
2.英文文獻 93
3.電子文獻 95


表目錄

頁數
表1. 非酒精性脂肪肝成因 9
表2. 文獻整理 27
表3. 研究樣本摘要表 35
表4. 研究樣本摘要表 36
表5. 混亂矩陣 41
表6. 變項資料標準化編碼說明 45
表7. 敏感度與特異度 47
表8. 隨機森林 混亂矩陣 50
表9. 支持向量機 混亂矩陣 53
表10. 多層次類神經網路 混亂矩陣. 54
表11. 邏輯斯迴歸 混亂矩陣 56
表12. 診斷脂肪肝各種工具的效能 57
表13. 混亂矩陣 58
表14. 多層感知類神經網路之敏感度與特異度 58
表15. 隨機森林 混亂矩陣 61
表16. 支持向量機 混亂矩陣 63
表17. 類神經網路 混亂矩陣 64
表18. 邏輯斯迴歸 混亂矩陣 66
表19. 診斷脂肪肝各種工具的效能 67
表20. 特徵選擇/變量選擇 68
表21. 各模型之多層次類神經網路模型比較 69
表22. 隨機森林 分類器參數選擇 72
表23. 依序剔除一項變項與全輸入變項比較模型 74
表24. 特徵選擇/變量選擇 76
表25. A 模型 選用全部變項比較各模組 77
表26. B 模型 選用變項比較各模組 78
表27. B 模型 選用變項比較各模組 79
表28. B 模型 選用變項比較各模組 80
表29. E 模型 選用變項比較各模組 81
表30. F 模型 選用變項比較各模組 82
表31. 方式一 採用the leave-one-out test 86
表32. 方式二 採用the leave-group-out test 86


圖目錄

頁數
圖1 脂肪肝的可能演變 9
圖2 生物神經元 14
圖3 類神經網路神經元示意圖 16
圖4 類神經網路研究模型示意圖 18
圖5 支持向量機分類示意圖 21
圖6 研究架構圖 30
圖7 研究樣本篩選處理流程圖 31
圖8 研究樣本篩選處理流程圖 32
圖9 接收者操作特徵曲線範例 43
圖10 測試組的ROC area: 0.919 48
圖11 整體的ROC area: 0.9067 49
圖12 隨機森林 AU ROC 52
圖13 支持向量機 AU ROC 53
圖14 多層次類神經網路AU ROC 55
圖15 邏輯斯迴歸 AU ROC 56
圖16 多層感知類神經網路 訓練組和驗證組ROC Curve 59
圖17 多層感知類神經網路 訓練組和測試組ROC Curve 60
圖18 多層感知類神經網路 訓練組、驗證組和測試組ROC Curve 60
圖19 隨機森林AU ROC 62
圖20 支持向量機AU ROC 63
圖21 類神經網路AU ROC 65
圖22 邏輯斯迴歸AU ROC 66
圖23 各變相組合多層次類神經網路模型比較敏感度,特異度 70
圖24 各變相組合MLP模型比較 71
圖25 隨機森林模型參數選擇比較 73
圖26 依序剔除一項變項與全輸入變項比較模型 75
圖27 選用全部變項各模組之比較 77
圖28 B 模型 選用變項比較各模組 78
圖29 C 模型 選用變項比較 79
圖30 B 模型 選用變項比較各模組 80
圖31 E模型 選用變項比較 81
圖32 F 模型 選用變項比較各模組 82

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李友專, 吳. (2013) . 憑藉臨床檢驗及血清生化檢驗值和運用類神經網路預測有無脂肪肝. Paper presented at the 2013 年國際醫學資訊聯合研討會.
李俊宏, & 古清仁. (2010) . 類神經網路與資料探勘技術在醫療診斷之應用研究. 工程科技與教育學刊, 7 (1) , 154-169.
卓達瑋. (2010) . 隨機森林分類方法於基因組顯著性檢定上之應用.
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朱峰正. (2012). 使用超音波散射統計參數影像評分肝纖維化程度: 理論分析與臨床研究.
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3.電子文獻

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系統識別號 U0007-1704200714541962
論文名稱(中文) 人類恆牙使用美白藥劑後對矯正用複合樹脂黏著強度之影響
論文名稱(英文) The effect of orthodontic bonding strength in bleached human teeth
校院名稱 臺北醫學大學
系所名稱(中) 牙醫學系碩博士班
系所名稱(英) Graduate School of Dentistry
學年度 93
學期 2
出版年 94
研究生(中文) 鄭翔宇
學號 M204091009
學位類別 碩士
語文別 中文
口試日期
論文頁數 62頁
口試委員 指導教授-蔡吉陽
指導教授-王蔚南
關鍵字(中) 牙齒美白
抗張黏著強度
複合樹脂
斷裂介面
關鍵字(英) bond strength
composite resin
bleaching
broken interface
學科別分類
中文摘要 本研究將探討以鹵素光驅動35%之過氧化氫美白牙齒美白藥劑在不同條件下處理後的人類第三大臼齒,再使用複合樹脂將矯正托架黏著於牙釉質上的拉張黏著強度變化,並以掃描式電子顯微鏡及能量散佈光譜儀分析各斷裂介面之分佈情形。本研究使用75顆拔下之人類第三大臼齒並將其平均分為五組,分別為控制組美白一、二及三次與美白一次再浸泡於水中三週後再進行矯正托架黏著。抗張黏著強度測量結果分別為10.62、10.70、10.55、10.73及10.58 MPa,經由One-way ANOVA分析後發現各組間並無顯著差異存在。 結果顯示使用35%過氧化氫鹵素光驅動臨床美白藥劑美白後立即進行矯正托架黏著對抗張黏著強度而言並沒有顯著影響。美白處理後延遲三週再進行矯正托架黏著,與美白後立即黏著矯正托架比較,在黏著強度上並沒有顯著差異。而若因應病患需求而增加美白循環次數,只要在廠商建議的使用範圍之內,不會影響矯正托架的黏著強度。此外,美白處理對於拆除矯正托架時的斷裂介面分佈並沒有顯著的影響。
英文摘要 The purpose of this study was to evaluate the effect of a 35% hydrogen peroxide (H2O2) agent on the tensile bond strength and the failure interface of metallic orthodontic brackets bonded to human enamel. 75 human third molars extracted from 20- to 35-year-old patients were randomly divided into five groups of 15 teeth each: untreated control, enamel treated with 35% H2O2 for 1, 2, or 3 cycles then water immersion for 24 hours, and treated with 35% H2O2 for 1 cycle then water immersion for 3 weeks. Following the treatment, a bracket was bonded to the enamel surface with composite resin and then debonded on a testing machine. The broken interface was recorded and analyzed with scanning electron microscopy and energy-dispersive x-ray spectrometry. The result of tensile bond strength were 10.62、10.70、10.55、10.73 and10.58 MPa for the five testing groups. The results indicated that the use of 35% H2O2 did not change significantly the tensile bond strength and the broken interface distribution of orthodontic brackets.
