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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81277完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉興華(Shin-Hwa Liu) | |
| dc.contributor.author | Sung-Chuan Chao | en |
| dc.contributor.author | 趙崧筌 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:40:19Z | - |
| dc.date.available | 2021-08-31 | |
| dc.date.available | 2022-11-24T03:40:19Z | - |
| dc.date.copyright | 2021-08-31 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-07-26 | |
| dc.identifier.citation | 1. Gelderblom, H. et al. The clinical approach towards chondrosarcoma. Oncologist 13, 320–329 (2008). 2. Fromm, J. et al. Survival and prognostic factors in conventional central chondrosarcoma. BMC Cancer. 18, 849 (2018). 3. Chen, X. et al. Is intralesional resection suitable for central grade 1 chondrosarcoma: A systematic review and updated meta-analysis. Eur J Surg Oncol. 43, 1718–1726 (2017). 4. van Praag Veroniek, V.M. et al. Incidence, outcomes and prognostic factors during 25 years of treatment of chondrosarcomas. Surg Oncol. 27, 402–408 (2018). 5. Thorkildsen, J. et al. Chondrosarcoma in Norway 1990-2013; an epidemiological and prognostic observational study of a complete national cohort. Acta Oncol. 58, 273–282 (2019). 6. Thorkildsen, J., Norum, OJ., Myklebust, T.A., Zaikova, O. Chondrosarcoma local recurrence in the Cancer Registry of Norway cohort (1990-2013): Patterns and impact. J Surg Oncol. 123, 510–520 (2021). 7. Nie, Z., Lu, Q., Peng, H. Prognostic factors for patients with chondrosarcoma: A survival analysis based on the Surveillance, Epidemiology, and End Results (SEER) database (1973-2012). J Bone Oncol. 13, 55–61 (2018). 8. Chen, Y.C., Wu, P.K., Chen, C.F, Chen, W.M. Intralesional curettage of central low-grade chondrosarcoma: a midterm follow-up study. J Chin Med Assoc. 80, 178–182 (2017). 9. Chen, Y.C., et al. Prognostic factors and survival in conventional chondrosarcoma: A single institution review. J Chin Med Assoc. 83, 669–673 (2020). 10. Kato, T. et al. Metaplastic breast carcinoma with chondrosarcomatous differentiation: Fine needle aspiration cytology findings. A case report. Diagn. Cytopathol. 34, 772–775 (2006). 11. Jamil, N., Howie, S., Salter, D. M. Therapeutic molecular targets in human chondrosarcoma. Int J. Exp. Pathol. 91, 387–393 (2010). 12. Saiko, P., Szakmary, A., Jaeger, W., Szekeres, T. Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat. Res. 658, 68–94 (2008). 13. Jang, M. et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218–220 (1997). 14. Frazzi, R. et al. Resveratrol mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation. Int. J. Cancer 132, 1013–1021 (2013). 15. Ulrich, S. et al. Peroxisome proliferator-activated receptor gamma as a molecular target of resveratrol induced modulation of polyamine metabolism. Cancer Res. 66, 7348–7354 (2006). 16. Bjo¨rklund, M., Roos, J., Gogvadze, V., Shoshan, M. Resveratrol induces SIRT1- and energy-stress-independent inhibition of tumor cell regrowth after low-dose platinum treatment. Cancer Chemother. Pharmacol. 68, 1459–1467 (2011). 