2,306 research outputs found
Investigated signaling pathways of YC-1 and EPOX as anticancer drugs and mechanisms of Twist to promote breast cancer metastasis
No full text腫瘤轉移為主要造成癌症病人死亡的原因，而其過程相當複雜，受到了許多因素調控。位於缺氧區域的腫瘤會促進血管新生，而提供了轉移的途徑，此時穿過局部組織和血管壁的癌細胞得以進入血流。當進入全身循環後，chemokine則會指引表現相對應受體的癌細胞分佈到特定器官，當進一步適應周圍環境之後，才能在遠端器官形成轉移的腫瘤。在本論文中，我們探討了抑制缺氧現象和血管新生的藥物機轉，也研究了chemokine receptor表現的調控。 Hypoxia-inducible factor 1 (HIF-1)是癌細胞適應缺氧環境時相當重要的一個轉錄因子，因此在本篇論文的第一部份以HIF-1作為研究對象，探討YC-1這個小分子藥物減少HIF-1累積的機轉。YC-1不會影響HIF-1α的穩定度和mRNA的含量，但是會抑制HIF-1αtranslation時相當重要的PI3K/Akt/mTOR/4E-BP途徑。我們也發現YC-1抑制NF-κB的活化(亦為Akt下游)。雖然投與兩種會影響Akt/NF-κB活化的藥物caffeic acid phenethyl ester和evodiamine會減少HIF-1α，但是過度表現NF-κB時只能減少wortmannin所抑制的HIF-1α-dependent transcriptional activity，對YC-1所造成的抑制沒有明顯的效果，說明NF-κB是Akt能夠增加HIF-1α表現的其中一個因素，但YC-1是否透過NF-κB來抑制HIF-1α仍待釐清。 在本論文的第二部份以內皮細胞作為篩選模式，評估一系列xanthone衍生物的抗血管新生活性，其中以3,6-di(2,3-epoxypropoxy)xanthone (EPOX)的效果最強。EPOX抑制血管新生的機轉是透過減少glutathione使得ERK的活性下降，造成Mcl-1被proteosome分解，因此釋放出Bim而啟動粒線體所媒介的凋亡。我們也進行了in vivo matrigel plug assay 和腫瘤的異體移植實驗，確認EPOX在體內的抗血管新生效果。綜合以上實驗顯示，EPOX是個值得進一步研發的抗血管新生先導藥物。 在腫瘤細胞中最常見過度表現的chemokine receptor就是CXCR4，而CXCR4的抑制劑如AMD3100和CTCE-9908也都進入了第二期臨床試驗，因此在本論文的最後一部份，我們以CXCR4作為研究對象，探討Twist這個轉錄因子增加CXCR4表現的機轉。Twist增加CXCR4表現並非藉由結合到CXCR4 promoter上，而是間接的移除抑制性的轉錄因子YY1。Twist將YY1由CXCR4 promoter上移除，因此正向性的轉錄因子SRF可結合而增加CXCR4 promoter活性。Twist也會減少YY1對CREB的抑制，而使CREB結合到CXCR4 promoter，更加有助於啟動轉錄。綜合以上實驗結果，我們發現Twist可以透過增加CXCR4表現而促進乳癌細胞轉移。The main cause of mortality in most cancer patients is metastasis. Metastasis is a complex multistep biological process most likely controlled by distinct genes and signaling pathways in each step. Tumor exposed to hypoxia induces angiogenesis to provide the route for entering in the systemic circulation. After cancer cells invade local tissue and migrate across the vascular wall, movement of cells is facilitated by up-regulation of particular chemokine receptors, enabling them to migrate to distant organ where the ligands are expressed. Similar to the primary site, adaption and reprogramming of the surrounding stroma is especially important for survival and growth of the metastasized cells. In this thesis, we investigated the mechanism of drugs targeting hypoxia and angiogenesis and studied the transcriptional regulation of chemokine receptors. Hypoxia-inducible factor 1 (HIF-1) is a critical regulator for tumor adaptation to hypoxia. In the first chapter, we studied the mechanism of YC-1 to prevent HIF-1αaccumulation in prostate cancer cells. Neither HIF-1αprotein half-life nor mRNA level was affected by YC-1. However, YC-1 was found to suppress the PI3K/Akt/mTOR/4E-BP pathway which serves to regulate HIF-1α expression at the translational step. We demonstrated that YC-1 also inhibited hypoxia-induced activation of NF-κB, a downstream target of Akt. Over-expression of NF-κB partly reversed the ability of wortmannin to inhibit HIF-1α and two inhibitors of the Akt/NF-κB pathway activation also decrease HIF-1α expression. It is therefore suggested that NF-κB contributes to Akt-mediated HIF-1α accumulation In the second chapter, we use endothelial cells as a model to find out potential antiangiogenic lead compound from a series of xanthone derivatives. 3,6-di(2,3-epoxy propoxy)xanthone (EPOX) was found to be the most effective one. The antiangiogenic actions of EPOX are proposed to involve inhibition of ERK in response to glutathione depletion leading to the degradation of Mcl-1, and then stimulation of mitochondria-mediated apoptosis in response to an increase in Mcl-1 free Bim. In vivo matrigel plug assay and tumor xenograft were also performed to supporting the potential of the EPOX as an angiognenesis inhibitor for cancer therapy.he most commonly found chemokine receptor on human cancer cells is the CXCR4 receptor. CXCR4 antagonists, such as AMD3100 and CTCE-9908 were also in phaseⅡclinical trial. In the last chapter, we studied the mechanism of Twist to upregulate