論文目次 目 錄 第一章 緒論………………………………………………….3 第一節 研究動機與重要性……………………………………………………….3 第二節 研究目的………………………………………………………………….4 第三節 研究假設………………………………………………………………….5 第二章 文獻回顧……………………………………………...7 第一節 複合樹脂黏著之原理…………………………………………………….7 一、黏著的基本原理…………………………………………………………...7 二、牙釉質與複合樹脂介面…………………………………………………...8 三、黏著劑……………………………………………………………………...9 四、影響黏著強度的因素……………………………………………………..11 第二節 美白藥劑對於黏著強度之影響……………………………….………...11 一、牙齒美白不影響黏著強度……………………………………….……….12 二、牙齒美白將降低黏著強度……………………………………….……….13 第三節 黏著強度的恢復………………………………………………….……...14 第四節 斷裂介面的分析…………………………………………………….…...15 第三章 研究材料與方法…………………………………….17 第一節 研究材料………………………………………………………………...17 一.牙齒………………………………………………………………………...17 二.酸蝕劑……………………………………………………………………...17 三.複合樹脂…………………………………………………………………...17 四.美白劑……………………………………………………………………...18 五.抗氧化劑…………………………………………………………………...18 六.矯正托架…………………………………………………………………...18 第二節 實驗儀器………………………………………………………………...18 一.萬能拉力試驗機…………………………………………………………...18 二.掃描式電子顯微鏡………………………………………………………...18 三.能量散佈光譜儀…………………………………………………………...18 四.鹵素光機…………………………………………………………………...18 第三節 研究方法………………………………………………………………...19 一.實驗設計…………………………………………………………………...19 二.抗張黏著強度測試………………………………………………………...22 三.斷裂介面之觀察與分析…………………………………………………...24 第四節 資料統計與方法………………………………………………………...26 一. 敘述性統計分析………………………………………………………….26 二. Tukey interval………………………………………………………….26 三. 統計顯著性檢定………………………………………………………….27 第四章 結果………………………………………………….28 第一節 抗張黏著強度測試及分析結果……………………………….………...28 第二節 斷裂介面之觀察與分析結果…………………………………………28第五章 討論…………….………...……………………….....30 第六章 結論…………………….………………..…………..37 第七章 致謝………………………………………………….38 圖表目錄 圖1. 微觀下可見之固體粗糙表面……………………………….……………….39 圖2. 電子顯微鏡下可見的牙釉質表面…………………………………………..40 圖3. 牙釉質與複合樹脂介面……………………………………………………..41 圖4. 斷裂面之分佈………………………………………………………………..42 圖5. Concise矯正用複合樹脂…………………………………………………...43 圖6. Pola office鹵素光驅動美白藥劑………………………………………...44 圖7. Cambridge S-360 掃描式電子顯微鏡……………………………………..45 圖8. 斷裂樣本以SEM放大21倍下所觀察之矯正托架…………………………46 圖9. EDAX分析以INCA-Mapping軟體繪出各元素的分佈圖……..………..…...47 圖10.牙釉質斷裂面之鈣(A)及矽(B)分佈圖………………………………..48 圖11.矯正托架斷裂面之鈣(A)、鐵(B)及矽(C)分佈圖…………………..49 圖12.牙齒表面及矯正托架基座底部上之斷面分佈示意模型………………..…50 圖13. analySIS軟體計算出各斷面所佔之百分比………………………….…..51 表1. 抗張黏著強度之測量結果…………………………………………………..52 表2. 抗張黏著強度之統計結果…………………………………………………..53 表3. 斷裂介面之測量與計算結果………………………………………………..54 表4. 各組中斷裂介面分佈之統計結果…………………………………………..55 表5. 各組間斷裂介面分佈之統計結果…………………………………………..56 參考文獻……………………………………………………...57
參考文獻 Newman GV. Epoxy adhesives for orthodontic attachments. Progress report. Am J Orthod, 51: 901-912, 1965. Sung EC, Chan SM, Mito R, Caputo AA. Effect of carbamide peroxide bleaching on the shear bond strength of composite to dental bonding agent enhanced enamel. J Prosthet Dent, 82: 595-599, 1999. Tancan U, Basciftci FA, ???mez S, Sari Z, Buyukerkmen A. Can previously bleached teeth be bonded safely? Am J Orthod Dentofacial Orthop, 123: 628-632, 2003. Miles PG, Pontier JP, Bahiraei D, Close J. The effect of carbamide peroxide bleach on the tensile bond strength of ceramic brackets: An in vitro study. Am J Orthod Dentofacial Orthop, 106: 371-375, 1994. Cavalli V, Reis AF, Giannini M, Ambrosano GMB. The effect of elapsed time following bleaching on enamel bond strength of resin composite Oper Dent, 26: 597-602, 2001. Josey AL, Meyers IA, Romaniuk K, Symons AL. The effect of a vital bleaching technique on enamel surface morphology and the bonding of composite resin to enamel. J Oral Rehabil, 23: 244-250, 1996. Bishara SE, Ortho D, Sulieman AH, Olson M. Effect of enamel bleaching on the bonding strength of orthodontic brackets. Am J Orthod Dentofacial Orthop, 104: 444-447, 1993. Murchison DF, Charlton DG, Moore BK. Carbamide peroxide bleaching: effects on enamel surface hardness and bonding. Oper Dent, 17: 181-185, 1992. Titley KC, Torneck CD, Ruse ND. The effect of carbamide-peroxide gel on the shear bond strength of a microfilm resin to bovine enamel. J Dent Res, 71: 20-24, 1992. Titley KC, Torneck CD, Smith DC, Adibfar A. Adhesion of composite resin to bleached and unbleached bovine enamel. J Dent Res, 67: 1523-1528, 1988. Lai SCN, Tay FR, Cheung GSP, MAK YF, Carvalho RM, Wei SHY, Toledano M, Osorio R, Pashley DH. Reversal of compromised bonding in bleached enamel. J Dent Res, 81: 477-481, 2002. Lai SCN, Mak YF, Cheung GSP, Osorio R, Toledano M, Carvalho RM, Tay FR , Pashley DH. Reversal of compromised bonding to oxidized etched dentin. J Dent Res, 80: 1919-1924, 2001. Brantley WA, Eliades T. Orthodontic materials: Scientific and clinical aspects, Thieme, New York, pp.190-191, 2001. Faust JB, Grego GN, Fan PL, Powers JM. Penetration coefficient, tensile strength, and bond strength of thirteen direct bonding orthodontic cements. Am J Orthod, 73: 512-525, 1978. Reynolds IR. A review of direct orthodontic bonding. Br J Orthod, 2: 171, 1975. Buzitta VAJ, Hallgren SE, Powers JM. Bond strength of orthodontic direct-bonding cement-bracket systems as studied in vitro. Am J Orthod, 81: 87-92, 1982. Brobakken BO, Zachrisson BU. Abrasive wear of bonding adhesives: studies during treatment and after bracket removal. Am J Orthod, 79: 134-147, 1981. Zachrisson BU, Brobakken BO. Clinical comparison of direct versus indirect bonding with different bracket types and adhesives. Am J Orthod, 74: 62, 1987. Graber TM, Vanarsdall RL Jr. Orthodontics: current principles and techniques. 3rd ed, CV Mosby, St Louis, pp. 571-573, 2000. Wang WN. Tensile bond strength of orthodontic resins on the human tooth surface. Proc Natl Sci Counc B ROC, 12: 228-235, 1988. Wang WN, Meng CL. A study of bond strength between light- and self-cured orthodontic resin. Am J Orthod Dentofacial Orthop, 101: 350-354, 1992. Wang WN, Lu TC. Bond strength with various etching times on young permanent teeth. Am J Orthod Dentofacial Orthop, 100: 72-79, 1991. Wang WN, Yeh CL, Fang BD, Sun KT, Arvystas MG. Effect of H3PO4 concentration on bond strength. Angle Orthod, 64: 377-382, 1994. Sheen DH, Wang WN, Tarng TH. Bond strength of younger and older permanent teeth with various etching times. Angle Orthod, 63: 225-230, 1993. Wang WN, Li CH, Chou TH, Wang DDH, Lin LH, Lin CT. Bond strength of various bracket base designs. Am J Orthod Dentofacial Orthop, 125: 65-70, 2004. Wang WN, Meng CL, Tarng TH. Bond strength: A comparison between chemical coated and mechanical interlock bases of ceramic and metal brackets. Am J Orthod Dentofacial Orthop, 111: 374-381, 1997. Meng CL, Wang WN, Tarng TH, Luo YC, Lai JS, Arvystas MG. Orthodontic resin under water immersion. Angle Orthod, 65: 209-213, 1995. Wang WN, Sheen DH. The effect of pretreatment with fluoride on the tensile strength of orthodontic bonding. Angle Orthod, 61: 31-34, 1991. Meng CL, Wang WN, Yeh IS. Fluoridated etching on orthodontic bonding. Am J Orthod Dentofacial Orthop, 112: 259-262, 1997. Meng CL, Li CH, Wang WN. Bond strength with APF applied after acid etching. Am J Orthod Dentofacial Orthop, 114: 510-513, 1998. Godoy FG, Dodge WW, Donohue M, O’Quinn JA. Composite resin