17. Bradamante, S., Barenghi, L., Villa, A. Cardiovascular protective effects of resveratrol. Cardiovasc. Drug Rev. 22, 169–188 (2004). 18. Sun, A. Y., Simonyi, A., Sun, G. Y. The “French paradox” and beyond: neuroprotective effects of polyphenols. Free Radic. Biol. Med. 32, 314–318 (2002). 19. Pervaiz, S. Resveratrol: from grapevines to mammalian biology. FASEB J. 17, 1975–1985 (2003). 20. Campagna, M., Rivas, C. Antiviral activity of resveratrol. Biochem. Soc. Trans. 38, 50–53 (2010). 21. Soleas, G. J., Diamandis, E. P., Goldberg, D. M. Resveratrol: a molecule whose time has come? And gone? Clin. Biochem. 30, 91–113 (1997). 22. Soleas, G. J., Diamandis, E. P., Goldberg, D. M. The world of resveratrol. Adv. Exp. Med. Biol. 492, 159–182 (2001). 23. Sun, N. J., Woo, S. H., Cassady, J. M., Snapka, R. M. DNA polymerase and topoisomerase II inhibitors from Psoralea corylifolia. J. Nat. Prod. 61, 362–366 (1998). 24. Fontecave, M., Lepoivre, M., Elleingand, E., Gerez, C., Guittet, O. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Lett. 421, 277–279 (1998). 25. Frojdo, S., Cozzone, D., Vidal, H., Pirola, L. Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem. J. 406, 511–518 (2007). 26. Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003). 27. Borra, M. T., Smith, B. C., Denu, J. M. Mechanism of human SIRT1 activation by resveratrol. J. Biol. Chem. 280, 17187–17195 (2005). 28. Lakshminarasimhan, M., Rauh, D., Schutkowski, M., Steegborn, C. Sirt1 activation by resveratrol is substrate sequence-selective. Aging 5, 151–154 (2013). 29. Jin, H. D. et al. Resveratrol inhibits chondrosarcoma via mitochondrial and PI3K/Akt signaling pathways. Chin. J. Pathophysiol. 30, 1379–1383 (2014). 30. Im, H. J. et al. Biological effects of the plant-derived polyphenol resveratrol in human articular cartilage and chondrosarcoma cells. J. Cell. Physiol. 227, 3488–3497 (2012). 31. Guarente, L. Diverse and dynamic functions of the Sir silencing complex. Nat. Genet. 23, 281–285 (1999). 32. Tanno, M., Sakamoto, J., Miura, T., Shimamoto, K., Horio, Y. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 282, 6823–6832 (2007). 33. Song, N. Y., Surh, Y. J. Janus-faced role of SIRT1 in tumorigenesis. Ann. N. Y. Acad. Sci. 1271, 10–19 (2012). 34. Liu, T., Liu, P. Y., Marshall, G. M. The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer. Cancer Res. 69, 1702–1705 (2009). 35. Yuan, H., Su, L., Chen, W. Y. The emerging and diverse roles of sirtuins in cancer: a clinical perspective. Onco. Targets Ther. 8, 1399–1416 (2013). 36. Lim, J. H. et al. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol. Cell 38, 864–878 (2010). 37. Cho, I. R. et al. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of beta-catenin. Biochem. Biophys. Res. Commun. 423, 270–275 (2012). 38. Simic, P. et al. SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep. 3, 1175–1186 (2013). 39. Kim, E. J., Kho, J. H., Kang, M. R., Um, S. J. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol. Cell 28, 277–290 (2007). 40. Kobayashi, Y., Furukawa-Hibi, Y., Chen, C. SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Int. J. Mol. Med. 16, 237–243 (2005). 