Cross-presentation by the others

The critical role of conventional dendritic cells in physiological cross-priming of immune responses to tumors and pathogens is widely documented and beyond doubt. However, there is ample evidence that a wide range of other cell types can also acquire the capacity to cross-present. These include not only other myeloid cells such as plasmacytoid dendritic cells, macrophages and neutrophils, but also lymphoid populations, endothelial and epithelial cells and stromal cells including fibroblasts. The aim of this review is to provide an overview of the relevant literature that analyzes each report cited for the antigens and readouts used, mechanistic insight and in vivo experimentation addressing physiological relevance. As this analysis shows, many reports rely on the exceptionally sensitive recognition of an ovalbumin peptide by a transgenic T cell receptor, with results that therefore cannot always be extrapolated to physiological settings. Mechanistic studies remain basic in most cases but reveal that the cytosolic pathway is dominant across many cell types, while vacuolar processing is most encountered in macrophages. Studies addressing physiological relevance rigorously remain exceptional but suggest that cross-presentation by non-dendritic cells may have significant impact in anti-tumor immunity and autoimmunity.     

Circular RNAs drive oncogenic chromosomal translocations within the MLL recombinome in leukemia

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Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the “occupancy-driven” model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.     

基于泛素—蛋白酶体途径探讨当归芍药散“肝脾同调-血水同治”治疗阿尔茨海默病的作用机制＊

阿尔茨海默病（Alzheimer’s disease,AD）是一种神经退行性疾病，β淀粉样蛋白（β-amyloid，Aβ）沉积形成老年斑、Tau蛋白过度磷酸化造成神经纤维缠结及神经元丢失是其主要病理特征。经方当归芍药散出自《金匮要略》，是体现仲景“肝脾同调-血水同治”思想的代表方剂，本为疗妇人之疾而设，但自二十世纪八十年代末被广泛用于治疗AD，且临床疗效确切，具有抗炎、抗氧化、神经保护、神经营养、调节神经递质及调控中枢神经系统等活性。泛素-蛋白酶体途径（ubiquitin-proteasome pathway,UPP）是目前已知最精细的蛋白降解途径，为真核细胞内蛋白质降解的主要途径，能有效清除多余的和错误折叠的蛋白。近年来，研究证实UPP功能出现障碍，不能及时有效地清除Aβ沉积和过度磷酸化Tau蛋白，在AD的发生发展进程中扮演了极其重要的角色，为科学阐释当归芍药散治疗AD的分子生物学机制提供了新视角。本文在总结当归芍药散“肝脾同调-血水同治”治疗AD的临床疗效及其作用机制研究基础上，从UPP角度提出新的假说，以期“古为今用”，秉承古方为现代临床治疗服务；“今为古用”，进一步开展相关实验研究积极阐释古方的科学内涵。     

基因DCAF8在多发性骨髓瘤中的临床意义

目的：寻找多发性骨髓瘤（MM）基因芯片数据集中的潜在致病基因、疾病诊断和预后相关因子并阐明其作用机制。方法：获取基因芯片数据集 GSE13591 和 Zhan Myeloma，使用 R 语言进行基因差异表达分析。对共同高表达基因进行 Meta分析，得到 P值中位秩次 TOP10基因。CCLE数据库分析 TOP10基因在各肿瘤细胞系中的 mRNA表达情况，筛选出蛋白酶体通路相关基因8（DCAF8）。cBioPortal数据库中分析DCAF8基因在各肿瘤细胞系的突变率。WB检测DCAF8蛋白在骨髓瘤细胞系中的表达情况。SPSS和Graph Pad软件分析DCAF8表达量和MM患者临床特征之间的相关性，进行受试者工作特征曲线（ROC曲线）绘制和生存分析。R语言Custer Profiler Package和Metascape数据库对DCAF8互作蛋白基因和共表达基因进行GO和KEGG功能富集分析。结果：数据集GSE13591和Zhan Myeloma的上调基因取交集得到477个共同高表达基因。在合并数据集中对上述基因进行 Meta分析，得到 P值中位秩次 TOP10基因，DCAF8在 MM细胞系中的平均表达水平最高。DCAF8基因在浆细胞骨髓瘤中的突变率位于各肿瘤细胞系的第一位。DCAF8蛋白在多种MM细胞系中的表达量显著升高（P<0.01）。DCAF8表达量与MM患者的肿瘤负荷显著正相关，1q21扩增阳性组的DCAF8的表达量显著高于1q21阴性组。ROC曲线显示DCAF8的表达水平可以很好地区分MM患者和正常人（P<0.01）。DCAF8高表达组比DCAF8低表达组中位生存时间显著缩短。蛋白互作网络显示DCAF8可与XPO1蛋白直接相互作用。GO和KEGG功能富集分析结果表明，DCAF8与蛋白酶体功能、剪切体活性、组蛋白乙酰化酶活性、RNA转运等功能相关。结论：DCAF8在MM中显著高表达，其表达水平可以很好地区分MM患者和正常人；其高表达与MM患者的生存预后显著负相关，且与1q21扩增和XPO1蛋白相关。     

胰凝乳蛋白酶样蛋白酶体的活性作为前列腺癌生物标志物的潜在应用

目的：探讨胰凝乳蛋白酶样蛋白酶体（chymotrypsin-like proteasome,CLP）活性作为前列腺癌生物标志物的可行性。方法：检测在体和离体的蛋白酶体活性，同时检测核因子κB的抑制蛋白α(inhibitory protein α of nuclear factorκB,IκB-α)、Bcl-2相关X蛋白（BCL-2 associated X protein,Bax）和细胞周期蛋白依赖性激酶抑制因子（cyclin-dependent kinase inhibitor,p27）的表达。结果：与正常前列腺上皮细胞及对照小鼠前列腺组织相比，前列腺癌细胞和前列腺肿瘤异种移植物中蛋白酶体底物蛋白IκB-α、Bax和p27的表达水平降低，CLP的离体和在体活性分别升高70%和23%。结论：CLP的活性可能是一种潜在的前列腺癌生物标志物，可能适合前列腺特异性抗原（prostate-specific antigen,PSA）在前列腺癌诊断中的补充。