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系統識別號 U0007-1704200714542184
論文名稱(中文) 靈芝子實體纖維之幾丁質及幾丁聚醣之製備
論文名稱(英文) Preparation of Sacchachitin and Sacchachitosan from the Residue of Ganoderma Fruiting Bodies
校院名稱 臺北醫學大學
系所名稱(中) 口腔科學研究所
系所名稱(英) Graduate Institute of Oral Science
學年度 93
學期 2
出版年 94
研究生(中文) 車立雯
學號 M214092003
學位類別 碩士
語文別 中文
口試日期
論文頁數 99頁
口試委員 指導教授-陳建中
關鍵字(中) 靈芝
靈芝幾丁質
靈芝幾丁聚醣
去乙醯值
關鍵字(英) Ganoderma
Sacchachitin
Sacchachitosan
Degree of de-acetylation
學科別分類
中文摘要 靈芝為傳統常用之中藥,為真菌類重要成員,其形體可分為菌柄及子實體兩部分,靈芝子實體的成份除了高分子多醣體、三?類、腺?和小分子蛋白外,其餘大部分的纖維均為幾丁質,因此非常適合作為生產幾丁質及其衍生物之原料來源。目前工業上之幾丁質等衍生物來源,主要由蝦、蟹殼經酸鹼溶液多項步驟反應所製得,由於蝦蟹殼來源分佈廣泛,且因種類、大小、區域等差異,使得幾丁質等衍生物之物化性質不盡相同。 本研究分別先將子實體殘渣經超微粒研磨機處理微小化後,再針對靈芝子實體纖維之衍生物:靈芝幾丁質、靈芝幾丁聚醣進行萃取,並在不同條件下,以H2O2為變因進行脫色處理來決定製程之標準化。進而利用膠體滴定法、IR、NMR測得其靈芝幾丁質、幾丁聚醣之去乙醯值及結構分析,再以IV測其分子量;在型態學上則以SEM觀察其巨觀之狀態。而針對靈芝幾丁聚醣部分,則再進行A.A.抗菌性試驗。 本研究之目的在於期望能藉由此製程進而提升靈芝的用途至幾丁質、幾丁聚醣等具開發性潛力之成份,並提供其更加安全、穩定的來源及附加價值高的商業性利用。
英文摘要 As an important member of fungi, Ganoderma has two main parts: the stems and the fruiting bodies. Besides polysaccharide, triterpene, nucleoside, and protein, the main component of the Ganoderma fruiting bodies is chitin, hence an excellent sources for chitin and its derivatives. Presently, through multiple and complicated steps of alkali and acid reactions, chitin and its derivatives were produced with crustacean shells as major sources. As crustacean shells may have many variables, such as variety, size, and region, the physic-chemical properties of chitin and its derivatives obtained from these sources might be different. To the contrary, Ganoderma can be farmed and harvested in controlled environments as a much more reliable biomaterial sources. Optimized preparation procedures for chitin from Ganoderma were proposed. Beginning with the grinding of the Ganoderma fruiting bodies, the product powder was treated with sodium hydroxide followed by the separation and bleaching processes. Depending on the procedures, the final products are sacchachitin and sacchachitosan. Degree of de-acetylation, the chemical structure of saccharchitin and its derivatives, were analyzed using the PVSK titration method, IR, and NMR. The molecular weight was then determined using viscosity meter, and the morphology was investigated using SEM. An antibiotic test for sacchachitosan was undertaken with A. actinomycetemcomitans. The purpose of this study is to ensure the full utilizations of Ganoderma, to produce not only chitin but also other high valued products. Furthermore, we provided a much safer and steadier sources materials, through optimized procedures.
論文目次 目錄 致 謝 I 中文摘要 II ABSTRACT IV 目錄 VI 表目錄 X 圖目錄 XI 第一章 緒論 13 1.1 研究動機與其重要性 13 1.2 研究目的 15 1.3 研究假設 16 第二章 文獻回顧 17 2.1 靈芝 17 2.1.1 生長與栽培 17 2.1.2 松杉靈芝的形態 18 2.1.3 靈芝的生理活性成分 19 2.2 幾丁質(CHITIN)與幾丁聚醣(CHITOSAN) 22 2.2.1 幾丁質與幾丁聚醣的由來 22 2.2.2 幾丁質與幾丁聚醣的分布 23 2.2.3 幾丁質與幾丁聚醣的結構 23 2.2.4 幾丁質之種類 24 2.2.5 幾丁質之製備 25 2.2.6 幾丁聚醣之製備 26 2.2.7 幾丁質與幾丁聚醣之生合成 27 2.2.8 幾丁質與幾丁聚醣之溶解特性 27 2.2.9 幾丁質與幾丁聚醣之應用 28 2.3 過氧化氫(HYDROGEN PEROXIDE,H2O2)漂白機制 31 2.3.1 過氧化氫在鹼性環境中之漂白機制 31 2.3.2 殘留過氧化氫之檢查法 33 2.4 奈米微小化技術 34 2.4.1 何謂奈米 34 2.4.2 奈米材料的結構效應 35 2.4.3 奈米材料的表面效應 35 2.4.4 奈米材料的體積效應 35 第三章 研究材料與方法 37 3.1 材料與試劑 37 3.2 儀器設備 38 3.3 研究方法 39 3.3.1 靈芝幾丁質(Sacchachtin)之製備 39 3.3.2 靈芝幾丁聚醣(Sacchachitosan)製備 39 3.3.3 產率之測量 40 3.3.4 灰份之測量 40 3.3.5 去乙醯化程度之測定 40 3.3.6 分子量之測定 42 3.3.7 SEM表面結構觀察 43 3.3.8 抗菌測試 43 3.3.9 統計方法 44 第四章 結果與討論 45 4.1 利用不同PH值條件下對漂白之速率影響 45 4.2 靈芝子實體殘渣之衍生物產率測試 46 4.3 SACCHACHITIN物性分析 47 4.3.1 SEM之表面結構觀察 47 4.3.2 ATR-IR之定性分析觀察 48 4.3.3 13C CP-MAS NMR之定性分析觀察 51 4.3.4 分子量之測定 52 4.4 SACCHACHITOSAN物性分析 52 4.4.1 SEM之表面結構觀察 52 4.4.2 ATR-IR之定性分析觀察 52 4.4.3 13C CP-MAS NMR之定性分析觀察 53 4.4.4 PVSK膠體滴定法之去乙醯程度測量 54 4.4.5分子量之測定 55 4.4.6抑菌測試 56 第五章 結論 57 參考文獻 58 附錄 98
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系統識別號 U0007-1704200714545916
論文名稱(中文) SACCHACHITIN P10對於寵物外傷及燙傷之傷口癒合作用
論文名稱(英文) Mode of Action on SACCHACHITIN P10 for Traumatic and Burn Wound of Pets
校院名稱 臺北醫學大學
系所名稱(中) 生物醫學材料研究所
系所名稱(英) Graduate Institute of Biomedical Materials
學年度 93
學期 2
出版年 94
研究生(中文) 陳朝澧
學號 M212092008
學位類別 碩士
語文別 中文
口試日期
論文頁數 91頁
口試委員 指導教授-蘇慶華
關鍵字(中) SACCHACHITIN P10
外傷
燙傷
寵物
關鍵字(英) SACCHACHITIN P10
Wound
Burn WOund
Pet
學科別分類
中文摘要 摘要 本研究目的在研發新的SACCHACHITIN劑型以方便使用於寵物皮膚外傷。我們以5%的CMC為基質加入10%的SACCHACHITIN製成軟膏狀的成品SAP10。動物實驗亦證實SAP10具有促進傷口癒合的功效。在大白鼠的皮膚生檢傷口癒合實驗以及燙傷實驗,傷口的組織病理變化、傷口面積、生長因子以及基質金屬型蛋白水解? (Matrix metalloproteinease, MMPs) 作為評估的項目。從組織病理以及傷口面積的改變,顯示SA P-10可以在癒合各期刺激分泌生長因子包括PDGF、TGF-β1以及VEGF的表現,同時也能抑制MMP-9以及依據分子量推測為MMP-2的表現。 另外在犬的燙傷實驗,由組織病理變化以及MMPs的表現分析,同時支持SAP10具有促進傷口癒合的功效。由於具有犬專一性的生長因子檢驗無法購得或製成而無法分析生長因子的表現。 在犬隻及大白鼠實驗中MMPs的表現呈現不一致的情況或許和動物種的差異有關,而生長因子不同的表現於大白鼠全層皮膚切除以及燙傷實驗或許和傷口形成的原因有關。 SAP10具有外型可塑性以及延展性的特性,無論毛髮的干擾均可與傷口充份接觸,也容易以繃帶包紮使敷料穩固於動物傷口,達到治療的目的。 本研究結論為SAP10對於全層皮膚切除以及全層皮膚燙傷之傷口具有良好的傷癒合口促進的功效以及臨床使用的方便性。
英文摘要 Summary The aim of the present study was to develop a new type wound dressing derived from SACCHACHITIN to meet the demands of pets. SACCHACHITIN P10 was composed of 10% SACCHACHITIN and 5% Carboxymethyl cellulose sodium salt (CMC). Animal models were employed to confirm the effectiveness of wound healing enhancement of SAP10. Skin biopsy full thickness excision and full thickness thermal burn were created on the back of Wistar rats and size of wound area, histopathological changes, growth factors matrix metalloproteinases (MMPs) contents were measured in the wound areas. The histopathological change and wound area revealed that SAP10 promote growth factors including PDGF, TGF-β1 and VEGF expression and that in good agreement with the healing process of inflammation, proliferation and remodeling in the model of full thickness excision. In the same time the activities of MMP-9 and presumed MMP-2 were found to be suppressed. In dog, experiment on thermal burn trauma was also carried out. Histopathological and wound area changes support that SAP10 was effective in accelerating wound healing. Zymographic results demonstrated that SAP10 suppressed MMP-9 and MMP-2 during the whole process of healing. However, growth factors specific for canine were unavailable that this part of data was devoid. The different expression of MMPs in rat and dog might be because of species difference. The wound type also affected the expression of growth factors in the wound area. SAP10 was in a viscous and amorphous paste form and it was able to be applied onto the wound of any animal surface with any shape for a stable bandage no matter with hair or not. In conclusion, SAP10 is an effective wound healing formulation to meet the special demands of pets for full thickness excision and full thickness thermal wound.
