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系統識別號 U0026-0102201522045400
論文名稱(中文) 探討機械性頸部失能症生物力學及神經肌肉適應特徵
論文名稱(英文) Characteristics of Biomechanical Kinematics and Neuromuscular Adaptation for Patients with Mechanical Neck Disorder
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 103
學期 1
出版年 104
研究生(中文) 楊家琪
學號 P88991076
學位類別 博士
語文別 英文
口試日期 2014-12-16
論文頁數 84頁
口試委員 指導教授-蘇芳慶
共同指導教授-郭藍遠
召集委員-呂東武
口試委員-林高田
口試委員-周一鳴
口試委員-郭立杰
關鍵字(中) 機械性頸部失能症
頸部工作空間
動作平滑度
神經肌肉適應
運動單元
運動單元短期同步化效應
關鍵字(英) Mechanical neck disorder
Cervical workspace
Smoothness of movement
Neuromuscular adaptation
Motor unit
Motor unit short-term synchronization
學科別分類
中文摘要 在現今的生活型態中,機械性頸部失能症已成為一普遍及惱人的肌肉骨骼系統疾病。根據流行病學統計,不僅機械性頸部失能症具有極高的盛行率,其復發率更是逐漸攀升。雖然造成機械性頸部失能症的病因仍存在爭議,機械性頸部失能症已受到臨床上及相關的研究領域極大的重視,同時,機械性頸部失能症對現今人類健康的威脅亦越來越嚴重。儘管過去研究證實異常的頸部活動度是機械性頸部失能症患者常見的臨床症狀,然而因為頸部複雜的解剖結構,導致目前尚無法清楚地釐清頸部的生物力學上運動學特徵。因此,本論文的目的將利用量化生物力學觀點來探討健康人與機械性頸部失能症患者間的頸部運動學特徵。首先,將以三維工作空間的概念取代臨床上常用的角度參數,來描述頸部執行環繞動作時的運動學。除此,也將延伸頻譜熵的概念來分析頸部執行環繞動作時運動學特性,如動作平滑度。另ㄧ方面,因為運動單元為神經肌肉系統基本運作組成單元且研究證實頸部失能症患者其頸部屈肌,如胸鎖乳突肌的肌電生理功能具有障礙現象,本論文亦將觀察頸部兩側主要表淺屈肌運動單元的肌電生理特徵。
由研究結果發現,相對於臨床上常用的角度參數,本論文所提出之頸部工作空間概念將是一合適且可用來量化覆雜的頸部運動學特徵的評估方式。其中,機械性頸部失能症患者有較低的正規化頸部工作空間,同時亦具有較不流暢的動作平滑度。另一方面,在機械性頸部失能症患者其胸鎖乳突肌運動單元也較無症狀的受試者有較高的徵招活化、平均活化頻率及較低的運動單元短期同步化效應。
經由本研究觀察,可以合理地推測由於神經肌肉系統運動單元徵招模式的改變,例如增加胸鎖乳突肌運動單元的徵招活化和平均活化頻率,使得機械性頸部失能症患者因此需要調整頸部肌肉動作控策略來執行頸部日常生活活動。因此由量化的生物力學及神經肌肉控制策略之觀點,除了進一步釐清了機械性頸部失能症患者的動作控制策略。此外,亦可作為提供臨床人員評估機械性頸部失能症患者失能程度及監控機械性頸部失能症臨床上復健計劃效益的客觀參考依據。
英文摘要 Mechanical neck disorder is commonly viewed as a widespread and unnerved musculoskeletal condition in modern lifestyle. Not only the prevalence of neck pain in the general population is considerably high, but the rate of recurrence of neck pain is also increasing. Although the etiology of MND is largely under debate, MND has attracted attention in clinical setting and research field for a long period of time and the threat to healthy issues is still getting more and more severe. Despite aberrant cervical mobility in patients with MND, published evidences still fail to comprehend thoroughly the complicated biomechanical kinematics because of the complexity of the anatomical structures of the cervical spine. Therefore, the objectives of this current dissertation aimed to further clarify the three-dimensional kinematics of the cervical spin for patients with MND and asymptomatic populations from quantitative biomechanical assessments. The concept of the three-dimensional workspace was modified to describe the complicated kinematics of the cervical spine during circumduction, which integrated the movements of all major anatomical planes instead of the conventional angular parameters. Furthermore, the quality of the kinematics of the cervical spine, such as the smoothness of movement during cervical circumduction was simultaneously observed using the concept of spectral entropy. On the other hand, since the motor units are fundamental functional units of the neuromuscular system and dysfunction in the cervical flexor muscles, especially the sternocleidomastoid muscles, has been found to be associated with neck pain, the electrophysiological properties of the motor units of the sternocleidomastoid muscles were also characterized.
Based on the findings of the current dissertation, it was found that the workspace during cervical circumduction was successfully proposed to be a feasible and alternative mathematical model for assessing the complicated kinematics of the cervical spine quantitatively, reporting significant reduction in the normalization of the cervical workspace. Meanwhile, less smooth cervical movements in patients with MND was identified in contrast to asymptomatic individuals. Finally, patients with MND exhibited higher values of initial and mean firing rates and lower short-term synchronization of the motor units pairs of the sternocleidomastoid muscles.
Thus, these convinced evidences indicated that patients with MND might be more likely to modify motor control strategies to execute the cervical activities of daily living due to alternations in neural recruitment strategies of the motor units, such as increased recruitment firing rates of the motor units of the sternocleidomastoid muscles. These valuable information could further offer a clinical relevance for clarifying characteristics of motor control strategies for patients with MND and allow guiding the clinicians to evaluate the extent of impairment of the cervical spine easily and quickly and monitor the efficacy of rehabilitation programs in patients with MND in clinical practice.
論文目次 Abstract I
中文摘要 III
誌謝 V
Table of Contents VI
List of Tables VIII
List of Figures IX
Chapter 1. General Introduction 1
1.1 Background and Significance 1
1.2 Epidemiology of MND 3
1.3 Quantitative biomechanical cervical kinematics for MND 4
1.4 Quality of cervical kinematics for MND 6
1.5 Neuromuscular adaptations for MND 7
1.6 Specified aims of the present dissertation 9
1.7 Outlines of the present dissertation 10
Chapter 2. A New Concept for Quantifying the Complicated Kinematics of the Cervical Spine and Its Application in Evaluating the Impairment of Patients with MND 11
2.1 Introduction 11
2.2 Materials and Methods 14
2.2.1 Subjects 14
2.2.2 Apparatus 15
2.2.3 Experimental Procedures 17
2.2.4 Data Processing 18
2.2.5 Data Analysis 20
2.3 Results 21
2.4 Discussion 23
2.5 Conclusion 29
Chapter 3. Comparison of Cervical Movement Smoothness between Patients with MND and Asymptomatic Individuals Using the Spectral Entropy Method 30
3.1 Background 30
3.2 Materials and Methods 33
3.2.1 Subjects 33
3.2.2 Apparatus 34
3.2.3 Experimental Procedures 35
3.2.4 Data Processing 36
3.2.5 Data Analysis 37
3.3 Results 37
3.4 Discussion 40
3.5 Conclusion 43
Chapter 4. Characteristics of the Motor Units of the Sternocleidomastoid Muscles between Patients with MND and Asymptomatic Individuals 44
4.1 Background 44
4.2 Materials and Methods 47
4.2.1 Subjects 47
4.2.2 Apparatus for electromyography signal detection 48
4.2.3 Experimental Procedures 49
4.2.4 Identification for individual motor unit action potential train 51
4.2.5 Data Processing 54
4.2.6 Recruitment characteristics of motor units 54
4.2.7 Motor unit short-term synchronization 57
4.2.8 Data Analysis 60
4.3 Results 60
4.4 Discussion 65
4.5 Conclusion 69
Chapter 5. General Conclusion 71
5.1 Overview of conclusion 71
5.2 Clinical applications 73
5.3 Limitations of the dissertation 75
References 76
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系統識別號 U0026-0107201415420200
論文名稱(中文) 環境不確定性下策略性採購、供應鏈敏捷性與組織績效關係之研究-以資訊電子業為例
論文名稱(英文) Environmental Uncertainty, Strategic Sourcing, Supply Chain Agility and Organizational Performance in the Information Technology Industry
校院名稱 成功大學
系所名稱(中) 交通管理科學系
系所名稱(英) Department of Transportation & Communication Management Science
學年度 102
學期 2
出版年 103
研究生(中文) 莊舒婷
學號 R56011305
學位類別 碩士
語文別 中文
口試日期 2014-06-13
論文頁數 99頁
口試委員 指導教授-林珮珺
共同指導教授-孫雅彥
口試委員-張瀞之
口試委員-林正章
關鍵字(中) 資訊電子業
策略性採購
供應鏈敏捷性
組織績效
環境不確定性
關鍵字(英) Information Technology Industry
Strategic Sourcing
Supply Chain Agility
Organizational Performance
Environmental Uncertainty
學科別分類
中文摘要 本研究以台灣資訊電子業為例,探討策略性採購、供應鏈敏捷性與組織績效間的影響關係,並以環境不確定性作為調節變數。經過民國102年12月至民國103年3月的問卷發放,共回收了163份有效樣本,透過結構方程模式(SEM)分析後,發現台灣資訊電子產業中策略性採購對供應鏈敏捷性有正向影響關係,供應鏈敏捷性對組織績效亦存在正向影響關係,然而策略性採購對於組織績效之研究假設並無得到顯著支持,但研究結果得知策略性採購可透過提升供應鏈敏捷性間接影響組織績效。另外,本研究透過階層迴歸進行調節效果分析,發現環境不確定性對於策略性採購與供應鏈敏捷性之影響中具有調節效果,環境不確定性對於供應鏈敏捷性與組織績效之影響中亦具有調節效果,但環境不確定性對策略性採購與組織績效之影響中不具有調節效果。最後根據本研究結果提出相關之建議,以供台灣資訊電子業者參考。
英文摘要 This study aims to evaluate the impact of strategic sourcing on supply chain agility and organizational performance in the information technology industry, and considering the moderating effects of environmental uncertainty. During four months of questionnaires distributed, a total of 163 valid samples were collected. A structural equation modeling (SEM) approach was used to test the research hypotheses. Result indicated that strategic sourcing had a positive effect on supply chain agility, and supply chain agility had a positive effect on organizational performance. The impact of strategic sourcing on organizational performance was not supported in this study, however, strategic sourcing had an indirect effect on organizational performance mediated by supply chain agility. Otherwise , this study used hierarchical regression analysis to analyze whether moderating effects existed or not. Result indicated that environmental uncertainty had a negative moderating effect between strategic sourcing and supply chain agility, and which had a positive moderating effect between supply chain agility and organizational performance. But environmental uncertainty didn’t exist moderating effect between strategic sourcing and organizational performance. Practical implications of the research findings for information technology companies were discussed.
論文目次 目錄 i
表目錄 iv
圖目錄vi
第一章 緒論1
1.1研究背景與動機1
1.2研究目的5
1.3研究範圍5
1.4研究流程5
第二章 文獻回顧8
2.1資訊電子業8
2.2策略性採購12
2.3供應鏈敏捷性17
2.4組織績效20
2.5環境不確定性23
第三章 研究方法27
3.1研究模式與假設27
3.2研究設計28
3.3資料分析方法與應用32
3.3.1敘述性統計分析32
3.3.2因素分析32
3.3.3信度與效度分析33
3.3.4變異數分析33
3.3.5結構方程模式34
3.3.6調節效果分析35
第四章 環境不確定性下策略性採購、供應鏈敏捷性與組織績效關係之分析37
4.1問卷回收結果與樣本結構分析37
4.1.1樣本結構分析38
4.2策略性採購、供應鏈敏捷性、組織績效與環境不確定性敘述性統計40
4.2.1策略性採購敘述性統計分析40
4.2.2供應鏈敏捷性敘述性統計分析42
4.2.3組織績效敘述性統計分析44
4.2.4環境不確定性敘述性統計分析44
4.3策略性採購、供應鏈敏捷性、組織績效與環境不確定性之信度分析46
4.4填答者特性與構面之變異數分析47
4.4.1填答者職位與各構面之變異數分析47
4.4.2公司營運型態與各構面之變異數分析48
4.4.3公司成立年數與各構面之變異數分析49
4.4.4公司營業額與各構面之變異數分析50
4.4.5公司規模與各構面之變異數分析52
4.5收斂效度與區別效度53
4.6結構方程式分析結果55
4.6.1結構方程模式分析與校估56
4.6.2中介效果驗證59
4.6.3策略性採購、供應鏈敏捷性與組織績效之因素SEM分析61
4.6.4不同企業規模之SEM分析66
4.7 調節效果68
第五章 結論與建議74
5.1結論74
5.2實務建議79
5.3研究貢獻81
5.4後續研究建議82
參考文獻83
一、中文部分83
二、英文部分84
三、網站部分94
附錄一 正式問卷95
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三、網站部分
1.Digitimes:http://www.digitimes.com.tw/tw/dt/p360.asp?CnlID=10
2.工業技術研究院:https://www.itri.org.tw/chi/iek/p11.asp?RootNodeId=070&NavRootNodeId=0753&NodeId=07534&ArticleNBR=4374
3.台灣經濟研究院:http://tie.tier.org.tw/index.asp
4.恩汎理財網:http://symy04.pixnet.net/blog/category/210187
5.財政部統計處:http://www.mof.gov.tw/mp.asp?mp=62

