http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16 Sat, 03 Oct 2026 14:17:20 GMT 2026-10-03T14:17:20Z http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/41749 標題: 鼻腔暴露與氣管灌注奈米氧化鋅微粒後動物體內肺部外鋅轉移情形研究; Extrapulmonary Translocation of Ultrafine Zinc Oxide Particles Following Nose-only Exposure and Intratracheal Instillation 作者: Chun-Nung Chang; 張淳農 摘要: 奈米氧化鋅被廣泛的應用在工業以及生產上，其大量的生產也造成了工人在製造、包裝及運輸過程中的暴露機會。有研究指出，奈米微粒進入生物體內會引發發炎、血栓以及心血管疾病，甚至進一步穿透細胞間隙進入循環系統，透過再分佈到達體內各器官、組織。本研究的目的在應用微透析技術連續採樣的優點，探討氧化鋅在動物循環系統的濃度變化情形。以及氣管灌注奈米氧化鋅至動物體內後，氧化鋅在器官、組織間的分布情形，並以此作為後續氧化鋅相關健康危害研究的基礎。 本研究使用七週大之 Sprague-Dawley 雄鼠，實驗分為呼吸暴露以及氣管灌注實驗兩個部份進行。微透析採樣部份以鼻腔暴露方式暴露於乾淨空氣1小時後 接續暴露50 nm 級之氧化鋅微粒4小時，暴露期間以微透析進行血液透析液連續採樣。第二部份將市售奈米氧化鋅及細微粒氧化鋅利用氣管灌注方式暴露至老鼠體內，每組實驗動物三隻，劑量為 5mg/kg，並在暴露後3小時、6小時、12小時、24小時分批進行犧牲，取得血清、血漿、全血、心臟、肺臟、肝臟、腎臟樣本，經微波消化後以感應耦合電漿質譜儀定量分析鋅濃度。 微透析透析液分析結果顯示，在體外實驗的回收率僅有4.3 %，在不同批次的實驗當中透析液的鋅濃度也未隨時間出現明顯變化趨勢。實驗動物體內高鋅背景值也對實驗結果造成影響。氣管灌注的實驗結果指出，在奈米氧化鋅以及細微粒氧化鋅實驗動物當中血清、全血，以及肝臟的鋅濃度有隨時間上升的趨勢，其他如血漿、心、肺臟及腎臟樣本中之鋅含量則未觀察到明顯的變化。實驗動物暴露不同粒徑大小微粒後各個器官的鋅濃度分布的差異也未達統計顯著。 本研究結果指出應用微透析採樣技術於奈米氧化鋅暴露實驗採樣並不成功，且需要進一步的調整實驗參數、介質與透析溶液，改進微透析對氧化鋅微粒的回收率，再應用於將來的實驗當中。氣管灌注實驗中，動物體內鋅背景值干擾器官與組織的鋅濃度定量，血漿、心、肺臟及腎臟中鋅的濃度並無顯著變化，但血清中的鋅濃度變化支持了氧化鋅微粒進入循環系統的假設。另外，於肝臟觀察到明顯的鋅濃度提升，有可能是氧化鋅經由循環系統再進入肝臟。但另一推測是實驗動物在灌注的過程中將氧化鋅食入消化道所導致，這部份仍需進一步實驗證明肝臟中的氧化鋅來源。後續研究將應用同位素技術以及發展微透析技術於奈米氧化鋅在體內之分布來解決背景值以及動物體間差異性的影響。; Nano-sized zinc oxide was applied in industries extensively, and many workers are exposed to zinc oxide directly or indirectly in factories, production facilities, and in operation where zinc oxide was proceeded, used, disposed, or recycled concurrently. However, there are literatures indicating that nano-sized particles may induce inflammation, thrombosis and cardiovascular diseases, or even penetrate into systemic circulation and redistribute to secondary organs. In our study, the aims were set to explore the zinc translocation in systemic circulation, characterize the distributions of the zinc levels in rat organs after exposing to fine and ultrafine particles intratracheally, and provide relevant the parameters for further kinetics studies. Seven-week old male Sprague-Dawley (SD) rats were used in this study. This study was conducted in two parts. In the first part, study animals were exposed to clean air for 1 hour and then exposed to airborne zinc oxide for 4 hours. Continuous microdialysis sampling was performed during the exposure experiment. On the other part, we intratracheally instilled ultrafine and fine zinc oxide particles of 50 nm and 325 Mesh, respectively, in PBS solution to the study animals at a dose of 5mg/kg, with three animals per group. Rats were sacrificed at 3, 6 ,12 and 24 hours post exposure, and the zinc concentrations in whole blood, plasma, serum, heart, lung, liver, kidney and dialysates of the study animals were determined by inductive coupled plasma mass spectrometry (ICP-MS) following the pretreatment process of freeze-drying and microwave digestion. The results of microdialysis revealed that in vitro recovery rate for zinc oxide was only 4.3%, and no obvious trend for zinc levels in