論文目次 目 錄 中文摘要....................................... i Abstract ..................................... ii 第壹章、緒論.................................... 1 壹、背景..................................... 1 貳、目的..................................... 1 ?、前人研究 ................................ 2 ㄧ、寵物皮膚生理 ......................... 2 二、寵物皮膚創傷生理 ...................... 3 三、皮膚癒合過程.......................... 4 (一) 急性炎症期 ...................... 4 1、急性炎症期早期 .................. 5 2、急性炎症期晚期 .................. 6 (二) 增生或肉芽組織形成期 ............. 6 1、纖維增生 ........................ 7 2、創口收縮 ........................ 7 3、血管新生 ........................ 7 4、表皮新生 ........................ 8 (三) 組織重組期 ....................... 8 肆、寵物燙傷................................... 9 ㄧ、引起燙傷的原因 ........................ 9 二、臨床症狀 ............................ 10 三、組織病理 ............................. 11 四、治療 ................................. 11 伍、獸醫傷口癒合學............................ 11 陸、SACCHACHITIN ............................ 13 一、敷料原料SACCHACHITIN的來源 ............. 13 二、利用SACCHACHITIN作為生物醫學材料 ........ 13 三、靈芝萃取物促進傷口之癒合................. 14 四、CHITIN的特性 .......................... 14 (一) 生物相容性 .......................... 14 (二) 生物降解性 .......................... 14 (三) 免疫刺激作用 ........................ 14 (四) 加速傷口的癒合 ...................... 15 五、研究傷口癒合的評估方式 .................. 15 (一) 基質金屬型蛋白水解?.................. 16 (二) 生長因子 ............................ 18 柒、本研究的評估方式選擇........................ 20 一、MMPs ................................. 20 二、生長因子 ............................. 20 三、皮膚組織病理 ......................... 20 四、傷口面積的計測 ........................ 21 捌、SACCHACHITIN對寵物之先期研究............... 21 玖、實驗假說.................................. 22 第貳章、材料與方法............................... 25 壹、實驗架構................................... 25 貳、材料...................................... 26 一、原料 ..................................... 26 二、實驗動物 .................................. 26 三、麻醉劑 ................................... 26 四、化學試劑 ................................. 26 五、敷料 ..................................... 26 ?、設備...................................... 27 肆、敷料製備方法............................... 27 一、粉末SACCHACHITIN傷口敷料的製備 .........27 二、SACCHACHITIN P-10的製作............... 28 伍、動物實驗................................... 28 一、實驗動物 .................................. 28 二、麻醉藥 .................................. 29 三、麻醉劑劑量及給藥法 ........................ 29 四、傷口製造 ................................. 30 五、觀察及取樣 ............................... 31 陸、臨床病例治療與觀察......................... 36 第參章、結果與討論 ............................. 38 壹、SACCHACHITIN P-10 (SAP10) ............... 38 貳、大白鼠皮膚傷口癒合實驗 ..................... 39 ?、大白鼠燙傷實驗............................. 55 肆、犬燙傷實驗................................ 67 伍、犬臨床病例................................ 76 第肆章、結論.................................... 82 參考文獻....................................... 84
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系統識別號 U0007-1704200714553941
論文名稱(中文) 以Lieber-DeCarli之動物模式探討慢性酒精毒性對於抗氧化狀態及肝臟形態變化之影響
論文名稱(英文) Effects of Chronic Alcoholic Toxicity on Antioxidative Status and Hepatic Morphologic Changes by Lieber-DeCarli Animal Model
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 93
學期 2
出版年 94
研究生(中文) 黃啟彰
學號 d301090007
學位類別 博士
語文別 中文
口試日期
論文頁數 223頁
口試委員 指導教授-楊素卿
關鍵字(中) 酒精、性別差異、四氯化碳、脂解?、雙醣?、氧化壓力、脂質過氧化、P450 2E1、黃嘌呤氧化?、骨髓過氧化?、脂肪肝、脂肪變性
硫巴比妥酸
過氧化氫
四氯化碳
胺酸轉胺
羥基丁酸
關鍵字(英) ethanol, gender differences, carbon tetrachloride, lipase, disaccharidase, oxidative stress, lipid peroxidation, CYP2E1, xanthin
學科別分類
中文摘要 本研究利用Lieber-DeCarli流質飲食模式,探討不同性別於酒精性肝臟疾病方面之表現。此外,本研究也針對酒精與四氯化碳所造成之肝傷害進行探討並作系統性之比較。 首先,在第一部份,不同性別對於長期攝取酒精所造成肝損傷之影響的研究中,使用年齡相同之雄性與雌性Wistar品系大白鼠,根據Lieber-DeCarli模式,分別餵食對照或含有酒精的液體飼料,為期12週。將40隻大白鼠依照血漿中肝功能指數天門冬胺酸轉胺?(aspartate aminotransferase, AST)與丙胺酸轉胺?(alanine aminotransferase, ALT)之活性分成4組:雄性對照組(MC)、雄性酒精組(ME)、雌性對照組(FC)以及雌性酒精組(FE),每組10隻。餵食酒精12週之後,結果顯示,長期餵食酒精會造成顯著的影響包括:增加相對肝重(%),提高血漿中AST與ALT之活性,增加血漿中總膽固醇(total cholesterol, TC)、高密度脂蛋白膽固醇(high density lipoprotein cholesterol, HDL-C)、乳酸(lactate)、游離脂肪酸(non esterified fatty acid, NEFA)、羥基丁酸(?-hydroxy- butyrate)與腫瘤壞死因子(tumor necrosis factor-?, TNF-?)之濃度,增加肝臟中三酸甘油酯(triglyceride, TG)與TC之含量,誘導肝臟中細胞色素P450 2E1 (CYP2E1)蛋白質之表現,提高肝臟中黃嘌呤氧化?(xanthine oxidase, XO)與骨髓過氧化?(myeloperoxidase, MPO)之活性,增加血漿與肝臟中脂質過氧化產物即硫巴比妥酸反應物質(thiobarbituric acid reactive substances, TBARS)之含量,減少肝臟中還原型麩胱甘?(glutathione, GSH)之含量並降低還原型麩胱甘?/氧化型麩胱甘?(oxidized glutathione, GSSG)之比值,降低肝臟中抗氧化酵素麩胱甘?過氧化?(glutathione peroxidase, GPX)、過氧化氫?(catalase, CAT)與超氧化物歧化?(superoxide dismutase, SOD)之活性,提高空腸中脂解?(lipase)之活性,降低空腸中雙醣?(sucrase、maltase與lactase)之活性,而且病理學上明顯有脂肪肝形成之情形。此外,相較於雄性組,雌性組大白鼠血漿中AST活性明顯升高,血漿中NEFA與?-hydroxybutyrate濃度顯著增加,肝臟中TG與TC含量明顯增加,肝臟中TBARS含量顯著增加,肝臟中GSH含量明顯減少、GSH/GSSG比值顯著下降,肝臟中抗氧化酵素GPX與CAT之活性均顯著降低,而且脂肪肝程度較嚴重。由此可知,不論雄性或雌性,長期攝取酒精都會造成空腸中消化酵素活性明顯受到影響。另外,長期攝取酒精也會導致肝功能指標上升、脂質代謝異常、氧化壓力上升、脂質過氧化產物增加、抗氧化物質含量減少、抗氧化酵素活性降低以及病理上造成肝損傷;其中又以雌性組所造成的影響更嚴重。 在第二部份,比較酒精與四氯化碳造成肝傷害之實驗中,以雄性Wistar大白鼠50隻作為實驗動物,依肝功能指標AST與ALT分成5組:對照組(C)、酒精組(E)、酒精治療組(ES)、四氯化碳組(CCL)以及四氯化碳治療組(CCLS),每組10隻,實驗期為12週。結果顯示,長期餵食酒精或注射四氯化碳都會造成的影響包括:肝重與相對肝重(%)明顯增加,血漿中AST與ALT活性於實驗期第2、4、6、8、10、12週皆明顯上升,血漿中TG濃度於實驗期第10、12週顯著減少,肝臟中TG與TC含量均顯著增加,肝臟中CYP2E1蛋白質表現量明顯受到誘導,肝臟中MPO活性顯著上升,血漿中TBARS濃度於實驗期第2、4、6、8、10、12週皆明顯增加,肝臟中TBARS含量顯著增加,肝臟中GSH含量顯著減少、GSH/GSSG比值明顯下降,肝臟中抗氧化酵素GPX與SOD活性皆顯著降低,而且病理學上明顯有脂肪肝與脂肪變性形成之情形。此外,於實驗結束後,相較於酒精組,四氯化碳組大白鼠肝重與相對肝重(%)均明顯增加,血漿中AST與ALT之活性均明顯上升,血漿中TG、TC與HDL-C濃度顯著減少,肝臟中TG與TC之含量均顯著增加,肝臟中XO與MPO活性均顯著升高,血漿中TBARS濃度明顯增加,肝臟中GSH含量顯著減少、GSSG含量顯著增加、GSH/GSSG比值明顯下降,肝臟中抗氧化酵素麩胱甘?還原?(glutathione reductase, GRD)與CAT活性皆顯著降低,而且脂肪肝與脂肪變性之情形更嚴重。由此可知,酒精與四氯化碳都會造成肝功能指標上升、脂質代謝異常、氧化壓力上升、脂質過氧化產物增加、抗氧化物質含量減少、抗氧化酵素活性降低以及病理上造成肝損傷;其中又以四氯化碳所造成的影響更嚴重。
