TOX is a critical regulator of tumour-specific T cell differentiation

Scott Andrew C.; Dundar Friederike; Zumbo Paul; Chandran Smita S.; Klebanoff Christopher A.; Shakiba Mojdeh; Trivedi Prerak; Menocal Laura; Appleby Heather; Camara Steven; Zamarin Dmitriy; Walther Tyler; Snyder Alexandra; Femia Matthew R.; Comen Elizabeth A.; Wen Hannah Y.; Hellmann Matthew D.; Anandasabapathy Niroshana; Liu Yong; Altorki Nasser K.; Lauer Peter; Levy Olivier; Glickman Michael S.; Kaye Jonathan; Betel Doron; Philip Mary; Schietinger Andrea

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TOX is a critical regulator of tumour-specific T cell differentiation

机译：TOX是肿瘤特异性T细胞分化的关键调节剂

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Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states(1-6). Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.

机译：肿瘤特异性CD8 T细胞功能异常是一种分化状态，不同于功能性效应器或记忆T细胞状态（1-6）。在这里，我们确定核因子TOX是肿瘤特异性T（TST）细胞分化的关键调节剂。我们表明在慢性病毒感染过程中，TOX在功能异常的TST细胞中从肿瘤和疲惫的T细胞中高度表达。 TOX的表达受慢性T细胞受体刺激和NFAT激活的驱动。 TOX异位表达在体外效应T细胞中诱导了与T细胞衰竭相关的转录程序。相反，肿瘤中TST细胞中Tox的缺失废除了精疲力尽的程序：删除Tox的TST细胞不会上调抑制性受体（如Pdcd1，Entpd1，Havcr2，Cd244和Tigit）的基因，而它们的染色质仍然难以接近，并且保留了TCF-1等转录因子的高表达。尽管具有正常的，“未用尽”的免疫表型，但已删除Tox的TST细胞仍然功能异常，这表明抑制性受体表达的调节与效应器功能的丧失无关。值得注意的是，尽管Tox缺失的CD8 T细胞在对急性感染的反应中正常分化为效应子和记忆状态，但Tox缺失的TST细胞未能在肿瘤中持续存在。我们假设在慢性抗原刺激（例如癌症）的环境中，TOX诱导的力竭程序可防止T细胞过度刺激和激活诱导的细胞死亡。

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《Nature》 |2019年第7764期|270-274|共5页
作者
Scott Andrew C.; Dundar Friederike; Zumbo Paul; Chandran Smita S.; Klebanoff Christopher A.; Shakiba Mojdeh; Trivedi Prerak; Menocal Laura; Appleby Heather; Camara Steven; Zamarin Dmitriy; Walther Tyler; Snyder Alexandra; Femia Matthew R.; Comen Elizabeth A.; Wen Hannah Y.; Hellmann Matthew D.; Anandasabapathy Niroshana; Liu Yong; Altorki Nasser K.; Lauer Peter; Levy Olivier; Glickman Michael S.; Kaye Jonathan; Betel Doron; Philip Mary; Schietinger Andrea;
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作者单位

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY USA;

Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA|Weill Cornell Med, Appl Bioinformat Core, New York, NY USA;

Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA|Weill Cornell Med, Appl Bioinformat Core, New York, NY USA;

Parker Inst Canc Immunotherapy, New York, NY 10017 USA|Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, 1275 York Ave, New York, NY 10021 USA;

Parker Inst Canc Immunotherapy, New York, NY 10017 USA|Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, 1275 York Ave, New York, NY 10021 USA|Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Med Coll, New York, NY USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA;

Parker Inst Canc Immunotherapy, New York, NY 10017 USA|Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA;

Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA;

Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA;

Parker Inst Canc Immunotherapy, New York, NY 10017 USA|Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, 1275 York Ave, New York, NY 10021 USA;

Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Med Coll, New York, NY USA;

Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA;

Parker Inst Canc Immunotherapy, New York, NY 10017 USA|Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Med Coll, New York, NY USA;

Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY USA|Weill Cornell Med Coll, Dept Dermatol, New York, NY USA;

Weill Cornell Med Coll, Dept Dermatol, New York, NY USA;

New York Presbyterian Hosp, Dept Cardiothorac Surg, Weill Cornell Med, New York, NY USA;

Aduro Biotech Inc, Berkeley, CA USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY USA;

Cedars Sinai Med Ctr, Dept Biomed Sci, Res Div Immunol, Los Angeles, CA 90048 USA;

