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这里是集才华与美貌的大胸xie
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Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer
新型ROR1抑制剂ARI-1抑制非小细胞肺癌的发展
Limited drug response and severe drug resistance confer the high mortality of non-small-cell lung cancer (NSCLC), a leading cause of cancer death worldwide. There is an urgent need for novel treatment against NSCLC. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is aberrantly overexpressed and participats in NSCLC development and EGFR-TKIs-induced drug resistance. Increasing evidences indicate that oncogenic ROR1 is a potential target for NSCLC therapy. However, nearly no ROR1 inhibitor was reported until now. Here, combining the computer-aided drug design and cell-based activity screening, we discover (R)-5,7-bis(methoxymethoxy)-2-(4-methoxyphenyl)chroman-4-one (ARI-1) as a novel ROR1 inhibitor. Biological evaluation demonstrates that ARI-1 specifically targets the extracellular frizzled domain of ROR1 and potently suppresses NSCLC cell proliferation and migration by regulating PI3K/AKT/mTOR signaling in a ROR1-dependent manner. Moreover, ARI-1 significantly inhibits tumor growth in vivo without obvious toxicity. Intriguingly, ARI-1 is effective to EGFR-TKIs-resistant NSCLC cells with high ROR1 expression. Therefore, our work suggests that the ROR1 inhibitor ARI-1 is a novel drug candidate for NSCLC treatment, especially for EGFR-TKIs-resisted NSCLC with high ROR1 expression.
【Journal】Cancer Lett
【IF】6.508
【摘要】有限的药物反应和严重的耐药性导致了非小细胞肺癌（NSCLC）高死亡率，同时也是全球癌症死亡的主要原因，所以针对NSCLC的新型治疗需求十分迫切。受体酪氨酸激酶样孤儿受体1（ROR1）异常过表达参与NSCLC进展和EGFR-TKIs诱导的耐药性。越来越多的证据表明，致癌的ROR1是NSCLC治疗的潜在靶点。然而，直到现在几乎没有报道过ROR1抑制剂。因此本研究中，作者结合计算机辅助药物设计和基于细胞的活性筛选，发现（R）-5,7-双（甲氧基甲氧基）-2-（4-甲氧基苯基）苯并二氢吡喃-4-酮（ARI-1）新型ROR1抑制剂。生物学评估表明，ARI-1特异性靶向ROR1的细胞外卷曲结构域，并通过以ROR1依赖性方式调节PI3K / AKT / mTOR信号传导而有效抑制NSCLC细胞增殖和迁移。此外，ARI-1可以显着抑制体内肿瘤生长而没有明显的毒性尤其是对具有高ROR1表达的EGFR-TKIs抗性NSCLC细胞有效。本文的研究数据表明，ROR1抑制剂ARI-1是NSCLC治疗的新型候选药物，特别是对于具有高ROR1表达的EGFR-TKIs抗性NSCLC。
【DOI】10.1016/j.canlet..05.016
tRNA-based prognostic score in predicting survival outcomes of lung adenocarcinomas
基于tRNA的预后评分预测肺腺癌的生存结果
As the most abundant noncoding RNA in cells, tRNA plays an important role in tumorigenesis and development. The report of tRNA on the pathogenesis of lung adenocarcinoma is rare. It is of great clinical significance to explore the relationship between tRNA expression and prognosis of lung adenocarcinoma. The expression level of tRNAs in lung adenocarcinoma tissues and paracarcinoma tissues was detected using a tRNA RT-qPCR array. A total of 104 lung adenocarcinomas were included in the analysis of the correlation between candidate tRNAs expression and prognosis. A tRNA-based prognostic model was constructed and validated using Cox proportional hazards regression. A nomogram was built to help clinicians develop treatment strategies. We screened a series of differentially expressed tRNAs between lung adenocarcinoma tissues and paracarcinoma tissues. Among these tRNAs, tRNA(Asn) ATT , tRNA(Ile) AAT , tRNA(Leu) TAA , mt-tRNA(Trp) TCA , mt-tRNA(Leu) TAA , tRNA(Pro) AGG , tRNA(Lys) CTT (-1) and tRNA(Leu) AAG were associated with the clinicopathological characteristics of lung adenocarcinoma. tRNA(Lys) CTT (-1) , mt-tRNA(Ser) GCT and tRNA(Tyr) ATA were associated with cancer-specific survival. We constructed a prognostic model for lung adenocarcinoma using specific tRNA expression levels as reference factors. Multivariate analyses showed that tRNA-based prognostic score was a significant and important prognostic factor. The prognostic model based on the tRNAs expression signatures can help predict the prognosis of patients with lung adenocarcinoma.