英文摘要 This dissertation had two major parts; one was to evaluate the correlation between gender differences and chronic alcoholic liver disease. In addition, effects of gender differences on jejunal lipase and disaccharidase activities, the liver function tests, metabolic disorders and oxidative damage were also examined. Another major part was to examine oxidative stress of alcoholic injury and carbon tetrachloride- induced damage in relation to risk factors for liver disease. The first part of this study was to investigate the effects of gender differences on alcoholic liver disease in rats with chronic ethanol consumption. Age-matched male and female Wistar rats were fed control or ethanol-containing liquid diets for 12 weeks following the Lieber-DeCarli model. According to both the plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, 40 rats were divided into four groups as follows: male control group (MC), male ethanol group (ME), female control group (FC), and female ethanol group (FE). After ethanol feeding for 12 weeks, the findings indicated significant main effects of ethanol consumption on increased relative liver weight (%); elevated plasma AST and ALT activities; raised plasma total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), lactate, non-esterfied fatty acid (NEFA), ?-hydroxybutyrate, and tumor necrosis factor-alpha (TNF-?) concentrations; increased hepatic triglyceride (TG) and TC contents; induction of hepatic microsomal cytochrome P450 2E1 (CYP2E1); elevated hepatic xanthine oxidase (XO) and myeloperoxidase (MPO) activities; increased both plasma and hepatic thiobarbituric acid reactive substances (TBARS) levels; reduced hepatic glutathione (GSH) content and the ratio of GSH/oxidized GSH (GSSG); decreased hepatic antioxidant enzymes, glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) activities; elevated jejunal lipase activity; lowered all jejunal disaccharidase, sucrase, maltase and lactase, activities; and the formation of fatty liver; when compared to control group. Furthermore, the results also showed significant main effects of gender differences on elevated plasma AST activity; increased both plasma NEFA and ?-hydroxybutyrate concentrations; augmented hepatic TG and TC contents; raised hepatic TBARS level; reduced hepatic GSH content and the ratio of GSH/GSSG; decreased hepatic antioxidant enzymes, GPX and CAT activities; and degree of fatty liver; when compared to male group. In conclusion, our results suggest that long-term ethanol consumption significantly increased jejunal lipase and decreased jejunal disaccharidase (sucrase, maltase, and lactase) activities in both male and female rats. Our results also show that chronic ethanol administration induced a greater susceptibility to liver damage in female rats than in male rats. In the second part, we examined the effects of ethanol- or carbon tetrachloride-induced liver injury in male Wistar rats following the Lieber-DeCarli liquid diet. According to both the plasma AST and ALT activities, 50 rats were assigned to five groups: C (control feeding), E (ethanol feeding), ES (ethanol feeding combined with the supplementation of silymarin, 200 mg/kg BW/day), CCL (CCl4 injection and control feeding) and CCLS (CCl4 injection and control feeding combined with the supplementation of silymarin, 200 mg/kg BW/day). Rats in groups CCL and CCLS were intraperitoneally injected with 0.75 mL/kg BW of 40% CCl4 dissolved in olive oil once a week, while rats in groups C, E and ES were intraperitoneally injected with 0.75 mL/kg BW of olive oil only. Our dada indicated significant main effects of both ethanol feeding and carbon tetrachloride injection on increased relative liver weight (%); elevated plasma AST and ALT activities at weeks 2, 4, 6, 8, 10 and 12; lowered plasma TG concentrations at weeks 10 and 12; increased hepatic TG and TC contents; induction of hepatic microsomal CYP2E1; elevated hepatic MPO activity; increased plasma TBARS concentrations at weeks 2, 4, 6, 8, 10 and 12; increased hepatic TBARS level; reduced hepatic GSH content and the ratio of GSH/GSSG; decreased hepatic antioxidant enzymes, GPX and SOD, activities; and pathologically changed liver; when compared to control feeding. Moreover, after 12 weeks, the results also showed significant main effects of carbon tetrachloride injection on increased relative liver weight (%); elevated plasma AST