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TEAD1/4 exerts oncogenic role and is negatively regulated by miR-4269 in gastric tumorigenesis
No full textM.Phil.Gastric cancer (GC) among the most common malignancies globally and is the third most frequent cause of cancer-related death. A wide variety of genetic, epigenetic and post-transcriptional alterations or aberrations underlies the initiation and progression of GC.This study was focusing on the involvement of Hippo pathway during gastric carcinogenesis. TEAD transcription factors are key components of the Hippo-YAP1 signaling pathway, but their functional role and regulatory mechanisms remain elusive. In our cohort, the clinicopathological association of TEAD4 in GC was revealed by immunohistochemistry on tissue microarray. Multivariate Cox Regression analysis indicated that TEAD4 predicts poor prognosis among gastric patients independently (P = 0.049). TEAD family, especially TEAD1 and TEAD4 were found to be high expressed in both primary gastric tumors and GC cell lines (P < 0.001). Knockdown of TEAD1/4 induced a significant anti-cancer effect in vitro and in vivo, which suggested that the enrichments of these genes promoted cell growth and cell invasive ability.Besides genetic and epigenetic regulations, this study also aimed to comprehensively explore the expression pattern and functional role of TEAD family in gastric carcinogenesis from post-transcriptional level, for example, the regulation of TEADs by microRNAs (miRNAs). The prediction of miRNAs which potentially target TEAD1/4 was screened by TargetScan and miRDB. The regulation of TEAD1/4 by miRNAs was confirmed by qRT-PCR, Western blot and luciferase activity assays. TEAD1 was confirmed to be a direct target of miR-377-3p and miR-4269, while TEAD4 was negatively regulated by miR-1343-3p and miR-4269. Ectopic expression of these miRNAs substantiated their tumor-suppressive effects. Among them, miR-4269 serves as the most effective inhibitor of TEAD1/4 for it also natively regulated the expression of TEAD downstreams, such as CTGF and Cyr61. In primary GC tumors, downregulation of miR-4269 was associated with poor disease-specific survival (P = 0.003) and showed a negative correlation with TEAD4 expression (P = 0.031). More importantly, re-overexpression of TEAD1 and TEAD4, in part, rescued the growth inhibitory effect of miR-4269 in GC.In conclusion, TEAD1 and TEAD4 are oncogenic factors, whose aberrant activation are, in part, mediated by the silence of miR-377-3p, miR-1343-3p and miR-4269. For the first time, the nuclear accumulated TEAD4 and down-regulated miR-4269 are proposed to serve as novel prognostic biomarkers in GC.胃癌是全球常見的惡性腫瘤之一，同時也是導致死亡率第三位的癌癥，一系列基因方面，表觀遺傳學方面以及轉錄後方面的改變是胃癌發生的潛在因素。本課題著重對目的基因TEAD進行深入研究。TEAD轉錄因子是Hippo-YAP信號通路的一個重要組成部分，但其在胃癌中的作用機制尚未被闡明。在研究隊列中，組織芯片的免疫組化證實，TEAD4在胃癌患者中有較高表達水平且其表達位置處於細胞核中。同時，多因素回歸分析證實TEAD4在胃癌病人中可以作為一個獨立的預後指標（P = 0.049）。體內外實驗表明，相對於陰性對照而言，TEAD家族，尤其是TEAD1 和TEAD4在胃癌臨床標本及胃癌細胞系中的表達水平都有顯著增加 (P < 0.001)。在實驗中，TEAD1和TEAD4表達的減少均可導致顯著的抑癌效果，這也說明瞭兩者在胃癌的中高表達能促進細胞生長及增強胃癌細胞的侵襲能力。除了基因水平，表觀修飾水平的因素外，本課題還意在研究胃癌中TEAD家族在轉錄後水平的調控機制。例如，微小核糖核酸對TEAD家族的調控。我們用TargetScan和 miRDB數據庫來預測潛在調控TEAD家族表達的微小核糖核酸，並用實時熒光定量PCR，免疫蛋白印跡以及熒光素酶實驗進行進一步確認。結果表明，TEAD1可被miR-377-3p和miR-4269直接調控，而TEAD4受到miR-1343-3p和miR-4269的直接調控。在細胞中過量表達這三個微小核糖核酸可顯著地抑制胃癌細胞的生長。其中，因miR-4269可同時通過調控TEAD1和TEAD4而下調Hippo通路的下游（如CTGF和Cyr61），故miR-4269對TEAD家族的調控作用最顯著。在胃癌臨床標本中，miR-4269的下調也預示著病人不良預後，且miR-4269的表達與TEAD4表達呈負相關。綜上所述，TEAD1和TEAD4均是促癌因子，其異常的激活在某種程度上是由於miR-377-3p，miR-1343-3p和 miR-4269這三者自身的下調所導致。通過本課題，我們首次提出TEAD4的細胞核聚集以及miR-4269的下調可作為胃癌患者不良預後的一個新指標。Zhou, Yuhang.Thesis M.Phil. Chinese University of Hong Kong 2017.Includes bibliographical references (leaves 117-131).Abstracts also in Chinese.Title from PDF title page (viewed on 05, February, 2020)