dialysate with times was observed. In addition, the high zinc background level in the study animal might interfere with the results of zinc analysis. In the part of intratracheal instillation study, zinc levels were found elevated in serum, whole blood and liver in both ultrafine and fine zinc oxide particle exposure groups. However, there was no obvious trend for plasma, heart, lung and kidney samples. The difference in zinc levels in organ and tissue samples between these two exposure groups was not statistically significant. The results indicated the application of microdialysis in inhalation study was not successful in this study. The elevations of zinc levels in serum, liver with time after exposing to nano-sized zinc oxide particles intratracheally supported that the particle translocation happened to systemic circulation, although the trends were not obvious. The elevation of zinc level in liver is probably attributed to the systemic translocation. However, another speculation is attributed to the absorption from gastrointestinal system while intratracheal instillation. Further study needs to clarify the exposure routes for zinc oxide particulates. Isotope technology is considered to be applied in the future study to differentiate the inhaled zinc content during experimental study from the background levels in organism. In general, the findings in our study provided preliminary information on the distribution of nano-sized ZnO particle in experimental animals after inhalation exposure for risk assessment. Thu, 01 Jan 2009 00:00:00 GMT http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/41749 2009-01-01T00:00:00Z http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29119 標題: 鼻咽癌與FAS、FASL、NF-κB 和 TRAF3基因多形性之流行病學研究; Epidemiological Study on Nasopharyngeal Carcinoma and Genetic Polymorphisms of FAS, FASL, NF-κB and TRAF3 作者: Guan-Yuan Liou; 劉冠嫄 摘要: 背景介紹:鼻咽癌 (nasopharyngeal carcinoma, NPC) 是一種在其他族群非常罕見，但卻是中國南方和東南亞常見的癌症。過去文獻指出遺傳因子和環境因子共同在鼻咽癌的發展過程中扮演重要角色，包括Epstein-Barr virus (EBV) 感染、飲食因子例如中國鹹魚、職業上的暴露、家族性聚集傾向，宿主易感受性遺傳因子都被證實和鼻咽癌的危險性有關。EB病毒在體內的持續性感染被視為鼻咽癌致病機轉的重要因素之ㄧ，EB病毒會引起B細胞的不朽化。腫瘤壞死因子受體相關因子3 (tumor necrosis factor receptor-associated factor3, TRAF3) 為細胞內辨識EB病毒進而引起第一型干擾素的重要因子，同時也會和EB病毒轉譯的潛伏膜蛋白1 (latent membrane protein 1, LMP1) 結合而引起B淋巴細胞的轉形。FAS (CD95, APO-1)、FAS配體 (FASL) 和 核因子-κB (nuclear factor-kappa B, NF-κB) 在細胞凋亡的訊息傳遞路徑扮演重要的角色。本研究欲探討細胞凋亡相關基因多形性與鼻咽癌發生的相關性。 研究方法:總共有317名經由組織病理學確認的鼻咽癌病患與268名符合條件的健康對照納入本研究。從台北市兩大醫院中選取確診為鼻咽癌的個案為病例組，依病例的性別、年齡(每五歲一組，在相同年齡組別中)、居住地作1:1個別配對，從戶籍資料系統中選取符合條件的為對照組。訪員對納入收案對象以結構式問卷進行標準化訪視，取得個案的社會人口學及暴露鼻咽癌相關危險因子的資料，抽取個案周邊血，血清進行EB病毒抗體標誌的檢測；白血球的DNA進行細胞凋亡相關基因的單一核苷酸多形性分析。結果以卡方檢定和費雪精確檢定分析病例組與對照組的基本人口學變項、危險因子狀態及基因頻率分布，以適合度檢定對照組的基因頻率是否符合哈溫平衡，利用非條件式羅吉斯迴歸方式評估單一核苷酸多形性(single nucleotide polymorphism, SNP) 標記對鼻咽癌的危險性。所有的危險性估計值都有調整年齡、性別、教育程度和種族。 結果: FAS (-1377)、FAS (-670)、FASL (-844) 和NF-kB(-94)之基因型與鼻咽癌發生的危險性沒有統計顯著相關，FAS (-1377) 和 FAS (-670) 所建構的haplotype和鼻咽癌的發生也沒有統計顯著相關，而在TRAF3基因上，若600的位置為AA或AG基因型有較高的鼻咽癌發生風險(ORadj, 1.85; 95% CI, 1.12-3.04)。將病例組以鼻咽癌家族病史進行分層分析，發現TRAF3基因型和鼻咽癌家族病史沒有統計顯著相關，。在對照組與病例組，EB病毒的抗體陽性狀態與TRAF3基因型也無統計顯著相關。