and ALT activities; reduced all the plasma TG, TC and HDL-C concentrations; augmented hepatic TG and TC contents; elevated hepatic XO and MPO activities; increased plasma TBARS concentration; reduced hepatic GSH content and the ratio of GSH/GSSG, whereas increased GSSG level; decreased hepatic antioxidant enzymes, GRD and CAT activities; and severe fatty change in livers; when compared to ethanol feeding. In conclusion, our results suggest that both long-term ethanol feeding and carbon tetrachloride injection significantly increased oxidative stress, lipid peroxidation, and decreases in GSH concentrations and the ratio of GSH/GSSG in rats. Our results also show that carbon tetrachloride injection induced a greater susceptibility to liver damage than ethanol feeding. Key words: ethanol, gender differences, carbon tetrachloride, lipase, disaccharidase, oxidative stress, lipid peroxidation, CYP2E1, xanthine oxidase, myeloperoxidase, fatty liver, fatty degeneration
論文目次 中文摘要………………………………………………………………… I 英文摘要………………………………………………………………… IV 致謝……………………………………………………………………… VII 目錄……………………………………………………………………… VIII 表目次…………………………………………………………………… XI 圖目次…………………………………………………………………… XIV 第一章 緒論………………………………………………………………1 第二章 文獻回顧…………………………………………………………4 第一節 肝臟的生理結構與功能………………………………………4 一、肝臟的構造與生理功能…………………………………………4 二、構成肝臟的細胞種類及其生理作用……………………………6 第二節 酒精性肝臟疾病形成之原因…………………………………9 一、酒精對於脂質代謝之影響………………………………………9 二、酒精對於肝臟氧化傷害之影響…………………………………10 三、酒精代謝產物乙醛之毒性作用…………………………………22 四、細胞激素(cytokine)與酒精性肝臟疾病之關係…………………25 五、內毒素(endotoxin)與酒精性肝臟疾病之關係…………………..26 六、不同性別在酒精性肝臟疾病方面之表現………………………..30 第三節 酒精性肝臟疾病動物模式之相關研究……………………… 32 一、Lieber-DeCarli model……………………………………………32 二、Tsukamoto-French model………………………………………33 第四節 四氯化碳造成肝損傷之作用機轉…………………………… 35 一、CCl4會促進氧化壓力形成而導致肝損傷………………………35 二、CCl4會造成脂質代謝異常而導致肝臟脂肪堆積………………38 三、CCl4會造成肝臟纖維化之形成…………………………………40 第五節 四氯化碳誘導肝損傷動物模式之相關研究…………………41 一、CCl4誘導肝損傷之方式……………………………………….. 41 二、CCl4所誘導之肝損傷於肝臟疾病方面的應用……………….. 42 第六節 保肝藥物Silymarin之相關研究……………………………..43 一、Silymarin之介紹……………………………………………….. 43 二、Silymarin與酒精性肝臟疾病之相關研究………………………44 三、Silymarin與四氯化碳誘導肝損傷之相關研究…………………46 第三章 不同性別對於長期攝取酒精所造成肝損傷之影響……………48 第一節 研究方法………………………………………………………48 一、實驗材料…………………………………………………………48 二、分析項目與測量方法……………………………………………52 三、統計分析方法……………………………………………………74 第二節 結果……………………………………………………………75 一、肝功能指數與肝臟病理觀察之結果……………………………75 二、空腸中消化酵素活性以及十二指腸病理觀察之結果…………77 三、脂質代謝之結果…………………………………………………78 四、其他血液生化值之結果…………………………………………79 五、造成氧化壓力上升相關酵素活性之結果………………………80 六、脂質過氧化之結果………………………………………………82 七、抗氧化物質含量之結果…………………………………………83 八、抗氧化酵素活性之結果…………………………………………86 第三節 討論……………………………………………………………89 一、肝功能指數與肝臟病理觀察方面………………………………89 二、空腸中消化酵素活性以及十二指腸病理觀察方面……………92 三、脂質代謝方面……………………………………………………95 四、其他血液生化值方面……………………………………………99 五、造成氧化壓力上升相關酵素活性方面…………………………103 六、脂質過氧化方面…………………………………………………106 七、抗氧化物質含量方面……………………………………………107 八、抗氧化酵素活性方面……………………………………………109 第四節 結論…………………………………………………………...111 第四章 酒精性肝損傷與四氯化碳肝傷害之系統性比較……………..112 第一節 研究方法……………………………………………………..112 一、實驗材料………………………………………………………..112 二、分析項目與測量方法……………………………………………115 三、統計分析方法……………………………………………………116 第二節 結果…………………………………………………………..118 一、肝功能指數與肝臟病理觀察之結果……………………………118 二、脂質代謝之結果…………………………………………………123 三、造成氧化壓力上升相關酵素活性之結果………………………129 四、脂質過氧化之結果………………………………………………131 五、抗氧化物質含量之結果…………………………………………133 六、抗氧化酵素活性之結果…………………………………………136 第三節 討論…………………………………………………………. 139 一、肝功能指數與肝臟病理觀察方面………………………………139 二、脂質代謝方面……………………………………………………141 三、造成氧化壓力上升相關酵素活性方面…………………………144 四、脂質過氧化方面…………………………………………………146 五、抗氧化物質含量方面……………………………………………147 六、抗氧化酵素活性方面……………………………………………148 第四節 結論…………………………………………………………..149 第五章 總結……………………………………………………………..150 第六章 參考文獻………………………………………………………..152 表目次 表一、不同性別大白鼠長期餵食酒精液體飼料對於初始體重、期末體重、肝臟總重以及相對肝臟重量(%)之影響………………………...173 表二、不同性別大白鼠長期餵食酒精液體飼料對於實驗初與實驗末血漿中肝功能指數AST與ALT活性之影響…………………………174 表三、不同性別大白鼠長期餵食酒精液體飼料對於空腸中脂解?以及雙醣?活性之影響………………………………………………… 175 表四、不同性別大白鼠長期餵食酒精液體飼料對於實驗末血漿中TG、TC、LDL-C與HDL-C濃度之影響………………………………176 表五、不同性別大白鼠長期餵食酒精液體飼料對於肝臟中TG與TC含量之影響…………………………………………………………… 177 表六、不同性別大白鼠長期餵食酒精液體飼料對於實驗末其他血漿中生化濃度之影響…………………………………………………… 178 表七、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中XO活性之影響…………………………………………………………… 179 表八、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中MPO活性之影響…………………………………………………………… 180 表九、不同性別大白鼠長期餵食酒精液體飼料對於血漿中脂質過氧化產物TBARS濃度之影響………………………………………… 181 表十、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中脂質過氧化產物TBARS含量之影響…………………………………… 182 表十一、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中抗氧化物質GSH含量之影響………………………………………...183 表十二、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中抗氧化物質GSSG含量之影響……………………………………… 184 表十三、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中抗氧化物質GSH/GSSG比值之影響………………………………… 185 表十四、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中抗氧化酵素GPX活性之影響………………………………………… 186 表十五、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中抗氧化酵素GRD活性之影響………………………………………… 187 表十六、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中抗氧化酵素CAT活性之影響………………………………………… 188 表十七、不同性別大白鼠長期餵食酒精液體飼料對於不同組織中抗氧化酵素SOD活性之影響…………………………………………189 表十八、長期餵食酒精或注射四氯化碳對於大白鼠初始體重、期末體重、每日體重增加量、肝臟重量以及相對肝臟重之影響…………190 表十九、長期餵食酒精或注射四氯化碳對於實驗期間大白鼠體重變化之影響……………………………………………………………..191 