Block Card 4269 River Road
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Ranch houses | 4269 River Road (Toledo, Ohio) | Dwelling | Arden Place Addition (Toledo, Ohio) | South Toledo Area (Toledo, Ohio
[Veto of H. 4269, R-178]
No full textThis veto message from Governor Mark Sanford vetoes H. 4269, R-178, a bill providing that beginning with school year 2003-2004, the starting date for the annual school term of Allendale, Bamberg, Barnwell, Calhoun and Hampton County School Districts must be set by the board of trustees of the respective school district
Northwest Africa 4269: a metal-rich eucrite from the Algerian Sahara
No full textInternational audienceNorthwest Africa (NWA) 4269 is an anomalous monomict eucrite that is characterized by a very high content of metallic iron (~ 3%). It shows various textures (relict magmatic subophitic, granulitic areas as coarse and fine-grained). NWA 4269 also shows petrographic evidence of secondary sub-solidus reheating events. Pyroxenes have homogeneous compositions and are iron-rich. NWA 4269 is metamorphosed type 5. It has a normal HED oxygen isotope composition. The chemical composition of NWA 4269 has characteristics similar to that of Nuevo-Laredo trend eucrites. Metal is extremely abundant in the finegrained areas (~ 10%). Metal also has a very low Ni content (Ni<0.1%) that excludes a direct origin from a chondrite-like impactor. Origin of the pure-Fe groundmass metal remains enigmatic. The high metal content in NWA 4269 can be interpreted as having formed via the reduction of FeO and probably also by desulfidation of pre-existing troilite. Iron metal could have formed by deposition from a Fe-rich fluid that, probably after an event that triggered sudden reduction. NWA 4269 has normal HED oxygen isotope compositions and interpreted as belonging to the 4-Vesta asteroid
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Northwest Africa 4269: a metal-rich eucrite from the Algerian Sahara
No full textNorthwest Africa (NWA) 4269 is an anomalous monomict eucrite that is characterized by a very high content of metallic iron (~ 3 %). It shows various textures (relict magmatic sub-ophitic, granulitic areas as coarse and fine-grained). NWA 4269 also shows petrographic evidence of secondary sub-solidus reheating events. Pyroxenes have homogeneous compositions and are iron-rich. NWA 4269 is metamorphosed type 5. It has a normal HED oxygen isotope composition. The chemical composition of NWA 4269 has characteristics similar to that of Nuevo-Laredo trend eucrites. Metal is extremely abundant in the fine-grained areas (~ 10 %). Metal also has a very low Ni content (Ni < 0.1 %) that excludes a direct origin from a chondrite-like impactor. Origin of the pure-Fe groundmass metal remains enigmatic. The high metal content in NWA 4269 can be interpreted as having formed via the reduction of FeO and probably also by desulfidation of pre-existing troilite. Iron metal could have formed by deposition from a Fe-rich fluid that, probably after an event that triggered sudden reduction. NWA 4269 has normal HED oxygen isotope compositions and interpreted as belonging to the 4-Vesta asteroid
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
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