在感染EB病毒之溶解期相關蛋白的抗體標誌陽性狀況下，TRAF3基因型與鼻咽癌發生有統計顯著相關。 結論: TRAF3 (codon 600) 的基因多形性與鼻咽癌的發生有密切相關；而FAS、FASL 和NF-kB的基因多形性，則與鼻咽癌無統計顯著相關。; Background: Epstein-Barr virus (EBV) infection is an important risk factor for nasopharyngeal carcinoma (NPC). EBV causes the immortalization and transformation of infected cells. Tumor necrosis factor receptor-associated factor 3 (TRAF3) is required for EBV recognition and initiation of type I interferon production. It is also required for activation of B lymphocytes by EBV latent membrane protein 1 (LMP1). FAS (CD95, APO-1), FAS ligand (FASL) and nuclear factor-kappa B (NF-κB) also play important roles in the apoptosis. This case-control study aimed to examine the associations between NPC and polymorphisms of these genes. Methods: A total of 317 cases affected with histologically confirmed NPC and 268 healthy community controls matched with cases on gender, age and residence were enrolled. Blood samples were collected for the examination of IgA antibodies against EBV-specific viral capsid antigen (anti-EBV VCA IgA) and Epstein-Barr nuclear antigen 1 (anti-EBNA 1 IgA) and IgG antibodies against DNA binding protein (anti-EBV DBP IgG) and DNase (anti-EBV DNase IgG). The real-time PCR assay was used for genotyping of TRAF3 (codon 600), FAS (-1377 and –670), FASL (-844) and NF-κB (-94). Logistic regression analysis was used to estimate multivariate-adjusted odds ratio (ORadj) with its 95% confidence interval (CI) for each genotype after adjustment for age, gender, educational level, and ethnicity. Results: Genetic polymorphisms of FAS (-1377), FAS (-670), FASL (-844) and NF-kB (-94) were not significantly associated with the risk of NPC. The haplotype of FAS (-1377 and -670) was not significantly associated with NPC risk either. Individuals with the TRAF3 (codon 600) AA or AG genotype had an increased NPC risk compared with GG genotype as the referent group (ORadj, 1.85; 95% CI, 1.12-3.04). In NPC cases, family NPC history was not associated with TRAF3 (codon 600) genotype. The seropositivity of various antibodies against EBV was not significantly associated with TRAF3 (codon 600) genotype in either NPC cases or controls. TRAF3 (codon 600) genotype was associated with an increased risk of NPC in those who were seropositive on anti-EBV VCA IgA, anti-EBV DBP IgG, and anti-EBV DNase IgG. Highest NPC risk was observed for those who were anti-EBV-seropositive with AA/AG genotype of TRAF3 (codon 600). Conclusions: There is a significant association with NPC for TRAF3 genotype, but not for FAS, FASL and NF-κB genotypes. TRAF3 (codon 600) AA/AG genotype was associated with an increased risk of NPC compared with GG genotype, especially in those who were seropositive on antibodies against EBV proteins expressed in lytic infection. Mon, 01 Jan 2007 00:00:00 GMT http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29119 2007-01-01T00:00:00Z http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/104508 標題: 鼻咽癌病患台灣本土預後模型開發與跨族群驗證; Development of a Taiwan-Specific Prognostic Model for Nasopharyngeal Carcinoma Patients and Cross- Ethnic Validation 作者: 班詠絜; Yung-Chieh Ban 摘要: 研究背景與目的 鼻咽癌在流行病學上有顯著的地理分佈差異,尤其在東亞與東南亞地區發生率較高。