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系統識別號 U0026-0302201515094400
論文名稱(中文) 模擬僵直性脊椎炎之頸椎有限元素分析
論文名稱(英文) Finite Elements Analysis of Cervical Spine Simulating Ankylosing Spondylitis
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 103
學期 1
出版年 104
研究生(中文) 張哲肇
學號 P86024166
學位類別 碩士
語文別 英文
口試日期 2015-01-24
論文頁數 30頁
口試委員 指導教授-張志涵
口試委員-李宜堅
口試委員-吳天賞
口試委員-蘇芳慶
關鍵字(中) 僵直性脊椎炎
竹節狀脊椎
椎間盤
頸椎骨折
有限元素分析
關鍵字(英) ankylosing spondylitis
bamboo spine
intervertebral disc
cervical spine fracture
finite elements analysis
學科別分類
中文摘要 僵直性脊椎炎是一系統性自體免疫疾病,主要發生於脊椎及腸骨薦椎關節之發炎反應。於長年罹患僵直性脊椎炎之病患上,其脊椎影像檢查可見其椎間盤部位周圍之骨化反應,且可能進展至竹節狀脊椎 (bamboo spine) 之脊椎外觀變化。此一變化將使病患之脊椎活動角度受限,另外也造成輕微外力撞擊即可能遭受重大脊椎骨折與創傷之情形。
文獻報導指出僵直性脊椎炎之頸椎骨折易發生於椎間盤周圍部位,且常與過度伸展性損傷 (hyperextension injury) 相關。但目前並無相關文獻探討僵直性脊椎炎之病程進展與其生物力學反應之變化,本研究採用電腦模型與有限元素分析方式,比較正常脊椎與僵直性脊椎炎模型於不同的僵直性脊椎炎病程中對於外力造成脊椎伸展性動作時其最大主應變 (maximum principal strain) 與最大主應力 (maximum principal stress) 之變化。
研究結果顯示當椎間盤骨化漸趨嚴重時,於相同之外力作用下脊椎對於外力作用產生之最大主應變將逐漸由集中於椎間盤部位轉變為擴散至周遭椎體內。另外最大主應力雖於椎體內並無明顯之變化趨勢,但於椎間盤內尤其是接近與椎體相接連部位,於椎間盤骨化越嚴重時,最大主應力也明顯上升。最大差異之部位主要發生於於第五/六頸椎與第六/七頸椎之椎間盤,如第六/七頸椎椎間盤於疾病進程後期其最大主應力之上升比例可較正常時增加約124.4% – 207.6%。
此研究結果亦與臨床觀察之結果相符,表示僵直性脊椎炎於病變過程中,其椎間盤周圍部位之骨化確為其易於發生頸椎骨折之主要因素。
英文摘要 Ankylosing spondylitis (AS) is a systemic autoimmune disease mainly affects spine and sacroiliac joints. In patients with AS, there is new bone formation in entheses of the intervertebral discs (syndesmophyte) and the spine will finally become fused and deformed “bamboo spine”, a characteristic image finding in AS. The formation of bamboo spine will limit the range of motion, and substantially fragile to minor injury, which may cause major fracture and neurological deficit. Some studies have reported the cervical spine fractures in AS mostly happened at the level of intervertebral disc in hyperextension injury. But currently there is no literature mentioned about the relationship of disease progression and the response of spine to external force. This study compare maximum principal strain and stress in the normal spine and AS spine model in different stages of AS by finite elements analysis.
The results in this study revealed that with the same external force applied on the models, the maximum principal strain will extended from intervertebral discs to vertebral bodies with the progressing stages of syndesmophyte. There is no obvious change of maximum principal stress in vertebral bodies compared different stages of syndesmophyte, but in the intervertebral discs, the maximum principal stress greatly increased especially near the entheses. The greatest change happened mainly in C56 and C67 disc, and the maximum principal stress increases up to 124.4% – 207.6% in C6-7 disc from normal disc to late stages of syndesmophyte formation.
The results are compatible to the clinical observation, which means the progression of new bone formation of entheses is a key factor in cervical spine fracture in AS.
論文目次 Abstract I
中文摘要 III
致謝 V
Contents VI
List of Tables VII
List of Figures VII
Chapter 1. Introduction 1
1.1 Ankylosing spondylitis and cervical spine fracture 1
1.2 Literature review 3
1.3 Motivation and objectives 4
Chapter 2. Material and Methods 6
2.1 Model creation 6
2.2 Finite elements analysis 9
2.2.1 Mechanical properties 9
2.2.2 Mesh creation 10
2.2.3 Boundary conditions of static structural analysis 10
2.2.4 Parameters used in results analysis 11
Chapter 3. Results 13
3.1 Maximum principal elastic strain 13
3.2 Maximum principal stress 16
3.3 Effect of changing lordotic curve 22
Chapter 4. Discussion 24
Chapter 5. Conclusion 28
References 29
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系統識別號 U0026-0302201517164400
論文名稱(中文) 重組人類表皮調節素的純化與分析
論文名稱(英文) Purification and characterization of recombinant human epiregulin
校院名稱 成功大學
系所名稱(中) 生物科技研究所
系所名稱(英) Institute of Biotechnology
學年度 103
學期 1
出版年 104
研究生(中文) 楊偉宏
學號 L66011085
學位類別 碩士
語文別 中文
口試日期 2015-01-05
論文頁數 94頁
口試委員 指導教授-蕭世裕
口試委員-陳宗嶽
口試委員-陳俊榮
關鍵字(中) 大腸癌
表皮調節素
雙硫鍵分析
重組蛋白
關鍵字(英) colon cancer
epiregulin
disulfide bond identification
recombinant protien
學科別分類
中文摘要 人類表皮調節素(epiregulin)為表皮生長因子家族成員之一,過去其他
的研究者發現其具有抑制A431 等癌症細胞株生長,以及促進人類表皮角
質細胞等正常細胞生長的生物活性,而實驗室先前的研究中發現,大腸
癌患者中有較高表現量的人類表皮調節素,則其存活率較高,為探討人
類表皮調節素是否具有抑制或促進大腸癌細胞之生長,本研究以基因工
程之方式將人類表皮調節素以大腸桿菌進行生產。表現之重組蛋白主要
具有組胺酸標籤、凝血酶切割位、人類表皮調節素編碼區等三個部分,
並以鎳親和力管柱與逆向層析管柱進行純化或分析,所純化分離之六產
物分子量均與預期之重組人類表皮調節素相同,且均形成三對雙硫鍵,
且六產物的α 螺旋與β 摺版之比例均與原生人類表皮調節素相似。在經過氧化再摺疊的過程後,對其主要產物進行雙硫鍵分析,發現其三對雙硫鍵結合之情形與原生人類表皮調節素之雙硫鍵形成均相同,最後以受體結合測試證明該產物具有與其受體EGFR 結合之能力,且其結合能力
在移除其組胺酸標籤後有增強的現象。本研究成功以大腸桿菌生產出重
組人類表皮調節素,其二級結構之比例與原生人類表皮調節素相似,而
雙硫鍵形成位置則與之完全相同,並具有與其受體EGFR 結合之活性。
英文摘要 In previous study, we know that patients suffer from colon cancer have higher survival rate when they have higher epiregulin mRNA expression level. To study the potential of epiregulin to be a novel protein drug, recombinant human epireguiln is produced by E.coli expression system. There are at least six conformational isomer found in HPLC analysis. Oxidative refolding method was introduced to get more stable conformational isomer. According the result of LC-MS-MS, the disulfide bond linkages of the stable conformational isomer are the same as native epiregulin. Finally, receptor binding assay
was also used to judge the binding ability of recombinant human epireguiln. In conclusion, purified recombinant human epireguiln has correct disulfide bond linkages and the ability to bind its receptor.
論文目次 目錄
中文摘要.................................................... I
英文摘要................................................... II
誌謝....................................................... VI
目錄...................................................... VII
圖目錄...................................................... X
縮寫表.................................................... XII
一、前言.................................................... 1
1-1 癌症與EGFR (Epidermal growth factor receptor)........... 1
1-2 EGFR 在癌細胞中的角色................................... 2
1-3 表皮調節素(Epiregulin).................................. 4
1-4 蛋白質藥物.............................................. 5
1-5 蛋白質的表現............................................ 6
二、研究目的................................................ 8
三、材料與方法.............................................. 9
3-1 實驗材料................................................ 9
3-2 實驗方法............................................... 12
3-2-1 重組人類epiregulin (rhEREG) 製備..................... 12
3-2-2 以高效液相層析儀(HPLC)分析重組人類Epiregulin......... 15
3-2-3 重組人類EREG 的再折疊(refolding) .................... 15
3-2-4 重組人類EREG 的雙硫鍵分析............................ 15
3-2-5 受體結合試驗(receptor binding assay) ................ 16
3-2-6 以圓二色光譜分析rhEREG 之二級結構.................... 18
四、結果................................................... 19
4-1 建構pET28a-EREG 質體................................... 19
4-2 以親和性色層分析法純化rhEREG........................... 19
4-3 以高效液相層析儀(HPLC)分析rhEREG....................... 20
4-4 以液相層析質譜儀(LC-MS)分析rhEREG...................... 20
4-5 以圓二色光譜分析rhEREG 之二級結構...................... 21
4-6 rhEREG 的再折疊(refolding) ............................ 23
4-7 以液相層析串聯式質譜儀分析rhEREG 雙硫鍵................ 23
4-8 以受體結合試驗(receptor binding assay)測試活性......... 25
五、討論................................................... 28
5-1 rhEREG 之表現.......................................... 28
5-2 rhEREG 之純化.......................................... 29
5-3 以液相層析質譜儀(LC-MS)分析rhEREG...................... 31
5-4 以圓二色光譜分析rhEREG 之二級結構...................... 32
5-5 rhEREG 的再折疊........................................ 34
5-6 以液相層析串聯式質譜儀分析rhEREG 雙硫鍵................ 36
5-7 以受體結合試驗測試rhEREG 活性.......................... 38
六、參考文獻............................................... 42
七、附錄................................................... 91
參考文獻 施慶彬,基因重組骨粘連蛋白對臍帶間質幹細胞、牙隨幹細胞與脂肪幹
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系統識別號 U0026-0307201419023000
論文名稱(中文) 創新特性、消費者特性與社會特性對奈米食品之嘗試意願:以產品不確定性為干擾因素
論文名稱(英文) Innovation, Consumer, and Social Characteristics on Trial Willingness of Use of Nano-foods: Product Uncertainty as the Moderator
校院名稱 成功大學
系所名稱(中) 企業管理學系
系所名稱(英) Department of Business Administration
學年度 102
學期 2
出版年 103
研究生(中文) 徐銘澤
學號 R46001243
學位類別 碩士
語文別 英文
口試日期 2014-06-04
論文頁數 146頁
口試委員 指導教授-張心馨
口試委員-王維聰
口試委員-劉佳玲
關鍵字(中) 奈米科技
奈米食品
創新擴散理論
知覺信賴
知覺利益
產品不確定性
關鍵字(英) Nanotechnology
Nano-foods
Diffusion of Innovation
Perceived trustworthiness
Perceived benefit
Product uncertainty
學科別分類
中文摘要 奈米科技的應用至今已延伸至醫療、民生用品、食品等各產業,其相關產品更能直接地在市面上購得。因此,本研究以奈米食品為研究主題,採用創新擴散理論(Diffusion of Innovation) 為研究基礎,探討消費者對於奈米科技產品之嘗試意願,並以產品創新特質、消費者特質及社會特質為前置因素,瞭解消費者對奈米食品的主觀知覺(含知覺信賴、知覺利益),進而探討產品不確定性是否會對前置因素與奈米產品的主觀知覺產生干擾效果。有效問卷總共獲得431份,並以階層迴歸進行資料分析,結果顯示創新產品特質(相對優勢、低可視性、新穎性)、消費者特質(知覺科技應用)及社會特質(權威信任)皆會影響知覺信賴或知覺利益;而社會影響對奈米食品的態度及嘗試意願則有直接影響。在干擾因素方面,產品不確定性於前置因素與奈米食品的主觀知覺之間具有顯著的干擾效果。根據統計分析結果,消費者較重視創新食品是否能帶來益處,因此本研究建議食品廠商在發展新奈米食品時,應善用食品包裝上的說明作為溝通橋梁,藉由包裝註明奈米食品的好處以提升嘗試意願,並減少消費者對奈米科技的憂慮及不安。此外,倘若廠商能協同權威單位(如:奈米研究人員),透過傳播媒體向社會大眾傳達正確的奈米科技及食品的資訊,將能有效的提升奈米產品的銷售與利益。
英文摘要 Nanotechnology applications have been extended to medical and consumer food products, and some nanotechnology products can even be obtained directly from marketplaces in developed countries. Therefore, the current study intends to take nano-foods as the research topic and to employ the Diffusion of innovation theory as the research basis by which to investigate consumer’s trial willingness to use nanotechnology products. Innovation, and consumer and social characteristics are employed as antecedents in order to examine if they will have any effect on perceived trustworthiness and perceived benefit. In addition, the study also takes product uncertainty as a moderator to examine the moderating effects among three characteristics and subjective perceptions of nanotechnology products. 431 valid questionnaires are collected. The research results from a hierarchical regression analysis indicated that innovation characteristics (Relative Advantage, Lack of Observability, and Novelty), consumer characteristics (Perceived Technology Application) and social characteristics (Authority Trust) all affect perceived trustworthiness or perceived benefit. Social influence also has a direct effect on attitude toward nano-foods and trial willingness. Product uncertainty significantly moderates the relationship between three characteristics and subjective perceptions. According to the research results, it is found that consumers pay more attention to the benefits of innovative food products. Therefore, when a new nano-foods is introduced, the current study suggests that food manufacturer use the description on the package as a communicative tool. Detailing the advantages of nano-foods on food packages might be a useful way to enhance trial willingness and to reduce fear and insecurities related to the use of nanotechnology. In addition, if food manufacturers could cooperate with units of authority (e.g. nanotechnology researchers) to disseminate correct information about nanotechnology and its related food products, it might be a good way to increase both sales and profits.
論文目次 中文摘要 I
Abstract II
誌謝 III
Table of Contents IV
List of Tables VIII
List of Figures IX
CHAPTER 1 INTRODUCTION 1
1.1 Research Background and Motivations 1
1.2 Research Objectives 6
1.3 Research Process 7
CHAPTER 2 LITERATURE REVIEW 9
2.1 Nanotechnology and Nano-foods 10
2.2 Diffusion of Innovations Theory 13
2.2.1 Relative Advantage 17
2.2.2 Lack of Observability 18
2.2.3 Novelty 19
2.3 Consumer Characteristics 21
2.3.1 Perceived Technologies Application 22
2.3.2 Knowledge of Nanotechnology 24
2.4 Social Characteristics 24
2.4.1 Authority Trust 25
2.4.2 Social Influence 27
2.5 Perceived Trustworthiness of Nano-foods 28
2.6 Perceived Benefit 29
2.7 Attitude toward Nano-foods 31
2.8 Trial Willingness 32
2.9 Product Uncertainty 32
2.10 Conceptual Model 34
2.11 Hypothesis Development 37
2.11.1 Relative Advantage, Perceived Trustworthiness and Perceived Benefit 37
2.11.2 Lack of Observability, Perceived Trustworthiness and Perceived Benefit 38
2.11.3 Novelty and Perceived Trustworthiness 39
2.11.4 Perceived Technology Application, Perceived Trustworthiness and
Perceived Benefit 40
2.11.5 Knowledge of Nanotechnology, Perceived Trustworthiness and Perceived Benefit 42
2.11.6 Authority Trust, Perceived Trustworthiness and Perceived Benefit 43
2.11.7 Perceived Trustworthiness, Perceived Benefit and Attitude toward Nano-foods 44
2.11.8 Attitude toward Nano-foods and Trial Willingness 46
2.11.9 Social Influence, Attitude toward Nano-foods and Trial Willingness 47
2.11.10 Perceived Benefit and Perceived Trustworthiness 48
2.11.11 The Moderating Effects - Product Uncertainty 49
CHAPTER 3 RESEARCH DESIGN & METHODOLOGY 52
3.1. Construct Definition and Hypotheses 52
3.1.1 Definition of Constructs 52
3.1.2 Summary of Hypotheses 55
3.2 Measurement Development and Questionnaire Design 56
3.3. Pilot Test Analysis 63
3.4. Data Analysis Procedure 67
3.4.1 Demographics Analysis 68
3.4.2 Confirmatory Factor Analysis 68
3.4.3 Reliability and Validity Analysis 68
3.4.4 Structural Equation Model 69
3.4.5 Hierarchical Regression Analysis 69
CHAPTER 4 DATA ANALYSIS & RESULT 70
4.1 Data Collection and Demographic Analysis 70
4.2 Descriptive Analysis 72
4.3 Measurement Model Analysis 75
4.3.1 Confirmatory Factor Analysis (CFA) 75
4.3.2 Reliability Analysis and Convergent Validity 78
4.3.3 Discriminant Validity Analysis 79
4.4 Structural Equation Models – Hypotheses Test (Direct Effect) 80
4.5 Hierarchical Regression Analyses – Hypotheses Test 81
4.5.1 Main Effects 81
4.5.2 Moderating Effect of Product Uncertainty 87
1. Perceived Trustworthiness as Dependent Variable 87
2. Perceived Benefit as Dependent Variable 91
4.5.3 Additional Analysis - Knowledge of Nanotechnology as Moderator 93
1. Perceived Trustworthiness as Dependent Variable 94
2. Perceived Benefit as Dependent Variable 97
4.5.4 Additional Analysis – Independent Sample t test 99
CHAPTER 5 CONCLUSIONS & RECOMMENDATIONS 101
5.1 Discussion 101
5.1.1 Innovation Characteristics 101
1. Relative Advantage, Perceived Trustworthiness and Perceived Benefit 101
2. Lack of Observability, Perceived Trustworthiness and
Perceived Benefit 102
3. Novelty and Perceived Trustworthiness 104
5.1.2 Consumer Characteristics 105
1. Perceived Technology Application, Perceived Trustworthiness and
Perceived Benefit 105

2. Knowledge of Nanotechnology, Perceived Trustworthiness and
Perceived Benefit 106
5.1.3 Social Characteristics 108
1. Authority Trust, Perceived Trustworthiness and Perceived Benefit 108
5.1.4 Subjective Perceptions 108
1. Perceived Trustworthiness and Attitude toward Nano-foods 108
2. Perceived Benefit and Attitude toward Nano-foods 109
3. Perceived Benefit and Perceived Trustworthiness 109
5.1.5 Attitude & Social Influence 110
1. Attitude toward Nano-foods and Trial Willingness 110
2. Social Influence, Attitude toward Nano-foods and Trial Willingness 110
5.1.6 Product Uncertainty - Moderator 111
5.1.7 Knowledge of Nanotechnology - Moderator 113
5.2 Implication 115
5.2.1 Theoretical Implications 116
5.2.2 Managerial Implication 118
5.3 Limitation and Directions for Future Research 121
REFERENCES 123
APPENDIX 1 Measurement Model of Factor Loading 142
APPENDIX 2 SEM Path Result of Direct Effects 143
APPENDIX 3 Questionnaire 144
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系統識別號 U0026-0402201512310400
論文名稱(中文) 老年病患負面社心資訊呈現之相關前文脈絡與言談機制:以台灣家醫科為例
論文名稱(英文) Discourse Contexts and Mechanisms Relevant to Elderly Patients’ Presentation of Psychosocial Concerns--A Case Study Based in the Family Medicine Practice in Taiwan
校院名稱 成功大學
系所名稱(中) 外國語文學系
系所名稱(英) Department of Foreign Languages & Literature
學年度 103
學期 1
出版年 104
研究生(中文) 周少柔
學號 K26001219
學位類別 碩士
語文別 英文
口試日期 2015-01-13
論文頁數 101頁
口試委員 指導教授-蔡美慧
口試委員-盧豐華
口試委員-高實玫
關鍵字(中) 負面社心資訊
社心話題
言談機制
醫病溝通
關鍵字(英) psychosocial concerns
a topic of psychosocial issue
discourse mechanisms
doctor-patient communication
學科別分類
中文摘要 醫病溝通互動中,取得病情相關的負面社會心理資訊(例如失業、離婚)除了可增進醫病關係,更有助於醫師釐清病患的社會心理(簡稱「負面社心」)狀態為生理不適的致因或加重因素,然而此類資訊對有些病患卻是難以啟齒或難以察覺與生理不適之相關性,因此對大部分醫師而言,引導病人提供此類資訊是一大挑戰。本研究以南部某教學醫院家醫科醫師與老年病患的問診互動為語料,從語言學角度分析病患呈現負面社心資訊時,相關之前文脈絡與言談機制為何。我們主要發現如下: (1)病患負面社心資訊的呈現很少由病患主動引發(14%),而是由醫師透過鋪陳負面社心氛圍而浮現(86%);(2)此鋪陳包含兩層並行機制:「時間的累積醞釀」與「語意的循序堆砌」,即醫師與病患須歷經多次發言來回,以及醫師發言用詞語意從中性(‘我想欲知影是講你陰暗睏未去是攏佇想啥?’)、一般性負面(‘最近人敢會感覺足操煩?’)、漸進至具體性負面(‘敢有想著流目屎未?’)的三種引子;(3)此二機制的運作反應了專業與常民對問診為「生理資訊的呈現先於社心資訊的呈現」的期待認知,並造就了「以生理話題引流負面社心資訊」的言談模式。上述的言談機制對於醫病溝通的啟發為:在問診過程中,醫師透過「時間的累積醞釀」及「語意的循序堆砌」所鋪陳的負面社心氛圍,即「以生理話題引流負面社心資訊」的言談模式,有助於鼓勵病患相關負面社心資訊的浮出台面。
英文摘要 Soliciting patients’ psychosocial concerns (e.g. unemployment or divorce) during the medical interview not only enhances doctor-patient relationship, but facilitates the doctor’s diagnosis as well. Information regarding patients’ psychosocial concerns helps doctors clarify whether the psychosocial status is a causative or aggravating factor for patients’ physical discomfort. However, it appears to be a challenging task for most doctors to lead patients to reveal this sort of information since patients might not be aware of the connection between psychosocial status and physical discomfort or might feel reluctant to voice their psychosocial problems. With the discourse data of medical interviews between family doctors and their elderly patients, this study examines the discourse mechanisms prior to patients’ presentation of psychosocial concerns and patients’ response in the negative (‘無啦/no’) when doctors engage in psychosocial issues. The aim of our research focuses on the interaction between family doctors and elderly patients and investigates what discourse contexts and mechanisms are relevant to patients’ revelation of psychosocial concerns. The main findings include the followings. First, patients seldom voluntarily initiate a topic of psychosocial issue and provide psychosocial concerns (14%). Most of the psychosocial concerns are presented following the negative psychosocial atmosphere created in doctors’ utterances (86%). Second, the discourse mechanisms that create such negative atmosphere include the concurrent use of ‘time accumulation’ and ‘semantic accumulation’. In other words, it involves several turn takes in the conversation and the sequential use of prompts, i.e., doctors start from the use of neutral prompt (‘I would like to know what you are thinking about when you fail to fall asleep at night’) to the use of general-negative (‘have you been troubled recently?’) or specific-negative prompts (‘did the idea of suicide ever come to you’). Third, the concurrent mechanisms of ‘time accumulation’ and ‘semantic accumulation’ in doctors’ utterances reflect both the professional doctors and the general public’s perception and expectation that ‘the presentation of psychosocial information is preceded by the biomedical information in medical interviews’. These perception and expectation lead to the discourse pattern that ‘patients’ psychosocial concerns are presented via a topic of biomedical issue’. The implication of the above findings for doctor-patient communication is addressed in the following. During medical interviews, the negative psychosocial atmosphere created in doctors’ utterances through the mechanisms of time accumulation and semantic accumulation, i.e., ‘collecting psychosocial concerns under the guise of biomedical issue, encourages patients to unveil their psychosocial status.
論文目次 ABSTRACT (CHINESE) ..............................................................................................i
ABSTRACT (ENGLISH) .............................................................................................ii
ACKNOWLEDGEMENTS .........................................................................................iv
TABLE OF CONTENTS ..............................................................................................v
LIST OF TABLES .....................................................................................................viii
LIST OF EXCERPTS ..................................................................................................ix