CXCR4. Twist enhances the expression of functional CXCR4 owing to its capacity to physically interact with YY1 instead of bound to the E-box element on CXCR4 promoter. Removal of YY1 from the CXCR4 promoter by Twist leads to the recruitment of the activator SRF to increase in CXCR4 promoter activity. Twist also dissociates the CREB from YY1 which becomes be able to bind to the CXCR4 promoter and further enhances the transcription of CXCR4. Taken together, we provide a mechanism for Twist-mediated breast tumor metastasis and establish a functional link between Twist and CXCR4 signaling pathways.口試委員審定書謝………………………………………………………………………1寫表……………………………………………………………………3文摘要…………………………………………………………………5 文摘要…………………………………………………………………7一章一節 研究動機與目的………………………………………………10二節 文獻回顧………………………………………………………12二章 實驗材料與方法一節 實驗材料………………………………………………………41二節 實驗方法………………………………………………………43三章 YC-1在前列腺癌抑制HIF-1表現的機轉探討:Akt/NF-κB訊息在缺氧時累積HIF-1α的重要性文摘要………………………………………………………………50文摘要………………………………………………………………51一節 緒論…………………………………………………………52二節 結果…………………………………………………………53三節 討論…………………………………………………………56四章 EPOX透過調控ERK/Mcl-1 途徑而抑制血管新生文摘要…………………………………………………………………64文摘要…………………………………………………………………65一節 緒論……………………………………………………………66二節 結果……………………………………………………………67三節 討論……………………………………………………………70五章 Twist藉由移除YY1而增加CXCR4的表現文摘要…………………………………………………………………84文摘要…………………………………………………………………85一節 緒論……………………………………………………………86二節 結果……………………………………………………………87三節 討論……………………………………………………………91六章 總結與展望……………………………………………………99作……………………………………………………………………102考文獻………………………………………………………………10
Efficient inferencing for sigmoid Bayesian networks by reducing sampling space
No full textA sigmoid Bayesian network is a Bayesian network in which a conditional probability is a sigmoid function of the weights of relevant arcs. Its application domain includes that of Boltzmann machine as well as traditional decision problems. In this paper we show that the node reduction method that is an inferencing algorithm for general Bayesian networks can also be used on sigmoid Bayesian networks, and we propose a hybrid inferencing method combining the node reduction and Gibbs sampling. The time efficiency of sampling after node reduction is demonstrated through experiments. The results of this paper bring sigmoid Bayesian networks closer to large scale applications
Re-ranking model based on document clusters
No full textIn this paper, we describe a model of information retrieval system that is based on a document re-ranking method using document clusters. In the first step, we retrieve documents based on the inverted-file method. Next, we analyze the retrieved documents using document clusters, and re-rank them. In this step, we use static clusters and dynamic cluster view. Consequently, we can produce clusters that are tailored to characteristics of the query. We focus on the merits of the inverted-file method and cluster analysis. In other words, we retrieve documents based on the inverted-file method and analyze all terms in document based on the cluster analysis. By these two steps, we can get the retrieved results which are made by the consideration of the context of all terms in a document as well as query terms. We will show that our method achieves significant improvements over the method based on similarity search ranking alone, (C) 2000 Elsevier Science Ltd. All rights reserved
Conjunctival resection combined with tenon layer excision and the involvement of mast cells in superior limbic keratoconjunctivitis.
No full textSupplemental_Material – Supplemental material for Examining the relationships between environmental barriers and leisure in community-dwelling individuals living with stroke
No full textSupplemental material, Supplemental_Material for Examining the relationships between environmental barriers and leisure in community-dwelling individuals living with stroke by Ada Tang, Billy Sun, Marco YC Pang and Jocelyn E Harris in Clinical Rehabilitation</p
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