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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱智賢(Chih-Hsien Chiu) | |
| dc.contributor.author | Hsin-Yi Chiu | en |
| dc.contributor.author | 邱欣怡 | zh_TW |
| dc.date.accessioned | 2022-11-24T09:25:14Z | - |
| dc.date.available | 2022-11-24T09:25:14Z | - |
| dc.date.copyright | 2021-08-04 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-07-26 | |
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JBI database of systematic reviews and implementation reports 14(1):140-173. doi: 10.11124/jbisrir-2016-2180 Peled, N., M. W. Wynes, N. Ikeda, T. Ohira, K. Yoshida, J. Qian, M. Ilouze, R. Brenner, Y. Kato, C. Mascaux, and F. R. Hirsch. 2013. Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. Cell Oncol 36(4):277-288. doi: 10.1007/s13402-013-0133-9 Perez-Soler, R. 2004. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clinical Cancer Research 10(12 Pt 2):4238s-4240s. doi: 10.1158/1078-0432.Ccr-040017 Pierre-Eugene, C., P. Pagesy, T. T. Nguyen, M. Neuillé, G. Tschank, N. Tennagels, C. Hampe, and T. Issad. 2012. Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2. PLoS One 7(7):e41992. doi: 10.1371/journal.pone.0041992 Pirker, R., F. J. Herth, K. M. Kerr, M. Filipits, M. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81649 | - |
| dc.description.abstract | "糖尿病對早期肺癌患者，接受肺癌切除手術的術後影響，以及糖尿病對於肺癌晚期病患，使用表皮生長因子酪胺酸激酶抑製劑（EGFR-TKI）的療效影響，仍存在爭議。我們在肺癌病患的世代研究中，調查肺癌病患同時合併糖尿病， 是否會造成較高風險的術後併發症或死亡率。我們還研究高胰島素血症與高血糖，在體外非小細胞肺癌細胞（HCC4006細胞株，具有表皮生長因子受體突變特性），是否影響吉非替尼（gefitinib）的治療效果。 本世代研究有 25,456 名接受肺切除手術的肺癌患者。我們將原本有糖尿病的患者與沒有糖尿病的患者按 1:1 做傾向評分匹配。結果在 8234 名傾向評分匹配的肺癌病人中，有糖尿病的患者，其器官/空間手術部位感染（勝算比：1.67；95%信賴區間：1.01 至 2.78；p = 0.04）、肺炎（勝算比：1.24；95%信賴區間：1.03 至 1.48；p = 0.02），心肌梗塞（勝算比：1.87；95%信賴區間：1.10 至 3.18；p = 0.02）的風險顯著高於對照組。因此，我們建議外科醫生採取預防措施，以盡量減少術後併發症，尤其是對於風險較高的糖尿病早期肺癌手術患者。 在體外試驗，我們使用增生測試(MTS proliferation assay)和西方點墨分析(Western blotting)，以及通過轉染小分子干擾核糖核酸 (siRNA transfection)，來評估吉非替尼(gefitinib)、長效胰島素(glargine)或合併兩種藥物(gefitinib 加glargine)的治療療效，以及對細胞增殖及 EGFR、IGFR、AKT 和 ERK 在細胞內蛋白表現量的影響。結果發現，高胰島素血症會促進肺癌細胞的增殖和存活，並降低吉非替尼(gefitinib)的療效。高胰島素血症抑制吉非替尼(gefitinib)功效可能是通過磷酸肌醇 3 激酶 (PI3K/AKT) 途徑，而不是絲裂原活化蛋白激酶細胞外信號調節激酶 (MAPK/ERK) 途徑介導的。此外，siRNA對AKT（絲胺酸/蘇胺酸激酶）的抑制作用，可以回復高胰島素血症造成的吉非替尼(gefitinib)藥效降低。本研究發現：高胰島素血症會降低吉非替尼(gefitinib)在EGFR突變的肺癌細胞的治療效果。然而還需要其他研究證實，例如共同靶向治療或抑制PI3K / AKT途徑的藥物，應用於晚期糖尿病肺癌病人，希望得以改善晚期肺癌且同時有糖尿病的病患在使用EGFR-TKI的療效。 " | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T09:25:14Z (GMT). No. of bitstreams: 1 U0001-2507202116355300.pdf: 4680584 bytes, checksum: f9d74085c16f7bb0d743eaf2846c3cef (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "謝辭 i 中文摘要 ii Abstract iv 目錄 vi List of Figures viii List of Tables x 1. Introduction 1 2. Literature Review 6 2.1 Epidemiology of lung cancer 6 2.2 Histology of lung cancer 7 2.3 Principle of lung cancer treatment 8 a. The treatment principle of SCLC 8 b. The treatment principle of NSCLC 9 2.4 EGFR mutation in NSCLC 10 a. Percentage of EGFR mutation of NSCLC in Asia and Taiwan 10 b. Introduction of EGFR pathway in lung cancer 10 c. EGFR-TKI as the first line for advanced NSCLC 11 d. Clinical challenge in TKI resistance. 