CHAPTER ONE INTRODUCTION 1
1.1 Psychosocial Information and ‘Biopsychosocial Model’ 1
1.2 Functions of Psychosocial Information 2
1.2.1 Rapport-building and Diagnosis Facilitating 2
1.2.2 Psychosocial Status as a Causative Factor for Biomedical Problems 3
1.2.3 Psychosocial Status as an Aggravating Factor for Biomedical Problems .5
1.2.4 Psychosocial Information and Misdiagnosis 5
1.3 Elderly Patients and Family Medicine 8
1.4 Purpose of the Present Study and Research Question 11
1.5 Preview of the Following Chapters.................................................................... 11
CHAPTER TWO LITERATURE REVIEW .13
2.1 The Importance of Psychosocial Information 13
2.2 The Current Situation for Doctors’ Practice of Soliciting Psychosocial Information 16
2.3 Suggested Interview Skills for Soliciting Psychosocial Information 20
CHAPTER THREE METHODOLOGY 29
3.1 Data Collection 29
3.2 Data Analysis 33
3.2.1 Semantic Components 37
3.2.2 The Creation of Negative Psychosocial Atmosphere in Doctors’ Utterances .......38
3.2.3 Discourse Mechanisms of the Context ‘Doctors Initiate a Psychosocial Topic but no Psychosocial Concerns are Presented’ 45
CHAPTER FOUR RESULTS 50
4.1 Distribution of the Participant who Initiated a Topic of Psychosocial Issue 50
4.2 Frequency of the Occurrence of the Discourse Mechanisms Relevant to Patients’ Presentation of Psychosocial Concerns 51
4.3 Frequency of the Occurrence of the Discourse Mechanisms Relevant to Patients’Response in the Negative to Doctors’ Psychosocial Questions 52
CHAPTER FIVE DISCUSSION 54
5.1 Patients Seldom Voluntarily Raise Psychosocial Concerns 54
5.2 The Emergence of Patients’ Concerns Follows the Negative Psychosocial Atmosphere Created in Doctors’ Utterances 55
5.3 Time Accumulation is Relevant to Patient Parties’ Presentation of Psychosocial Concerns 62
5.3.1 The Timepoint at which Psychosocial Concerns Emerge 62
5.3.2 The Cases of Cross-stage Creation of Negative Psychosocial Atmosphere in Doctors’ Utterances 65
5.3.3 Patients Delay Initiating a Topic of Psychosocial Issue 66
5.3.4 The Cases where Doctors Initiate a Topic of Psychosocial Issue but do not Continue the Topic 69
5.4 Semantic Accumulation is Relevant to Patient Parties’ Presentation of Psychosocial Concerns 72
5.4.1 Doctors Use Neutral Prompts Followed by General-negative or Specific-negative Prompts to Create Negative Psychosocial Atmosphere 72
5.4.2 Without Semantic Accumulation in Doctors’ Utterances, Patient Parties Immediately Respond in the Negative 75
5.5 Overall Discussion 78
5.5.1 ‘Collecting Patients’ Psychosocial Concerns Under the Guise of Biomedical Issue’ Follows the Maxim of Relation 79
5.5.2 Time Accumulation and Semantic Accumulation Satisfy Face Need 82
5.5.3 Strategies for Difficult Communication: Time Accumulation and Semantic Accumulation 84
CHAPTER SIX CONCLUSION AND IMPLICATIONS 88
6.1 Summary of Main Findings 88
6.2 Implications of the Present Study 89
6.3 Contributions 92
6.4 Limitations of the Present Study 93
6.5 Suggestions for Further Studies 94
REFERENCES ............................................................................................................96
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系統識別號 U0026-0402201516342100
論文名稱(中文) 隱私關注與其他相關因素對雲端儲存使用者之持續使用意願影響研究
論文名稱(英文) The Effects of Privacy Concern and Other Related Factors to the Continuance Use among Cloud Storage Users
校院名稱 成功大學
系所名稱(中) 國際經營管理研究所碩士在職專班
系所名稱(英) Institute of International Management (IIMBA--Master)(on the job class)
學年度 103
學期 1
出版年 104
研究生(中文) 鍾欣芸
學號 RA7991178
學位類別 碩士
語文別 英文
口試日期 2015-01-15
論文頁數 108頁
口試委員 指導教授-陳正忠
召集委員-林清河
口試委員-王鈿
關鍵字(中) 隱私關注
信任
雲端儲存服務
使用意願
溝通隱私管理理論
DeLone and McLean理論
資訊系統成功模型
關鍵字(英) Privacy concerns
Trust
Cloud storage service
Intention to use
Communication privacy management
DeLone and McLean theory
IS success model
學科別分類
中文摘要 在IT科技領域中,雲端服務是其中發展最迅速的產業之一,隨著智慧手機與電腦攜帶裝置的普及化,消費者對雲端儲存容量如多媒體資料、個人資訊、行事曆、或其他工作相關資料的需求遽增。在消費者在享受雲端系統的便利時,卻也同時擔心雲端儲存的安全性,且學者也指出在電子商務領域,消費者對隱私的擔憂亦是造成電子商務相關銷售下滑的關鍵原因之一。
然而,有鑒於在先前研究中,學者在探討雲端相關議題時,多限於個人使用者領域,而缺乏對組織使用者與隱私關注之相關研究。為使研究更加周延,本文將針對探討個人與組織使用者對雲端隱私關注與擔憂,及影響使用者持續使用意願之因素。本研究應用溝通隱私管理理論與資訊系統成功模型,來探討使用者的隱私相關議題。在收集與分析雲端儲存使用者之相關問卷資料後,本研究發現隱私關注確實會對使用者對雲端持續使用意願造成相當程度之影響。
英文摘要 Could computing service is a fast growing industry in IT market. With the increasing usage of smartphone and multi-computer device, consumers are craving for large storage capacity to storage data including multimedia, personal document, schedule or other work related files. Users are tend to acquire larger space in storage and enjoy the convenience of the cloud storage service, but they still worry about service security issues while adopting cloud storage service. Therefore, privacy concerns are considered as a major issue restricting e-commerce growing and decreasing sales from internet (Dinev & Hart, 2006).
However, it is limited in individual usage in prior studies, and the linkage of organizational users and privacy concerns in cloud storage service is still missing. In order to fill the gap, we try to explore users’ privacy issue in both individual and organizational level in this research. Besides, communication privacy management (CPM) and information system (IS) theory are utilized in exploring privacy issue in cloud storage service. After analyzing the data of organizational and personal users, our study reconfirm the privacy issue is crucial for users’ intention in adopting the cloud storage service.
論文目次 ABSTRACT I
摘要 II
ACKNOWLEDGMENTS III
TABLE OF CONTENTS IV
LIST OF TABLES IX
LIST OF FIGURES X
CHAPTER ONE INTRODUCTION 1
1.1 Research Background. 1
1.2 Research Motivation. 3
1.2.1 Introduction of Cloud Computing. 3
1.2.2 Privacy Concern. 4
1.2.3 Research Motivation. 4
1.3 Research Objective. 6
1.4 Research Structure. 6
1.5 Research Procedure. 7
CHAPTER TWO LITERATURE REVIEW 9
2.1 Theoretical Foundation. 9
2.1.1 Communication Privacy Management Theory. 9
2.1.2 DeLone and McLean’s Theory. 10
2.1.3 Post-Adoptive Theory. 11
2.2 Construct Definition for Individual Users. 12
2.2.1 Perceived Effectiveness of Privacy Policy (PP). 12
2.2.2 Perceived Effectiveness of Industry Self-Regulation (ISR). 12
2.2.3 Perceived Privacy Control (CONT). 13
2.2.4 Perceived Privacy Risk (RISK). 14
2.2.5 Disposition to Value Privacy (DTVP). 14
2.2.6 Cloud Storage Services Privacy Concerns (PC). 15
2.2.7 Intention to Continuance Use Cloud Storage Services (USE). 15
2.2.8 Trust in Cloud Storage Services Provider (T). 15
2.3 Construct Definition for Organizational Users. 16
2.3.1 Information Quality. 16
2.3.2 System Quality. 16
2.3.3 Service Quality. 17
2.3.4 Perceived Usefulness. 17
2.3.5 Continuance Use. 18
2.3.6 User's Satisfaction. 18
2.3.7 Privacy Concern. 19
2.3.8 Security Concern. 19
2.4 Hypotheses Development for Individual Users. 19
2.4.1 Perceived Effectiveness of Privacy Policy and Perceived Privacy Control. 19
2.4.2 Perceived Effectiveness of Privacy Policy and Perceived Privacy Risk. 20
2.4.3 Perceived Effectiveness of Industry Self-Regulation and Perceived Privacy Control. 20
2.4.4 Perceived Effectiveness of Industry Self-Regulation and Perceived Privacy Risk. 21
2.4.5 Perceived Privacy Control and Cloud Storage Services Privacy Concerns. 22
2.4.6 Perceived Privacy Control and Trust in Cloud Storage Services Provider. 22
2.4.7 Perceived Privacy Risk and Cloud Storage Service Privacy Concerns. 22
2.4.8 Perceived Privacy Risk and Trust in Cloud Storage Services Provider. 23
2.4.9 Disposition to Value Privacy and Cloud Storage Services Privacy Concerns. 23
2.4.10 Cloud Storage Services Privacy Concerns and Intention to Continuance Use Cloud Storage Services. 24
2.4.11 Cloud Storage Services Privacy Concerns and Trust in Cloud Storage Services Provider. 24
2.4.12 Trust in Cloud Storage Services Provider and Intention to Continuance Use Cloud Storage Services. 25
2.5 Hypotheses Development for Organizational Users. 25
2.5.1 Information Quality and Continuance Use. 25
2.5.2 Information Quality and User's Satisfaction. 26
2.5.3 System Quality and Continuance Use. 26
2.5.4 System Quality and User's Satisfaction. 27
2.5.5 Service Quality and Continuance Use. 27
2.5.6 Service Quality and User's Satisfaction. 28
2.5.7 Perceived Usefulness and Continuance Use. 29
2.5.8 User's Satisfaction and Continuance Use. 29
2.5.9 Security Concern and Privacy Concern. 29
2.5.10 Security Concern and Continuance Use. 30
2.5.11 Privacy Concerns and Continuance Use. 30
CHAPTER THREE RESEARCH DESIGN AND METHODOLOGY 32
3.1 Conceptual Model. 32
3.1.1 Conceptual Model of Individual User. 35
3.1.2 Conceptual Model of Organization User. 36
3.2 Hypotheses to be Tested for Individual Users. 36
3.3 Hypotheses to be Tested for Organizational Users. 37
3.4 Questionnaire Design. 38
3.5 Sampling Plan. 44
3.6 Data Analysis Method. 45
CHAPTER FOUR RESEARCH ANALYSIS RESULTS 47
4.1 Sample Analysis. 47
4.1.1 Data Collection. 47
4.1.2 Characteristics of Respondents. 48
4.2 Descriptive Analysis. 59
4.3 Result of Partial Least Square (PLS) Analysis. 63
4.3.1 Convergent Validity. 63
4.3.2 Discriminant Validity. 66
4.3.3 R Square. 68
4.3.4 Path Coefficient. 69
CHAPTER FIVE CONCLUSION AND SUGGESTIONS 73
5.1 Research Result. 73
5.2 Research Conclusions. 75
5.2.1 Conclusion of Individual User. 75
5.2.2 Unsupported Hypotheses Discussions of Individual User. 76
5.2.3 Conclusion of Organizational User. 77
5.2.4 Unsupported Hypotheses Discussions of Organizational User. 78
5.2.5 Conclusion Comparison. 79
5.3 Managerial Implications and Contributions. 80
5.4 Research Limitations and Further Research Suggestions. 83
REFERENCES 85
APPENDICES 93
Appendix 1: Questionnaires for Individual User Survey-English. 93
Appendix 2: Questionnaires for Organizational User Survey-Chinese. 97
Appendix 3: Questionnaires for Organizational User Survey-English. 100
Appendix 4: Questionnaires for Organizational User Survey-Chinese 103
Appendix 5: Output by PLS of Individual User 107
Appendix 6: Output Bootstrapping by PLS of Individual User 107
Appendix 7: Output by PLS of Organizational User 108
Appendix 8: Output Bootstrapping by PLS of Organizational User 108
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系統識別號 U0026-0412201408085300
論文名稱(中文) 上消化道癌症中 RUNX3 及 Pin1 對 β-catenin/cyclin D1 的調控
論文名稱(英文) RUNX3 And Pin1 Regulate β-catenin/cyclin D1 in Cancers of Upper Digestive Tract
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 1
出版年 103
研究生(中文) 林逢嘉
學號 S98971055
學位類別 博士
語文別 英文
口試日期 2014-11-28
論文頁數 100頁
口試委員 召集委員-王憶卿
口試委員-劉校生
口試委員-林進清
口試委員-陳尚文
指導教授-許博翔
指導教授-呂佩融
關鍵字(中) RUNX3
Pin1
Akt1
β-catenin
cyclin D1
胃癌
食道鱗狀細胞癌
關鍵字(英) RUNX3
Pin1
Akt1
β-catenin
cyclin D1
gastric cancer
esophageal squamous cell carcinoma
學科別分類
中文摘要 癌症是重要的人類健康問題,胃癌及食道鱗狀細胞癌是常見且致命的疾病。雖然整合運用了各種的治療方式,多數病人依然死於疾病或治療引起的副作用,為了改善現有的及發展新穎的診斷與治療癌症的方式,癌症致病機轉必須更清楚地被研究。
RUNX3是癌症抑制基因,它的抑癌作用最早是在胃癌中被確認,在大約八成的胃癌中RUNX3會有低表現或失去功用的情形。雖然RUNX3已知會透過調控許多分子的表現或作用而抑制胃癌的生成,但是其機轉仍未被透徹地瞭解。所以我的博士論文研究胃癌中RUNX3對β-catenin/ cyclin D1的調控,RUNX3被發現會抑制Akt1的轉錄並降低Akt1的表現量,進而促使β-catenin被分解及cyclin D1的低表現,結果顯示在胃癌中RUNX3的失去功能會促使癌化的進行,其機轉包括Akt1/ β-catenin/ cyclin D1訊息途徑的活化。
β-catenin與cyclin D1也都是Pin1基質,而Pin1已被證實會藉由調控許多抑癌或致癌分子而促使癌症的生成。所以我的博士論文研究食道鱗狀細胞癌中RUNX3對β-catenin與cyclin D1的調控,以細胞株的實驗證明了將Pin1的表現量降低會抑制 β-catenin與cyclin D1的表現量及食道鱗狀細胞癌的生成,也確認在接受手術治療的食道鱗狀細胞癌病患中,Pin1的高表現量與不良預後有相關性,上述結果顯示Pin1會透過β-catenin與cyclin D1而增進食道鱗狀細胞癌惡性度。
綜言之,β-catenin與cyclin D1在胃癌中會被RUNX3抑制,而在食道鱗狀細胞癌中會被Pin1正相關地調控,我的博士論文讓上消化道癌症的致病機轉更清楚地被了解,期望對未來癌症診療業務的改進與發展有所助益。
英文摘要 Cancer is one of major health issues. Gastric cancer and esophageal squamous cell carcinoma (ESCC) are common and fatal malignancy. Despite multi-modality therapies, most patients eventually die from the disease or treatment-related complications. More comprehensive investigations of carcinogenesis and tumor progression are necessary for developing novel diagnostic and therapeutic strategies for these cancers.
RUNX3 is recognized as a tumor suppressor. The tumor suppressive functions of RUNX3 were first reported in gastric epithelial cells. RUNX3 was inactivated by gene silencing or protein mislocalization in more than 80% of gastric cancers. Although restoration of RUNX3 in gastric cancer cells could inhibit tumorigenesis through regulating several target genes, the mechanisms were not clearly understood. The role of RUNX3 in regulating β-catenin and cyclin D1 in gastric cancer was studied in my thesis. RUNX3 repressed Akt1 expression through transcriptional inhibition. Two RUNX3-binding sites on Akt1 promoter were identified. The inhibition of Akt1 facilitated β-catenin degradation followed by cyclin D1 downregulation. The data suggested loss of RUNX3 in gastric cancer promoted tumorigenesis through Akt1/β-catenin/cyclin D1 signaling pathway.
β-catenin and cyclin D1 are well known substrates of Pin1 which is a peptidyl-prolyl isomerase and promotes oncogenesis by regulating multiple oncogenic signaling at various levels. Pin1/β-catenin/cyclin D1 signaling pathway in ESCC was investigated. The experimental evidences were provided that Pin1 knockdown inhibited expression of β-catenin/cyclin D1 and tumorigenesis of ESCC cells. The inhibited tumorigenesis in cells with Pin1 knockdown was partially recovered by cyclin D1 restoration. In addition, high Pin1 expression was correlated with poor prognosis of ESCC patients. The results supported that Pin1 may promote ESCC aggressiveness through β-catenin and cyclin D.
In summary, β-catenin and cyclin D1 are repressed by tumor suppressor RUNX3 but positively regulated by Pin1 in cancers of upper digestive tract. The results of my thesis can help people understand carcinogenic mechanisms and provide rationales for developing novel target therapy of cancer in the future.
論文目次 TABLE OF CONTENTS
Abstract in Chinese II
Abstract in English III-IV
Acknowledgement V
Table of Contents VI-VIII
Table Contents IX
Figure Contents X-XII
Chapter One: Introduction 1
1.1 Cancer 2
1.2 Gastric cancer 2
1.3 Esophageal squamous cell carcinoma 3
1.4 β-catenin 4
1.5 Cyclin D1 4
1.6 RUNX3 5
1.7 Protein interacting with NIMA (never in mitosis A)-1 (Pin1) 6
1.8 The goal and specific aims 8
Chapter Two: Materials and Methods 9
2.1 Cell lines and cell culture 10
2.2 Patients and clinical specimens 10
2.3 Generation of recombinant plasmids 10
2.4 Gene transfection 11
2.5 Western blot analysis 11
2.6 RNA extraction and reverse transcription-polymerase chain reaction 12
2.7 Cell proliferation assay 13
2.8 Colony formation assay 13
2.9 Xenograft tumor growth 13
2.10 Luciferase reporter assay 13
2.11 Immunohistochemistry analysis 14
2.12 Flow cytometry analysis 15
2.13 Human phospho-kinase array 15
2.14 Quantitative real-time polymerase chain reaction 15
2.15 Chromatin immunoprecipitation assay 16
2.16 Immunofluorescence studies 17
2.17 Degradation assay 17
2.18 Statistical analysis 17
Chapter Three: Results 19
3.1 Loss of RUNX3 activates the Akt1/bcatenin/cyclin D1 signaling pathway that promotes tumorigenesis in gastric cancer 20
3.1.1 Restoration of RUNX3 caused cell cycle arrest and inhibited cell proliferation 20
3.1.2 RUNX3 directly repressed Akt1 transcription 21
3.1.3 RUNX3 attenuated the Akt1/-catenin/cyclin D1 signaling pathway 23
3.1.4 RUNX3 reduced -catenin nuclear localization, transactivation and protein stability 24
3.1.5 Restoration of cyclin D1 reversed RUNX3-mediated cell growth inhibition and cell cycle arrest 26
3.2 Pin1 positively affects tumorigenesis of esophageal squamous cell carcinoma and correlates with poor survival of patients 27
3.2.1 Pin1 knockdown inhibites proliferation, clonogenicity and tumorigenesis of ESCC 27
3.2.2 Pin1 upregulation was identified in clinical ESCC specimens and correlated with poor prognosis of patients 27
3.2.3 β-catenin and cyclin D1 were positively regulated by Pin1 28
Chapter Four: Discussion and Conclusion 30
Chapter Five: Tables and Figures 42
Chapter Six: References 87
Theses-related Publications 97
Curriculum Vitae 98
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系統識別號 U0026-0602201510192800
論文名稱(中文) 第四型膠原蛋白/整合素所活化之訊息傳遞在調控腫瘤細胞軟硬度及基質纖維母細胞浸潤的新穎機制
論文名稱(英文) A novel mechanism regulates the tumor cell rigidity and cancer-associated fibroblast infiltration through the collagen IV/integrin-initiated signaling pathway
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 1
出版年 104
研究生(中文) 陳勝義
學號 S58971251
學位類別 博士
語文別 英文
口試日期 2015-01-23
論文頁數 83頁
口試委員 指導教授-楊倍昌
召集委員-江美治
口試委員-凌斌
口試委員-王仰高
口試委員-許秉寧
口試委員-戴明泓
關鍵字(中) 第四型膠原蛋白
纖維母細胞
A型血小板衍生生長因子
細胞硬度
細胞爬行
關鍵字(英) type IV collagen
cancer-associated fibroblast
PDGF-A
cell stiffness
cell migration
學科別分類
中文摘要 細胞外基質及腫瘤微環境在腫瘤的進程中扮演重要的角色。第四型膠原蛋白過度堆積在腫瘤微環境中,可影響腫瘤細胞的侵襲能力、基質細胞的行為及組織張力的平衡。為了了解其中的分子機制,我們利用慢病毒攜帶干擾核糖核酸 (shRNA),抑制了腫瘤細胞中第四型膠原蛋白alpha 1基因的表現。這些細胞株命名為shCol細胞。雖然shCol-B16F10細胞在體外的生長速率沒有改變,它在C57BL/6小鼠皮下所長成的腫瘤明顯變小,而且alpha平滑肌肌動蛋白陽性纖維母細胞在腫瘤的浸潤明顯較少。當第四型膠原蛋白基因表現受抑制,或者利用抗體阻斷膠原蛋白與整合素之間的結合,皆可以降低纖維母細胞的趨化因子:「A型血小板衍生生長因子」的表現。此外,促進整合素的聚合可提升小鼠B16F10細胞、人類U118MG和Huh7細胞表現A型血小板衍生生長因子。透過A型血小板衍生生長因子專一的shRNA及中和性抗體,皆能抑制纖維母細胞的穿透爬行。在shCol細胞培養液中加入A型血小板衍生生長因子,可恢復其吸引纖維母細胞穿透移動的能力。以上的證據支持A型血小板衍生生長因子是本研究中,腫瘤吸引纖維母細胞的主要趨化因子。整合素活化而表現A型血小板衍生生長因子需要透過Src及ERK激酶的活化。由觀察肝癌及腦瘤病人的病理組織染色切片,也發現第四型膠原蛋白與A型血小板衍生生長因子的表現,位於同一細胞區塊上。因此,透過膠原蛋白與整合素結合而活化Src及ERK激酶的訊息傳遞路徑,將導致A型血小板衍生生長因子的表現。而這是造成腫瘤組織中,纖維母細胞浸潤關鍵的主要原因。
在另一方面,我們也進一步分析第四型膠原蛋白如何影響細胞軟硬度及爬行能力。雖然生長速率無差異,在細胞的型態上,shCol細胞比控制組細胞較為攤平。而且,shCol細胞的細胞硬度較高、爬行較慢。利用β1或α2β1整合素阻斷型抗體,或利用PP1與U0126抑制Src及ERK激酶,皆能有效地降低細胞的爬行能力、增加細胞硬度。如前所述,在shCol細胞中,Src及ERK激酶的活化程度下降。大量表現β1整合素不只刺激Src及ERK激酶的磷酸化,而且會降低細胞的鋼性、增加細胞的爬行能力。在C57BL/6小鼠的實驗性肺轉移動物模式中, B16F10-shCol細胞所產生的肺部腫瘤較少、也較小。因此,膠原蛋白也會促進腫瘤轉移。
綜合本研究的結果:在腫瘤微環境中,第四型膠原蛋白的堆積可刺激腫瘤細胞之整合素訊息活化及產生A型血小板衍生生長因子,吸引纖維母細胞浸潤。另外,它也會改變細胞的硬度,增加腫瘤轉移的能力。
英文摘要 It has been recognized that stromal cells and tumor microenvironment play pivotal roles in tumor progression. Collagen IV deposition in tumor microenvironment can influence cancer cells invasive capacity, stromal cell behaviors, and tissue tension homeostasis. To gain a better understanding of the underlying molecular mechanism, we knocked-down the type IV collagen alpha 1 gene (Col4A) of cells by the lentiviral-mediated RNA interference strategy, designated as shCol cells. Although there was no obvious effect on cell growth in vitro, silencing the Col4A gene decreased the tumorigenicity of B16F10 in C57BL/6 mice, which was accompanied by a reduction in the stromal infiltration of alpha-smooth muscle actin-positive (-SMA+) fibroblasts. Silencing Col4-Agene or disrupting integrin engagement by blocking antibody reduced the expression of platelet-derived growth factor A (PDGF-A), a potent chemotactic factor for fibroblasts. Furthermore, ectopic expression of the autoclustering integrin mutant significantly stimulated PDGF-A expression in murine B16F10, human U118MG, and Huh7 cells. PDGF-A-specific sh-RNA and neutralizing anti-PDGF-A antibody effectively inhibited the transwell migration of fibroblasts. Adding recombinant PDGF-A back to shCol cells-conditioned media restored the fibroblast-attraction ability, supporting the notion that PDGF-A is a major chemotactic factor for fibroblasts in the current model. The integrin-associated PDGF-A production correlated with the activation of Src and ERK. High type IV collagen staining intensity colocalized with elevated PDGF-A expression was observed in tumor tissues obtained from hepatoma and glioma patients. The integrin signal pathway was activated by collagen engagement through Src and ERK, leading to enhanced PDGF-A production, which serves as a key regulator of fibroblast recruitment.
Further to understand how type IV collagen affects mechanical rigidity and migration. Although having similar growth rates, shCol cells featured a flatter morphology compared to that of the corresponding controls. Notably, knocking-down the Col4A1gene endowed the cells with higher levels of elasticity and lower motility. Exposure to blocking antibodies against human β1integrin, α2β1integrin or the pharmacological inhibition of Src and ERK activity by PP1 and U0126, respectively, effectively reduced cell motility and raised cell stiffness. Reduced Src and ERK activities in shCol cells indicate the involvement of a collagen IV/integrin signaling pathway. The forced expression of β1 integrin significantly stimulated Src and ERK phosphorylation, reduced cell stiffness, and accelerated cell motility. In an experimental metastasis assay using C57BL/6 mice, B16F10 shCol cells formed significantly fewer and smaller lung nodules, confirming the contribution of collagen to metastasis.
In summary, the integrin signaling pathway activated in a tumor environment with collagen deposition appears to be responsible for cancer-associated fibroblast recruitment, low cell elasticity and high metastatic ability.
論文目次 Table of Contents
中文摘要 I
Abstract (English) III
Acknowledgement V
Table of Contents VII
List of table and figures X
List of abbreviations XII
1. Introduction 1
1.1 The relationship between type IV collagen and cancer-associated fibroblast infiltration 1
Extracellular matrix 1
Basement membrane 1
Type IV collagen 2
Integrin and non-integrin receptors of collagen IV 3
Collagen IV deposition in tumors 4
Cancer-associated fibroblast 5
Collagen and PDGF expression 6
1.2 The association of type IV collagen in cellular stiffness and migration ability 6
Cell movement regulated through ECM substrate rigidity 7
Type IV collagen promotes tumor metastatic ability 7
Higher cell stiffness with lower metastatic potential 8
Integrin signaling regulates cell stiffness 9
2. Rationale and Specific Aims 10
3. Materials and Methods 11
3.1 Materials 11
Chemicals and Reagents 11
Antibodies 13
Commercial Kits 14
Materials of Cell Culture 14
Materials for Western Blotting 15
Materials for Bacteria Culture 15
Machinery 16
Cell Lines 17
Media and Buffers 17
3.2 Methods 24
Cell culture 24
Bacterial strain store 24
Plasmid DNA Extraction 25
Lentivirus production 25
Quantitative real-time PCR 26
Reverse-Transcription Polymerase Chain Reaction (RT-PCR) 27
Western blot analysis 27
Single cell motility assay 28
Polarized cell migration assay 28
In vitro chemo-attractive invasion assay 29
Cell stiffness measurement 29
Immunofluorescence staining 29
In vivo experimental pulmonary metastasis assay 30
In vivo tumor formation 31
Statistical analysis 31
4. Results 32
Impaired tumorigenesis of B16F10 cells and reduced myofibroblast infiltration by knocking-down Col4A1 gene 32
Correlation of type IV collagen with PDGF-A expression 32
Contribution of integrin signaling to collagen-associated PDGF-A expression 33
Effect of kinase inhibitors on PDGF-A expression 34
Knocking-down Col4A1 gene-altered cell morphology, but not in vitro proliferation 35
Increase in cell stiffness after knocking-down Col4A1 gene 35
Modulation of cell stiffness by collagen IV/integrin downstream signaling through Src and ERK 36
Association of Col4A1 gene with cell migration 37
Association of Col4A1 gene with metastasis in vivo 38
5. Discussion 39
5.1 The relationship of type IV collagen and cancer-associated fibroblast infiltration 39
Collagen IV-related signaling modulates the expression of PDGF-related factors, and may also contribute to fibroblast recruitment 39
Tissue rigidity and receptor activation may be altered by knock-down of the collagen IV gene 40
β1 integrin receptor is the candidate for PDGF production by engagement of collagen IV 41
Over-expression of β1 integrin is responsible for Src and ERK activation and PDGF-A expression 41
5.2 The association of type IV collagen in cellular stiffness and migration ability 42
Consistency with prior evidence of shCol cells that elevated cell stiffness correlates with flatter morphology 42
Cell rigidity may be directly regulated by β1integrin receptor engagement with collagen IV 43
Upregulated cell stiffness but reduced cell migration through Col4A1 gene knock-down 44
6. Conclusion 45
7. References 46
8. Tables and Figures 56


