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Jian li xin de yao wu zu he yi ke fu EGFR ba xiang liao fa de nai yao xing huo zeng qiang hua xue zhi liao zai fei ai zhong de kang ai zuo yong
No full textResearch Background and Objectives: In advanced non-small cell lung cancer (NSCLC), epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are used as first-line agents for treating patients with EGFR mutation whereas platinum-based chemotherapy is routinely used for patients without EGFR mutation and those relapse on EGFR TKIs. However, the efficacy of EGFR TKIs is severely compromised by drug resistance mediated by various mechanisms. Conventional chemotherapeutic drugs have only limited anticancer activity and they are also notorious for causing severe adverse effect. This study aimed to (i) identify new drug combinations to overcome resistance to 1st generation EGFR TKIs (due to secondary EGFR T790M mutation or insufficient autophagy induction) and (ii) enhance the anticancer effect to cisplatin (through enhancing DNA damage). Two research approaches, including in silico structure-based docking analysis and experimental screening for modulation of specific molecular targets, were used to identify suitable drug candidates to use in combination with the anticancer drugs for resistance circumvention or enhancement of anticancer effect. In silico docking analysis was used to identify clinically approved drug candidates capable of targeting the EGFR T790M mutation to overcome acquired EGFR TKI resistance. Selected molecular targets regulating autophagy or DNA damage were used as endpoints for evaluating non-oncology drugs capable of modulating the two pathways to overcome EGFR TKI and to enhance the anticancer effect of cisplatin, respectively.Methods: NSCLC cell lines (HCC827, H1975, H1650, A549 and H460) harboring different genetic abnormalities and covering a range of drug resistance mechanisms were employed. To identify suitable drugs for repurposing to overcome EGFR T790M-mediated resistance to 1st generation EGFR TKI, a free and open-source protein-ligand docking software “idock” was used to conduct in silico molecular docking analysis to screen clinically approved small-molecule drugs that can preferentially bind to the resistance-causing EGFR T790M mutant. To identify suitable compounds or drugs for repurposing to overcome EGFR TKI resistance due to insufficient autophagy induction or reduced DNA damage to chemotherapy, Western blot analysis was used to screen a list of putative compounds or non-oncology drugs that can regulate mediators of autophagy induction and DNA damage. Sulforhodamine B assay was used to evaluate their combination effect with either EGFR TKI or chemotherapy. The underlying mechanisms were evaluated by quantitative real-time PCR and Western blot analysis to measure the expression of relevant genes and proteins, respectively. Annexin V apoptosis assay was used to investigate the apoptotic effect. Flow cytometric cell cycle analysis