预约演示

更新于：2025-05-07

TCF7L2

更新于：2025-05-07

基本信息

别名

HMG box transcription factor 4、hTCF-4、T-cell factor 4

+ [6]

简介

Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as a repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine.

关联

靶点

TCF7L2

作用机制

TCF7L2调节剂

在研机构

Myeloid Therapeutics, Inc.

原研机构

Myeloid Therapeutics, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TCF7L2 相关的临床结果

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100 项与 TCF7L2 相关的转化医学

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0 项与 TCF7L2 相关的专利（医药）

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1,727

项与 TCF7L2 相关的文献（医药）

2025-12-01·Genes & Nutrition

Changes in triglyceride-rich lipoprotein particle profiles in response to one-week on a low fat or Mediterranean diet by TCF7L2 rs7903146 genotype: a randomized crossover dietary intervention trial

Article

作者: Lai, Chao-Qiang ; Gervis, Julie E ; Parnell, Laurence D ; Ordovas, Jose M ; Lichtenstein, Alice H

AbstractBackgroundThe TCF7L2 gene is a significant genetic factor contributing to the risk of metabolic and cardiovascular diseases (CVD). We previously found that subjects with the TT genotype of TCF7L2 rs7903146 variant, who consume a low-fat diet (LF) had a higher incidence of stroke than subjects with the CC genotype. Yet this association was abolished in subjects with the TT genotype who consumed a Mediterranean-type diet (MetD). However, the mechanism by which MetD diet modulates the association between TCF7L2 and CVD risk is unclear. This study aims to validate these findings under real-world conditions and clinical practice to elucidate the biological mechanisms involved in this correlation.MethodsThirty-five participants with BMI ranging from 27 to 34 kg/m2 were recruited based on rs7903146 genotype. Of those consented to participate, 21 had the CC and 14 had the TT genotype. Participants were randomly assigned to two dietary intervention groups, ensuring an equal distribution of CC and TT carriers. Each participant followed one of two diets (LF or MetD) for one week, followed by a 10-day washout period before switching to the other diet for one week. Blood samples were collected before and after each diet for metabolomic analysis using nuclear magnetic resonance (NMR) spectroscopy. The differential effect of the diets on triglyceride-rich lipoproteins was determined based on TCF7L2 genotype.ResultsThe MetD significantly reduced triglyceride-rich lipoprotein concentrations compared to the LF diet. After consuming the LF diet, TT carriers exhibited more small VLDL particles, potentially contributing to CVD risk compared to CC carriers. However, this difference in risk was not observed with the MetD. Furthermore, the order in which the two diets were crossed affected the triglyceride-rich lipoprotein profile, with LF-MetD regimen showing a stronger effect on triglyceride-rich lipoproteins (TRL) levels than the MetD-LF regimen.ConclusionsOur findings suggest that rs7903146 TT carriers benefit more from a MetD than a LF diet in terms of their triglyceride-rich lipoprotein profile, which may reduce their risk of CVD. These results support the notion that genotype is a factor in determining the extent to which the MetD affects cardiovascular health.

2025-06-01·Food and Chemical Toxicology

Elaidic acid induces testicular oxidative stress, inflammation, Wnt/β-catenin disruption and abnormalities in steroidogenesis, spermatogenesis and histo-architecture in Sprague Dawley rats

Article

作者: Al-Emam, Ahmed ; Alzahrani, Khalid J ; Alsuwat, Meshari A ; Akbar, Ali ; Zahara, Syeda Sania ; Alzahrani, Fuad M ; Hayat, Muhammad Faisal

Elaidic Acid (EA) is a major trans-fatty acid that has garnered significant attention due to its potential role in inducing systemic toxicity. The current investigation was conducted to assess the toxic effects of EA (50 mg/kg, 100 mg/kg, and 150 mg/kg) on testicular tissues of Sprague Dawley rats. EA intoxication disrupted Wnt/β-catenin via downregulating the expression of WNT3A and TCF7L2 while upregulating the expression of AXIN1 and GSK-3β. The activities of antioxidant enzymes were reduced while the levels of cellular oxidative stress were escalated following the EA exposure. EA administration disrupted the process of steroidogenesis as well as spermatogenesis through the downregulation of CYP11A1, 5α-reductase, 3β-HSD, CYP17A1, and StAR while elevating spermatogenic abnormalities in head, tail and neck of sperm cells. The levels of LH, androgen binding protein, FSH, inhibin B, plasma testosterone and estradiol were lowered after EA administration. Testicular tissues showed inflammatory responses after EA exposure that is evident by elevated levels of TNF-α, IL-1β, COX-2, IL-6 and NF-κB. The expressions of Bax and Caspase-3 were upsurged while expression of Bcl-2 was reduced following the EA intoxication. These findings showed EA exerted toxic effects on testicular tissues via elevating oxidative stress, inflammation and apoptosis.