List of table and figures
Table 1. Quantitative real-time PCR oligonucleotide primers used in this study 56
Table 2. RT-PCR oligonucleotide primers used in this study 57
Figure 1. Knocking-down of type IV-α1 chain collagen. 58
Figure 2. Reduced tumor growth and fibroblast infiltration of B16F10-derived shCol cells. 60
Figure 3. Reduction of fibroblast recruitment ability and PDGF-A expression of B16F10-derived shCol cells. 61
Figure 4. Impaired fibroblast recruitment by knock-down PDGF-A expression. 63
Figure 6. Contribution of integrin signaling to collagen-associated PDGF-A expression. 68
Figure 7. Suppression of PDGF-A expression by ERK and Src inhibitors. 69
Figure 8. Alteration of PDGF genes by knocking-down type IV-α1 collagen. 70
Figure 9. Reduced expression of PDGF genes by ERK inhibitor. 71
Figure 10. Proposed model for tumor fibroblast infiltration mediated by PDGF production through type IV collagen-β1 integrin-Src-ERK signaling pathway. 72
Figure 11. Alteration of cell morphology but not in vitro proliferation by knocking-down Col4A1 gene. 73
Figure 12. Increase in cell stiffness after knocking-down Col4A1 gene. 74
Figure 14. Over-expression of β1 integrin decreased cell stiffness. 77
Figure 15. Reduced integrin signal stabilizes F-actin structure. 79
Figure 16. Knocking-down Col4A1 gene decreased cell migration. 80
Figure 17. Knocking-down the Col4A1 gene of B16F10 cells decreased lung metastasis. 82
Figure 18. Proposed model for cell stiffness and cell migration ability mediated by type IV collagen-β1 integrin-Src-ERK signaling pathway. 83
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系統識別號 U0026-0707201422144100
論文名稱(中文) 影響獨資型會計師事務所之經營績效研究-以台南地區為例
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校院名稱 成功大學
系所名稱(中) 企業管理學系碩士在職專班
系所名稱(英) Department of Business Administration (on the job class)
學年度 102
學期 2
出版年 103
研究生(中文) 蕭兆欽
學號 R47011314
學位類別 碩士
語文別 中文
口試日期 2014-06-18
論文頁數 52頁
口試委員 指導教授-康信鴻
口試委員-莊雙喜
口試委員-鄭美幸
口試委員-傅英芬
口試委員-周信輝
關鍵字(中) 最小平方法
獨資型會計師事務所
經營績效
關鍵字(英) Ordinary least square
Sole certified public accounting firm
Performance
學科別分類
中文摘要 近年來,會計師事務所設立家數逐漸攀升,以致於產業內的競爭日趨激烈,進而影響事務所經營績效。本研究係採用行政院金融監督管理委員會彙總整理,2007年至2012年會計師服務業調查報告之資料,並以自身經營會計師事務所為研究動機,針對會計師事務所登記所在地於台南地區者,瞭解獨資型會計師事務所經營狀況受當地產業內部競爭者及外部整體環境之影響,及台南縣市合併前後,對於獨資型會計師事務所經營績效是否有顯著差異等兩大研究目的。
本研究方法以計量經濟學中的古典線性迴歸模型(classical linear regression model, CLRM)作為基礎迴歸模型,採用最小平方法(ordinary least square, OLS)取得最佳線性不偏估計式(best linear unbiased estimators, BLUE)。
實證結果顯示,影響台南地區獨資型會計師事務所經營績效之要素,以「市場佔有率」和「事務所開業年資」兩自變數較為顯著;而綜觀整體影響台南地區會計師事務所經營績效之要素,則以「市場佔有率」、「經驗年資合計數」和「會計師事務所組織型態」等三項自變數較為顯著。另外,台南縣市合併對獨資型會計師事務所或當地整體會計師事務所經營績效而言,皆有正面助益。
英文摘要 Due to the number of accounting firms arising gradually, the competition inside the industry is widespread and has impact on the performance of accounting firm in recent years. According to the survey of certified public accounting firms’ performance in Tainan City from 2007 to 2012, which is published by Financial Supervisory Commission, this study in the view of management experience by my own attempts to understand how a sole certified public accounting firm’s performance can be affected between internal competitors and external local environment in this period. In addition, is there any difference in operating a sole certified public accounting firm after the merge of Tainan City and Tainan County? Based on classical linear regression model as prototype, this study tries to measure the best linear unbiased estimators by using ordinary least square principle. Firstly, the empirical results show a significant relevance between market share, firm operating years ,and the performance of a sole certified public accounting firm’s operation. Secondly, they also show that market share, experience accumulation, and firm type have positive significant influence on the performance of certified public accounting firm’s operation. Furthermore, whether the accounting firm type is sole certified or not, there is positive influence after the merge of Tainan City and Tainan County.
論文目次 中文摘要……………………………………………………………… Ⅰ
英文摘要……………………………………………………………… Ⅱ
誌謝…………………………………………………………………… Ⅵ
目錄…………………………………………………………………… Ⅶ
表目錄………………………………………………………………… Ⅸ
圖目錄………………………………………………………………… VII
第一章 緒論……………………………………………………… 1
第一節 研究背景與動機…………………………………… 1
第二節 研究目的…………………………………………… 2
第三節 研究問題…………………………………………… 2
第四節 研究架構…………………………………………… 3
第五節 研究流程…………………………………………… 4
第二章 文獻回顧及探討…………………………………………… 5
第一節 文獻回顧…………………………………………… 5
第二節 文獻探討…………………………………………… 9
第三節 本文之努力方向…………………………………… 14
第三章 研究方法…………………………………………………… 16
第一節 建立研究模型……………………………………… 16
第二節 假說設定與變數確認……………………………… 17
第四章 實證結果分析……………………………………………… 22
第一節 初步資料統計……………………………………… 22
第二節 獨資型實證分析…………………………………… 25
第三節 綜合型實證分析…………………………………… 30
第五章 結論與建議………………………………………………… 36
第一節 研究結論…………………………………………… 36
第二節 研究貢獻與實務意涵……………………………… 40
第三節 研究限制與建議…………………………………… 43
第四節 作者實務心得感想………………………………… 45
參考文獻……………………………………………………………… 49
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系統識別號 U0026-0812201422052100
論文名稱(中文) 癌症病人接受化學治療引發周邊神經病變與住院跌倒相關性探討
論文名稱(英文) Falls Among Hospitalized Cancer Patients with Chemotherapy-Induced Peripheral Neuropathy
校院名稱 成功大學
系所名稱(中) 護理學系
系所名稱(英) Department of Nursing
學年度 103
學期 1
出版年 104
研究生(中文) 吳靜儀
學號 T26004100
學位類別 碩士
語文別 中文
口試日期 2014-11-26
論文頁數 64頁
口試委員 指導教授-顏妙芬
口試委員-郭律廷
口試委員-顏家瑞
關鍵字(中) 癌症病人
化學治療
周邊神經病變
跌倒
關鍵字(英) cancer patients
chemotherapy
peripheral neuropathy
falls
學科別分類
中文摘要 化學治療引發周邊神經病變(chemotherapy-induced peripheral neuropathy, CIPN)是指使用某特定類化學治療藥物(Vinca alkaloids類、Taxane類、Platinum類等)導致感覺或運動神經傳導損傷,其症狀主要是手腳麻木、針刺感、步態不穩及平衡失調等問題,是造成化學治療病人發生跌倒原因之一。本研究旨在探討接受化學治療引發周邊神經病變之癌症病人住院跌倒的重要預測因子,作為預防腫瘤科病房病人跌倒措施之參考。研究設計採回溯性病例對照研究法(Retrospective Case-Control),採用癌症治療副作用護理評估表及個案基本特質調查表,針對南部某區域教學醫院自2009年1月至2013年12月住院期間內癌症病人具有CIPN且發生有紀錄跌倒為研究對象,對照組則為癌症病人具有CIPN未跌倒者,共計2組收案163位病人。研究結果發現罹病時間(Odds ratio [OR], 3.079; 95% Confidence interval [CI], 1.256~7.549, p = 0.014)、CIPN嚴重度(OR, 0.008; 95%CI, 0.001~0.209, p=0.004)等變項達統計上顯著差異,為具CIPN之癌症病人跌倒危險因素;另外化學藥物Oxaliplatin及Cisplatin的累積劑量與跌倒有顯著正相關(p < 0.05)。本研究分析結果指出罹病時間、CIPN嚴重度及化學藥物累積劑量為癌症病人接受化學治療引發周邊神經病變跌倒之相關危險因素,在臨床上將有助於護理人員準確評估及預防周邊神經病變症狀,建立跌倒防範措施,進而確保病人安全,達到提升照護品質。
英文摘要 Chemotherapy-induced peripheral neuropathy (CIPN) is one of the side effects caused by chemotherapy, and its symptoms are related with sensory or motor nerve injury, resulting in numbness, unsteady gait. This study aims to investigate the important impacting factors of peripheral neuropathy on falls in cancer patients receiving Taxanes, Vinca alkaloids and Platinum-based chemotherapy. It was the retrospectively case-control study, enrolling 163 hospitalized patients who had CIPN with and without falls between January 2009 and December 2013 in southern teaching hospital oncology ward. Using logistic regression model, the risk of falls were significantly associated with the more longer disease duration (odds ratio [OR] = 3.079; 95% confidence interval [CI], 1.256~7.549, p = 0.014)、the severity of CIPN(OR = 0.008; 95%CI, 0.001~0.209, p=0.004). Besides, the accumulating doses of oxaliplatin and cisplatin were significantly associated with the risk of falls(p<0.05)。All the results may provide the information on reducing injurious falls of inpatients with CIPN in oncology ward and avoiding interruption of cancer treatment, thus it will ensure patient safety and improve the quality of care.
論文目次 中文摘要 I
ABSTRACT II
致謝 V
第一章 緒論 1
第一節 研究背景與重要性 1
第二節 研究目的 3
第二章 文獻查證 4
第一節 化學治療引發周邊神經病變 4
第二節 化學藥物引發周邊神經病變與跌倒的影響 12
第三章 研究方法 15
第一節 研究設計 15
第二節 研究架構 16
第三節 研究對象與選樣 17
第四節 名詞解釋 19
第五節 研究工具 20
第六節 資料收集過程 22
第七節 倫理考量 24
第八節 資料分析 25
第四章 研究結果 26
第一節 癌症病人接受化學治療引發周邊神經病變基本資料與分析 26
第二節 癌症病人接受化學治療引發周邊神經病變之跌倒危險因素分析 34
第三節 癌症病人接受化學治療引發周邊神經病變跌倒因素多變項分析 39
第五章 討論 42
第一節 癌症病人接受化學治療引發周邊神經病變跌倒之人口學因素 42
第二節 癌症病人接受化學治療引發周邊神經病變跌倒之身體功能狀態 44
第三節 癌症病人接受化學治療引發周邊神經病變跌倒之化學治療特性 46
第六章 結論與建議 49
第一節 結論 49
第二節 研究貢獻 50
第三節 研究限制 51
參考文獻 53
中文部分 53
英文部分 55
表目錄
表一 化學治療引起周邊神經病變症狀評估 6
表二 化學治療引發周邊神經病變症狀嚴重度評估分級說明 11
表三 癌症病人具CIPN之人口學變項與有無跌倒相關因素分析 28
表四 癌症病人具CIPN之身體功能狀態與有無跌倒相關因素分析 30
表五 癌症病人具CIPN之化學治療特性變項與有無跌倒相關因素分析 32
表六 癌症病人具CIPN之化學治療特性變項與有無跌倒相關因素分析 33
表七 影響是否跌倒之多變項分析 41
圖目錄
圖一 研究架構圖 16
圖二 收案流程圖 18
附錄
附錄一 個案基本特質調查表 63
附錄二 癌症治療副作用護理評估表 64

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------------------------------------------------------------------------ 第 12 筆 ---------------------------------------------------------------------
系統識別號 U0026-0902201512263300
論文名稱(中文) The Personalization –Privacy Paradox: An Exploratory Study on the Intention to Disclose via Mobile Phone Applications
論文名稱(英文) The Personalization –Privacy Paradox: An Exploratory Study on the Intention to Disclose via Mobile Phone Applications
校院名稱 成功大學
系所名稱(中) 國際經營管理研究所
系所名稱(英) Institute of International Management
學年度 103
學期 1
出版年 104
研究生(中文) 楊重名
學號 RA6017426
學位類別 碩士
語文別 英文
口試日期 2015-01-09
論文頁數 84頁
口試委員 召集委員-王維聰
指導教授-王鈿
口試委員-高如妃
口試委員-葉耕榕
關鍵字(中) none
關鍵字(英) Privacy calculus
Intention to disclose
Privacy concerns
Information privacy
Mobile applications
學科別分類
中文摘要 none
英文摘要 This study investigates the issue of consumer intention to disclose personal information via mobile applications. The study proposed a theoretical framework that were integrated protection motivation behavior on the basis of privacy calculus in order to explain an individual’s information disclosure behavior. Self-presentation, personalized services, perceived severity, importance of information transparency and perceived control were served as direct antecedents of perceived benefits and perceived risks. This study extends intention to disclose personal information literature by theoretically develop and empirically test the model within the current occurrence of disclosing personal information via mobile applications. Implications and future research are also discussed in this paper.
論文目次 TABLE OF CONTENTS
ABSTRACT I
ACKNOWLEDGEMENTS II
TABLE OF CONTENTS III
LIST OF TABLES VII
LIST OF FIGURES VIII
CHAPTER ONE INTRODUCTION 1
1.1 Research Background and Motivation. 1
1.1.1 Research Background. 1
1.1.2 Research Motivation. 2
1.2 Research Objectives and Contribution. 4
1.2.1 Research Objectives. 4
1.2.2 Research Contribution. 5
1.3 Research Procedure. 6
CHAPTER TWO LITERATURE REVIEW 8
2.1.2 Protection Motivation Theory. 8
2.1 Theoretical Background. 9
2.1.1 Privacy Calculus. 9
2.1.3 Development of an Integrated Theoretical Framework. 12
2.1.4 Previous Intention to Disclose Personal Information Literature. 13
2.2 Definitions of Relevant Research Variables. 21
2.2.1 Perceived Severity. 21
2.2.2 Importance of Information Transparency. 22
2.2.3 Perceived Control. 22
2.2.4 Self-Presentation. 23
2.2.5 Personalized Services. 23
2.2.6 Perceived Benefits. 23
2.2.7 Perceived Risks. 24
2.2.8 Intention to Disclose. 24
2.3 Development of Hypotheses. 25
2.3.1 The Relationship between Self-Presentation, and Personalized Services and Perceived Benefits. 25
2.3.2 The Relationship between Perceived Severity, and Importance of Information Transparency and Perceived Risks. 26
2.3.3 The Relationship between Perceived Control and Perceived Risks. 28
2.3.4 The Relationship between Perceived Benefits and Perceived Risks and Intention to Disclose via Mobile Applications. 29
CHAPTER THREE RESEARCH DESIGN AND METHODOLOGY 31
3.1 Conceptual Model. 31
3.2 Construct Measurement and Definitions of Variables. 32
3.3 Summary of Hypotheses. 33
3.4 Sampling Plan & Data Collection. 33
3.5 Measurement Scale of Variables. 34
3.5.1 Measurement Scale of Variables. 34
3.5.2 Control Variables. 36
3.6 Data Analysis Procedure. 36
3.6.1 Descriptive Statistical Analysis. 36
3.6.2 Confirmatory Factor Analysis (CFA). 37
3.6.3 Common Method Variance. 37
3.6.4 Validity and Reliability Test. 38
3.6.5 Partial Least Squares Regression (PLS) Path Modeling. 38
CHAPTER FOUR DATA ANALYSIS AND RESULTS 40
4.1 Respondent’s Characteristics. 40
4.2 Descriptive Analysis for Confirmatory Model. 43
4.3 PLS Approach: Confirmatory Factor Analysis and Validity and Reliability Test of the Measurement Variables. 46
4.3.1. Confirmatory Factor Analysis. 46
4.3.2. Discriminant Validity Test. 49
4.4 Common Method Bias. 52
4.5 PLS Approach: Assessment of Structural Model. 54
4.5.1 Model Analysis and Global Fit Measure for PLS Path Modeling. 54
4.5.2 Global Fit Measure for PLS Path Modeling. 54
4.5.3 The Main Effects Model. 55
CHAPTER FIVE CONCLUSIONS AND SUGGESTIONS 61
5.1 Discussions and Conclusions. 61
5.1.1 Discussion. 61
5.1.2 Conclusion. 62
5.2 Theoretical and Managerial Implications. 64
5.2.1 Theoretical Implications. 64
5.2.2 Managerial Implications. 65
5.3 Limitations and Future Researches. 67
REFERENCES 69
APPENDICES 75
Appendix 1: English Survey Questionnaire. 75
Appendix 2: Vietnamese Survey Questionnaire. 80