using propidium iodide DNA staining was used to determine cell cycle distribution.Results: By molecular docking, three clinically approved drugs (indacaterol, canagliflozin and cis-flupenthixol) were selected that can interact with the EGFR T790M mutant. The drugs were shown to induce more substantial apoptosis in H1975 cells harbouring EGFR T790M mutation than other NSCLC cell lines tested. Moreover, the combination of indacaterol with gefitinib (1st generation EGFR TKI) gave rise to synergistic anticancer effect in H1975 cells through enhanced inhibition of EGFR and its downstream signaling molecules. Recent literature suggests that the lack of autophagy induction by gefitinib causes drug resistance in a subset of NSCLC cell lines. A few putative autophagy modulators were examined by evaluating their effect on the expression of two key autophagy protein markers (LC3 and p62). Loperamide, an antidiarrheal drug, was found to be the most potent autophagy inducer and it was selected for in-depth investigation. Loperamide promoted the formation of autophagosomes and induced degradation of autophagic substrate protein. Its combination with gefitinib gave rise to synergistic cytotoxic effect specifically in NSCLC cell lines (which carry mutant KRAS and wild-type EGFR) exhibiting primary resistance to gefitinib). The synergistic effect was further shown to be mediated by increased apoptosis but independent of autophagy induction. DNA damage represents the major anticancer mechanism for cisplatin. Two key DNA damage markers (p53 and γ-H2AX) were used to examine a list of compounds that can potentiate cisplatin-mediated DNA damage in NSCLC cells. Quercetin, a flavonoid present in many fruits and vegetables, was chosen for detailed investigation. It was found to potentiate the anticancer effect of cisplatin preferentially in p53-proficient NSCLC cell lines (A549, H460 and H1975) but not in p53-deficient NSCLC cell line (H1650), through augmenting DNA damage. The drug combination also led to enhanced apoptosis.Conclusions: New drug combinations have been identified by virtual computational docking analysis and experimental investigation of specific molecular targets (autophagy and DNA damage mediator) to overcome resistance to gefitinib and to enhance the anticancer effect of cisplatin in NSCLC cells. The former approach identified indacaterol to overcome acquired gefitinib resistance in NSCLC cells bearing EGFR T790M through enhanced inhibition of EGFR and its downstream signaling molecules. The latter approach identified loperamide to overcome primary resistance to gefitinib resistance in NSCLC harboring mutant KRAS and wild-type EGFR through increased apoptosis but independent of autophagy induction. Quercetin was also identified to enhance the anticancer effect of cisplatin in specific NSCLC cells by augmenting DNA damage.Significance: Drug resistance to EGFR TKIs and the limited efficacy of chemotherapeutic drugs are hindering the sustained disease control in lung cancer patients. This study has significant public health implications because overcoming drug resistance and enhancing efficacy of anticancer drugs could substantially improve clinical outcome and quality of life of NSCLC patients not responding to existing therapy. Moreover, by repurposing drugs already in routine clinical use, the findings are poised for rapid clinical translation.