Weill Cornell Med, Appl Bioinformat Core, New York, NY USA|Weill Cornell Med, Dept Med, Div Hematol & Med Oncol, New York, NY USA|Weill Cornell Med, Inst Computat Biomed, New York, NY USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA|Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol & Oncol, Nashville, TN USA;

Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY USA|Parker Inst Canc Immunotherapy, New York, NY 10017 USA;

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专利

1. TOX is a critical regulator of tumour-specific T cell differentiation [J] . Scott Andrew C., Dundar Friederike, Zumbo Paul, Nature . 2019,第7764期

机译：TOX是肿瘤特异性T细胞分化的关键调节因子
2. Cell cycle regulators are critical for maintaining the differentiation potential and immaturity in adipogenesis of adipose-derived stem cells. [J] . Park H, Cho JA, Lim EH, Differentiation: The Journal of the International Society of Differentiation . 2011,第3期

机译：细胞周期调节剂对于维持脂肪干细胞在脂肪形成中的分化潜能和不成熟至关重要。
3. The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells [J] . WangH., GengJ., WenX., Nature immunology . 2014,第7期

机译：转录因子Foxp1是卵泡辅助性T细胞分化的关键负调控因子
4. Retinoic acid is a potential negative regulator for differentiation of human periodontal ligament cells [C] . Natsuko Shibuya, Eiji Nemoto, Sousuke Kanaya, International Symposium for Interface Oral Health Science . 2005

机译：视黄酸是一种潜在的负调节剂，用于分化人牙周韧带细胞
5. A novel approach for distribution-based single-cell screening for regulators of pluripotency and differentiation in mouse embryonic stem cells [D] . Gingold, Julian Abraham 2013

机译：基于分布的单细胞筛选小鼠胚胎干细胞多能性和分化调节剂的新方法
6. The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells [O] . Haikun Wang, Jianlin Geng, Xiaomin Wen, -1

机译：转录因子Foxp1是卵泡辅助性T细胞分化的关键负调控因子
7. 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An in vivo study349Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis in vitro and in vivo via EMMPRINEndothelium352Reciprocal regulation of GRK2 and bradykinin receptor stimulation modulate Ca2+ intracellular level in endothelial cells353The roles of bone morphogenetic proteins 9 and 10 in endothelial inflammation and atherosclerosis354The contribution of GPR55 to the L-alpha-lysophosphatidylinositol-induced vasorelaxation in isolated human pulmonary arteries355The endothelial protective ACE inhibitor Zofenoprilat exerts anti-inflammatory activities through H2S production356A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction357Endothelial progenitor cells to apoptotic endothelial cell-derived microparticles ration differentiatesas preserved from reduced ejection fractionheart failure358Proosteogenic genes are activated in endothelial cells of patients with thoracic aortic aneurysm359Endothelin ETB receptors mediate relaxing responses to insulin in pericardial resistance arteries from patients with cardiovascular disease (CVD)Smooth muscle and pericytes362CX3CR1 positive myeloid cells regulate vascular smooth muscle tone by inducing calcium oscillations via activation of IP3 receptors363A novel function of PI3Kg on cAMP regulation, role in arterial wall hyperplasia through modulation of smooth muscle cells proliferation364NRP1 and NRP2 play important roles in the development of neointimal hyperplasia in vivo365Azithromycin induces autophagy in aortic smooth muscle cellsCoagulation, thrombosis and platelets368The real time in vivo evaluation of platelet-dependent aldosterone prothrombotic action in mice369Development of a method for in vivo detection of active thrombi in mice370The antiplatelet effects of structural analogs of the taurine chloramine371The influence of heparin anticoagulant drugs on functional state of human platelets372Regulation of platelet aggregation and adenosine diphosphate release by d dimer in acute coronary syndrome (in vitro study)Oxygen sensing, ischaemia and reperfusion375Sirtuin 5 mediates brain injury in a mouse model of cerebral ischemia-reperfusion376Abscisic acid: a new player in cardiomyocyte protection from ischaemia?377Protective effects of ultramicronized palmitoylethanolamide (PEA-um) in myocardial ischaemia and reperfusion injury in vivo378Identification of stem cell-derived cardiomyocytes using cardiac specific markers and additional testing of these cells in simulated ischemia/reperfusion system379Single-dose intravenous metformin treatment could afford significant protection of the injured rat kidney in an experimental model of ischemia-reperfusion380Cardiotoxicity of long acting muscarinic receptor antagonists used for chronic obstructive pulmonary disease381Dependence antioxidant potential on the concentration of amino acids382The impact of ischemia-reperfusion on physiological parameters,apoptosis and ultrastructure of rabbit myocardium with experimental aterosclerosisMitochondria and energetics385MicroRNA-1 dependent regulation of mitochondrial calcium uniporter (MCU) in normal and hypertrophied hearts386Mitochondrial homeostasis and cardioprotection: common targets for desmin and aB-crystallin387Overexpression of mitofusin-2 (Mfn2) and associated mitochondrial dysfunction in the diabetic heart388NO-dependent prevention of permeability transition pore (MPTP) opening by H2S and its regulation of Ca2+ accumulation in rat heart mitochondria389G protein coupled receptor kinase 2 (GRK2) is fundamental in recovering mitochondrial morphology and function after exposure to ionizing radiation (IR)Gender issues392Sex differences in pulmonary vascular control; 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V Garcia-Martinez, C Lopez Sanchez, W Hamed, 2016