12 e. Definition of primary and acquired resistance of EGFR-TKIs 13 2.5 Diabetes Mellitus: hyperglycemia, hyperinsulinemia, insulin resistance, and Insulin/IGF-1 signaling pathway 13 a. Hyperglycemia 14 b. Hyperinsulinemia and insulin resistance 14 c. Receptors of the insulin-like growth factor receptor (IGFR) and insulin receptor (IR) systems and downstream signaling 16 d. The Insulin/ IR and IGF-IR receptor 16 e. The IR and IGF-IR signaling pathways. 19 f. The role of IR/IGF-1R signaling pathways in DM and cancer 22 2.6 The relationship between pre-existing diabetes mellitus and lung cancer 23 a. Comorbidities and lung cancer 23 b. Diabetes and lung cancer 23 c. Overall survival rate in lung cancer patients: DM vs non-DM 24 d. Disease-free survival rate in lung cancer patients: DM vs non-DM 24 e. Controversy over diabetes effects on postoperative outcomes in lung cancer patients 25 f. Unknown effects of exogenous insulin therapy on postoperative outcomes in lung cancer patients 25 g. Crosstalk of the IGF-IR system with EGFR tyrosine kinase receptors. 26 2.7 Hypothesis 28 3. Materials and methods 29 3.1 Data acquisition and cohort selection. 29 3.2 Study variables and outcomes. 30 3.3 Cell lines and cell cultures. 31 3.4 Reagents. 32 3.5 Proliferation assay. 32 3.6 Western blot analysis. 34 3.7 siRNA transfection. 35 3.8 Statistical analysis. 36 4. Results 38 4.1 DM versus the control groups in lung cancer patients undergoing pulmonary resections 38 4.2 Insulin use versus oral antidiabetic agents in diabetes patients undergoing pulmonary resections 39 4.3 Effect of gefitinib treatment on NSCLC cells harboring EGFR mutations. 40 4.4 Long acting insulin glargine did not significantly affect the NSCLC cells. 41 4.5 Mechanism of hyperinsulinemia on gefitinib efficacy. 42 4.6 AKT knockdown by siRNA recovered the suppressed efficacy of gefitinib induced by glargine. 45 5. Discussion 49 6. Conclusion 61 7. Figures 63 Figure 1. Flowchart of the study on postoperative outcomes in resected lung cancer patients. 63 Figure 2. Effect of gefitinib treatment on HCC 4006 lung cancer cells harboring EGFR mutations. 64 Figure 3. Effect of gefitinib and glargine treatment on HCC 4006 lung cancer cells harboring EGFR mutations in RPMI medium with 11mM glucose. 65 Figure 4. Effect of gefitinib and glargine treatment on HCC 4006 lung cancer cells harboring EGFR mutations in RPMI medium with 22 mM glucose. 66 Figure 5. Levels of pAKT and tAKT with the addition of porcine insulin in HCC4006 cells. 67 Figure 6. Evaluation of the effect of long acting insulin (glargine) on HCC 4006 lung cancer cells. 68 Figure 7. Evaluation of the effects on HCC 4006 cells treated with different concentrations of glargine (0-100 nM), and 32 µM gefitinib in RPMI medium (11 mM glucose). 70 Figure 8. Evaluation of the effects on HCC 4006 cells treated with different concentrations of glargine (0-100 nM), and 32 µM gefitinib in RPMI medium (22 mM glucose). 71 Figure 9. The levels of pEGFR/tEGFR on HCC4006 cells cotreated with gefitinib and glargine. 72 Figure 10. The levels of pIGFR/tIGFR on HCC4006 cells cotreated with gefitinib and glargine. 73 Figure 11. The levels of pAKT/tAKT on HCC4006 cells cotreated with gefitinib and glargine. 