表二十、長期餵食酒精或注射四氯化碳對於實驗期間大白鼠血漿中肝功能指數AST活性之影響………………………………………192 表二十一、長期餵食酒精或注射四氯化碳對於實驗期間大白鼠血漿中肝功能指數ALT活性之影響…………………………………193 表二十二、長期餵食酒精或注射四氯化碳對於實驗期間大白鼠血漿中TG濃度之影響…………………………………………………194 表二十三、長期餵食酒精或注射四氯化碳對於實驗期間大白鼠血漿中TC濃度之影響…………………………………………………195 表二十四、長期餵食酒精或注射四氯化碳對於實驗期間大白鼠血漿中低密度脂蛋白膽固醇濃度之影響……………………………196 表二十五、長期餵食酒精或注射四氯化碳對於實驗期間大白鼠血漿中HDL-C濃度之影響…………………………………………197 表二十六、長期餵食酒精或注射四氯化碳對於大白鼠肝臟中TG與TC含量之影響……………………………………………………198 表二十七、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中XO活性之影響……………………………………………………199 表二十八、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中MPO活性之影響……………………………………………………200 表二十九、長期餵食酒精或注射四氯化碳對於實驗期間大白鼠血漿中脂質過氧化產物TBARS濃度之影響………………………201 表三十、長期餵食酒精或注射四氯化碳對於大白鼠組織中脂質過氧化產物TBARS含量之影響……………………………………202 表三十一、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中GSH含量之影響……………………………………………………203 表三十二、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中GSSG含量之影響…………………………………………………204 表三十三、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中GSH/GSSG比值之影響……………………………………205 表三十四、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中抗氧化酵素GPX活性之影響………………………………………206 表三十五、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中抗氧化酵素GRD活性之影響………………………………………207 表三十六、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中抗氧化酵素CAT活性之影響………………………………………208 表三十七、長期餵食酒精或注射四氯化碳對於大白鼠不同組織中抗氧化酵素SOD活性之影響………………………………………209 圖一、餵食酒精之後,液體飼料(A)與大白鼠血液(B)中酒精濃度變化之影響…………………………………………………………………210 圖二、不同性別大白鼠長期餵食酒精液體飼料對於肝臟病理切片結果之影響………………………………………………………211 圖三、不同性別大白鼠長期餵食酒精液體飼料對於十二指腸病理切片結果之影響…………………………………………………212 圖四、不同性別大白鼠長期餵食酒精液體飼料對於肝臟中微粒體細胞色素P450 2E1蛋白質表現之影響…………………………213 圖五、長期餵食酒精或注射四氯化碳對於大白鼠肝臟組織外觀之影響…………………………………………………………………214 圖六a、C組大白鼠肝臟病理切片圖(H&E stain) ………………………215 圖六b、E組大白鼠肝臟病理切片圖(H&E stain) ………………………216 圖六c、ES組大白鼠肝臟病理切片圖(H&E stain) ……………………217 圖六d、CCL組大白鼠肝臟病理切片圖(H&E stain) ……………………218 圖六e、CCLS組大白鼠肝臟病理切片圖(H&E stain) …………………219 圖七、長期餵食酒精或注射四氯化碳對於大白鼠肝臟微粒體中細胞色素P450 2E1蛋白質表現之影響……………………………………220 附錄………………………………………………………………………221
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系統識別號 U0007-1704200714554277
論文名稱(中文) 香煙中的尼古丁對於人類乳癌影響之分子機制研究
論文名稱(英文) The Studies on the Carcinogen Effect of Nicotine on Human Breast Cancer and its Molecular Mechanism
校院名稱 臺北醫學大學
系所名稱(中) 醫學檢驗生物技術學研究所
系所名稱(英) Graduate Institute of Biomedical Technology
學年度 93
學期 2
出版年 94
研究生(中文) 李嘉華
學號 M109092005
學位類別 碩士
語文別 中文
口試日期
論文頁數 60頁
口試委員 指導教授-何元順
關鍵字(中) 即時性
表現量
細胞株
墨點法
發生率
關鍵字(英) nAchR
學科別分類
中文摘要 先前有許多文獻指出吸煙是引發肺癌的重要因子之ㄧ(1,2)。我們在先前(Toxicology and Applied Pharmacology, 2004)也發表過尼古丁引發致癌因子的是仰賴肺臟表皮細胞中尼古丁接受體將NF-Κb活化後會結合至cyclin D1的啟動子位置上,進而達到加速細胞生長且維持細胞存活的目的(3,4)。為了深入探討吸煙習慣和乳癌發生率的相關性(5-7),因此我們認為在乳癌的發生部位應該可以找到特定尼古丁接受體(nAchR)。在本實驗中我們在臺灣女性乳癌病人的腫瘤中找到特定的尼古丁接受體(nAchR),我們也是第一個發現在乳癌細胞株MCF-7和MDA-MB-231有共同的α5、α9尼古丁接受體。接著我們收集了四十位女性乳癌病人的正常及腫瘤部位做個別尼古丁在mRNA上的表現中發現nAchR ubtype α9及α10是在正常及腫瘤組織中最常發現的尼古丁接受體。利用即時性PCR (RealTime-PCR)定量mRNA的表現也發現腫瘤組織中α9尼古丁接受體的表現量有明顯的高於正常組織中α9尼古丁接受體的表現量的情況。接著在西方墨點法中也發現經由尼古丁刺激細胞而調控的蛋白最主要是依靠PI3K/AKT訊息傳遞路徑。我們也利用了Si RNA的技術做出了抑制α5和/或α9尼古丁接受體蛋白表現的MDA-MB-231乳癌細胞株,結果發現抑制α9尼古丁接受體的細胞生長速率明顯的比未抑制α9尼古丁接受體的乳癌細胞慢,以上的結果可能顯示α9尼古丁接受體可能在尼古丁所引發的乳癌中扮演非常重要的角色。
英文摘要 Previous study indicated that tobacco-smoking is a well nderstanding carcinogenic factors that promote the lung cancer formation(1,2). The mechanisms of nicotine-induced carcinogenesis were demonstrated in our recent report (Toxicology and Applied Pharmacology, 2004, in press) indicated as specific binding of nicotine to the nicotinic acetylcholine receptor (nAchRs) in lung epithelial cells by activation of the cyclin D1 promoter through the NFkB signaling proteins to induced cell proliferation(3,4). To further investigate the tobacco smoking habits and its correlations of breast tumor formation(5-7), therefore, we suggested that specific nAchR subunits will be identified in the breast tumor. In this study, our results demonstrated that (nAchR) was detected in breast tumor tissue in Taiwanese patients. We first demonstrated that the a5 and a9 nAchRs were detected in both the MCF-7 and MDA-MB-231 breast cancer cell lines. We further study the expression of the nAchR mRNA levels in breast tumor tissues collected from forty cases of breast cancer patients in Taiwan and found that the α9 and α10 subunits of the nAchR was the most prevalence in both normal and tumor tissue. Quantitative assays of the mRNA levels of the nAchRs was measured by Real-time PCR analysis technique and revealed that expression of the a9-nAchR was higher in the tumor tissue when compared to the normal tissue which dissected form the tumor margin. Western blotting analysis was then performed and demonstrated that the PI3K/Akt-regulated proteins were the major signaling pathway that involved in cell proliferation stimulated by nicotine treatment. Different clones of cell lines that inhibited the a9 and?a5 receptor expression by SiRNA technique was established in the MDAMB 231 cells. We found that cell growth curve was significant inhibited in the a9-siRAN-nAchR cells. Such results implied that the a9-nAchR may play some important role involved in nicotine-mediated breast tumor carcinogenesis.