2025-06-01·Contemporary Clinical Trials Communications

An exploratory, open-label, parallel group, randomised controlled trial evaluating the effect of gene based nutritional intervention in type 2 diabetes: The protocol for NUDGE clinical trial

Article

作者: Kushwaha, Savitesh ; Gupta, Pramod Kumar ; Sagar, Vivek ; Khanna, Poonam ; Thakur, Jarnail Singh ; Gupta, Madhu ; Srivastava, Rachana ; Bhadada, Sanjay Kumar

IntroductionType 2 diabetes mellitus (T2DM) presents significant public health challenges in India, where unique genetic and phenotypic characteristics elevate susceptibility. Recent research highlights the interaction of genetic polymorphisms and dietary factors in T2DM management, forming the basis of personalised nutrition interventions. This study outlines the protocol for NUDGE clinical trial to evaluate the efficacy of gene-based dietary strategies compared to standard recommendations in T2DM management.MethodsThe NUDGE trial is an exploratory, open-label, parallel-group, randomised controlled clinical trial conducted across healthcare settings in Chandigarh, India. A total of 300 participants diagnosed with T2DM will be randomised into intervention and control groups. The intervention group will receive personalised diet plans based on genetic polymorphisms (TCF7L2 and PPARG), anthropometric, and lifestyle data, while the control group follows standard dietary advice. Baseline and endline assessments will measure fasting blood glucose, HbA1c, anthropometric parameters, and adherence.DiscussionPrimary outcomes focus on changes in FBG, while secondary outcomes include weight and blood pressure. Statistical analyses will evaluate gene-diet interactions and adherence to dietary plans. The trial aims to establish evidence for precision nutrition in T2DM by leveraging gene-diet interactions to tailor interventions. Findings will provide insights into the role of personalised nutrition in improving glycemic control.ConclusionThe NUDGE trial seeks to advance precision nutrition in T2DM management, paving the way for individualised dietary recommendations to mitigate disease progression and complications.Ctri reg noCTRI/2021/09/036121 Clinical Trial Registry of India.