机译：早期心脏腔室specification291Bmp2期间海报会议2Morphogenetic mechanisms290MiR-133调控对视黄酸途径在早期心脏具有或不具有2型糖尿病mellitus295Association循环的α2B肾上腺素受体基因插入/缺失多态性的缺失等位基因和高血压的formationDevelopmental genetics294Association通过的miR-130调节心房分化陷波的作用：Vascular298Gamma分泌酶抑制剂阻止增殖和动脉导管未闭的迁移平滑肌细胞 - 内源性大麻素1型受体（CNR1）与冠状动脉疾病（CAD）的2型糖尿病mellitusCell生长，分化和干细胞的G1359A多态性的在出生后的闭合信令导管arteriosus299Mesenchymal基质状从诱导的多能干细胞（iPS）衍生的单元（MLC）细胞：有希望的治疗选项，以促进neovascularization300Sonic刺猬促进间充质干细胞分化为vascula ř平滑肌细胞cardiovacsular disease301Proinflammatory细胞因子分泌和在内皮细胞中表观遗传学修饰处理的LPS-GinfivalisCell死亡和细胞凋亡 - Vascular304Mitophagy充当针对人血管平滑肌细胞中的保障机制凋亡诱导动脉粥样硬化lipidsTranscriptional控制和RNA种类 - 在Vascular307MicroRNA-34a的作用利用后缺氧内皮cells310Specific循环微RNA水平的血管injury309Long非编码RNA景观临床适用的方法衰减新内膜形成与miR-146a的抑制剂的血管calcification308Local递送关联与高血压，高血糖和功能失调的HDL在急性冠状动脉综合征patientsCytokines和细胞炎症 - Vascular313Phosphodiesterase5A向上调控血管内皮促炎性条件下进行：为ω-3polyunsaturated aatty酸二十二碳六acid31一个新公开的抗炎活性4Cardiovascular风险修改与超低剂量抗细胞因子药物在人M-CSF的巨噬细胞的类风湿arthritis315Conversion成泡沫细胞降低了其经典M1偏振activation316Lymphocytic心肌炎具有增加斑块炎症和在冠状动脉中的斑块出血一致时，促进心肌infarction317Serum骨保护素水平的促炎性应答通过抑制手段Heart323A新的合成肽对肥大体外 - predictsdeclined众多患者的代谢syndromeGrowth因子和神经激素循环内皮 - 衍生的细胞和单核衍生的祖细胞 - 胃泌素释放肽（GRP）对血管inflammationSignal转导的Vascular320Effect p38的α图激酶nfkb324Inducible成纤维细胞特异性敲除是在异丙基肾上腺素诱导的心脏hypertrophy325Regulation的小鼠模型中的心脏保护β-肾上腺素受体诱发由抑制性肌力响应ORY G蛋白，腺苷酸环化酶同种型5,6和phosphodiesterases326Binding到RGS3和M2毒蕈碱性乙酰胆碱受体调制的刺激p190RhoGAP的翻译后修饰，parylation和脱乙酰化中LMNA的心脏myocytes327Cardiac调节底物特异性扩张的心肌病小鼠model328Beta肾上腺素能调节所述b56delta / PP2A全酶在心肌细胞通过b56delta磷酸化丝氨酸573Nitric氧化物和活性氧 - Vascular331Oxidative应激诱导的miR-200c的破坏SIRT1，FOXO1和eNOS332Antioxidant疗法防止氧化应激诱导内皮功能障碍和提高之间的调节环路伤口Healing333Morphological和在冠状动脉diseaseCytoskeleton红细胞和机械传导的生化特征 - Heart336Novel肌球蛋白的活化剂，JSH化合物，ratsExtracellular矩阵增加心肌收缩力没有变时作用和纤维化 - 的Vascular339Ablation Toll样受体9通过衰减增殖和心脏fibroblasts340Altered血管在因子VII小鼠后肢缺血模型重塑活化蛋白酶（FSAP）deficiencyVasculogenesis，血管生成和proly的arteriogenesis343Pro血管生成作用的分化导致心肌梗死后心脏破裂羟化酶抑制剂及其在用于冠状动脉总occlusion344Nrf2驱动治疗性血管生成的新颖的策略的使用潜在的血管生成转录非依赖性方式：氧化应激response345Angiogenic基因治疗的主调节器的新功能，尽管高效血管生长，不能改善上在鼠后肢侧支血管生长PAR-1抑制的毛细动脉和shunting346Effect在含氧量正常或慢性缺血性后肢的兔肌肉功能-Role model347Quaking是内皮细胞分化的关键调节剂，新血管形成和angiogenesis348在鸡胚绒毛尿囊膜（CAM）“新兴血管生成”。