【Journal】Int J Cancer
【IF】1.746
【摘要】作为细胞中最丰富的非编码RNA，tRNA在肿瘤发生和发展中起重要作用。虽然在肺腺癌发病机制中关于tRNA的报道很少见，但是探讨tRNA表达与肺腺癌预后的关系具有重要的临床意义。本研究中，作者使用tRNA RT-qPCR阵列检测肺腺癌组织和癌旁组织中tRNA的表达水平。使用Cox比例风险回归对104个肺腺癌对象构建并验证基于tRNA的预后模型。同时建立了诺模图，以帮助临床医生制定治疗策略。作者本次筛选的tRNA中，tRNA（Asn）ATT，tRNA（Ile）AAT，tRNA（Leu）TAA，mt-tRNA（Trp）TCA，mt-tRNA（Leu）TAA，tRNA（Pro）AGG，tRNA（Lys）CTT（ -1）和tRNA（Leu）AAG与肺腺癌的临床病理特征相关；tRNA（Lys）CTT（-1），mt-tRNA（Ser）GCT和tRNA（Tyr）ATA与癌症特异性存活相关。作者使用特异性tRNA表达水平作为参考因子构建了肺腺癌的预后模型，多变量分析数据显示基于tRNA的预后评分是重要且重要的预后因素。本研究证明，基于tRNA表达特征的预后模型可以帮助预测肺腺癌患者的预后。
【DOI】10.1002/ijc.32250
Alteration in tumoural PD-L1 expression and stromal CD8-positive tumour-infiltrating lymphocytes after concurrent chemo-radiotherapy for non-small cell lung cancer
非小细胞肺癌同时放化疗后肿瘤PD-L1表达和基质CD8阳性肿瘤浸润淋巴细胞的变化
BACKGROUND: Consolidation treatment with an anti-PD-L1 antibody, durvalumab, following concurrent chemo-radiotherapy (cCRT) has become a new standard of care for locally advanced non-small cell lung cancer (NSCLC). The rationale of PD-L1 blockade after cCRT is based on preclinical evidence suggesting that chemotherapy and radiotherapy up-regulate tumoural PD-L1 expression, which has not been shown in clinical studies.
METHODS: To examine alteration in tumoural PD-L1 expression (tumour proportion score, TPS) and density of stromal CD8-positive tumour-infiltrating lymphocytes (CD8 + TILs) after cCRT, paired NSCLC samples obtained before and after cCRT were reviewed in comparison with those obtained before and after drug therapy.
RESULTS: PD-L1 expression was significantly up-regulated after cCRT (median TPS, 1.0 at baseline versus 48.0 after cCRT; P < 0.001), but not after drug therapy. There was no significant correlation between baseline TPS and post-cCRT TPS. CD8 + TIL density was significantly increased after cCRT (median, 10.6 versus 39.1; P < 0.001), and higher post-cCRT CD8 + TIL density was associated with a higher pathologic response and with a favourable survival (P = 0.019).
CONCLUSION: Tumoural PD-L1 expression was up-regulated after cCRT, which provides pathologic rationale for PD-L1 blockade following cCRT to improve prognosis. Stromal CD8 + TIL density was also increased after cCRT, and higher post-cCRT CD8 + TIL density was a favourable prognostic indicator.
【Journal】Br J Cancer
【IF】5.416
【摘要】背景：使用抗PD-L1抗体巩固治疗，durvalumab，同时放化疗（cCRT）已成为局部晚期非小细胞肺癌（NSCLC）的新标准治疗方法。cCRT后PD-L1阻断的基本原理是基于临床前证据，但是化疗和放疗上调肿瘤PD-L1表达在临床研究中尚未显示。方法：检查cCRT后肿瘤PD-L1表达（肿瘤比例评分，TPS）和基质CD8阳性肿瘤浸润淋巴细胞（CD8+ TILs）密度的变化，分析cCRT前后和药物治疗前后获得的配对NSCLC样本。结果：cCRT后PD-L1表达显着上调（基线中位数为TPS，基线时为1.0，而cCRT后为48.0; P <0.001），但药物治疗后没有此表现。基线TPS与cCRT后TPS之间无显着相关性。cCRT后CD8 + TIL密度显着增加（中位数，10.6对39.1; P <0.001），cCRT后CD8 + TIL密度越高，病理反应越高，存活率越高（P = 0.019）。结论：cCRT后肿瘤PD-L1表达上调，为cCRT后PD-L1阻断提供了病理学依据，可改善预后。在cCRT后，基质CD8 + TIL密度也增加，并且更高的cCRT后CD8 + TIL密度是有利的预后指标。
【DOI】10.1038/s41416-019-0541-3
文献编译：李艺媛
图文编辑：林章宇
质量控制：卢天健