74 Figure 12. The levels of pERK/tERK on HCC4006 cells cotreated with gefitinib and glargine. 75 Figure 13. The effect of gefitinib treatment on HCC4006 cells with AKT knockdown. 76 Figure 14. The effect of 100 nM glargine on pAKT/tAKT levels in HCC4006 cells with or without AKT knockdown. 77 Figure 15. The effect of 100 nM glargine on pIGFR/tIGFR levels in HCC4006 cells with or without AKT knockdown. 78 Figure 16. The effect of (1) only gefitinib or (2) glargine plus gefitinib on cell survival of HCC4006 cells with or without AKT knockdown. 79 Figure 17. The effects of (1) only glargine or (2) glargine plus gefitinib on pIGFR/tIGFR and pAKT/tAKT levels in HCC4006 cells with or without AKT knockdown. 80 Figure 18. The effects of (1) only glargine or (2) glargine plus gefitinib on pERK/tERK levels in HCC4006 cells with or without AKT knockdown. 81 8. Tables 82 Table 1. Characteristics of the DM and non-DM groups (Unadjusted) 82 Table 2. Characteristics of the DM and non-DM groups (Adjusted: PSM) 84 Table 3. Postoperative results between Non-DM and DM patient 86 Table 4. Postoperative results between Non-DM and DM groups 87 Table 5. Characteristics of diabetes patients between insulin use and oral antidiabetic agents (Unadjusted) 89 Table 6. Characteristics of diabetes patients between insulin use and oral antidiabetic agents (Adjusted, PSM) 91 Table 7. Postoperative results of diabetes patients between insulin use and oral antidiabetic agents 93 Table 8. Postoperative results of diabetes patients between insulin use and oral antidiabetic agent 94 9. References 96 " | |
| dc.language.iso | en | |
| dc.subject | 傾向評分匹配 | zh_TW |
| dc.subject | 高胰島素血症 | zh_TW |
| dc.subject | 手術後併發症 | zh_TW |
| dc.subject | 表皮生長因子受體酪胺酸激酶抑製劑 | zh_TW |
| dc.subject | 糖尿病 | zh_TW |
| dc.subject | 胰島素 | zh_TW |
| dc.subject | 肺癌 | zh_TW |
| dc.subject | epidermal growth factor receptor tyrosine kinase inhibitor | en |
| dc.subject | diabetes | en |
| dc.subject | insulin | en |
| dc.subject | postoperative complication | en |
| dc.subject | propensity score match | en |
| dc.subject | hyperinsulinemia | en |
| dc.subject | lung cancer | en |
| dc.title | 糖尿病對肺癌治療的影響：對於手術治療的肺癌病患術後影響及標靶藥物在肺癌細胞的影響 | zh_TW |
| dc.title | The Impact of Diabetes on Lung Cancer Treatment: Postoperative Outcomes in Lung Cancer Patients and EGFR-TKI Treatment of Lung Cancer Cells | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.author-orcid | 0000-0002-4698-5322 | |
| dc.contributor.coadvisor | 江逸凡(Yi-Fan Jiang) | |
| dc.contributor.oralexamcommittee | 吳玉琮(Hsin-Tsai Liu),謝明哲(Chih-Yang Tseng),鍾德憲,吳兩新,陳億乘,黃啓彰 | |
| dc.subject.keyword | 糖尿病,表皮生長因子受體酪胺酸激酶抑製劑,高胰島素血症,胰島素,肺癌,手術後併發症,傾向評分匹配, | zh_TW |
| dc.subject.keyword | diabetes,epidermal growth factor receptor tyrosine kinase inhibitor,hyperinsulinemia,insulin,lung cancer,postoperative complication,propensity score match, | en |
| dc.relation.page | 133 | |
| dc.identifier.doi | 10.6342/NTU202101722 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2021-07-27 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 動物科學技術學研究所 | zh_TW |
| 顯示於系所單位： | 動物科學技術學系 | |
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