背景和目的：在晚期非小細胞肺癌 (NSCLC) 中，上皮生長因子受體 (EGFR) 的酪氨酸激酶抑製劑(TKIs) 是治療EGFR突變患者的第一線治療藥物。鉑類化學療法通常用於治療沒有EGFR突變和在EGFR TKIs治療後復發的患者。然而， EGFR TKIs的功效被各種機制所引致的耐藥性所限制。鉑類化學療法的功效亦有限。因此，這項研究旨在建立新的藥物組合，以克服第一代EGFR TKI的耐藥性 (因EGFR 二次突變T790M及因自噬不足) ，以及增強順鉑 (cisplatin) 的抗癌作用 (通過增強DNA損傷) 。是次研究採用了兩種方法去找出針對特定靶標的小分子: 電腦模擬分子對接分析法和實驗篩選法。被選出來的藥物或小分子會與抗癌藥物一併使用，以克服耐藥性或增強抗癌作用。電腦模擬分子對接分析會用作選定能夠靶向EGFR T790M突變的臨床認可小分子藥物，以克服EGFR TKI的耐藥性。另外，實驗篩選法會用作選定能增強自噬或DNA損傷的小分子，分別用於克服EGFR TKI的耐藥性和增強順鉑的抗癌作用。方法：是次研究採用了具有不同基因異常和涵蓋了不同耐藥性機制的NSCLC細胞系 (HCC827、H1975、H1650、A549和H460)。為了克服第一代EGFR TKI的耐藥性 (EGFR T790M) ，我們使用了免費的蛋白質-配體對接軟件“idock”進行分子對接分析，以選出臨床認可的小分子藥物，與引起耐藥性的EGFR T790M突變體結合。為了克服EGFR TKI因自噬不足引致的耐藥性，以及為了提高化學療法的DNA損傷，我們使用了蛋白免疫印迹法 (Western blot analysis) 來篩選分別可增加自噬和增加DNA損傷的化合物或非腫瘤臨床藥物。磺胺多巴酚B (Sulforhodamine B, SRB) 用於測試藥物組合對細胞活力的影響。為探討藥物組合的作用機制，即時聚合酶鏈鎖反應 (real-time PCR) 測量了相關基因的表達，蛋白免疫印迹法則測量了相關蛋白質的表達。 凋亡檢測試劑 (Annexin V apoptosis assay) 用於測量藥物組合對細胞凋亡的作用。碘化丙啶 (propidium iodide) DNA染色法用於進行流式细胞術细胞週期分析。結果：通過電腦模擬分子對接分析法，我們選擇了三種可與EGFR T790M突變體相互作用的臨床認可藥物 (茚達特羅、卡那列淨和順氟噴他醇)。與其他細胞系相比，這些藥物在具有EGFR T790M突變的H1975細胞中引起更多的細胞凋亡。此外，茚達特羅與吉非替尼 (第一代EGFR TKI) 組合後，增強了對EGFR及其下游信號分子的抑制作用，並在H1975細胞中產生了協同的抗癌作用。最近的文獻顯示，吉非替尼在部分NSCLC細胞系因缺乏自噬作用而引致耐藥性。通過測試不同小分子對兩種關鍵的自噬蛋白表達 (LC3和p62) 的影響，篩選了一些可調節自噬的小分子。由於洛哌丁胺(臨床認可的止瀉藥) 是當中最有效的自噬誘導劑，因此被選中作深入研究。洛哌丁胺促進了自噬體的形成，並誘導自噬基質蛋白的降解。它與吉非替尼的組合在NSCLC細胞系 (具有突變型KRAS和野生型EGFR) 產生了協同的細胞毒性作用。但進一步研究顯示其協同作用是由細胞凋亡所引致的，與自噬誘導無關。 DNA損傷是順鉑抗癌的主要機制。我們使用兩個關鍵的DNA損傷標 (p53和γ-H2AX) 來篩選可增強DNA損傷的化合物或藥物。槲皮素是一種存在於許多水果和蔬菜中的類黃酮。它在A549、H460和H1975細胞中增強了順鉑的抗癌作用，但在H1650中卻不能。當中的機制為增加順鉑所造成的DNA損傷，以增加p53依賴性細胞凋亡。結論：通過電腦模擬分子對接分析法和實驗篩選法，我們針對NSCLC 細胞建立了新的藥物組合，以克服吉賽替尼的耐藥性和增強順鉑的抗癌作用。前者確定了茚達特羅可通過增強對EGFR及其下游信號分子的抑制作用，來克服具有EGFR T790M耐藥性的NSCLC細胞。後者確定了洛哌丁胺可通過增加與自噬誘導無關的細胞凋亡，來克服吉非替尼在具有突變型KRAS和野生型EGFR的NSCLC的耐藥性。後者亦確定了槲皮素增可通過增加DNA損傷和p53依賴性細胞凋亡，來增強順鉑在特定NSCLC細胞系中的抗癌作用。意義：EGFR TKIs的耐藥性和化療藥物有限的療效阻礙了對NSCLC患者的疾病控制。這項研究具有重大的公共衛生意義，因為克服耐藥性和提高抗癌藥的功效將大大改善對現有療法無反應的NSCLC患者的臨床效果和生活質素。此外，通過重新定位現時臨床使認可的藥物，可使這些新的藥物組合在臨床上更快得以應用。Tong, Wing Sum."November 2020."Ph.D. Chinese University of Hong Kong 2021.Includes bibliographical references (leaves 171-220).Abstracts also in Chinese.Title from PDF title page (viewed on October 17, 2022).Tong, Wing Sum
論《紅梨記》和《贈書記》敘事程式的正依和變奏
Get PDF有關明清傳奇敘事程式的研究，林鶴宜的《規律與變異：明清戲曲學辨疑》首先提出各項基本和輔助程式，幫助研究及釐清戲曲作品的敘事脈絡。林鶴宜認為明清傳奇的敘事程式大致有三：「結構性程式」、「環節性程式」和「修飾性程式」1。本文發現《紅梨記》和《贈書記》有按照規律程式鋪排劇情，獲得既定效果；同時亦有透過變奏程式，為情節帶來創新的演繹。本文將集中討論《紅梨記》和《贈書記》的「結構性程式」和「環節性程式」，仔細探討其表演和文學的規守及演繹變化。本文分為七部分：第一章為緒論。第二章為《紅梨記》程式規範考。第三章為論《紅梨記》特殊敘事程式和關鍵情節。第四章為《贈書記》程式規範考。第五章為《贈書記》特殊敘事程式和關鍵情節。第六章為兩劇「磨難試煉程式」比較。第七章為全文總結
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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