雖然傳統的美國聯合癌症聯合委員會 (AJCC) 分期系統提供了統一的臨床預後評估標準,但其主要基於解剖學範圍,未能納入臨床病理特徵及生活習慣等重要預後因子,因此本研究旨在開發一個整合臨床病理參數與生活行為因子的多變項預測模型,並透過內外部驗證提升鼻咽癌患者在整體存活率、癌症特異性存活率及無病存活率上的精準度。 研究方法 本研究利用台灣癌症登記資料庫 (TCR) 進行模型開發與內部驗證。主要建構兩個不同的多變項 Cox 比例風險模型:模型 1 為單變項顯著且可透過美國監測、流行病學及最終結果計畫 (SEER) 驗證的參數,包含年齡、性別、T 與 N分期、腫瘤分級及組織學類型;模型 2 則進一步納入 BMI、抽菸、飲酒及嚼食檳榔等行為因子。主要透過 10 倍交叉進行內部驗證,並利用 SEER 資料庫針對模型 1 進行跨種族(亞裔、白人、非裔)的外部驗證,以 Harrell’s C-index 與校正分析評估模型表現。 研究結果 本研究模型在各個存活預測指標上均有穩定精準的辨別力。在內部驗證中,模型 1 與模型 2 的整體存活率 C-index 分別為 0.7152 與 0.7155;癌症特異性存活率也都達到 0.7174,校正分析也顯示預測事件數與實際觀察值具高度一致性;外部驗證進一步證實了該框架在亞洲族群中具備良好的預測外推性。相較於單純使用 AJCC 分期系統在各存活終點的預測局限,其 C-index 僅介於0.613 至 0.647 之間,本研究模型提供了實質的預測增益。 結論 本研究整合臨床病理特徵,建立了一個針對台灣族群的鼻咽癌預後預測模型,相較傳統 AJCC 分期能提供更精準的風險分層,且具外部驗證效力,能為臨床決策提供實質建議與價值。; Background and Objectives The epidemiology of nasopharyngeal carcinoma (NPC) is characterized by a remarkable geographic heterogeneity, demonstrating a disproportionately high prevalence within East and Southeast Asian populations. Although the conventional AJCC staging system is a cornerstone for clinical prognosis, its primary focus on anatomical extent overlooks critical prognostic factors such as clinicopathological characteristics and lifestyle behaviors. This study aimed to develop a multivariable prognostic framework integrating clinicopathological and lifestyle variables. By employing both internal and external validation, the research sought to enhance predictive accuracy for overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) in patients with NPC. Methods The Taiwan Cancer Registry (TCR) was utilized for model development and internal validation. Two distinct multivariable Cox proportional hazards models were constructed: Model 1 included univariate significant factors verifiable within the Surveillance, Epidemiology, and End Results (SEER) Program, specifically age, sex, T and N categories, tumor grade, and histological type; Model 2 further incorporated BMI and lifestyle factors, including smoking, alcohol consumption, and betel nut chewing. Internal validation was performed using 10-fold cross-validation, while external validation of Model 1 was conducted across racial subgroups (Asian, White, and Black) using the SEER database. Model performance across both validation phases was evaluated using Harrell’s C-index and calibration analysis to assess discriminative ability and reliability. Results The integrated models demonstrated robust discriminative ability across all survival endpoints. In the internal validation, the C-indices for OS reached 0.7152 in Model 1 and 0.7155 in Model 2, while both models achieved a C-index of 0.7174 for CSS. Calibration analysis confirmed a high degree of agreement between predicted events and actual observed outcomes. External validation supported the generalizability of the models to Asian populations. Compared to the prognostic limitations of the conventional AJCC staging system alone across survival endpoints, which provided C-index ranging modestly