論文目次 目錄 中文摘要 英文摘要 第一章 緒論 一、AKT路徑 二、吸煙和乳癌 第二章 實驗材料與方法 一、實驗材料 (一)、試劑與藥品 (二)、常用儀器 (三) 、常用溶液 二、實驗方法 (一)、細胞培養 (二)、 細胞生長曲線之測定 (三)、反轉錄–聚合?連鎖反應 (四)、西方墨點法 第三章 實驗結果 ㄧ、人類乳癌細胞株的nAchR表現型態 二、人類乳癌細胞株對於尼古丁的訊息傳遞路徑 三、利用抑制劑確認尼古丁的活化路徑 四、台灣地區乳癌細胞的nAchR表現型態 五、即時性定量比較nAchRα9在正常及腫瘤組織的表現 六、利用siRNA抑制nAchRα9並觀察乳癌細胞的生長狀況 第四章、討論 第五章、圖表 Figure 1a, 1b Figure 2 Figure 3 Figure 4 Table 1a Table 1b Figure 5a, 5b Figure 5c Figure 5d Figure 5e Figure 6 Figure 7 Figure 8 第五章、參考文獻
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系統識別號 U0007-2301201322483900
論文名稱(中文) 利用太平洋紫杉醇治療胃癌轉移與胃癌轉移相關基因之研究
論文名稱(英文) Studies of Gastric Tumor Metastasis-Associated Genes and Paclitaxel Treatment on Gastric Tumor Metastasis
校院名稱 臺北醫學大學
系所名稱(中) 醫學科學研究所
系所名稱(英) Graduate Institute of Medical Sciences
學年度 101
學期 1
出版年 102
研究生(中文) 段宗帆
學號 D102092004
學位類別 博士
語文別 英文
口試日期 2013-01-09
論文頁數 215頁
口試委員 指導教授-黃玲玲
共同指導教授-陳炯東
委員-李易展
委員-李文森
委員-阮淑慧
委員-施能耀
委員-蕭哲志
關鍵字(中) 癌症
腫瘤
轉移
正位

太平洋紫杉醇
腹腔內
瀰漫
微陣列
關鍵字(英) cancer
tumor
metastasis
orthotopic
stomach
gastric
paclitaxel
intraperitoneal
dissemination
microarray
學科別分類
中文摘要 胃癌是造成癌症死亡的疾病之一,臨床上證實擴散型(diffuse type)胃癌細胞會轉移至腹腔及肝臟,是造成胃癌死亡的主要原因。在這篇研究中,探討靜脈注射太平洋紫杉醇(paclitaxel)在擴散型胃癌細胞轉移上的治療效果,並利用該細胞找出可能與胃癌轉移有關的基因。藉由動物及Transwell®篩選系統,本研究利用持續有綠色螢光(GFP)表現的MKN45擴散型胃癌細胞建立具有高轉移能力的細胞亞株,分別為MKN45-GFP-ip4、MKN45-GFP-4、MKN45-GFP-10及MKN45-GFP-12。其中MKN45-GFP-ip4及MKN45-GFP-12相較於其他細胞亞株有很高的轉移能力。MKN45-GFP-ip4細胞亞株被用來評估靜脈注射太平洋紫杉醇在治療胃癌轉移上的效果,發現該治療方式能夠有效抑制擴散型胃癌的轉移。另一方面,利用互補去氧核醣核酸微陣列(cDNA microarray)分析MKN45-GFP、MKN45-GFP-4、MKN45-GFP-10及MKN45-GFP-12細胞亞株的全基因訊息核糖核酸(mRNA)表現量,藉此找出基因表現與細胞轉移能力的關係。研究發現有許多可能與擴散型胃癌細胞轉移有關的基因表現特殊,其中包含從未發現或研究過的新基因。這些基因及蛋白質產物將可進一步用來研究其與癌症轉移的機轉,藉由分析病患組織的分子資訊、基因轉譯及蛋白質表現,這些基因可能成為有用的生物標記,用來評估、治療及預防胃癌。更重要的是,可以利用這些分子標記研究與開發治療胃癌轉移的藥物。
英文摘要 Gastric cancer is one of the leading causes of cancer death and its malignancy, resulted from the disseminated cancer cells of diffuse type, is clinically manifested as metastases to the liver and peritoneum. The present study is to investigate the efficacy of intravenously administered paclitaxel treatment and identify putative tumor metastasis-associated genes in human gastric cancer cells of diffuse type. MKN45 cell line constitutively expressing green fluorescent proteins (MKN45-GFP) was established and selected using orthotopically animal and Transwell® system for invasive sublines MKN45-GFP-ip4, MKN45-GFP-4, MKN45-GFP-10 and MKN45-GFP-12. MKN45-GFP-ip4 and MKN45-GFP-12 are highly invasive compared to the others. The effects of intravenously administered paclitaxel against the growing peritoneally disseminated and metastasized tumors in nude mice were monitored by MKN45-GFP-ip4 subline. The intravenous paclitaxel is active against the metastases of human gastric cancer of peritoneal diffuse type, which encourages further investigations on optimizing the perioperative paclitaxel therapeutic regimens for gastric cancer in patients. On the other hand, the mRNA levels of whole genes were measured with cDNA microarray and correlated with their invasion abilities in MKN45-GFP, MKN45-GFP-4, MKN45-GFP-10 and MKN45-GFP-12 sublines. The putative gastric tumor metastasis-associated genes, including novel genes, were identified. These genes and their protein products are to be further explored for functional roles associated with tumor metastasis. The molecular profiles of these identified genes, gene transcripts, and proteins in the patient specimens are likely to be useful biomarkers for diagnostic, therapeutic, and/or prognostics. Most importantly, they may be used as molecular targets for discovery of anti-tumor metastasis drugs against human gastric cancer.
論文目次 List of Figures V
List of Tables VII
Abbreviations List VIII
中文摘要 XI
Abstract XIII
Chapter 1 Background 1
Tumor Metastasis 2
Tumor Metastasis-Associated Genes 5
Gastric Cancer 13
Treatment of Metastatic Gastric cancer 15
Rationale and Hypothesis 17
Specific Aim 19
Chapter 2 Materials and Methods 21
Cell Line and Transfection 22
In vitro Selection of Highly Invasive MKN45-GFP Sublines 23
In vivo Selection of Invasive MKN45-GFP Sublines 24
In vitro Invasion Assay of MKN45-GFP Sublines 25
Cell Proliferation Activity 26
Orthotopic Tumor Growth and Metastasis in Nude Mice 27
Measurement of Cell Doubling Time and Growth Inhibition by Paclitaxel 28
MMP9 Expression after Paclitaxel Treatment by Western Blot Assay 30
Evaluating Anti-Invasive Activity of Paclitaxel by In vitro Invasion Assay 31
Metastatic and Intraperitoneal Tumor Growth and Paclitaxel Treatments 32
cDNA Microarray Assay 34
RT-PCR Analysis of Selected Genes 36
Western Blot Analysis of Selected Genes 38
One Step Real-Time PCR Analysis 40
Immunohistochemistry of Human Tissue Array 42
Statistical Analysis 43
Chapter 3 Establishment of GFP or RFP-Expressing Human Cancer Cells 45
Introduction 46
Human Gastric Cancer MKN-45 Cells 46
GFP-Transfection of MKN45 Cells 46
Results 48
Stable GFP-Expressing MKN45 Cells 48
Chapter 4 Establishment of Pro-Metastatic Human Gastric Cancer Cells 49
Introduction 50
In vitro Selection of Sublines with Differently Metastatic Ability in Human Gastric Cancer MKN45 50
In vivo Selection of Sublines with Differently Metastatic Ability in Human Gastric Cancer MKN45 51
Results 53
Establishment of MKN45-GFP Cell Sublines 53
Establishment of MKN4-GFP-ip4 Cells 53
MKN45-GFP Cell Sublines with Differential in vitro Invasion Abilities 54
Invasion Ability of MKN45-GFP-ip4 Cells 55
Incidences of Ascites Caused by MKN45-GFP and MKN45-GFP-12 Cells in Nude Mice 56
Orthotopic Tumorigenesis and Liver Metastasis of MKN45-GFP and MKN45-GFP-12 Cells in Nude Mice 56
Chapter 5 Intravenous Paclitaxel against Metastasis of Human Gastric Tumors of Diffuse Type 59
Introduction 60
Paclitaxel in Human Gastric Cancer Treatment 60
Results 62
Inhibition of the Invasive Ability of MKN45-GFP-ip4 by Paclitaxel Treatments 62
Growth Inhibition in MKN45 Sublines by Paclitaxel Treatments 63
Orthotopic Growth of MKN45-GFP-ip4 Cells Intraperitoneally Inoculated in Nude Mice 63
Paclitaxel Inhibited the Orthotopic Growth of MKN45-GFP-ip4 Cells in Nude Mice 64
Chapter 6 Putative Tumor Metastasis-Associated Genes in Human Gastric Cancer 66
Introduction 67
Molecular Approaches of Human Gastric Cancer Metastasis 67
Oxytocin Receptor in Tumor Metastasis 70
Results 72
cDNA Microarray Analyses of Genes in MKN45-GFP Cell Sublines 72
mRNA Transcript Levels in MKN45-GFP Cell Sublines 76
Protein Expression Levels in MKN45-GFP Cell Sublines 77
Preliminary Study of Oxytocin Receptor Associated to Gastric Cancer Metastasis 77
Chapter 7 Discussion 80
Chapter 8 Conclusion and Perspective 100
References 104
Appendix Establishment of pro-metastatic human lung cancer cells 166
Introduction 167
Human Lung Cancer H1299 Cells 167
Materials and Methods 168
Cell Line and Transfection 168
In vitro Selection of Highly Invasive H1299-RFP Sublines 169
Results 171
Stable GFP and RFP-Expressing H1299 Cells 171
Discussion 172
References 173

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