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系統識別號 U0026-1102201503555800
論文名稱(中文) 於體外試驗及原部位腫瘤小鼠模式中合併新穎組織蛋白去乙醯酶抑制劑協同增強etoposide對乳癌細胞之毒殺能力
論文名稱(英文) A novel histone deacetylase inhibitor synergistically enhances etoposide cytotoxicity in breast cancer cells in vitro and in an orthotopic mouse model
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 103
學期 1
出版年 104
研究生(中文) 洪奇薇
學號 s76014099
學位類別 碩士
語文別 中文
口試日期 2015-01-27
論文頁數 64頁
口試委員 指導教授-王應然
口試委員-潘敏雄
口試委員-郭靜娟
口試委員-何元順
口試委員-黃步敏
口試委員-黃東裕
關鍵字(中) 乳癌
拓撲異構酶抑制劑
組織蛋白去乙醯酶抑制劑
DNA修復
泛素化
關鍵字(英) breast cancer
topoisomerase inhibitor
histone deacetylase inhibitor
DNA repair
ubiquitination
學科別分類
中文摘要 乳癌是現代婦女最常見的癌症,也是癌症死亡的第二大原因,過去十年,雖然乳癌的死亡率逐漸下降,但發病率正逐漸增加,目前能透過外科手術、放射治療、藥物治療、免疫治療等方式治療乳癌,但臨床上的一些化療藥物常伴隨著副作用的產生,像是噁心、體重下降、掉髮、白血球及血小板數過低等,另外也需解決三重陰性乳癌對傳統藥物治療效果較差的情形,因此我們仍需要新穎且更有效的治療策略,使病人在較低的負擔下達到更好的療效,其中合併治療能透過化療藥物間不同的分子機制,增加細胞毒殺效果、降低抗藥性、並使重疊的毒性最小化。Etoposide是typeⅡ的拓撲異構酶抑制劑,會使癌細胞產生DNA錯誤,造成DNA雙股斷裂並且誘發細胞凋亡,另外組織蛋白去乙醯酶抑制劑(HDACi)則被發現會抑制DNA修復並誘發細胞凋亡,但HDACi抑制DNA修復的分子機制目前尚有待釐清。因此我們利用體外試驗以及原部位乳癌動物模式,探討新的HDACi YCW-3合併處理etoposide是否對乳癌細胞具有協同毒殺效果,並了解是否與HDACi抑制DNA的修復有關,並進一步探討HDACi抑制DNA的修復是否為透過調控蛋白質泛素化的結果。在體外試驗方面,分別以etoposide和YCW-3單獨與合併處理小鼠三重陰性乳腺癌細胞株4T1,以MTT assay分析細胞毒殺效果;利用流式細胞儀測定細胞死亡模式;透過彗星試驗及西方墨點法分析DNA之損傷與修復;另外使用免疫沉澱觀察蛋白的泛素化及蛋白之間的交互作用;mRNA的表現程度則透過即時聚合酶鏈式反應分析。在動物試驗方面,建立原部位乳癌動物模式,並利用活體影像系統監測腫瘤的生長,犧牲後取出腫瘤利用免疫組織化學染色及西方墨點法分析相關蛋白的表現量變化。本研究首先比較了YCW-3與傳統組織蛋白去乙醯酶抑制劑SAHA,發現YCW-3在藥物動力學、組織蛋白去乙醯酶抑制能力及細胞毒殺效果方面皆優於傳統藥物,表示YCW-3具有發展的潛力。於細胞及動物實驗中,相較於單獨處理組別,合併處理YCW-3與etoposide能協同增強細胞毒殺效果並有效抑制腫瘤生長。為釐清協同作用的機制,首先利用彗星試驗發現藥物合併處理組別比單獨處理產生更嚴重的DNA損傷,且DNA損傷指標蛋白γH2AX的表現量於合併處理的組別也有明顯的增加。而在處理YCW-3的組別中發現DNA關鍵修復蛋白DNA-PK的表現量會受到抑制;透過即時聚合酶鏈鎖反應分析,得知處理YCW-3細胞中DNA-PK mRNA表現程度並無顯著差異。而透過處理MG132能夠恢復YCW-3抑制的DN-PK表現量,表示DNA-PK蛋白的抑制是透過泛素-蛋白酶體路徑所降解;進一步利用免疫沉澱法發現YCW-3會促進DNA-PK與其E3連接酶RNF144A之間的交互作用,並誘發DNA-PK蛋白的泛素化,最後使DNA-PK受到蛋白酶體降解。於細胞死亡模式的研究結果中也發現合併處理的組別會顯著增加細胞凋亡和細胞自噬的百分比,並且細胞自噬是扮演促進死亡的角色。綜合以上結果得知,合併處理YCW-3可經由調控修復蛋白泛素化以抑制DNA修復,增加etoposide對於乳癌細胞之抗癌效果。
英文摘要 Breast cancer is the most common cancer in modern women. Although there are currently a variety of therapeutic methods for the treatment of breast cancer, severe problems still exist due to serious side effects triggered by clinical drugs and less anti-cancer activity in triple negative breast cancer. In this study, triple negative breast cancer cell line was applied to investigate the anti-cancer effects of new histone deacetylase inhibitor, YCW-3 alone or in combination with topoisomerase inhibitor, etoposide and to determine the mechanisms of these effects in vitro and in vivo. Firstly, we confirm that YCW-3 is a potent pan-HDAC inhibitor in which expressed a higher capability to inhibit HDACs and superior pharmacokinetics profile than traditional HDACi. Combination treatment with YCW-3 and etoposide resulted a synergistic cytotoxicity effect and induced remarkable programmed cell death in breast cancer cell line. The combined treatment enhanced significantly DNA damage, quantified by comment assay, when compared to YCW-3 or etoposide treatment alone. From a mechanistic insight, YCW-3 inhibited the expression level of the crucial DNA repair protein, DNA-PK. The effect of YCW-3 on the degradation of DNA-PK protein could be through the ubiquitin proteasome pathway, and the proteasomal degradation of DNA-PK protein was suggested by enhancing the association of DNA-PK with the ubiquitin E3 ligase RNF144A.Thus, our results demonstrated that the combination of YCW-3 and etoposide exerts strong cytotoxic effects in breast cancer and deserve further clinical-related investigation.
論文目次 第一章、序論 1
第二章、文獻回顧 2
第一節、乳癌(Breast cancer) 2
第二節、合併治療(combination therapy) 3
第三節、拓撲異構酶抑制劑(topoisomerase inhibitor, TOPi) 4
第四節、組織蛋白去乙醯酶抑制劑(histone deacetylase inhibitor, HDACi) 6
第五節、DNA雙股斷裂與DNA修復(DNA double strand break and DNA repair) 7
第六節、泛素化 (ubiquitination) 9
第七節、細胞凋亡與細胞自噬(Apoptosis and autophagy) 10
第三章、研究目的 13
第四章、研究材料與方法 14
第一節、研究材料 14
第二節、研究方法與實驗步驟 20
第五章、研究架構 27
In vitro study 27
In vivo study 28
第六章、實驗結果 29
第一節、YCW-3與傳統的組織蛋白去乙醯酶抑制劑SAHA之比較 29
第二節、拓撲異構酶抑制劑Etoposide合併組織蛋白去乙醯酶抑制劑YCW-3對於4T1細胞之毒性的劑量效應 29
第三節、探討合併處理YCW-3與Etoposide所誘發之DNA損壞及DNA修復 30
第四節、探討組織蛋白去乙醯酶抑制劑YCW-3抑制DNA修復蛋白DNA-PK之作用機制 31
第五節、分析合併處理YCW-3與Etoposide影響4T1細胞之細胞凋亡與細胞自噬的變化 32
第六節、探討合併處理YCW-3與Etoposide對4T1細胞誘發自體吞噬的現象 33
第七節、乳癌原部位腫瘤動物模式 34
第七章、討論 36
第八章、結論及建議 40
第九章、參考文獻 41
圖表 50
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系統識別號 U0026-1302201513285900
論文名稱(中文) 初診斷乳癌婦女接受化療時其癌因性疲憊之預測因子
論文名稱(英文) The predictors of cancer-related fatigue among women with newly diagnosed breast cancer undergoing chemotherapy
校院名稱 成功大學
系所名稱(中) 護理學系
系所名稱(英) Department of Nursing
學年度 103
學期 1
出版年 104
研究生(中文) 莊雅雯
學號 T26004045
學位類別 碩士
語文別 中文
口試日期 2015-01-09
論文頁數 58頁
口試委員 指導教授-林梅鳳
口試委員-李中一
口試委員-郭耀隆
口試委員-方素瓔
關鍵字(中) 初診斷乳癌婦女
癌因性疲憊
焦慮憂鬱
預測研究
關鍵字(英) women with newly diagnosed breast cancer
cancer-related fatigue
anxiety and depression
predictive study
學科別分類
中文摘要 本研究以前瞻式、縱貫式的研究設計,目的在探討乳癌婦女於初接受單劑化療一個月期間其癌因性疲憊的變化、及其與生理、心理因子的相關性隨時間之變化情形、並找出其預測因子。以南部某醫學中心接受前三劑化學治療的初診斷乳癌婦女為研究對象,由2013年11月至2014年10月收集共73位,於化學治療前、化學治療當天、後一週、後兩週進行人口學與疾病相關資料、癌因性疲憊、睡眠品質、症狀困擾、焦慮憂鬱等評量,並以藍芽無線生理回饋系統收集皮膚電阻、心率變異資料,透過病歷查閱的方式收集化療前後的白血球與血紅素數值。以GEE統計分析法找出單劑化療的癌因性疲憊之重要相關與預測因子。結果發現:一、癌因性疲憊在化學治療後一週最為困擾,並於化學治療後兩週較輕微;二、生理因子(症狀困擾、心率變異)及心理因子(睡眠品質、憂鬱、焦慮)與癌因性疲憊有顯著正相關,且隨時間有不同變化;三、焦慮(β= 1.57)、症狀困擾(β= .55)、睡眠品質(β= .48)、心率變異(β= -.004)是癌因性疲憊的顯著預測因子。
依據本研究發現的疲憊感嚴重度與變化趨勢,提供臨床照護者瞭解初診斷乳癌病人接受單劑化療過程之照護知識與策略,將與癌因性疲憊有關之生理、心理因子納為照護疲憊感患者之評估監測項目;且從疲憊感重要預測因子進一步尋求緩解焦慮、症狀困擾、睡眠品質或心率變異的介入策略;提供更為積極性的疲憊照護處置,提升乳癌婦女於化學治療期間的生活品質。
英文摘要 Cancer-related fatigue (CRF) is defined as a distressing, persistent, subjective sense of physical, emotional, and cognitive tiredness or exhaustion related to cancer or cancer treatment that is cannot relieve with rest. This study aims to examine how cancer-related fatigue (CRF) changed from the time of with newly diagnosed breast cancer undergoing chemotherapy. And to investigate whether specific variables predicted the CRF among women with newly diagnosed breast cancer undergoing chemotherapy. It was the descriptive, longitudinal study, enrolling 73 women with stage I–IIIA breast cancer who received the first three primary or adjuvant chemotherapy. Predictors of CRF were higher levels of trait anxiety, higher symptom distress, higher Sleep disturbances. And heart rate variability also to be significant predictors of CRF. Nurses could use knowledge of predictor of CRF , in order to identify patients at risk for higher levels of CRF and establish an evaluation and screen for CRF prior to initial chemotherapy treatment and at 1-week after chemotherapy, thus it will improve the quality of care.
論文目次 摘要 I
Abstract II
致謝 VI
第壹章、 緒論 1
第一節 研究背景與重要性 1
第二節 研究目的 3
第三節 研究假設 4
第貳章、 文獻回顧 5
第一節 癌因性疲憊 5
第二節 影響癌因性疲憊產生的相關因素 8
第三節 癌因性疲憊的預測性研究 13
第參章、 研究方法學 15
第一節 研究設計 15
第二節 研究對象與場所 16
第三節 研究工具 17
第四節 研究流程 22
第五節 資料分析 23
第六節 倫理考量 24
第肆章、 研究結果 25
第一節 樣本人口學特質 25
第二節 生理及心理因子與癌因性疲憊隨時間變化 27
第三節 生理及心理因子與癌因性疲憊隨時間變化之相關性 31
第四節 影響乳癌婦女癌因性疲憊之預測因子 32
第伍章、 討論 36
第陸章、 結論與應用 39
第一節 結論 39
第二節 臨床實務應用 39
第三節 未來研究應用 39
第四節 研究限制 40
第柒章、 參考文獻 41
第捌章、 附錄 53
附錄一 中文版短型多軸向疲倦測量表(MFSI-SF-C) 53
附錄二 匹茲堡睡眠品質指標量表(Pittsburgh Sleep Quality Index,PSQI) 55
附錄三 住院焦慮憂鬱量表(Hospital Anxiety and Depression Scale) 57
附錄四 症狀困擾量表(Symptom Distress Scale,SDS) 58
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系統識別號 U0026-1712201416494200
論文名稱(中文) Sp1介導microRNAs的表現在肺癌進程中所扮演的角色
論文名稱(英文) The role of Sp1-mediated microRNAs expression in lung cancer progression
校院名稱 成功大學
系所名稱(中) 生物資訊與訊息傳遞研究所
系所名稱(英) Insitute of Bioinformatics and Biosignal Transduction
學年度 103
學期 1
出版年 103
研究生(中文) 楊文賓
學號 Z18981026
學位類別 博士
語文別 英文
口試日期 2014-12-12
論文頁數 135頁
口試委員 指導教授-洪建中
召集委員-林以行
口試委員-劉校生
口試委員-呂佩融
口試委員-呂增宏
口試委員-張文昌
口試委員-郭明良
口試委員-洪文俊
關鍵字(中) Sp1
肺癌
miRNA
miR-182
FOXO3
CD44
關鍵字(英) Sp1
Lung cancer
miRNA
miR-182
FOXO3
CD44
學科別分類
中文摘要 我們近年來的研究指出,Sp1的過量表現會促使肺癌細胞的增長,同時也抑制其轉移能力。在本研究中,我們發現Sp1的表現會去增加FOXO3的轉錄活性,然而其蛋白質的表現量卻是下降的。Sp1藉由增加miR-182的表現,進而與FOXO3 mRNA的3'端未轉譯區域結合,抑制其轉譯活性。當miR-182靜默時會抑制肺癌細胞的生長,但是能藉由增加N-cadherin的表現來增強癌細胞的侵略與遷移能力。在miR-182靜默之細胞株抑制FOXO3的表現能部分逆轉miR-182所造成的細胞侵略影響,証明了miR-182促使肺癌細胞的生長與轉移是藉由調控FOXO3的表現所導致。我們也觀察到一群與癌細胞轉移相關之基因,像是ADAM9、CDH9和CD44的表現量,也隨著miR-182的下降其表現量有增加的情形。此外,我們發現Sp1可能透過調控一群miRNAs (miR-106a, miR-150, miR-182, miR-183*, miR-193a-5p and miR-212-5p) 的表現進而透過CD44的3'端未轉譯區域來抑制其表現,Sp1和CD44的表現在臨床關聯性上也呈現高度負相關的情形,CD44表現量的增加會促使肺癌細胞具有高度遷移與侵略能力。這些發現可以更加證明Sp1具有抑制肺癌轉移的能力。最後,我們進行了染色質免疫沉澱結合次世代定序與小片段RNA 定序技術,發現了50個Sp1可能直接調控的miRNAs,功能分析也指出這些miRNAs參與在細胞凋亡和細胞生長的過程中。綜合上述,我們的研究成果對於Sp1如何調控肺癌發展提供了一個新的見解,在肺癌發展的早期,Sp1藉由刺激miR-182的表現進而降低FOXO3的表現,這樣的調控導致腫瘤的生長。然而在晚期,Sp1和Sp1所調控的miRNAs表現量下降,於是FOXO3和CD44的表現量增加,進而導致肺腫瘤的轉移,由此突顯出miRNAs的生合成在癌症中的重要性。
英文摘要 Our recent study indicated that the expression of Sp1 at a high level enhances the proliferation of lung cancer cells, but represses the metastatic activity of lung cancer. In this study, we found that the transcriptional activity of the FOXO3 was increased, but its protein levels decreased following Sp1 expression. Further studies revealed that Sp1 increased the expression of the miRNA, miR-182, which was then recruited to the 3'-untranslated region of FOXO3 mRNA to silence its translational activity. Knockdown of miR-182 inhibited lung cancer cells growth, but enhanced the invasive and migratory abilities of these cells through increased N-cadherin expression. The repression of FOXO3 expression in the miR-182 knockdown cells partially reversed this effect, suggesting that miR-182 promotes cancer cell growth and inhibits cancer metastatic activity by regulating the expression of FOXO3. The expression of several cancer metastasis-related genes such as ADAM9, CDH9 and CD44 was increased following miR-182 knockdown. Furthermore, we found that Sp1 may regulate the expression of a cluster of miRNAs (miR-106a, miR-150, miR-182, miR-183*, miR-193a-5p and miR-212-5p) to negatively regulate CD44 through 3'-UTR regulation. Clinical relevance indicated that Sp1 expression is negatively correlated with CD44 expression. Enhancement of CD44 expression promoted lung cancer cell migration and invasion abilities. These findings could verify why Sp1 suppresses lung cancer metastasis. Finally, we performed chromatin immunoprecipitation coupled to next-generation sequencing combining with small RNA sequencing technology to identify 50 of mature miRNAs which were potential directly regulated by Sp1. Functional analysis also indicated that these miRNAs were involved in apoptotic process and cell proliferation. In conclusion, our findings provide a new insight of Sp1 regulated lung cancer progression through miRNAs regulation. In the early stages of lung cancer progression, Sp1 stimulates miR-182 expression, which in turn decreases FOXO3 expression. This stimulates proliferation and tumor growth. In the late stages, Sp1 and Sp1-regulated miRNAs decline, thus increasing FOXO3 and CD44 expression, which leads to lung metastasis, thereby highlighting the importance of miRNAs biosynthesis in cancer.
論文目次 摘要 i
Abstract ii
誌謝 iv
Contents vi
Abbreviations x
Chapter 1. Introduction
I. Post-transcriptional regulation 1
II. Lung cancer 3
III. miRNAs in lung cancer 4
IV. Specificity protein 1 (Sp1) 5
V. Involvement of Sp1 in cancer development 5
VI. Sp1-mediated miRNAs biogenesis 8
VII. MicroRNA-182 (miR-182) 9
VIII. Research Aims and significance of the current study 9
Chapter 2. Materials and methods
I. Materials 11
II. Methods 19
Chapter 3. Results
I. Identification of potential Sp1-regulated miRNAs in lung cancer 28
II. Sp1 regulates miR-182 expression 29
III. miR-182 increases lung tumor growth 30
VI. Sp1 inhibits FOXO3 expression by inducing miR-182 expression 31
V. miR-182 inhibits lung cancer metastasis activity 33
VI. Sp1 inhibits CD44 expression through 3-UTR regulation 35
VII. CD44 enhances lung cancer cell migration and invasion abilities 37
Chapter 4. Discussion
I. Identification of a regulatory mechanism for Sp1-mediated repression through miR-182 38
II. Sp1-regulated a cluster of miRNAs is involved in lung cancer metastasis 41
III. Large-scale screening of Sp1-promoter interactions by ChIP coupled to next-generation sequencing 42
IV. Identification of Sp1-regulated miRNAs by combining the techniques of ChIP-Seq and small RNA-Seq 44
V. Future application in human lung cancer therapy 45
Chapter 5. Conclusion 47
Chapter 6. References 48
Tables and Figures
Table 1. miRNAs differentially expressed between lung cancer and normal lung tissues, which were potentially regulated by Sp1. 62
Table 2. Putative Sp1-mediated miRNAs targeting CD44. 63
Figure 1. Sp1 regulates miR-182 expression. 64
Figure 2. Transcriptional activation by binding of Sp1 to miR-182 promoter sequence. 65
Figure 3. The miR-182 level correlates to Sp1 level. 67
Figure 4. Bioinformatics analysis reveals potential target genes of miR-182. 68
Figure 5. miR-182 regulates cell cycle progression. 69
Figure 6. Depletion of miR-182 inhibits lung tumor growth. 70
Figure 7. Regulation of FOXO3 by miR-182 and Sp1. 72
Figure 8. Sp1 negatively regulates FOXO3 expression. 73
Figure 9. Sp1 is involved in both transcriptional and post-transcriptional regulation of FOXO3. 74
Figure 10. Depletion of miR-182 alters cell morphology. 76
Figure 11. miR-182 attenuates lung cancer cell metastasis. 77
Figure 12. Depletion of miR-182 increases the expression of migration-associated genes. 79
Figure 13. Sp1 inhibits CD44 expression through 3'-UTR regulation. 81
Figure 14. Inverse correlation between Sp1 and CD44 mRNA level and protein levels in human lung cancer tissue. 82
Figure 15. CD44 enhances lung cancer cell migration and invasion abilities. 83
Figure 16. Proposed model. 84
Appendixes 86
Curriculum vitae 108
Publications (First author) 110
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系統識別號 U0026-1803201517285200
論文名稱(中文) 針對癌症治療發展對於整合蛋白αvβ3和/或α5β1具有選擇性和親和力的去整合蛋白
論文名稱(英文) Development of Selective and Potent Integrin αvβ3- and/or α5β1-specific Disintegrins for Cancer Therapy
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 黃俊豪
學號 S58971497
學位類別 博士
語文別 中文
口試日期 2015-01-26
論文頁數 116頁
口試委員 指導教授-莊偉哲
口試委員-謝奇璋
口試委員-鄭宏祺
口試委員-王淑鶯
口試委員-符文美
口試委員-陳金榜
關鍵字(中) 蛇毒蛋白
馬來腹蛇
整合蛋白
癌症治療
關鍵字(英) Rhodostomin
integrin
disintegrin
cancer therapy
學科別分類
中文摘要 整合蛋白(integrin)是一群由α和β兩個次單元所組成的異質雙體,其參與許多細胞過程。整合蛋白的配體在與其相互結合時,RGD、NGR和LDV這些胺基酸序列是主要的辨認位置。在含有RGD序列的配體中,其RGD序列周遭區域、協同區域和C端區域可以調節對整合蛋白結合的親和力與專一性。在第一型纖維連結蛋白(fibronectin)之第五(Fn-I5)和第七(Fn-I7)模組中,NGR序列可與整合蛋白α5β1結合,且其自發性去胺基作用會產生isoDGR序列,進而成為一個可以與整合蛋白αvβ3結合的序列,並且在調控纖維連結蛋白的纖維組裝,及調控內皮細胞的黏著和增生都扮演重要的角色。在我的研究中使用含有RGD序列的去整合蛋白,馬來腹蛇的蛇毒蛋白(Rhodostomin,Rho)為一個骨架去探討在去整合蛋白中可能與整合蛋白作用的區域。利用細胞黏著實驗、核磁共振、X光結晶學和分子嵌合模擬去研究整合蛋白與去整合蛋白之間結構和功能的關係。迄今,我們已經成功利用Rho設計出對整合蛋白具有親和力和專一性的抑制劑,包含了對整合蛋白αvβ3具有專一性的48ARLDDL突變株,和對整合蛋白αvβx和α5β1具有專一性的KG突變株。在我的研究中發現RGD的N端區域(殘基39-43)對於整合蛋白αvβ3、αIIbβ3和α5β1的結合扮演重要的角色。細胞黏著實驗顯示馬來腹蛇蛇毒蛋白突變株含有39KKKRT序列有最高的抑制效果,對整合蛋白αvβ3、αIIbβ3和α5β1分別有3.6、4.6和6.2倍的抑制效果提升。相對來說,Rho突變株含有46DD對於整合蛋白αvβ3、αIIbβ3和α5β1分別有7.2、124.5和>582.0倍的抑制效果下降。而RGD的C端區域突變株將54DD置換成54YY對於整合蛋白αvβ3和α5β1的抑制有2.7和3.8倍的提升。野生型Rho、KKKRT和R46E突變株的三維結構已經以X光結晶學解出。而結構的分析顯示,在KKKRT序列中的R42與C端區域的Y67和H68間有交互作用,且在野生型Rho的SRAGK序列沒有發現這樣的交互作用,而KKKRT突變株和整合蛋白嵌合模型中,也顯示R42是與整合蛋白β1和β3次單元中的D216交互作用,而這些作用也沒有在野生型Rho與整合蛋白的嵌合模型中發現。Rho野生型R46側鏈與R46E突變株的E46側鏈方向相反,且在嵌合模型中發現R46可與整合蛋白αIIb次單位的D159形成鹽橋,然而在R46E突變株中E46卻不能形成。這些結果顯示在去整合蛋白中RGD序列附近區域會去影響他們對於整合蛋白之間結合與交互作用。將GNGRG序列放入Rho中去研究其對於整合蛋白的結合,而質譜與核磁共振結果顯示,NGR會轉換成DGR和isoDGR異構物。在細胞黏著的實驗顯示兩個異構物對於整合蛋白αvβ3的IC50約為250 μM,而對於整合蛋白α5β1有較高的抑制能力,isoDGR異構物的IC50為4.5 μM,而isoDGR異構物相較於DGR異構物的抑制能力有6倍增加,且含有isoDGR序列的蛋白對於整合蛋白α5β1是一個較好的配體。流式細胞儀和西方墨點法結果顯示整合蛋白β3降低的A375細胞已經建立,而其黏著實驗顯示細胞無法黏著在纖維蛋白原(fibrinogen)上。細胞爬行實驗顯示Rho、RLD和ARLDDL可以抑制A375細胞的爬行其IC50分別為9.3,3.7和45.1 nM,相對來說Rho、RLD和ARLDDL對整合蛋白β3降低的A375細胞抑制能力為0.5,3.0和>100 μM。這些結果顯示對整合蛋白αvβ3專一性的突變株抑制人類的黑色素細胞瘤是取決於整合蛋白β3的路徑。我們發現Rho和其突變株可以有效抑制管柱形成、細胞爬行和生長,其IC50為5-50 nM。並且也發現可以抑制胰臟癌細胞(AsPC-1、BxPC-3、PANC-1和Mia paca-2)的在vitronectin和fibronectin上的黏著。然而無法抑制黑色素細胞瘤A375細胞在fibronectin的黏著。而Rho和KG抑制胰臟癌和黑色素細胞瘤細胞爬行能力的IC50為40-250 nM。細胞存活實驗也顯示Rho和KG可以抑制細胞生長和藉由Akt/caspase-3途徑誘導細胞凋亡。異種移植動物模型也顯示KG可以抑制胰臟癌腫瘤的生長。這些研究結果可以提供對於癌症治療去設計高度專一性整合蛋白藥物提供一個新的觀點。