41. Pasinetti, G. M. et al. Neuroprotective and metabolic effects of resveratrol: Therapeutic implications for Huntington's disease and other neurodegenerative disorders. Exp. Neurol. 232, 1–6 (2011). 42. Li, Y., Bäckesjö, C. M., Haldosén, L. A., Lindgren, U. Resveratrol inhibits proliferation and promotes apoptosis of osteosarcoma cells. Eur. J. Pharmacol. 609, 13–18 (2009). 43. Campagna, M., Rivas, C. Antiviral activity of resveratrol. Biochem. Soc. Trans. 38, 50–53 (2010). 44. Frobert, P. et al. The role of reconstructive surgery after soft tissue sarcoma resection. Ann Chir Plast Esthet. 65, 394–422 (2020). 45. Suresh, V. et al. The Role of Reconstructive Surgery After Skeletal and Soft Tissue Sarcoma Resection. Ann Plast Surg. 80, S372–S376 (2018). 46. Song, K. et al. Can a Nomogram Help to Predict the Overall and Cancer-specific Survival of Patients With Chondrosarcoma? Clin Orthop Relat Res. 476, 987–996 (2018). 47. Zhang, J. et al. Development and validation of a nomogram containing the prognostic determinates of chondrosarcoma based on the Surveillance, Epidemiology, and End Results database. Int J Clin Oncol. 24, 1459–1467 (2019). 48. Bongers, M.E.R. et al. Does the SORG Algorithm Predict 5-year Survival in Patients with Chondrosarcoma? An External Validation. Clin Orthop Relat Res. 477, 2296–2303 (2019). 49. Bongers, M.E.R. et al. How Does the Skeletal Oncology Research Group Algorithm's Prediction of 5-year Survival in Patients with Chondrosarcoma Perform on International Validation? Clin Orthop Relat Res. 478, 2300–2308 (2020). 50. MacDonald, I.J., Lin, C.Y., Kuo, S.J., Su, C.M., Tang, C.H. An update on current and future treatment options for chondrosarcoma. Expert Rev Anticancer Ther. 19, 773–786 (2019). 51. Monga, V., Mani, H., Hirbe, A., Milhem, M.. Non-Conventional Treatments for Conventional Chondrosarcoma. Cancers (Basel). 12, 1962 (2020). 52. Kim, E. J., Um., S. J. SIRT1: roles in aging and cancer. BMB Rep. 41, 751–756 (2008). 53. Ren, Z. et al. Resveratrol inhibits NF-κB signaling through suppression of p65 and IκB kinase activities. Pharmazie 68, 689–694 (2013). 54. Rosato, R. R., Almenara, J. A., Grant., S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1. Cancer Res. 63, 3637–3645 (2003). 55. Fong, Y. C. et al. 2-Methoxyestradiol induces apoptosis and cell cycle arrest in human chondrosarcoma cells, J. Orthop. Res. 25, 1106–1114 (2007). 56. Nakata, R., Takahashi, S., Inoue, H. Recent advances in the study on resveratrol. Biol. Pharm. Bull. 35, 273–279 (2012). 57. Gruber, J., Tang, S. Y., Halliwell, B. Evidence for a trade-off between survival and fitness caused by resveratrol treatment of Caenorhabditis elegans. Ann. N. Y. Acad. Sci. 1100, 530–542 (2007). 58. Shimizu, T. et al. Resveratrol induces apoptosis of human malignant B cells by activation of caspase-3 and p38 MAP kinase pathways. Biochem. Pharmacol. 71, 742–750 (2006). 59. Shore, D., Squire, M., Nasmyth, K. A. Characterization of two genes required for the position-effect control of yeast mating-type genes. EMBO J. 3, 2817–2823 (1984). 