一种不同于心肌祖细胞体内study349Exosomes和间充质干细胞刺激血管生成的体外和GRK2的体内经由EMMPRINEndothelium352Reciprocal调节和血管舒缓激肽受体刺激调制的Ca 2+的细胞内骨的内皮cells353The角色形态发生蛋白9和10在内皮炎症和atherosclerosis354The贡献水平GPR55在分离的人将L-α-溶血磷脂酰肌醇诱导的血管舒张肺arteries355The内皮保护ACE抑制剂Zofenoprilat通过H2S production356A类新的糖模拟药物发挥抗炎活性，以防止游离脂肪酸诱导的内皮dysfunction357Endothelial祖细胞凋亡的内皮细胞从降低喷射fractionheart failure358Proosteogenic基因保留衍生微粒配给differentiatesas在患者的胸主动脉aneurysm359Endothelin ETB REC内皮细胞活化通过经由PI3Kg的对cAMP调节，在动脉的作用IP3 receptors363A新颖功能的激活诱导的钙振荡eptors调解放松来自患有心血管疾病（CVD）的平滑肌和pericytes362CX3CR1阳性髓样细胞在心包阻力动脉到胰岛素应答调节血管平滑肌紧张壁增生，通过平滑肌细胞proliferation364NRP1和NRP2的调制内膜增生的发展vivo365Azithromycin诱导自噬在主动脉平滑肌cellsCoagulation，血栓形成和platelets368The实时血小板依赖性醛固酮促血栓形成作用的体内评价mice369Development玩的方法的重要作用用于体内在mice370The活性血栓的检测抗血小板的血小板聚集和腺苷的人类platelets372Regulation的功能状态肝素抗凝药物的牛磺酸chloramine371The影响结构类似物的效果二磷酸酯的释放通过d二聚体在急性冠状动脉综合征（体外研究）氧传感，局部缺血和脑缺血reperfusion376Abscisic酸的小鼠模型reperfusion375Sirtuin 5介导的脑损伤：在从局部缺血心肌保护的新播放ultramicronized十六酰胺乙醇的377Protective效果（？ PEA-UM）在干细胞衍生的心肌细胞的vivo378Identification心肌缺血再灌注损伤的使用心脏特异性标志物，并在这些细胞中的额外的测试模拟缺血/再灌注system379Single剂量静脉二甲双胍治疗能买得起在受伤大鼠肾脏的显著保护的长效用于慢性阻塞性肺disease381Dependence抗氧化潜力上的缺血 - 再灌注的生理参数，细胞凋亡和超微结构氨基acids382The冲击浓度毒蕈碱性受体拮抗剂缺血reperfusion380Cardiotoxicity的实验模型兔心肌实验aterosclerosisMitochondria和energetics385MicroRNA-1在正常线粒体钙单向转运体（MCU）的依赖性调节和肥大hearts386Mitochondrial稳态和心脏保护：在糖尿病heart388NO结蛋白和线粒体融合蛋白-2 AB-crystallin387Overexpression（Mfn2的）和相关的线粒体功能障碍共同目标依赖性预防通透性转换孔（MPTP）的开口由H 2 S和其在大鼠心脏mitochondria389G蛋白偶联受体的Ca 2+积累的调节激酶2（GRK2）是在回收曝光后线粒体形态和功能于电离辐射（IR）性别issues392Sex差异基本在肺血管的控制;注重与射血分数一氧化氮pathwayAging395Heart失败开发当馈送西方饮食到衰老加速mice396Cardiovascular标志物的中老年大鼠与体积连接蛋白43在老年高血压patients397Changes认知衰退的预测过载慢性心脏failureGenetics和epigenetics400Calcium内容在主动脉瓣与1G相关联> 