英文摘要 Integrins are a family of α/β heterodimeric receptors and modulate many cellular processes. These integrin ligands employ a variant of the RGD, NGR, or LDV motifs as a key element of their major recognition site. RGD-containing ligands are shown to collaborate with specific flanking residues, synergistic site, and C-terminal region to control their integrin binding affinity and specificity. The NGR motif in the 5th and 7th type I repeats of fibronectin is known to bind integrin α5β1, and the spontaneous deamidation of NGR to isoDGR, an integrin αvβ3-binding motif, plays an important role in fibronectin fibril assembly and in regulating endothelial cell adhesion and proliferation. In my study I used rhodostomin (Rho), a disintegrin containing a 48PRGDMP53 motif, as a protein scaffold to investigate the regions of disintegrins involved in integrin interactions. The cell adhesion assay, NMR technique, X-ray crystallography, and molecular docking were used to study structure and functional relationships of disintegrin and integrins. To date, we have successfully used Rho to design potent and selective integrin-specific antagonists, including 48ARLDDL, an integrin αvβ3-specific mutant, and KG, an integrin αvβx-specific mutant. In my study I found the N-terminal region (residues 39-47) adjacent to the RGD motif that plays an important role in interacting with integrins αvβ3, αIIbβ3 and α5β1. The cell adhesion analysis of N-terminal mutants showed that Rho mutant with a 39KKKRT sequence exhibited the highest inhibitory activity with 3.6-, 4.6-, and 6.2-fold increases in inhibiting integrins αIIbβ3, αvβ3, and α5β1 in comparison with those of Rho 48ARGDNP-67NGLYG mutant. We also showed that Rho N-terminal mutant with a 46RR sequence exhibited 3.7- and 3.8-fold increases in inhibiting integrins αvβ3 and α5β1. In contrast, Rho mutant with a 46DD sequence exhibited 7.2-, 124.5-, and >582.0-fold decreases in inhibiting integrins αIIbβ3, αvβ3, and α5β1. The C-terminal mutations of 54DD into YY caused the increases 2.7- and 3.8-fold increases in inhibiting integrins αvβ3 and α5β1. 3D structures of Rho, KKKRT, and R46E mutants were determined by X-ray crystallography. Structural analysis showed that R42 of Rho KKKRT mutant interacted with C-terminal Y67 and H68 residues, which was not found from Rho with a SRAGK sequence. The docking of Rho and its KKKRT mutant into integrins showed that the sidechain of the R42 residue of KKKRT mutant interacted with the residue D216 of β1 and β3. In contrast, these interactions were absent in the Rho-integrin complexes. The sidechain orientation of the R46 residue in Rho and the E46 residue in R46E mutant were different. The docking analysis showed that the sidechain of R46 of Rho, but not E46 of R46E mutant, formed a salt bridge with D159 of αIIb subunit. These results demonstrate that the regions adjacent to the RGD motif in disintegrins affect their function and interactions with integrins. The incorporation of GNGRG amino acid sequence into Rho was used to study its role in integrin recognition. Mass and NMR analyses found that it can be converted into isoDGR and DRG isomers. The cell adhesion analysis showed that two isomers exhibited similar integrin αvβ3 inhibitory activity with the IC50 value of ~250 μM. In contrast, two isomers exhibited higher integrin α5β1 inhibitory activity. The DGR isomer had the IC50 value of 4.5 μM that is 6-fold more active than that of isoDGR isomer, suggesting that integrin ligands with an isoDGR motif are better ligands for integrin α5β1. Flow cytometry and western blot analysis showed that integrin β3-knockdown A375 cells were established. The adhesion analysis showed that the β3-knockdown cells cannot adhere on fibrinogen. The migration analysis showed that Rho, RLD and ALRDDL mutants inhibited A375 cell with the IC50 values of 9.3, 37.4, and 45.1 nM. In contrast, Rho, RLD and ALRDDL mutants inhibited the migration of β3-knockdown cells with the IC50 values of 0.5, 3, and > 100 μM. This result demonstrated that integrin αvβ3-specific mutant inhibited migration of human melanoma cells A375 cells via an integrin β3-dependent pathway. The use of Rho, ARLDDL and KG mutants in inhibiting angiogenesis, pancreatic cancer, and melanoma were evaluated. We found that they effectively inhibited tube formation, migration, and cell growth of endothelial cells with the IC50 values of 5-50 nM. They also inhibited the adhesion of pancreatic cancer cells (AsPC-1, Bx-PC-3, PANC-1, and Mia Paca-2) to vitronectin and fibronectin. In contrast, they cannot inhibit the adhesion of human melanoma A375 cell to fibronectin. We found that Rho and KG inhibited the migration of pancreatic cancer and melanoma cells with the IC50 values of 40-250 nM. The cell viability analysis showed that they also inhibited cell growth and induced cell apoptosis via AKT/caspase-3 pathway. Xenograft animal model showed that KG can inhibit the growth of pancreatic tumor. The results of this will provide new insight into the design of integrin-specific drugs for cancer therapy.
論文目次 CHINESE ABSTRACT I
ABSTRACT III
ACKNOWLEDGMENT V
TABLE OF CONTENTS VI
LIST OF TABLES XI
LIST OF FIGURES XII
ABBREVIATION XIV
CHAPTER 1 INTRODUCTION 1
1.1 RATIONALE 1
1.2 INTEGRINS 1
1.2.1 Overview of integrins 1
1.2.2 Integrin structures 2
1.2.3 Integrins and cancers 3
1.2.4 Integrins and melanoma 4
1.2.5 Integrins and pancreatic cancer 5
1.2.6 Integrins and angiogenesis 5
1.3 INTEGRINS AND ITS LIGANDS 6
1.4 DISINTEGRINS 8
1.4.1 Overview of disintegrins 8
1.4.2 Biomedical applications of disintegrins 9
1.5 RHODOSTOMIN (Rho) 10
1.5.1 Functions of Rhodostomin 10
1.5.2 Structure of Rhodostomin 11
1.5.3 Potent and selecitive Rhodostomin mutants 11
1.6 INTEGRINS AND NGR-COTAINING LIGANDS 12
1.7 STRUCTURE-BASED TECHNIQUE IN PROTEIN DRUG DEVELOPMENT 13
1.7.1 Nuclear magnetic resonance (NMR) 13
1.7.2 X-ray crystallography 13
1.7.3 Molecular docking 14
1.8 SPECIFIC AIMS AND RATIONALES 15
1.8.1 N-terminal region adjacent to RGD loop of disintegrin in integrin recognition 15
1.8.2 Rho and αvβx and α5β1-specific Rho mutant, 39KKART43-46AR47- 48GRGDNP53, in pancreatic cancer therapy 16
1.8.3 Rho and αvβ3-specific Rho mutant 48ARLDDL53 in melanoma 16
1.8.4 Rho and αvβx and α5β1-specific Rho mutant, 39KKART43-46AR47- 48GRGDNP53, in angiogenesis and tumor progression 17
1.8.5 Deamidation of NGR containing ligands 17
CHAPTER 2 MATERIALS AND METHODS 19
2.1 EXPRESSION AND PURIFICATION OF RHO AND ITS MUTANTS 19
2.2 CELL LINES 20
2.3 ANTIBODIES 20
2.4 PLATELET AGGREGATION ASSAY 20
2.5 CELL ADHESION ASSAY 21
2.6 PROTEIN CRYSTALLOGRAPHY 22
2.7 MOLECULAR DOCKING 23
2.8 FLOW CYTOMETRY 25
2.9 MIGRATION AND INVASION ASSAYS 25
2.10 VIABILITY ASSAY 26
2.11 TRANSFECTION OF A375 CELL 26
2.12 CELL APOPTOSIS ASSAY 27
2.13 TUBE FORMATION ASSAY 27
2.14 DEAMIDATION OF RHO MUTANTS 28
CHAPTER 3 RESULTS 29
3.1 EXPRESSION, PURIFICATION AND MASS CHARACTERIZATION OF RHO AND ITS MUTANTS 29
3.2 THE EFFECT OF N-TERMINAL REGION ADJACENT TO RGD LOOP ON INTEGRIN RECOGNITION 29
3.2.1 The effect of N-terminal region (residues 39-43) adjacent to RGD loop on platelet aggregation 30
3.2.2 The effect of N-terminal region (residues 39-43) adjacent to RGD loop on cell adhesion 30
3.2.3 The effect of N-terminal region (residues 46-47) adjacent to RGD loop on platelet aggregation 31
3.2.4 The effect of N-terminal region (residues 46-47) adjacent to RGD loop on cell adhesion 33
3.3 STRUCTURAL ANALYSIS AND DOCKING MODELS OF RHO AND ITS MUTANTS 35
3.3.1 Crystal structures of Rho KKKRT and R46E mutant 35
3.3.2 Structural differences between Rho and KKKRT mutant 36
3.3.3 Interactions in docking model of Rho KKKRT mutant 37
3.3.4 Structural differences between Rho and R46E mutant 38
3.3.5 The differences between the integrin αIIbβ3 complexes of Rho and R46E mutant 38
3.4 EFFECTS OF RHO AND αvβx- AND α5β1-SPECIFIC MUTANT ON HUMAN PANCREATIC CANCER CELL LINES 39
3.4.1 Integrin expression profile of pancreatic cancer cell lines 39
3.4.2 Inhibition of pancreatic cell adhesion by Rho and αvβx- and α5β1-specific mutant 40
3.4.3 Inhibition of pancreatic cell migration by Rho and αvβx- and α5β1-specific mutant 41
3.4.4 Inhibition of cell viability by Rho and αvβx- and α5β1-specific mutant 42
3.4.5 Inhibition of Mia paca-2 cell vibility by Rho and αvβx- and α5β1-specific through inducing apoptosis and reduction akt phosphorylation 43
3.5 EFFECT OF αvβ3-SPECIFIC MUTANT ON MELANOMA 44
3.5.1 Inhibition of melanoma cell adhesion, migration and invasion by integrin αvβ3-specific mutants 44
3.5.2 Involvement of integrin αvβ3 with melanoma cell adhesion, migration and invasion 45
3.6 EFFECTS OF ANGIOGENESIS BY RHO AND ITS INTEGRIN SPECIFIC MUTANTS 46
3.6.1 Inhibition of HUVEC viability by Rho and its mutants 46
3.6.2 Inhibition of serum-induced HUVEC migration by Rho and and its mutants 46
3.6.3 Inhibition of tube formation by Rho and and its mutants 47
3.7 DEAMIDATION OF NGR CONTAINING DISINTEGRINS AND INTEGRIN RECOGNITION 47
CHAPTER 4 DISCUSSION 49
4.1 EFFECT OF N-TERMINAL REGION ADJACENT TO RGD LOOP ON INTEGRINS BINDING 49
4.2 BINDING MECHANISM OF RGD LIGANDS TO INTEGRINS 49
4.2.1 Comparison of synergy region of fibronectin and the N-terminal region adjacent to RGD loop of Rhodostomin 50
4.2.2 Integrin binding site of the N-terminal and C-terminal region adjacent to RGD loop of Rhodostomin 51
4.3 DISINTEGRINS FOR THE TREATMENT OF PANCREATIC CANCER 52
4.4 DISINTEGRINS FOR THE TREATMENT OF MELANOMA 54
4.5 DISINTEGRINS FOR THE INHIBITION OF ANGIOGENESIS 56
4.6 BINDING MECHANISM OF NGR LIGANDS TO INTEGRINS 57
CHAPTER 5 CONCLUSIONS 58
REFERENCES 61
TABLES 70
FIGURES 78
PUBLICATIONS 106
APPENDIX 107
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系統識別號 U0026-2003201522465300
論文名稱(中文) 腫瘤浸潤巨噬細胞與癌細胞間的交互作用及其對胰臟癌幹細胞特性的影響
論文名稱(英文) The mutual interaction between tumor associated macrophages and cancer cells and its impact on pancreatic cancer stemness
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 侯雅琴
學號 S58994128
學位類別 博士
語文別 英文
口試日期 2015-03-20
論文頁數 117頁
口試委員 指導教授-沈延盛
召集委員-賴明德
口試委員-湯銘哲
口試委員-謝達斌
口試委員-陳立宗
口試委員-洪文俊
關鍵字(中) 胰臟癌
癌幹細胞
腫瘤微環境
腫瘤浸潤巨噬細胞
巨噬细胞移動抑制因子
介白素8
趨化激素5
關鍵字(英) Pancreatic cancer
Cancer stem cells
Tumor microenvironment
Tumor-associated macrophages
MIF
IL-8
CCL5
學科別分類
中文摘要 胰臟癌在全世界癌症死亡排名第四位,每年新增病例數目和死亡病例數目幾乎相等,且在台灣發生率正逐年增加。手術切除腫瘤是目前主要的治療方法,但約有90%的患者因診斷較晚已合併遠端轉移、或因嚴重發炎導致組織固化而無法接受手術根除治療,這些患者的五年存活率低於5%,顯示現有疾病的診斷與治療效果有限。研究證實腫瘤相關巨噬細胞的浸潤和癌幹細胞的參與會導致癌細胞增殖、侵犯和轉移,與病患的存活率降低、易復發及喪失對原本有效藥物的反應等結果有關,但目前兩者在胰臟癌所扮演的角色與作用機制尚未清楚。因此我們想要研究胰臟癌細胞與腫瘤浸潤巨噬細胞間的交互作用為何及其對胰臟癌幹細胞活性之影響。首先我們以包含96個胰臟癌病人的組織微陣列進行螢光染色發現腫瘤浸潤巨噬細胞標記C204的表現量和胰臟癌幹細胞標記CD44和CD133呈正相關,且同時高表現CD204和CD44/CD133的病人之存活率是所有組別中最差的,顯示腫瘤浸潤巨噬細胞和胰臟癌幹細胞的存在有密切關係。為了探討兩者間的作用關係,我們將癌細胞與單核球細胞進行共同培養以模擬腫瘤微環境,結果發現胰臟癌細胞中具有癌幹細胞特性的細胞族群會增加,且單核球細胞也因胰臟癌細胞的刺激而分化成腫瘤浸潤巨噬細胞,將胰臟癌幹細胞接種至免疫缺陷老鼠,結果顯示同時接種胰臟癌幹細胞和腫瘤浸潤巨噬細胞的組別會較單獨接種胰臟癌幹細胞的組別形成較大的腫瘤,推論腫瘤浸潤巨噬細胞的存在可以促進胰臟癌幹細胞活性,進一步透過RNA microarray和cytokine protein array的分析,我們認為MIF、IL-8及CCL5可能參與胰臟癌細胞與腫瘤浸潤巨噬細胞間的交互作用,利用MetaCore、即時聚合酶鏈式反應和西方墨點法的結果確認癌細胞會分泌MIF使單核球活化成腫瘤浸潤巨噬細胞,並誘導腫瘤浸潤巨噬細胞分泌IL-8和CCL5去調控胰臟癌幹細胞活性,此一效應可被NF-κB抑制劑所抑制,利用藥物或siRNA抑制MIF的活性可有效減少IL-8和CCL5的產生,進而減少胰臟癌幹細胞和腫瘤浸潤巨噬細胞的族群,此結果也在動物模式上得到驗證,最後分析組織微陣列和病人血清中MIF、IL-8及CCL5的表現量,顯示這3個分子之間呈正相關的關係且與病人預後有關。總結我們的研究發現,腫瘤浸潤巨噬細胞對調控胰臟癌幹細胞扮演一個重要的角色,合併抑制MIF和腫瘤浸潤巨噬細胞的作用能提供治療胰臟癌可針對的標靶。
英文摘要 Pancreatic cancer (PC) is the fourth commonest cause of cancer-related mortality across the world, with incidence equaling mortality. The incidence of PC is gradually increased in Taiwan. Surgery is the primary method to treat patients with PC, but only 10% of the diagnosed patients can be treated by surgical resection. These unresectable cases were divided into two groups on metastasis or locally advanced PC. The five-year survival rate is less than 5%, suggesting the limited in diagnosis and treatment of PC. Recently reports illustrate tumor associated macrophages (TAMs) infiltration in tumor tissue and the existence of cancer stem cells (CSCs) may promote cancer cells proliferation, invasion, and metastasis. Both TAMs and CSCs were associated with poor prognosis. However, the interaction between CSCs and TAMs and the way by which TAMs sustain CSCs mediates PC progression remains to be explored. In this study, we found that CD204-positive TAMs expression related with CD44 and CD133-positive CSCs in tissue microarray containing 96 clinical PC specimens, and coexpression of CSCs and TAMs predicted poor prognosis. Furthermore, we established a coculture system of pancreatic cancer cells and monocytes to monitor how the interplay between CSCs and TAMs accelerates tumor development and progression. The results showed that cancer cells induced TAMs activation via coculture. TAMs promoted cancer stemness and tumorigenesis in vitro and in vivo. On the basis of RNA microarray and cytokine array data, we proposed the interplay between CSCs and TAMs was mediated by secreting MIF, IL-8, and CCL5. We also verified these results by MetaCore, quantitative real-time PCR, and Western blot analysis, and found that CSC growth was regulated in a paracrine manner by TAMs through MIF/IL-8/CCL5 axis; in particular, the inhibition of MIF signaling using a specific inhibitor could suppress cancer stemness and tumour growth. Importantly, the induction of MIF, IL-8, or CCL5 in response to coculture was abolished by NF-κB inhibitor BAY 11-7082. Finally, we confirmed these findings in a cohort of 96 PC patients and determined the clinical significance of MIF/IL-8/CCL5 paracrine signaling on PC progression. Taken together, our results suggest that tumor microenvironment TAMs may play an important role in maintaining cancer stemness. Simultaneous targeting cancer-derived MIF and TAMs is a new therapeutic strategy for PC.
論文目次 中文摘要....I
Abstract....III
致謝....V
Contents....VI
Abbreviation list.....X
Chapter 1:Introduction...1
1-1 Pancreatic cancer...2
1-2 Pancreatic cancer stem cells...2
1-3 Tumor microenvironment in pancreatic cancer...4
1-4 Tumor associated macrophages...5
1-5 Role of TAMs in pancreatic cancer progression...7
1-6 Interplay between CSCs and TAMs...10
1-7 Macrophage migration inhibitory factor...13
1-8 IL-8....14
1-9 CCL5.....16
1-10 Rationales.....18
1-11 Specific aims...19
Chapter 2:Materials and Methods....20
2-1 Patients and TMA construction....21
2-2 Primary cell culture...21
2-3 Monocyte isolation from human peripheral blood..21
2-4 Cell culture....22
2-5 Sphere formation and CSCs harvest..22
2-6 Lentiviral transduction and stable cell line generation...23
2-7 Flow cytometric analysis and cell sorting (FACS) ..23
2-8 Methyl-thiazol-tetrazolium (MTT) assay..23
2-9 Adhesion assay....24
2-10 Phagocytosis assay....24
2-11 RNA extraction, reverse transcription, and quantitative real-time PCR..24
2-12 Cell lysis and Western blot analysis...25
2-13 Cytokine array...25
2-14 ELISA....26
2-15 Immunofluorescence staining and measurement..26
2-16 Tumor formation in NOD/SCID or C57BL/6 mice and drug treatment..27
2-17 Statistics.....28
Chapter 3:Results....29
3-1 Clinicopathological characteristics and outcomes...30
3-2 CD44+/CD133+ CSCs or CD204+ TAMs expression in normal and cancer are..30
3-3 CD44+/CD133+ CSCs or CD204+ TAMs expression versus clinicopathological
characteristics...31
3-4 Clinicopathological features and expression of CD44+/CD133+ CSCs or CD204+
TAMs versus survival....31
3-5 Coexpression of CD44/CD133 and CD204 associated with poor outcomes in PC..32
3-6 CSCs and TAMs are co-present in pancreatic tumors...33
3-7 Coculture of monocytes with pancreatic cancer cells leads to TAMs activation.33
3-8 CD44+CD133+ cells have high CSCs capacity..34
3-9 TAMs support pancreatic CSCs maintenance and promote tumorigenicity.35
3-10 A paracrine network mediates interaction between pancreatic cancer cells and
TAMs....35
3-11 MIF contribute to TAMs activation..36
3-12 MIF trafficking and secretion regulate a paracrine signaling to affect CSCs
subsets.....37
3-13 IL-8 and CCL5 cooperate to improve CSCs activities...38
3-14 MIF signaling is a target to suppress pancreatic cancer progression.39
3-15 MIF/IL-8/CCL5 levels correlate with poor prognosis.39
Chapter 4:Discussion and Conclusion....41
References.....49
Tables and Figures....68
Table 1. Clinicopathological parameters and clinical outcome (n=96) ..68
Table 2. Clinicopathological parameters and expression of CD44, CD133, CD44/CD133, and CD204 (n=96) ...69
Table 3. Multivariate analysis of prognostic factors for overall and disease-free
survival...70
Table 4. Significant genes of pancreatic cancer cells after coculture with U937 cells by
microarray analysis...71
Table 5. Significant genes of U937 cells after coculture with pancreatic cancer cells by
microarray analysis...74
Figure 1. Expression of CSCs markers CD44 and CD133 in TMA and the corresponding
full sections of PC tissue. ....75
Figure 2. Expression of TAMs marker CD204 in TMA and the corresponding full
sections of PC tissue. ...77
Figure 3. The correlation between CD44+/CD133+ CSCs and CD204+ TAMs in PC.79
Figure 4. CSCs and TAMs are co-present in fresh pancreatic tumors and ascites
fluids....81
Figure 5. Pancreatic cancer cells promote TAMs activation...83
Figure 6. Functional characterizations of pancreatic cancer stem cells. ..86
Figure 7. TAMs enhance CSCs properties..88
Figure 8. Pancreatic cancer cells-monocytes crosstalk via paracrine networks mediate
TAMs activation and cancer stemness..91
Figure 9. The MIF/IL-8/CCL5 axis is involved in microenvironmental paracrine
signalling for regulating monocyte-TAMs differentiation and maintaining
cancer stemness....94
Figure 10. Depletion of MIF decreased the presence of CSCs. .97
Figure 11. Blockage of MIF signaling suppresses pancreatic cancer stemness and
tumorigenicity. ....99
Figure 12. The coexpression of MIF, IL-8, and CCL5 are correlated with pancreatic
cancer patients outcomes. ...101
Publication .....103
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系統識別號 U0026-2301201516362700
論文名稱(中文) 靜脈血栓溶解治療於台灣缺血性腦中風病人合併腎臟功能不良之安全性與療效
論文名稱(英文) Safety and Effectiveness of Intravenous Thrombolytic Therapy for Acute Ischemic Stroke Patients with Renal Dysfunction in Taiwan
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 103
學期 1
出版年 104
研究生(中文) 謝鎮陽
學號 TB8981015
學位類別 博士
語文別 英文
口試日期 2014-11-28
論文頁數 81頁
口試委員 指導教授-高雅慧
召集委員-李中一
口試委員-賴明亮
口試委員-林瑞泰
口試委員-曾美君
關鍵字(中) 腦中風
靜脈血栓溶解治療
安全性與療效
腎臟功能不良
症狀性腦出血
關鍵字(英) stroke
intravenous thrombolytic therapy
safety and effectiveness
renal dysfunction
symptomatic intracerebral hemorrhage
學科別分類
中文摘要 研究背景:
腦中風是國人十大死因第三位與成人殘障原因第一位,而缺血性腦中風是最常見的腦中風類別。靜脈使用組織胞漿素酶原活化劑 (rtPA)是目前對於缺血腦中風唯一核准之有效治療。由於擔憂治療後可能出現的嚴重症狀性腦出血,rtPA在台灣的缺血性腦中風病人之使用率偏低,但是實際的全國性藥物處方型態還未知。此外,腎臟功能不良是腦中風病人常見的共病症,而且可能跟rtPA治療後症狀性腦出血有關聯性,但是這樣的關聯性目前尚有爭議,徒增臨床上治療決策的困難。