60. Yuan, H., Su, L., Chen, W. Y. The emerging and diverse roles of sirtuins in cancer: a clinical perspective. Onco. Targets Ther. 6, 1399–1416 (2013). 61. Chen, W. Y. et al. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437–448 (2005). 62. Yuan, H. et al., Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 119, 1904–1914 (2012). 63. Firestein, R. et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One 3, e2020 (2008). 64. Feng, H. et al. The expression of SIRT1 regulates the metastatic plasticity of chondrosarcoma cells by inducing epithelial-mesenchymal transition. Sci Rep. 7, 41203 (2017). 65. Jin, H. et al. Resveratrol inhibits phosphorylation within the signal transduction and activator of transcription 3 signaling pathway by activating sirtuin 1 in SW1353 chondrosarcoma cells. Mol Med Rep. 14, 2685–2690 (2016). 66. Baarine, M. et al. Proapoptotic versus anti-apoptotic properties of dietary resveratrol on tumoral and normal cardiac cells. Genes Nutr. 2, 161–169 (2011). 67. Kauppinen, A., Suuronen, T., Ojala, J., Kaarniranta, K., Salminen, A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell. Signal. 25, 1939–1948 (2013). 68. Yao, H., Rahman, I. Perspectives on translational and therapeutic aspects of SIRT1 in inflammation and senescence. Biochem. Pharmacol. 84, 1332–1339 (2012). 69. Thomas, W. Bioavailability of resveratrol. Ann N Y Acad Sci. 1215, 9–15 (2011). 70. Mukherjee, S., Dudley, J.I., Das, D.K. Dose-dependency of resveratrol in providing health benefits. Dose Response. 8, 478–500 (2010). | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81277 | - |
| dc.description.abstract | "軟骨肉瘤(chondrosarcoma)，為一群具有透明軟骨分化的異質性傾向之惡性骨腫瘤，是僅次於骨肉瘤的第二常見的原發性惡性骨腫瘤，約占百分之二十，約為惡性骨肉瘤的零點七倍，其中八成至九成為傳統型軟骨肉瘤。與骨肉瘤的差別，在於軟骨肉瘤大多發生在中年人，好發年紀在10歲至80歲，病程相對於其他的惡性骨腫瘤，較不會發生遠處的轉移。因為軟骨肉瘤對於化學療法與放射線療法的反應不佳，目前共識是以廣泛性腫瘤廓清手術的治療為主。根據歐美(荷蘭及美國國家級)資料庫研究，罹患軟骨肉瘤病人之預後，與年齡、診斷年份、肉瘤腫瘤大小、發生位置、組織分期，以及遠處轉移有關係。然而本土資料庫的研究數據，則鳳毛麟角。鑒於軟骨肉癌對化學療法和放射線療法的反應不佳，而廣泛性腫瘤廓清手術，常因為腫瘤位置至關重要，如骨盆或脊椎，或為了保留肢體功能，無法達成，以致病灶容易復發，甚至進展成遠處轉移致死。白藜蘆醇(resveratrol)，首先在1940年從白嚏根草(white hellebore)的根部提取出，為一種天然酚類的化合物，存在於葡萄、桑椹和花生等蔬果中。自1997年起，陸續有研究指出白藜蘆醇透過多種分子標的物的調控，達到抑制大腸癌、乳癌及淋巴瘤的效果。故此本論文，分為兩個主題。先進行台灣族群軟骨肉瘤病人資料庫分析，自一所三級轉診的醫學中心，收集跨時十八年資料庫研究，欲提出本土軟骨肉瘤的預後因子與五年存活率之預測模型。然後從先前研究得知白藜蘆醇，sirtuin 1 (SIRT 1)的強力致效劑，抑制腫瘤生長之特性，故運用in vivo和in vitro研究方法，進行其針對軟骨肉癌可能治療效果之研究與分子機轉的探討。 第一個部份進行本土資料庫研究，我們利用單變項羅吉斯迴歸(univariate logistic regression)，找出確診時的年齡 (OR, 1.09; 95% CI, 1.04 - 1.15; P < 0.001) 和在確診五年內不同的病情變化 (與手術治療後，無復發無遠處轉移組別間比較)，同為預後之危險因子。其他因子包括：性別、腫瘤大小與位置、組織學分類、手術廓清程度與輔助療法，對於軟骨肉瘤患者的預後，則無統計學上的顯著意義。接著以多變項羅吉斯迴歸(multivariate logistic regression)，推導出確診時的年齡 (OR, 1.12; 95% CI, 1.04 - 1.20; P =0.002)，以及在確診五年內經手術治療後，若有局部復發或殘餘腫瘤時(OR, 15.86; 95% CI, 1.05 - 239.38; P = 0.036)及確診時即有遠處轉移(OR, 20.70; 95% CI, 1.18 - 362.57; P = 0.042) 為預後的危險因子。依據統計結果，我們描繪出接收者操作特徵曲線 (ROC curve)，並建立一個具有良好預測能力的五年存活預後模型 (AUC, 0.93; Youden’s Index best cutoff value, 0.44; specificity, 0.93, sensitivity, 0.92)。 第二部份研究，我們提出以白藜蘆醇(resveratrol)，sirtuin 1 (SIRT1)強力致效劑，來治療軟骨肉癌之可能性。首先，白藜蘆醇，以劑量依存性地，顯著減少人類軟骨肉癌細胞株(JJ012)的存活，與誘發細胞凋亡。同時在細胞裡發現SIRT1的蛋白質表現與活性增加。白藜蘆醇藉由將NF-κB複合體中的次單位p65去乙醯化 (deacetylating)作用，造成NF-κB訊號傳遞被顯著地抑制。