项与 TCF7L2 相关的新闻（医药）

2024-12-18

·国际糖尿病idiabetes

李小英教授、夏明锋教授综述：2型糖尿病精准医疗的现状与展望

点击“蓝字”关注我们编者按糖尿病已成为全球公共卫生危机。尽管降糖药物不断发展，但血糖控制达标率仍不理想。糖尿病的异质性决定了精准医疗的必要性。复旦大学附属中山医院李小英教授、夏明锋教授共同发表的综述[1]从遗传学和表观遗传学的角度总结了糖尿病异质性的进展，并介绍了一种2型糖尿病（T2DM）临床亚分层方法，旨在为糖尿病的精准诊断和治疗提供解决方案。糖尿病是全球性的公共健康问题，其中T2DM占比高达95%。尽管新型降糖药物的研发取得了巨大成功，但血糖控制达标的患者比例并未如预期般上升。糖尿病的异质性决定了“一刀切”的策略并不合适。李小英教授、夏明锋教授综述了糖尿病精准治疗的进展，围绕遗传学、表观遗传学、临床分层、个体化预防及治疗等方面，为糖尿病的精准诊疗提供参考（图1）。图1.糖尿病管理中的精准医疗糖尿病的异质性与精准医疗的必要性糖尿病的异质性虽早已被认识，但传统分类方法如1型糖尿病（T1DM）、T2DM、单基因糖尿病和妊娠期糖尿病等无法满足精准治疗需求。不同患者对降糖治疗的反应存在差异，受糖尿病病程、合并症、预期寿命、体重、年龄、家族史、处方药物及治疗费用等因素影响。不同病因和种族的患者对降糖药物的反应也不同。因此，基于遗传背景和病理生理机制对糖尿病患者进行分层，有助于实现精准医疗。糖尿病的遗传学研究单基因糖尿病的精准药物治疗已成功指导临床治疗。然而，单基因糖尿病的识别未能解决T2DM患者对降糖药物反应的个体差异。 2007年首项T2DM全基因组关联研究（GWAS）[2]发表。然而，至今已发现的400多个遗传变异仅能解释18%的糖尿病风险，且单个变异与风险关联微弱（TCF7L2基因变异除外）。因此，基因组信息对T2DM精准医疗的指导价值有限。相比之下，T1DM的GWAS发现的遗传变异能较好预测风险，遗传风险评分的敏感性和特异性均超过80%。糖尿病的表观遗传学研究表观遗传学代表了与环境因素和临床表型相关的可遗传且可逆的基因组修饰。表观遗传学探究非DNA序列变异改变表型的机制，包括DNA甲基化、组蛋白修饰、非编码RNA调控等。由于表观遗传模式具有很大的可塑性，T2DM中的表观遗传改变可作为个性化治疗的靶点。非编码RNA（尤其是microRNA）可调节蛋白编码基因或表观遗传调节因子表达，其变化与T2DM胰岛素抵抗水平相关，有望成为一种生物标志物。整合遗传和表观遗传风险因素可能为T2DM亚分类提供解决方案。糖尿病的分层 01 基于聚类分析的分层 T2DM存在多种致病机制和结局，聚类分析可利用高维数据（如电子病历或组学数据）识别亚型。2018年瑞典研究基于6个临床变量识别出5种成人发病糖尿病亚型，包括严重自身免疫型糖尿病、严重胰岛素缺乏型糖尿病、严重胰岛素抵抗型糖尿病、轻度肥胖相关糖尿病和轻度年龄相关糖尿病，各亚型在遗传易感性、临床特征和疾病预后等方面存在差异，新的分类方法在不同种族队列中得到验证，且有助于指导个体化治疗[3]。 02 人工智能（AI）在分层中的应用 AI技术的应用能够以提供的格式（文本、图像/视频、生物特征数据）全面摄取所有所需参数进行分析，从而预测糖尿病的发病率以及对糖尿病人群进行风险分层。AI在糖尿病管理中的应用可以基于广泛的候选参数，建立更准确和客观的T2DM分层。糖尿病的精准预防糖尿病的综合管理包括饮食和运动干预、患者教育、血糖监测和药物治疗。在糖尿病确诊时，近半数患者已发生组织损伤。对糖尿病前期患者进行早期干预可降低新发糖尿病的风险，并改善远期结局。然而，糖尿病前期患者对生活方式或药物干预的反应存在较大差异，且受遗传变异影响。例如，DPP研究中，二甲双胍降低糖尿病发病的保护作用与SLC47A1基因变异有关。对生活方式改变反应不佳的糖尿病前期患者，可通过其他方法更好地治疗，但需要更多研究来正确识别这一亚群。同时，人们也在努力通过饮食干预和/或免疫靶向方法预防存在≥2种胰岛自身抗体的高危儿童发生T1DM。遗憾的是，以往大多数干预性研究无法减缓、停止或逆转β细胞破坏，也无法延缓T1DM进展。糖尿病的精准治疗 01 药物治疗的个体差异 FDA批准的10类糖尿病药物疗效存在异质性，不同病因和种族的患者对药物反应不同。同时，个体对特定抗糖尿病药物的反应也存在种族差异。 02 遗传学指导药物治疗遗传学已在单基因糖尿病治疗中成功应用，但T2DM受多种因素影响，传统遗传研究关注与病因或药物代谢相关的候选基因，如SLC22A1和MATE1基因变异影响二甲双胍反应，KCNJ11/ABCC8和TCF7L2基因变异分别增加和降低磺脲类药物的血糖反应，PPARG基因变异与噻唑烷二酮类药物反应相关。GWAS为糖尿病药物遗传学提供了新见解，识别出ATM和SLC2A2基因变异与二甲双胍反应有关，但仍需更多此类研究建立药物反应预测系统。 03 糖尿病管理中的新技术除药物治疗外，葡萄糖监测、患者教育和生活方式干预也很重要。远程持续葡萄糖监测（CGM）可全面了解血糖控制情况，为个体化生活方式干预提供依据。基于AI的决策支持系统Advisor Pro可远程确定胰岛素剂量，AI有望推动糖尿病管理从传统策略向数据驱动的精准治疗转变。此外，干细胞治疗糖尿病取得进展，对T1DM和T2DM均有益处，但仍面临诸多挑战，如干细胞来源多样性、制备和评估系统不一致以及安全性问题等。展望糖尿病的异质性为精准医疗带来挑战，但精准医疗在糖尿病治疗中的应用不断发展，有望造福新诊断和长期血糖控制不佳的糖尿病患者。多学科合作有助于深入理解糖尿病，随着对糖尿病发病机制和药物反应相关遗传背景知识的增加，以及AI在糖尿病管理中的应用，精准医疗有望实现糖尿病的早期干预、预防和准确管理。尽管仍有很长的路要走，但精准医疗将成为未来糖尿病管理的驱动力。参考文献： 1.Xia M, Li X. Updates of precision medicine in type 2 diabetes. Camb PrismMed. 2023; 1: e24. 2.Sladek R, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445(7130):881-885. 3.Ahlqvist E, et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 2018;6(5):361-369. 声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！（来源：《国际糖尿病》编辑部）版权声明版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。