between 0.613 and 0.647, this integrated framework delivered a substantial predictive increment. Conclusions This study established a prognostic prediction model for NPC tailored to the Taiwanese population by integrating diverse clinical variables. Compared to the traditional AJCC staging system, this framework provides more refined risk stratification and possesses strong external validation efficacy, offering substantial recommendations and practical value for clinical decision-making. Thu, 01 Jan 2026 00:00:00 GMT http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/104508 2026-01-01T00:00:00Z http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99915 標題: 鼻咽癌患者經放射治療後缺血性腦中風的預防與預測; Prevention and Prediction of Ischemic Stroke in post Radiotherapy Nasopharyngeal Carcinoma Patients 作者: 林傳益; Chuan-Yi Lin 摘要: 背景：在台灣，鼻咽癌是第二常見的頭頸癌，佔所有癌症病例的5%以及頭頸癌的50%。放射治療是治療鼻咽癌最有效的方法，然而放射線治療照射部位包含顱底與頸部可能導致頸動脈狹窄，進而增加缺血性中風的風險。在現代，結合強度調控放射治療與全身化學治療，非遠端轉移的末期鼻咽癌患者的預後極佳。隨著長期存活者人數增加，預測與預防晚期放射治療相關併發症的重要性日益提升。 研究目的與方法：第一個研究目標（研究一）是評估在接受標準同步化學放射治療之晚期鼻咽癌患者中，使用他汀類藥物對缺血性中風風險的影響。在研究一中，我們使用了台灣癌症登記資料庫（TCRD）與台灣全民健康保險研究資料庫（NHIRD）連結的全國性資料。我們採用逆機率加權（IPTW）Cox 回歸分析，以探討在同步化學放射治療期間使用他汀類藥物與缺血性中風風險之間的關聯性。第二個研究目標（研究二）是建立一套風險預測模型，以辨識在接受放射治療後可能發展為中度以上內頸動脈狹窄的高風險鼻咽癌患者族群。研究二的資料來源為台大醫院整合醫療資料庫（NTUH-iMD）中的電子病歷資料。我們分析接受放射治療後鼻咽癌患者頸內動脈狹窄的風險因子，並利用逐步變數選擇法建立 Cox 比例風險模型的風險預測模型。此外，我們建立了接收者操作特徵曲線（ROC curve）與布萊爾分數（Brier score)，以評估該風險預測模型的判別能力與整體表現。第三個研究目標（屬於研究二）是釐清接受放射治療後鼻咽癌患者進行頸動脈超音波篩檢的最佳起始時機。為了闡明風險的時間分布，我們應用多變量廣義線性混合模型（Generalized Linear Mixed Model, GLMM），以判定放射治療後與發生中度以上內頸動脈狹窄最密切相關的年度時間點。 結果：在研究一中，相較於未使用他汀類藥物的族群，使用他汀類藥物患者的缺血性中風調整後風險比（aHR）為0.70（95%信賴區間：0.54–0.92；P 值為 0.0107）。累積規定日劑量（cDDD）分析顯示劑量反應關係，在 cDDD 較高的四分位數中觀察到較低的缺血性中風風險。此外，日定義劑量（DDD）大於 1 的患者缺血性中風風險降低，其 aHR 為 0.49（95%CI：0.31–0.63）；而DDD 小於或等於 1 的患者，其 aHR 為 0.59（95% CI：0.40–0.84）。在研究二中，根據我們建立的預測模型，風險分數達 5 分以上的高風險族群，其發生中度或以上內頸動脈狹窄的風險明顯增加，且可能在接受放射治療後的第四年即開始出現。此外，我們發現，相較於整體族群的平均風險，發生中度或以上內頸動脈狹窄的風險大約在放射治療後第七年左右開始顯著且持續上升。 結論：我們的研究一提供了證據，支持在接受標準同步化學放射治療的晚期鼻咽癌患者中，他汀類藥物於治療期間使用，能有效降低放射治療引起的缺血性中風風險。在研究二中，根據我們提出的風險預測模型，我們建議鼻咽癌患者於放射治療後第七年開始進行頸動脈超音波篩檢，而高風險族群患者則應提早開始於放數線治療後第四年即開始篩檢。; Introduction: In Taiwan, nasopharyngeal carcinoma (NPC) is the second most common type of head and neck cancer, accounting for approximately 5% of all cancer cases and representing nearly 50% of all head and neck malignancies. Radiotherapy (RT) serves as the most effective treatment for NPC but can induce carotid stenosis and increase the risk of ischemic stroke. In modern era of intensity modulated radiation therapy (IMRT) and effective systemic chemotherapy, prognosis of patients with localized NPC is excellent. With larger number of long-term survivors, the prediction and prevention of late RT-related complications has become important. Study Aims and Methods: The aim 1 of this doctoral dissertation (study 1) is to evaluate the impact of statin use on ischemic stroke risk in patients with advanced NPC undergoing standard concurrent chemoradiotherapy (CCRT). In the first study, we utilized nationwide data from the Taiwan Cancer Registry Database (TCRD), which was linked