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- 六君子湯對於非小細胞肺癌病人以化學治療後其免疫調控基因組表現及臨床預後之影響(2-2)
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題 名 | 六君子湯對於非小細胞肺癌病人以化學治療後其免疫調控基因組表現及臨床預後之影響(全程總報告)=Genomic Expressions and Outcomes in non Small Cell Lung Cancer Patients Treated with Combinations of Liu Jun Zi Tang (六君子湯) and Chemotherapy (Final Report) |
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作 者 | 林孟志; | 書刊名 | 中醫藥年報 |
卷 期 | 29:8 2011.09[民100.09] |
頁 次 | 頁347-378 |
專 輯 | 中醫藥基因體相關研究 |
分類號 | 414.53 |
關鍵詞 | 非小細胞肺癌; 六君子湯; 全人類基因組表現; Non small cell lung cnacer; Liu jun zi tang; Microarray gene expression; |
語 文 | 中文(Chinese) |
中文摘要 | 研究目的:四君子湯有增強機體免疫力的作用。六君子湯已被證實可以改善胃腸,免疫及肺功能。本研究希望評估化療期間服用六君子湯是否可延長存活期,改善腫瘤的反應,改善生活品質,以及評估對化療相關毒性的影響。 研究方法:利用隨機雙盲之臨床研究方法,預定將收集本院32病例非小細胞肺癌病人(stag IIIB or IV),將其隨機分為16 例對照組(化療+安慰劑),16 例治療組(化療+六君子湯)。每組在接受化療治療之間隔,接受六君子湯或安慰劑治療。在治療過程中,一方面觀察病人臨床反應,一方面在進行治療之前、中、後,共三次抽血,進一步利用全人類基因組表現晶片(whole genome assay, Human ref-8 beadchip)之分析方法鑑定出其免疫基因組表現。 結果與討論:本計畫已完成32 個病例收集資料建檔,其中已皆完成第一次抽血及基因晶片分析。部分病例已完成第二次抽血及基因晶片分析。根據第一次基因晶片(正常組與疾病組比較)分析比較,結果發現其中有兩倍差異之基因表現共有142 個,五倍差異之基因表現共有七個基因,包括histone cluster 1 H2ac (HIST1H2AC), defensin alpha 4 corticostatin (DEFA4), hemoglobin delta (HBD), hemoglobin gamma A (HBG1), hemoglobin gamma G (HBG2), elastase 2 neutrophil (ELA2)及killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 2 (KIR3DL2)。其中有五種基因為第一次發現與肺癌相關。 本研究最後收納三十二名肺癌末期病人及二十名健康人,其中九名病人接受兩種化療及六君子湯四個療程的治療,八名病人接受兩種化療的治療。我們將其白血球的全基因表現作以下的比較:肺癌比健康人有547 個表現不同的基因,化療前後有849 個表現不同的基因,第四期比三b 期有151 個表現不同的基因,化 療加六君子湯有206 個表現不同的基因,嗜中性白血球減少者比無減少者有188個表現不同的基因。肺癌和期別差異最相關的共同代謝途徑牽涉到arachidonic acid 的產生,典型補體途徑,及經由GP6 的血小板活化。化療和嗜中性白血球減少共同的最相關的代謝途徑牽涉到抗細胞凋零, 轉譯因子NF-Κb 及 Lymphotoxin-beta 受器的訊息傳遞。Prostaglandin-H2D-isomerase 是化療加六君子湯和嗜中性白血球減少唯一且共同的表現不同的基因。 |
英文摘要 | Aim: The Chinese Medicine liu jun zi tang (六君子湯) has been thought to be able to improve gastrointestinal, immunological and pulmonary functions. We aim to determine whether liu jun zi tang (六君子湯) can reduce toxicity rate and increase response rate of chemotherapy for patients with NSCLC during chemotherapy. Furthermore, the mechanism of liu jun zi tang would be invetigated through microarray gene expression analysis. Method: We plan to enroll about 32 patients with stage IIIB or IV advanced non-small cell lung cancer, and divide them into two groups: standard combination chemotherapy group (Cisplatin and Gemcitabine) or chemotherapy plus 六君子湯group. Whole blood samples will be obtained before, during and after treatment. Total RNA from polymorphonuclear cells and mononuclear cells will be isolated respectively and analyed with microarray genomic expression and its software. Selective gene expression alterations in patients with chemotherapy alone or chemotherapy plus 六君 子湯will be determined. Results & Discussion: Thirty two patients with non-small cell lung cancers has been screened for preliminary survey and nine of them were excluded because of different treatment regimens and unwillingness of the patients. The first analysis have been done by the whole genome assay, Human ref-8 beadchip, from the Illumina Company. There are 142 genes with 2 folds different expression. 7 genes with 5 folds of different expression, including histone cluster 1 H2ac (HIST1H2AC), defensin alpha 4 corticostatin (DEFA4), hemoglobin delta (HBD), hemoglobin gamma A (HBG1), hemoglobin gamma G (HBG2), elastase 2 neutrophil (ELA2), killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 2 (KIR3DL2), were found. This study aims to identify candidate genes for blood-based tumor diagnosis, and to investigate underlying mechanisms of medication-induced neutropenia by cDNA microarray method. Microarray was used to analyze expression patterns of 24,500 transcripts of blood leukocyte in 32 advanced non-small cell lung cancer patients, and 20 sex- and age-matched healthy subjects. Seventeen of the 32 patients were double -blindly randomized to receive 4 cycles of cisplatin and gemcitabine with or without daily use of liu jun zi tang (a Chinese medicine). Hierarchical clustering analysis failed to show significant segregation of patients. The following comparisons of gene expression data were made: lung cancer versus healthy subjects, stage 4 versus 3b, post CT versus baseline, post CT plus liu jun zi tang versus baseline, and neutropenia versus no neutropenia. The largest number of differentially expressed genes (DEGs), with fold change ≧ 2 and p-value < 0.05, was found in post-CT versus baseline (849), with most of the genes being down-regulated in post-CT. The second largest group of DEGs originated from the comparison of the lung cancer versus healthy subjects (547), with most of the genes being up-regulated in lung cancer. The other comparisons resulted in a smaller numbers of DEGs (151, 206, 188). In the intersection of the first two comparisons, the mostly related pathways specific to lung cancer and stage involve arachidonic acid production, classical cmplement, and GP6-dependent platelet activation. In the intersection of the 3rd and 5th comparisons, the mostly related pathways specific to CT and neutropenia involve anti-apoptotic, NF-κB, and Lymphotoxin-beta receptor signaling. Prostaglandin-H2D-isomerase is the only DEG in the intersection of 4th and 5th comparisons. This study revealed candidate genes and pathways that may contribute to a better understanding of the effects of lung cancer and its treatment on blood leukocytes, making it possible to find biomarkers for early diagnosing lung cancer and predicting medication-induced neutropenia. |
本系統中英文摘要資訊取自各篇刊載內容。