研究目的:
我們欲探討2003-2010年我國缺血性腦中風病人使用rtPA的比率,並將探討rtPA在合併腎臟功能不良之台灣缺血性腦中風病人的安全性與療效。

研究方法:
首先,我們使用全民健康保險研究資料庫來分析2003-2010台灣缺血性腦中風病人的rtPA使用現況,以及預測rtPA使用與否的相關因子;之後,我們使用多中心腦中風登錄資料庫分析腎臟功能不良與缺血性腦中風病人經rtPA治療後產生症狀性腦出血的關聯性,以及腎臟功能不良與rtPA對於所有在發作4.5小時內到院的缺血性腦中風病人的預後(三個月後modified Rankin Scale 3-6)之影響有無交互作用。

結果:
首先,在2003-2010年全國394,9881筆缺血性腦中風住院資料中,僅有0.60%使用rtPA治療,其使用率從2003年的0.03%微幅增加至2010年的1.51%。腦中風病人的共病症越多,接受到rtPA治療的機率越低 (相較於Charlson comorbidity index [CCI] = 0者, CCI = 1的病人接受rtPA的勝算比: 0.45; 95% 信賴區間: 0.40-0.50; CCI ≥ 2者的勝算比: 0.30; 95% 信賴區間: 0.26-0.34)。
經過多變量分析657位經rtPA治療的缺血性腦中風病人資料,腎臟功能不良與症狀性腦出血並不相關 (勝算比: 1.03; 95%信賴區間: 0.55-1.92)。在另一個針對929位4.5小時內到院之缺血性腦中風病人的分析,rtPA與腎臟功能不良對於預後不佳的勝算比分別為0.70 (95%信賴區間: 0.51-0.96)與0.97 (95%信賴區間: 0.71-1.33),而兩者無顯著的交互作用 (p = 0.218)。

結論:
靜脈血栓治療在我國缺血性腦中風病人之使用率偏低,而低使用率可部分歸因於醫師擔心某些共病症會增加出血的風險。而從我們的臨床資料發現,腎臟功能不良既不會增加症狀性腦出血的風險,亦不會改變rtPA的治療效益。腎臟功能不良本身不應該是缺血性腦中風病人接受rtPA的禁忌症。
英文摘要 Background:
Stroke is the third leading cause of death and first leading cause of adult disability, while acute ischemic stroke (AIS) is the most common type of stroke in Taiwan. Intravenous thrombolytic therapy with recombinant tissue-type plasminogen activator (rtPA) is currently the only approved effective treatment for AIS worldwide. Partly due to concern of the devastating symptomatic intracranial hemorrhage (SICH), rtPA is underutilized in Taiwanese AIS patients. However, the exact utilization pattern has not been determined. Furthermore, renal dysfunction, a common comorbidity of stroke patients, might be associated with SICH after treatment with rtPA in AIS patients. However, such association is controversial and increases the uncertainty when deciding rtPA treatment.

Objective:
We aimed to determine the real utilization rate, and factors predicting utilization of rtPA in all Taiwanese AIS patients from 2003 through 2010. Then we aimed to determine the safety and effectiveness of rtPA in our AIS patients with renal dysfunction.

Method:
Firstly, the nationwide survey of intravenous rtPA for AIS patients was done using the National Health Insurance Research Database from 2003 through 2010. Then we used a multicenter stroke registry database to determine the association of renal dysfunction and SICH in AIS patients treated with intravenous rtPA, and the effect of renal dysfunction and rtPA, as well as their interaction on poor outcome (modified Rankin Scale 3-6 at 3 months) for all AIS patients admitted within 4.5 hours of onset.

Results:
Firstly, of the 394,988 AIS admission from 2003 through 2010, only 0.60% received rtPA. The utilization rate increased from 0.03% in 2003 to 1.51% in 2010. Patients with more comorbidities were less likely to receive rtPA (adjusted odds ratio [OR] for Charlson comorbidity index [CCI] = 1: 0.45; 95% CI: 0.40-0.50; OR for CCI ≥ 2: 0.30; 95% CI: 0.26-0.34, compared to those with CCI = 0).
After multivariable analysis of 657 AIS patients treated with rtPA, renal dysfunction was not associated with SICH (OR: 1.03; 95% confidence interval [CI]: 0.55-1.92). In another analysis for 929 AIS patients within 4.5 hours of onset, the OR for rtPA and renal dysfunction on poor outcomes were 0.70 (95% CI: 0.51-0.96) and 0.97 (95% CI: 0.71-1.33), respectively, without significant interaction (p = 0.218).