to the National Health Insurance Research Database (NHIRD) of Taiwan. In Study 1, We applied an inverse probability of treatment-weighted (IPTW) Cox-proportional hazards regression model to examine the association between statin use during CCRT and the risk of ischemic stroke. The aim 2 of this doctoral dissertation (Study 2) is to develop a risk prediction model to identify high-risk groups of NPC patients who are likely to develop moderate or greater internal carotid artery (ICA) stenosis after receiving RT. In the second study, the data source is from electronic medical record from National Taiwan University Hospital, integrative Medical Database (NTUH-iMD). We investigated the risk factors of ICA stenosis in post-RT NPC patients and developed risk prediction model by using stepwise variable selection in Cox proportional hazard model. The Receiver Operating Characteristic (ROC) curve and integrated Brier score were constructed to assess the discriminatory ability and overall performance of our risk prediction model. The aim 3 of this doctoral dissertation (study 2) is to determine the optimal timing for initiating carotid ultrasound screening in post RT NPC patients. To elucidate the temporal pattern of risk, a multivariable Generalized Linear Mixed Model (GLMM) was applied to determine the post-radiotherapy year most strongly associated with the onset of moderate or greater ICA stenosis. Results: In Study 1, the adjusted hazard ratios (aHR) for ischemic stroke in the statin group compared to the non-statin group was 0.70 (95% CI: 0.54–0.92). Analysis based on cumulative defined daily doses (cDDD) demonstrated a clear dose–response relationship, with a progressively lower risk of stroke observed in higher cDDD quartiles. Furthermore, patients with a daily defined dose (DDD) greater than 1 had a significantly reduced stroke risk (aHR: 0.49; 95% CI: 0.31–0.63), whereas those with a DDD of 1 or less also showed a protective effect (aHR: 0.59; 95% CI: 0.40–0.84). In study 2, according to our predictive model, patients in the high-risk group (risk score≥5) have significantly increased risk of moderate or greater ICA stenosis, which may begin to manifest as early as the fourth year after receiving radiation therapy. Additionally, we found that, compared to the average risk of the entire cohort, the risk of developing moderate-to-severe ICA stenosis began to increase significantly and persistently around the seventh year after radiotherapy. Conclusions: Study 1 provides compelling evidence supporting the beneficial effects of statin use during the CCRT period in reducing the risk of radiation-induced ischemic stroke among patients with advanced NPC undergoing definitive CCRT. In the study 2, according to our proposed risk prediction model, we recommend that carotid ultrasound screening begin in the seventh year following radiation therapy, while high-risk patients should start screening earlier, beginning in the fourth year. Wed, 01 Jan 2025 00:00:00 GMT http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99915 2025-01-01T00:00:00Z