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Abstract 6741: Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer
No full textAbstract Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide, causing substantial mortality. The urgent need for effective treatments has driven research into immune checkpoint blockade (ICB) therapies, which have demonstrated significant clinical benefits across various cancer types. Despite the success of ICB therapies, a significant proportion of CRC patients exhibit resistance to treatment, prompting the identification of mechanisms that hinder therapy resistance or enhance treatment response. CRC cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro-tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. In this study, we found that colorectal tumors with high glutaminase (GLS) expression exhibit reduced T-cell infiltration and cytotoxicity, leading to poor clinical outcomes. To validate these findings, we applied the ovalbumin (OVA)/OT-I T cell-based cytotoxicity assay and the CRC patient-derived organoids (PDOs)/autologous T cell killing assay. Our results indicated that inhibition of GLS significantly enhanced T-cell cytotoxicity in vitro and ex vivo. Mechanistically, we elucidated that inhibition of GLS activated reactive oxygen species-related signaling pathways in tumor cells, thereby potentially increasing tumor immunogenicity by promoting antigen presentation. The combinational therapy of GLS inhibitor and ICB exhibited a superior tumor growth inhibitory effect in comparison with either of the monotherapies. These findings shed new light on clinical therapeutic strategies for CRC patients, offering a promising approach to enhance the efficacy of ICB therapy. Citation Format: Tao Yu, Kevin Van der Jeught, Haiqi Zhu, Zhuolong Zhou, Samantha Sharma, Sheng Liu, Ka Man So, Haniyeh Eyvani, Xiyu Wang, George E. Sandusky, Yunlong Liu, Mateusz Opyrchal, Sha Cao, Jun Wan, Chi Zhang, Xinna Zhang. Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6741
Mechanistic insights into the role of miR‐6741‐3p in oral squamous cell carcinoma pathogenesis
No full textMany functional studies and clinical analysis have linked miRNA dysregulation as a causative factor for tumor initiation and progression. Overexpression of oncogenic miRNAs and downregulation of tumor suppressor miRNAs are widely reported to drive the process of carcinogenesis. Epigenetic silencing of miRNAs with tumor suppressor features by DNA hypermethylation is a common hallmark of many cancers including OSCC. We, therefore, used the drug 5-Azacytidine, a DNMT inhibitor, for reactivation of tumor suppressor miRNAs silenced due to DNA hypermethylation. Treatment of cells from an OSCC cell line SCC131 with control and 5-Azacytidine, followed by the miRNA microarray analysis revealed upregulation and downregulation of 50 and 28 miRNAs respectively. miR-6741-3p was one of the miRNAs found to be upregulated following the 5-Azacytidine treatment.
We validated the upregulation of miR-6741-3p following the 5-Azacytidine treatment using qRT-PCR and demonstrated its anti-proliferative activity in OSCC cells. miRNAs are epigenetic regulators which exert their effect through binding to one or more cognate target mRNAs and regulating their expression. Using bioinformatics and molecular approaches, we showed that miR-6741-3p post-transcriptionally regulates the expression of the oncogene SRSF3 at the protein level in OSCC by interacting with its 3’UTR in a sequence-specific manner. We analyzed the expression of miR-6741-3p transcript and SRSF3 protein in different cell lines and OSCC patient samples, and the results showed that the interaction between miR-6741-3p and SRSF3 is of physiological and clinical relevance. We demonstrated that miR-6741-3p reduced cell proliferation and anchorage-independent growth of OSCC cells, in part, by targeting the 3’UTR of SRSF3 and promoted apoptosis of OSCC cells independent of SRSF3. OSCC xenografts in nude mice using a synthetic miR-6741-3p mimic and a synthetic miR-6741-3p inhibitor indicated that miR-6741-3p suppresses tumor formation in OSCC, in part, by targeting SRSF3. We also demonstrated that miR-6741-3p decreases signaling through both the PI3K-AKT-MTOR and the ERK/MAPK pathways, in part, via the miR-6741-3p-SRSF3-ERK1/2-S6K1 axis.
We also demonstrated that the intronic miR-6741-3p is involved in the autoregulation of its host gene PYCR2 and inhibits its expression at both the transcript and protein levels in OSCC cells by interacting with a target site present in the 3’UTR in a sequence-specific manner. Expression analysis of miR-6741-3p and PYCR2 across different cell lines and OSCC patient samples suggested that the interaction between miR-6741-3p and PYCR2 is of physiological and clinical relevance.