Conclusion:
Intravenous thrombolytic therapy was underutilized in our AIS patients, partly due to concern of increased bleeding risk under certain comorbidity. From our practice-based data, renal dysfunction neither increased the risk of SICH after rtPA nor modified the effectiveness of rtPA for AIS. Renal dysfunction alone should not be a reason for withholding treatment from otherwise-eligible AIS patients.
論文目次 Part I. Introduction 1
1. Stroke and Renal Dysfunction 1
1.1 Disease Burdens 2
1.2 Cerebrorenal Interaction 3
2. Intravenous Thrombolytic Therapy for Stroke with Renal Dysfunction 5
2.1 Intravenous Thrombolytic Therapy for Acute Ischemic Stroke 5
2.2 Effect of Renal Dysfunction on Intravenous Thrombolytic Therapy 9
2.3 Statement of the Research Questions 11
3. Specific Aims 11
4. Significance 12
Part II. National Survey of Thrombolytic Therapy for Acute Ischemic Stroke in Taiwan 13
1. Introduction 13
2. Methods 13
2.1 Data Source and Study Design 14
2.2 Definition of Acute Ischemic Stroke Admission and Thrombolytic Therapy 14
2.3 Dissemination of Thrombolytic Therapy across Taiwan over Time 15
2.4 Covariates and Outcomes 15
2.5 Statistical Analysis 16
3. Results 16
3.1 Dissemination of Thrombolytic Therapy through the Hospitals and Counties 17
3.2 Factors Predicting Thrombolytic Therapy 17
3.3 Factors Predicting Complications after Thrombolytic Therapy 18
4. Discussion 18
5. Strength and limitations 21
6. Conclusion 22
Part III. Is Renal Dysfunction Associated with Adverse Stroke Outcome after Thrombolytic Therapy? 33
1. Introduction 33
2. Methods 33
2.1 Data Source 34
2.2 Study design and population 34
2.3 Outcome and covariates 35
2.4 Statistical analysis 35
3. Results 36
3.1 Baseline characteristics of patients 36
3.2 Adjusted effect of renal dysfunction on outcome 37
4. Discussion 37
5. Limitations 39
6. Conclusion and Implications for Future Studies 39
Part IV. Does Renal Dysfunction Modify the Effect of Intravenous Thrombolysis for Acute Ischemic Stroke within 4.5 Hours of Onset? 44
1. Introduction 44
2. Methods 44
2.1 Study Population 45
2.2 Outcomes Measures 46
2.3 Statistical Analysis 46
3. Results 47
3.1 Baseline Characteristics of Patients 47
3.2 Effect of Thrombolytic Therapy and Renal Dysfunction on Outcomes 48
4. Discussion 48
5. Limitations 50
6. Conclusion 51
Part V. Summary and Implications for Future Study 60
Part VI. References 61
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系統識別號 U0026-2405201518183600
論文名稱(中文) 輪椅坐姿系統之研發與生物力學評估
論文名稱(英文) Development and Biomechanical Evaluation of Wheelchair Seating System
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 103
學期 2
出版年 104
研究生(中文) 李俊廷
學號 P88971092
學位類別 博士
語文別 英文
口試日期 2015-05-12
論文頁數 65頁
口試委員 指導教授-張志涵
指導教授-蔡昆宏
口試委員-張立東
口試委員-葉純妤
口試委員-許瑞廷
關鍵字(中) 背痛
壓瘡
肺功能
坐姿
輪椅
高齡者
關鍵字(英) back pain
pressure ulcer
pulmonary function
sitting
wheelchair
elderly
學科別分類
中文摘要 罹患下肢疾病的高齡族群需要仰賴輪椅代步,然而久坐輪椅會導致許多併發症。目前臨床非常重視的併發症包括:背痛、壓瘡及肺功能降低問題。輪椅坐姿系統是重要的關鍵因素之一,它會影響坐姿時的脊椎角度、背部肌肉活動性、介面壓力、肺功能及主觀不舒適性等。儘管過去許多輪椅坐姿系統被發表,但上述問題仍有改善的空間。為了降低因久坐輪椅導致背痛、壓瘡及肺功能降低之風險。本研究提出一新型的輪椅坐姿系統:胸椎後移結合股骨上移支撐坐姿系統。本研究目的主要是評估胸椎後移結合股骨上移支撐坐姿系統在生物力學的影響,包括脊椎角度、背部肌肉活動性、介面壓力、肺功能及主觀不舒適評比。
本研究共招募二十位高齡者參與相關實驗。胸椎後移結合股骨上移支撐坐姿(TF)會與鬆散坐姿(RS)、平背坐姿(FB)、腰椎前凸支撐坐姿(PL)及胸椎後移支撐坐姿(BT)進行比較。本研究進行脊椎角度(胸椎、腰椎及骨盆角度)、背部肌肉活動性(對側T9等級胸豎脊肌、胸段髂肋腰肌、腰豎脊肌及腰多裂肌之最大自主收縮值)、介面壓力(背墊與坐墊之總接觸面積、平均壓力及尖峰壓力)、肺功能(用力肺活量、一秒用力呼氣量及尖峰呼氣流速)及主觀不舒適評比(頸部、肩部、上背部、中背部、下背部、上臂部、下臂部、臀部、大腿部及小腿部)的測量與比較。
在脊椎角度測量結果方面:TF相較於RS、FB及PL有顯著較大的胸椎後凸及腰椎前凸,相較於BT則無顯著性差異;TF相較於RS及PL有顯著較中立的骨盆角度,相較於FB及BT則無顯著性差異。在背部肌肉活動性測量結果方面:TF相較於RS有顯著較大的背部肌肉活動性,相較於FB及PL有顯著較小的背部肌肉活動性,相較於BT則無顯著性差異。在介面壓力測量結果方面:TF相較於其它坐姿有顯著較大的輪椅背墊之總接觸面積、平均壓力及尖峰壓力;BT相較於其它坐姿有顯著較小的輪椅坐墊之平均壓力及尖峰壓力;然而,TF相較於BT有顯著較小的坐墊後半區及較大的坐墊前半區之總接觸面積、平均壓力及尖峰壓力。在肺功能測量結果方面:TF相較於RS、FB及PL有顯著較高的肺功能參數值,相較於BT則無顯著性差異。在主觀不舒適評比結果方面:TF相較於RS、FB及PL有顯著較小的上背部、中背部、下背部的主觀不舒適,相較於BT則無顯著性差異。TF相較於其它坐姿有顯著較小的臀部及較大的大腿部之主觀不舒適程度。
本研究研發之胸椎後移結合股骨上移支撐系統能維持較大腰椎前凸結合較中立骨盆傾斜、減少背部肌肉活動性、降低坐骨粗隆壓力、增進肺功能及舒緩背臀部主觀不舒適程度,幫助維持較佳的輪椅坐姿進而降低罹患背痛、壓瘡及肺功能降低的風險。本研究成果能幫助使用者、醫師及製造商在購買、治療及設計輪椅坐姿系統時的決策處理過程。
英文摘要 Elderly adults with lower limb disorders sitting on a wheelchair for an extended period of time may experience numerous complications. Critical complications in clinical practice include back pain, pressure ulcers, and decreased pulmonary function. Wheelchair seating system is a key factor that influences spinal angle, back muscle activation, interface pressure, pulmonary function, and subjective discomfort. Although numerous studies on wheelchair seating systems have been conducted, it seems that the aspect of aforementioned problems can still be further improved. For reduce the risks of back pain, pressure ulcers, and decreased pulmonary function in wheelchair sitting posture. This study proposed a novel wheelchair seating system concept: the backward thoracic with upward femur support seating system. The purpose of this study was to evaluate the spinal angle, back muscle activation, interface pressure, pulmonary function, and subjective discomfort when using the backward thoracic with upward femur support seating system in the elderly population.
Twenty elderly people were recruited for this study. the backward thoracic with upward femur support sitting (TF) was compared with the relaxed slouching sitting (RS), flat back support sitting (FB), prominent lumbar support sitting (PL), and backward thoracic support sitting (BT). Spinal angle (thoracic, lumbar, and pelvic angles), back muscle activation (maximal voluntary isometric contraction of the thoracic erector spinae at T9, iliocostalis lumborum pars thoracis, lumbar erector spinae, and lumbar multifidus on both sides), interface pressure (total contact area, average pressure, and peak pressure on backrest and seat), pulmonary function (forced vital capacity, forced expiratory volume in 1 second, and peak expiratory flow), and subjective discomfort (neck, shoulder, upper-back, mid-back, lower-back, upper-arm, lower-arm, buttock, thigh, and leg) were measured and compared.
The results of spinal angle measurement: the TF showed relatively higher thoracic kyphosis and lumbar lordosis when compared with the RS, FB and PL, no significant difference when compared with the BT; and it also showed a relatively neutral pelvic tilt when compared with the RS and LP, no significant difference was observed when compared with the FB and BT. The results of back muscle activation measurement: the TF showed relatively higher back muscle activity when compared with RS and lower back muscle activity when compared with the FB and PL in all tested muscles, no significant differences when compared with the BT. The results of interface pressure measurement: the TF showed relatively higher total contact area, average pressure and peak pressure on backrest when compared with the other sitting postures; and the BT showed relatively lower average pressure and peak pressure on seat when compared with the other sitting postures; nevertheless, the TF showed relatively lower total contact area, average pressure, and peak pressure on the back part of seat and higher total contact area, average pressure, and peak pressure on the front part of seat when compared with the BT. The results of pulmonary function test: the TF showed relatively higher pulmonary function values when compared with the RS, FB, and PL in all tested parameters, no significant differences were observed when compared with the BT. The results of subjective discomfort evaluation: the TF showed relatively lower subjective discomfort in upper-back, mid-back, and lower-back when compared with the RS, FB, and PL, no significant difference when compared with the BT; and it also showed relatively lower subjective discomfort in buttock and higher subjective discomfort in thigh when compared with other sitting postures.
The backward thoracic with upward femur support seating system concept was suggested because it maintains an increased lumbar lordosis with rather neutral pelvic tilt, decreased back muscle activation, diminished pressure on the ischial tuberosities, improved pulmonary function, and lessened subjective discomfort in back and buttock which may help maintains a better wheelchair sitting posture for reduce the risks of back pain, pressure ulcers, and pulmonary function decline. The achievements of this study contribute to the decision-making processes of wheelchair seating systems for consumers, clinicians, and manufacturers.
論文目次 摘要 I
ABSTRACT III
誌謝 VI
CONTENTS VII
LIST OF TABLES IX
LIST OF FIGURES X
ABBREVATIONS XII
CHAPTER 1 INTRODUCTION 1
1.1 Population ageing and wheelchair sitting complications 1
1.2 Sitting related to back pain 2
1.3 Sitting related to pressure ulcers 7
1.4 Sitting related to pulmonary function decline 11
1.5 Existing wheelchair seating system 13
1.6 Motivation and purposes 16
CHAPTER 2 MATERIALS AND METHODS 17
2.1 Participants 17
2.2 Wheelchair seating system design 17
2.3 Experimental protocol 20
2.4 Spinal angle measurement 22
2.5 Back muscle activation measurement 25
2.6 Interface pressure measurement 27
2.7 Pulmonary function test 28
2.8 Subjective discomfort evaluation 30
2.9 Statistical analysis 31
CHAPTER 3 RESULTS 32
3.1 Recruited participants 32
3.2 Outcome of spinal angle measurement 32
3.3 Outcome of back muscle activation measurement 35
3.4 Outcome of interface pressure measurement 37
3.5 Outcome of pulmonary function test 41
3.6 Outcome of subjective discomfort evaluation 43
CHAPTER 4 DISCUSSION 46
4.1 Investigation of spinal angle with each sitting posture 46
4.2 Investigation of back muscle activation with each sitting posture 47
4.3 Investigation of interface pressure with each sitting posture 48
4.4 Investigation of pulmonary function with each sitting posture 49
4.5 Investigation of subjective discomfort with each sitting posture 51
4.6 Limitations 52
CHAPTER 5 CONCLUSION 53
5.1 Achievements 53
5.3 Future works 53
REFERENCES 55
APPENDIX: HUMAN STUDY APPROVAL 65
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系統識別號 U0026-2501201517413000
論文名稱(中文) 結晶化對SiO2-Li2O-K2O-P2O5玻璃之機械與光學性質之影響
論文名稱(英文) Effect of Crystallization on Mechanical and Optical Properties of SiO2-Li2O-K2O-P2O5 Glass
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 103
學期 1
出版年 104
研究生(中文) 陳聖涵
學號 P86015010
學位類別 碩士
語文別 英文
口試日期 2015-01-23
論文頁數 63頁
口試委員 指導教授-葉明龍
共同指導教授-郭榮富
共同指導教授-方冠榮
口試委員-莊淑芬
關鍵字(中) 二矽酸鋰
玻璃陶瓷
熱處理
結晶化
機械性質
透明度
透光度
關鍵字(英) Lithium disilicate
Glass-ceramic
Heat treatment
Crystallization
Mechanical properties
Translucency
學科別分類
中文摘要 牙體修復材料的演變已由全金屬材料、陶瓷融和金屬材料、至全陶瓷及玻璃陶瓷材料。現今以陶瓷材料系統最被廣泛使用在醫美牙體修復上,其因陶瓷顏色較接近自然牙顏色。由於二矽酸鋰陶瓷陶瓷材料有足夠的強度以及優異的著色表現使其在牙體修復之美學領域更優於氧化鋯及氧化鋁陶瓷材料。二矽酸鋰玻璃陶瓷之化學組成、結晶化熱處理溫度與著色成份的改變皆會影響其機械強度及其視覺上之美感。
本研究以SiO2-Li2O-K2O-P2O5系統作為二矽酸鋰玻璃陶瓷材料之主要組成,並藉由不同之結晶化熱處理程序探討SiO2-Li2O-K2O-P2O5玻璃陶瓷之機械強度與色澤性質之影響。此材料中SiO2:Li2O之莫爾比為2.39:1之共晶點組成。Li2Si2O5結晶頃向朝(010)之優選方向成長而形成針狀晶粒 此針狀晶粒間則因互相交錯形成連鎖(interlocking)效應而使此材料具有良好的強度與韌性表現。玻璃陶瓷是個既高透度又較容易著色的材料,藉由添加Ce2O3 (黃色)、Er2O3 (粉紅色)及 V2O5(籃色)成份使玻璃陶瓷材料得著上獨立顏色及高透光、透明度表現。
在熱處理製程中 Li2O將首先與SiO2以莫爾比1比1之比例反應形成偏矽酸鋰(Li2SiO3)結晶相。而P2O5則於600℃一段式熱處理開始,因P5+離子有較高的field strength所以打斷原有的Si-Li鍵而形成磷酸鋰(Li3PO4) 所謂的成核因子。在650℃一段式熱處理,大部份的偏矽酸鋰成形而少部分的二矽酸鋰異質成核再磷酸鋰上。在兩段式熱處理於650℃成核熱處理後升溫至700℃時,過量的方晶石(Cristobalite)(SiO2)結晶相形成但因熱能驅動力不足導致偏矽酸鋰未能和方晶石反應形成二矽酸鋰(Li2Si2O5)結晶相。直到兩段式熱處理從650℃成核熱處理後升溫至740℃結晶化熱處理開始,Li2SiO3與過量之SiO2快速反應轉化而形成二矽酸鋰Li2Si2O5。再兩段式熱處理於650℃成核熱處理後升溫至800℃結晶化熱處理,玻璃相才幾乎以完全轉為二矽酸鋰相。
二矽酸鋰由熔融、淬火與兩段式熱處理於650℃成核熱處理後再於740℃結晶化熱處理,試片之雙軸彎曲強度(Biaxial flexural strength)達392MPa,維氏硬度(Vickers’ hardness)則為586HV,韌性則為2.27 K_IC (MPa∙√m)
對添加著色劑的玻璃陶瓷在強度上只有添加1體積比的Er2O3才有明顯的強度降低變化。透光度量測顯示1mm及0.5mm厚度的玻璃陶瓷有明顯的透光度差異。而添加Ce2O3及Er2O3之玻璃陶瓷在添加超過0.8體積比時才有明顯的透光度差異性。透明度量測顯示玻璃陶瓷添加0.4及0.6體積比的Ce2O3有效提其透明度 而添加0.4至1體積比的Er2O3及V2O5會因添加的量上升而降低其透明度。
英文摘要 The evolutions of dental restoration begin with metal, porcelain fused metal, to ceramic or glass-ceramic dental restorative. Nowadays, glass-ceramic system has been extensively used in esthetic dental restoration due to the advantage of natural tooth-like color of glass-ceramic appearance. Lithium disilicate as a glass-ceramic material is superior in esthetic region and sufficient strength than zirconia dioxide and aluminum dioxide based dental restoration. Therefore, with the changes of compositions, heat treatment temperatures, and coloring agents may alter the mechanical properties and esthetic of lithium disilicate glass-ceramic system.
In this study, lithium disilicate glass-ceramic based on SiO2-Li2O-K2O-P2O5 system is used to investigate the relationship between the crystallization with the mechanical and optical properties of the glass-ceramic system. In the lithium disilicate glass-ceramic, the molar ratio of SiO2:Li2O is 2.39:1 which the eutectic composition of SiO2-Li2O-K2O-P2O5 system. The lithium disilicate phase and quartz phase tend to form a high strength lamellar eutectic structure. The (010) orientation is the preferred growth direction for Li2Si2O5 crystal that result in needle-like grains. The interlocking network formed by needle-like grains provides better toughness performance. Glass-ceramic has a high transmittance independent color by staining Ce2O3 (yellow), Er2O3 (pink), and V2O5 (blue) coloring agents.
During the heat treatment process, Li2O initially react with SiO2 with a molar ratio of 1:1 to form lithium metasilicate (Li2SiO3). As the heat treatment temperature increased to 600℃, P5+ ions from P2O5 break the Si-Li bonds due to P5+ ions has a higher field strength. As the heat treatment increase to 650℃, mainly lithium metasilicate has formed with small amount of lithium disilicate appear due to the heterogeneous nucleation. As the two-stage heat treatment of 650℃ followed by 700℃, excess of cristobalite formed, however, lithium disilicate does not occur due to insufficient in driving force. As the two-stage heat treatment of 650℃ followed by 740℃, lithium metasilicate reacted with excess silicon dioxide and precipitate to lithium disilicate. As the second-stage heat treatment increased to 800℃, most of the glass phase has completely transform into lithium disilicate.
With the process of melting, cooling, and two-stage heat treatment of 650℃ followed by 740℃, lithium disilicate has a biaxial flexural strength of 392MPa, Vickers’ hardness of 586HV, and fracture toughness of 2.27 K_IC (MPa∙√m)
Lithium disilicate stained coloring ions Ce2O3, Er2O3, and V2O5 show different level of color changes into yellow, pink and blue respectively. Their combination can be adjusted into further nature looking color. In most case of low concentration of coloring agent addition, the mechanical properties of lithium disilicate do not have significant changes. Lithium disilicate stained with coloring agents shows only Er2O3 with 1 volume percentage has a decrease in flexural strength. The Contrast Ratio shows a decrease in CR value as the specimens thickness increase from 0.5mm to 1mm. Glass-ceramic stained with more than 0.8 volume percentage of Ce2O3 and Er2O3 has a significant different in CR value from normal glass-ceramic. Adding of 0.4 and 0.6 volume percentage of Ce2O3 has an increase in translucency compare with glass-ceramic without staining color.
This study concludes the success of fabrication of lithium disilicate with matching mechanical properties with commercial product and color adjustability.
論文目次 Table of Content
中文摘要 I
Abstract III
Acknowledgement V
Table of Content VI
List of Tables VIII
List of Figures IX
Chapter 1 Introduction 1
Chapter 2 Literature Review 12
2.1 Lithium Disilicate 12
2.2 Optical Analysis 13
Chapter 3 Objective 15
Chapter 4 Materials and Methods 16
4.1 The flow chart of this study 16
4.1.1 Powder Preparation 18
4.1.2 Glass formation 19
4.1.3Crystallization 20
4.2 Properties Analysis 23
4.2.1 Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES) Analysis 23
4.2.2 High Temperature Differential Scanning Calorimetry (HT-DSC) 23
4.2.3 X-Ray Diffractometer (XRD) Analysis 23
4.2.4 Scanning Electron Microscope (SEM) Analysis 24
4.3 Mechanical Properties 24
4.3.1 Vickers Hardness 24
4.3.2 Fracture Toughness 25
4.3.3 Biaxial Flexural Strength 26
4.4 Optical Properties 28
4.4.1 Contrast Ratio (CR) 28
4.4.2 Translucency Parameter (TP) 28
4.5 Statistic Analysis 30
Chapter 5 Results and Discussion 31
5.1 Investigation of the Mechanisms of Nucleation and Crystallization of Glass-Ceramic Formation 31
5.1.1 Thermal Analysis of glass-ceramic 31
5.1.2 Crystallization Analysis of the Various Heat Treatment Process 33
5.1.3Effect of Heat treatment on Microstructure of Lithium Disilicate 38
5.2 The Mechanical Properties of Crystallized Lithium Disilicate 42
5.2.1 Mechanical strength of lithium disilicate with different heat treatment 42
5.2.2 Mechanical Strength of Lithium Disilicate Doped with Color Agents 48
5.3 Optical Properties 51
5.3.1 Contrast Ratio of Lithium Disilicate Glass-Ceramic Doped with Color Agents: Cerium Oxide, Erbium Oxide, and Vanadium Oxide 54
5.3.2 Translucency Parameter of Lithium Disilicate Doping with Coloring Agents: Cerium Oxide, Erbium Oxide, and Vanadium Oxide 56
Chapter 6 Conclusion 59
References 61


List of Tables
Table1-1. The dental ceramic materials 1
Table 4-1. Powders information 18
Table 5-1. Fracture toughness diagram. Profile (III) is glass-ceramic heat- treated at 650℃for30min followed by 740℃for30min 46


List of Figures
Figure 1-1. Lithium disilicate (Li2Si2O5) Layer Silicate 4
[Obtained from W. Höland and G.H. Beall (2012) under fair use, 2015] (Holand & Beall, 2012) 4
Figure 1-2. The structure of a crystalline ceramics and an amorphous glass 5
[Obtained from El-Meliegy and van Noort (2012) under fair use, 2015](El-Meliegy & van Noort, 2012) 5
Figure 1-3. SiO2-Li2O Binary phase diagram 6
[Obtained from Levin et al., (1964); West and Glasser, (1971); Hasdemir et al., (1998); Soares et al.,(2008) under fair use, 2015](Hasdemir, Bruckner, & Deubener, 1998; Levin, Robbins, & McMurdie, 1975; Soares, Zanotto, Fokin, & Jain, 2003; West & Glasser, 1971) 6
Figure 1-4. Processing diagram for the formation of glass-ceramic 8
Figure 1-5. From glass to glass-ceramic. (a) Nuclei formation, (b) crystal growth on nuclei, and (c) glass-ceramic microstructure. 8
[Obtained from Höland and Beall (2012) under fair use, 2015](Holand & Beall, 2012) 8
Figure1-6. CIEL*a*b* Diagram (El-Meliegy & van Noort, 2012) 10
Figure1-7. The Visible Light Diagram (El-Meliegy & van Noort, 2012) 10
Figure1-8. The Chormacity Diagram (El-Meliegy & van Noort, 2012) 11
Figure 4-1. Experimental flow chart of lithium disilicate glass powder preparation 16
Figure 4-2. Experimental flow chart of glass-ceramic formation. 17
Figure 4-3. Graph of temperature versus time for the calcination of initial powder 21
Figure 4-4. Graph of temperature versus time for the melting process 21
Figure 4-5. Heat treatment temperature profile of glass-ceramic’s morphology. 22
Figure 4-6. Heat treatment temperature profile of glass-ceramic. 22
Figure 5-1. DSC diagram of the glass specimen 32
Figure 5-2. XRD patterns of the glass with different heat treatment profile. 34
Figure 5-3. Epitaxial growth of cristobalite, lithium metasilicate, and lithium disilicate on lithium orthophosphate crystal. LS= lithium metasilicate, CR= cristobalite, LS2= lithium disilicate, and LP=lithium orthophosphate [obtained from Headley et al. (1984) under fair use, 2015](Headley & Loehman, 1984) 37
Figure 5-4. SEM micrograph of glass-ceramic heat treated at 650℃for 30 minutes with 10,000x magnification 39
Figure 5-5. SEM micrograph of glass-ceramic heat treated at 650℃for 30 minutes and 700℃for 30 minutes with 10,000x magnification. 40
Figure 5-6. SEM micrograph of glass-ceramic heat treated at 650℃ for 30 minutes and 740℃for 30 minutes with 10,000x magnification. 40
Figure 5-7. SEM micrograph of glass-ceramic heat treated at 650℃ for 30 minutes and 800℃for 30 minutes with 10,000x magnification. 41
Figure 5-8. Vickers’ hardness of glass-ceramic heat treated with varies heat treatment temperatures. (I) Heat-treated at 650℃for 30minutes, (II) Heat-treated at 650℃ for 30minutues then 700℃ for 30minutes, (III) Heat-treated at 650℃ for 30minutues then 740℃ for 30minutes, (IV) Heat-treated at 650℃ for 30minutues then 800℃ for 30minutes 43
Figure 5-9. Statistical analysis of biaxial flexure strength vs heat treatment 44
Figure 5-10. Biaxial flexure strength of glass-ceramic with varies heat treatment temperature. (I) Heat-treated at 650℃for 30minutes, (II) Heat-treated at 650℃ for 30minutues then 700℃ for 30minutes, (III) Heat-treated at 650℃ for 30minutues then 740℃ for 30minutes, (IV) Heat-treated at 650℃ for 30minutues then 800℃ for 30minutes 45
Figure 5-11. The crack lengths of glass loaded with 10N and hold for 15seconds. 47
Figure 5-12. The crack lengths of profile (III) loaded with 10N and hold for 15seconds 47
Figure 5-13: Biaxial flexure strength of glass-ceramic doped with volume percentage of CeO2 49
Figure 5-14: Biaxial flexure strength of glass-ceramic doped with volume percentage of Er2O3 49
Figure 5-15: Biaxial flexure strength of glass-ceramic doped with volume percentage of V2O5 50
Figure 5-16. The XRD diagram of glass-ceramic doped with one volume percentage of coloring agents. a) Vanadium oxide, b) Erbium oxide, c) Cerium oxide. 50
Figure 5-17. Glass-ceramic doped with vol% of cerium oxide. From left to right: 1vol%, 0.8vol%, 0.6vol%, 0.4vol%, and normal glass-ceramic 51
Figure 5-18. Glass-ceramic doped with vol% of erbium oxide. From left to right: 1vol%, 0.8vol%, 0.6vol%, 0.4vol%, and normal glass-ceramic 52
Figure 5-19. Glass-ceramic doped with vol% of vanadium oxide. From left to right: 1vol%, 0.8vol%, 0.6vol%, 0.4vol%, and normal glass-ceramic 52
Figure 5-20. Glass-ceramic doped with 0.4 vol% of three types coloring agents. From left to right: cerium oxide, erbium oxide, vanadium oxide, and normal glass-ceramic 53
Figure 5-21. Glass-ceramic doped with 1 vol% of three types coloring agents. From left to right: cerium oxide, erbium oxide, vanadium oxide, and normal glass-ceramic. 53
Figure 5-22. Contrast ratio diagram of glass-ceramic doped with volume percentages of cerium oxide. 54
Figure 5-23 Contrast ratio diagram of glass-ceramic doped with volume percentages of erbium oxide 55
Figure 5-24. Contrast ratio diagram of glass-ceramic doped with volume percentages of vanadium oxide 55
Figure 5-25. Translucency parameter diagram of glass-ceramic doped with volume percentages of cerium oxide 57
Figure 5-26. Translucency parameter diagram of glass-ceramic doped with volume percentage of erbium oxide 57
Figure 5-27. Translucency parameter diagram of glass-ceramic doped with volume percentage of vanadium oxide 58
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