2G矩阵男性高血压并发和不复杂的与脂蛋白脂肪酶的常见多态性与PON1基因的慢性心脏failure403Association与代谢综合征金属蛋白酶1个polymorphism401Neuropeptide受体基因S（NPSR1）多态性与睡眠disturbances402Endothelin-1基因Lys198Asn多态性社区participantsGenomics，蛋白质组学，代谢组样品中使用复用颜色编码的探针对脂质组学和glycomics405Gene表达定量，以确定在经受的橄榄油的新抗炎性质基于injury407Transcriptome-缺血/再灌注鉴定2型糖尿病心脏的零星心脏myxoma406Large规模磷酸化研究RNA含量羟基酪醇在血管内皮细胞在人类心室动作potentialMetabolism，糖尿病三个国家的最先进的车型在基础和促炎conditions408Gene多态性组合和心肌infarctionComputer建模，生物信息学和复极储备的大data411Comparison的风险细胞和单核细胞obesity414Endothelial激活多肽-II型糖尿病-I mellitus415Admission葡萄糖水平改善心脏功能的左心室功能受损患者急性心肌梗死的独立预测因子：二维斑点追踪超声心动图脂质谱和炎症反应，在高血压患者腹部obesity417Multiple常见共病血管壁的刚度的生化标志物之间ýstudy416Association产生左心室冠状动脉微血管功能障碍，氧化应激和心肌stiffening418Investigating的抗逆转录病毒药物的心血管作用有关的舒张功能障碍贫和高脂肪/非酒精性脂肪性肝炎（NASH）的治疗obesity419Statins的蔗糖饮食大鼠模型。我们在康斯坦察县2年的前瞻性研究经验，Romania420Epicardial脂肪组织心血管结果的ACS患者接受PCI？动脉及肺动脉hypertension423Dependence心脏节律disorers和ACE基因ID多态性与高血压patients424Molecular机制背后的有益预测在TGF-β轴和在人类升主动脉中prehypertension427Vascular微循环和大循环异常aneurysms426Early迹象肾素 - 血管紧张素系统的动作的肺动脉hypertension425Inhibition尿皮质素2的影响平滑肌细胞表达的血管tone428Cardiac铁2控制和血管重塑在开发在一个新颖的猪modelBiomarkers431Arrhythmogenic心肌病慢性血栓栓塞性肺动脉高压：一个新的，非侵入性的biomarker432Can循环微RNA区分类型1和类型2心肌梗塞433Design的高通量含多处？前蛋白质组学测定，以确定左室舒张功能障碍diabetes434Monocyte衍生和P-选择携带微粒不同由低脂肪饮食的患者心血管危险因素谁将会和谁不会被开发宽度评估心血管event435Red血细胞分布修改在慢性心脏failure436Invasive和患者的治疗低温对脑的水平心房fibrillation437The效果射频诱导的心脏去神经支配的质量的非侵入性评价薄膜的多色干涉显微镜中的血清衍生的神经营养因子（BDNF）以下心肺resustitation438Novel生物标志物来预测结果患者心脏衰竭和冠状动脉graftingInvasive，非侵入性和分子imaging443Diet组成的影响Ø链接抑郁和焦虑心血管disease440Troponins和肌红蛋白动态重度主动脉瓣stenosis439Biological因素n中的鼠ob突变的基因分型，：心脏功能，宏观和微观循环和使用IV-OCT定量分析猪冠状动脉和兔子主动脉的病变的肝steatosis444Characterization的微超声表征：与histologyGene疗法和细胞相关性therapy447Enhancing存活和小鼠心房间充质cells448VCAM-1在实验性心肌梗塞表达及其与骨髓来源的单核细胞retentionTissue engineering451Advanced多层支架增加干细胞衍生的工程改造的心脏组织的人类cardiomyocytes452Response的成熟到模拟缺血/再灌注的血管生成潜力急性高血糖conditions453Serum白蛋白水凝胶的存在防止新生儿cardiomyocytes454A新颖画笔技术的去分化为低粘度的转印紫外光可固化青色甲基丙烯酸酯上的盐水浸没在体外羊心脏

TOX is a critical regulator of tumour-specific T cell differentiation

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