We observed that MIR6741 lacks an independent promoter and seems to be co-transcribed with the PYCR2 transcript, using its host gene PYCR2 promoter. We identified and validated the host gene promoter activity and identified PAX6 as a positive regulator of the PYCR2 promoter activity. Using a combination of in silico analysis, ChIP analysis, and dual-luciferase reporter assays, we propose that PAX6 interacts with the PYCR2 promoter via an indirect mechanism. We further demonstrated that promoter methylation of the tumor suppressor gene PAX6 is responsible for the downregulation of miR-6741-3p in OSCC cells and speculate the involvement of the same mechanism in other cancers.CSIR, DB
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
6741 sayılı kanun kapsamında Türkiye Varlık Fonu Yönetimi AŞ. ve Türkiye Varlık Fonu hakkında bir inceleme
Get PDF19.08.2016 tarihli ve 6741 sayılı “Türkiye Varlık Fonu Yönetimi Anonim Şirketinin Kurulması İle Bazı Kanunlarda Değişiklik Yapılmasına Dair Kanun” ile Türkiye Varlık Fonu Yönetimi Anonim Şirketi (TVYF A.Ş.) ve Şirket tarafından yönetilecek olan Türkiye Varlık Fonu kurulmuştur. Fonun hedefleri sermaye piyasalarının araç çeşitliliğini sağlamak, Otoyollar, Kanal İstanbul, Üçüncü Köprü ve Havalimanı, Nükleer Santral gibi büyük altyapı projelerine finansman oluşturmak, önemli sektörlerde yer alan yerli şirketlerin hem sermaye hem de proje bazında desteklemek ve stratejik sektörlere bürokratik kısıtlamalara tabi olmadan doğrudan yatırım yapmaktır. Varlık fonları özellikle cari açık fazlası veren ülkelerde görülmekle birlikte, iç ekonomideki dalgalanmaların önlenmesi ve çeşitli yatırımların desteklenmesi için günümüzde gelişmekte olan ülkelerde de (İtalya, Brezilya vb.) kurulmaktadır. Varlık fonlarının uluslararası literatürde çeşitli yararlarının bulunduğu ileri sürülmekle birlikte şeffaf olmamaları ve denetim imkânlarının kısıtlı olması açısından da oldukça eleştirilmekte; ayrıca ulusal varlık fonlarının yaptığı yatırımların arkasında bazen ekonomik kaygılardan ziyade siyasi nedenlerin bulunduğu ileri sürülmektedir. Bu çalışmanın amacı, Türkiye’de yeni bir kurum olan Türkiye Varlık Fonu Yönetimi Anonim Şirketi’ni ve Şirketin yöneteceği Türkiye Varlık Fonunu mevzuat çerçevesinde incelemek ve 6741 sayılı Kanun kapsamında Şirkete ve Fona tanınan muafiyetler ile mevzuatta öngörülen denetim mekanizmalarının işlevselliğini değerlendirmeye çalışmaktadır.The Turkish Sovereign Wealth Fund Management Company (TVYF Inc.) and the Turkish Sovereign Wealth Fund have been established by the Law No. 6741. TVYF Inc. aims to finance large infrastructure projects such as Otoyollar, Kanal Istanbul, Third Bridge and Airport, Nuclear Power Plant; support domestic companies in important sectors on both capital and project basis; and invest directly in strategic sectors without being subject to bureaucratic restrictions. While sovereign funds are usually established in countries that has current account deficits, some emerging countries as well (eg Italy, Brazil, etc.) have these Funds in order to prevent fluctuations in the domestic economy and to support various investments. While sovereign funds are claimed to have various benefits in international literature, they are highly criticized for their lack of transparency and limited control possibilities. It is also argued that behind the investments made by sovereign wealth funds are sometimes political reasons instead of economic worries. The aim of this study is to examine the new entity, Turkey Sovereign Wealth Fund Management Corporation and the Turkish Sovereign Wealth Fund within the scope of the legislation and to evaluate the exemption granted to the Company and Fund within the framework of Law No. 6741 and the functioning of the supervision mechanisms envisaged in the legislation
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