而此白藜蘆醇抑制NF-κB訊號傳遞的效果，則可以被轉染的siRNA-SIRT1或去乙醯化抑制劑MS-275所反轉。接著發現白藜蘆醇促使人類軟骨肉癌細胞株凋亡，與caspase-3介導的機制有關。而siRNA-SIRT1轉染，與去乙醯化抑制劑MS-275，皆能顯著地抑制由白藜蘆醇所誘導人類軟骨肉癌細胞株caspase-3的裂解與活性。此外，在腫瘤異種移植的免疫缺陷裸鼠模式，將白藜蘆醇做腹腔內注射後，可以大幅縮減腫瘤體積，同時發現腫瘤檢體內的SIRT1與裂解的caspase-3表現增加。以上結果揭櫫白藜蘆醇誘發人類軟骨肉癌細胞株的凋亡，是藉由活化SIRT1導致NF-κB 路徑被抑制，同時提升caspase-3的裂解與活性所致。此拮抗軟骨肉瘤的效果亦在動物實驗中獲得驗證。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:40:19Z (GMT). No. of bitstreams: 1 U0001-2407202118292200.pdf: 4483908 bytes, checksum: aac96896c54c8a10d5d6bb0ccae05adc (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 口試委員會審定書 i 誌謝 ii 中文摘要 iii Abstract v Abbreviation x 1. Introduction 1 2. Materials and Methods 11 2.1. Prognostic factors for patients with chondrosarcoma in a tertiary referral hospital in Taiwan 11 2.2. Induction of sirtuin-1 signaling by resveratrol induces human chondrosarcoma cell apoptosis and exhibits antitumor activity 13 3. Results and discussion 19 3.1. Prognostic factors for patients with chondrosarcoma in a tertiary referral hospital in Taiwan 19 3.1.1. Results 19 3.1.1.1. Characteristics of chondrosarcoma in Taiwanese population in a single institution 19 3.1.1.2. ROC curve shows good predictive ability of survival 20 3.1.2. Discussion 21 3.2. Induction of sirtuin-1 signaling by resveratrol induces human chondrosarcoma cell apoptosis and exhibits antitumor activity 32 3.2.1. Results 32 3.2.1.1. Resveratrol induces cell apoptosis in human chondrosarcoma cells. 32 3.2.1.2. Resveratrol induces the expression and activity of SIRT1 32 3.2.1.3. Resveratrol attenuates NF-κB activation through the reduction of p65 acetylation 33 3.2.1.4. Deacetylation inhibitor reduces resveratrol-increased caspase-3 activation 33 3.2.1.5. Resveratrol significantly retards tumor growth in Nu/Nu nude mice xenograft model of JJ012 cells 34 3.2.2. Discussion 35 4. Conclusion and future perspectives 49 5. References 52 List of publications 60 | |
| dc.language.iso | en | |
| dc.subject | 局部復發 | zh_TW |
| dc.subject | 預後因子 | zh_TW |
| dc.subject | 白藜蘆醇 | zh_TW |
| dc.subject | NAD-依賴性去乙醯化酶Sirtuin-1 | zh_TW |
| dc.subject | 軟骨肉瘤 | zh_TW |
| dc.subject | sirtuin 1 (SIRT1) | en |
| dc.subject | chondrosarcoma | en |
| dc.subject | prognostic factors | en |
| dc.subject | local recurrence | en |
| dc.subject | resveratrol | en |
| dc.title | 軟骨肉瘤之台灣單一醫學中心資料庫研究及白藜蘆醇治療策略開發 | zh_TW |
| dc.title | Studies on chondrosarcoma in Taiwanese population in a tertiary referral hospital and therapeutic strategy development using resveratrol | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.author-orcid | 0000-0002-5758-0494 | |
| dc.contributor.oralexamcommittee | 姜至剛(Hsin-Tsai Liu),楊榮森(Chih-Yang Tseng),許美鈴,陳瑞明 | |
| dc.subject.keyword | 軟骨肉瘤,預後因子,局部復發,白藜蘆醇,NAD-依賴性去乙醯化酶Sirtuin-1, | zh_TW |
| dc.subject.keyword | chondrosarcoma,prognostic factors,local recurrence,resveratrol,sirtuin 1 (SIRT1), | en |
| dc.relation.page | 60 | |
| dc.identifier.doi | 10.6342/NTU202101710 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-07-27 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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