临床研究

2024-11-28

·今日头条

具有抗肿瘤活性和低毒性！复旦大学合作发文：发现有前景的抗肿瘤药物

【导读】 Wnt/β-catenin/转录因子（TCF）转录活性在结直肠癌（CRC）的发生发展中起着不可或缺的作用。然而，迄今为止，靶向该通路的药物由于不良和严重的副作用而未用于临床实践。 11月27日，复旦大学与上海交通大学研究人员共同在期刊《Advanced Science》上发表了研究论文，题为“Targeting the NOTCH2/ADAM10/TCF7L2 Axis-Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer”，本研究中，研究人员发现Wnt通路的转录调控在CRC中被激活并与肝转移相关。通过对12种结直肠癌和3种结直肠类器官的24种抑制剂的高通量筛选，研究人员发现爱达维特在结直肠类器官中表现出抗肿瘤活性和低毒性，且不依赖于经典的Wnt/β-catenin信号通路。机制上，ADAM10被筛选为爱达维特的靶点，特异性调控NOTCH2的蛋白表达，介导Wnt通路的转录调控。NOTCH2不直接与经典Wnt/β-catenin信号通路的关键下游转录因子TCF7-like 2 （TCF7L2）相互作用，而是直接激活TCF7L2和Wnt靶基因的转录，如MYC、JUN和CCND1/2。此外，使用爱达维特或阻断ADAM10/NOTCH2/TCF7L2信号通路可增强CRC细胞的化疗敏感性。总之，这项研究为开发小分子抑制剂提供了一个有前景的候选药物，并揭示了CRC的潜在治疗靶点。 https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202405758 背景知识 01 结直肠癌（CRC）是最常见的恶性肿瘤之一，也是癌症相关死亡率的主要原因。约50%的结直肠癌患者发生肝转移，5年生存率低于10%。手术干预、全身化疗和靶向治疗（如西妥昔单抗和贝伐珠单抗）是CRC肝转移的主要治疗选择。由于其高度的异质性和复杂性，CRC对化疗和靶向治疗的反应不一，治疗过程中的获得性耐药严重阻碍了治疗效果。改善化疗耐药转移性CRC患者的预后仍然是一项挑战。因此，迫切需要新的治疗靶点来克服CRC治疗的耐药性。结直肠癌是由APC、TP53、KRAS等多个基因突变累积引起的。具体而言，APC突变介导的Wnt信号通路过度激活是CRC发生的关键驱动因素，约80%的CRC病例携带APC突变。机制上，APC突变加速β-catenin的核内聚集，导致其与转录因子(TCF)/淋巴增强因子（LEF）结合，激活经典Wnt通路下游靶基因的转录，包括MYC、JUN等。此外，Wnt通路的激活还通过影响肿瘤微环境、细胞增殖、凋亡、自噬、代谢、侵袭和迁移促进CRC的进展。另外，Wnt通路对肿瘤的治疗具有重要意义。虽然Wnt通路在肿瘤的发生和发展中起着至关重要的作用，但越来越多的研究报道其受其他通路的调控，包括KRAS、磷脂酰肌醇3-激酶- akt和Notch通路。这些发现表明，靶向关键的上游调控成分可能是治疗Wnt通路活性CRC的理想方法。研究进展 02 免疫荧光分析显示，爱达维特24 h后，ADAM10在细胞膜和细胞质中表达降低，NOTCH2在细胞膜、细胞质和细胞核中表达降低。而β-catenin和TCF7L2的表达无明显变化。与结直肠癌原发灶和肝转移灶相比，正常结直肠组织中ADAM10和NOTCH2表达水平较低。胞核-胞质分离实验结果显示，NOTCH2在细胞质和胞核中的表达均降低。此外，研究人员没有在细胞质中检测到MYC和JUN的表达，但在细胞核中观察到表达减少。爱达维特24小时处理后没有改变TCF7L2的表达，但在48小时降低了TCF7L2的表达。使用Cut&Tag和qRT-PCR检测，爱达维特24小时处理后，与TCF7L2启动子结合的NOTCH2被减弱。强制MYC和JUN表达恢复了爱达维特24小时诱导的CRC类器官的生长抑制。接下来，研究人员检测了用ADAM10， NOTCH2和TCF7L2 sirna处理的结直肠癌类器官中MYC和JUN蛋白水平的下降。为了探索NOTCH2， MYC和JUN是否介导ADAM10诱导的类器官生长，研究人员在CRC类器官中上调ADAM10的表达，并观察CRC类器官的生长。这种生长被MYC， JUN和NOTCH2敲低所逆转。敲低ADAM10减弱了MYC和JUN过表达的作用。研究亮点 03 研究人员证明爱达维特通过干扰Wnt通路抑制结直肠癌类器官的生长。Wnt通路的激活与CRC的化疗耐药相关。因此，研究人员研究了爱达维特是否能减轻CRC的化疗耐药性。最初，研究人员评估了CRC类器官对亚叶酸、氟尿嘧啶和奥沙利铂（FOLFOX）方案的敏感性，发现不同类器官的反应不同。研究人员利用P2类器官和LM5R类器官成功构建folfox抗性类器官，分别命名为P2F和LM5RF。在P2和LM3类器官中，ADAM10过表达诱导了对FOLFOX方案的耐药性，这被NOTCH2， MYC和JUN的敲低所缓解。对于MYC和JUN的敲低，研究人员用三种siRNA处理结直肠癌类器官，并选择最有效的siRNA进行后续实验。在体内实验中，爱达维特联合FOLFOX方案对P2F和LM5RF类器官的生长具有较好的抑制作用。在P2F和LM5RF类器官中，敲低ADAM10减弱了对FOLFOX方案的耐药性。根据AUC值，研究人员选择对FOLFOX方案中度敏感的类器官（P3类器官）和对FOLFOX方案耐药的类器官（LM5L类器官）建立PDOX模型。爱达维特联合FOLFOX方案对P3和LM5L类器官的抑制作用最强，对LM5L类器官的抑制作用更强。免疫组织化学结果显示，联合治疗组Ki67表达水平最低，caspase 3表达水平最高，单一治疗组为中等水平。爱达维特组和联合治疗组ADAM10和NOTCH2的表达水平降低。结语 04 综上所述，本研究对肿瘤类器官和组织进行了整合转录组学分析，以评估Wnt通路的转录调控及其与结直肠癌肝转移的关系。通过体外和体内筛选靶向Wnt通路的抑制剂，研究人员确定爱达维特是一种有前景的CRC治疗抗癌药物。在机制上，爱达维特通过抑制ADAM10/NOTCH2/TCF7L2信号通路来激活Wnt靶基因的转录。这项研究提供了一种有前景的抗肿瘤药物，并表明了CRC治疗的潜在靶点。【参考资料】 https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202405758 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

申请上市临床研究临床1期

2024-09-05

·drugs

World Trade Center Exposure Linked to Increased DNA Methylation

THURSDAY, Sept. 5, 2024 -- World Trade Center (WTC) exposure is associated with increased DNA methylation, which may contribute to breast cancer , according to a study published in the June issue of Environmental Epidemiology . Stephanie Tuminello, Ph.D., M.P.H., from the NYU Grossman School of Medicine in New York City, and colleagues examined the DNA methylation profiles of WTC-exposed community members who remained cancer -free versus those who developed breast cancer. The study included 64 WTC-exposed women (32 cancer-free, 32 with breast cancer) and 32 WTC-unexposed women from the NYU Women's Health Study (16 cancer-free and 16 with prediagnostic breast cancer). The researchers found that compared with unexposed participants, WTC-exposed women more often had hypermethylated cytosine-phosphate-guanine probe sites (14.3 versus 4.5 percent). In WTC-exposed groups (breast cancer patients and cancer-free individuals), cancer-related pathways were overrepresented. Forty-seven epigenetically dysregulated genes were identified among WTC-exposed breast cancers compared with the unexposed breast cancer patients. A network was formed from these genes, including Wnt/β-catenin signaling genes WNT4 and TCF7L2 ; dysregulation of these genes contributed to cancer immune evasion. "WTC exposure is associated with global and site-specific DNA methylation changes. This was observed among cancer-free WTC-exposed survivors as well as those with breast cancer," the authors write. "Several cancer-related genes and pathways appear to be impacted, and, specifically, WTC exposure may compromise the ability of the immune system to identify and eliminate cancer cells contributing to cancer immune evasion." Abstract/Full Text Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

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