“磨玻璃影”特征的早期肺腺癌中MPP成分的突变特征分析及ZNF469基因的探索

背景与目的目前,肺癌依然是我国发病率和死亡率最高的恶性肿瘤。而在早期肺腺癌(lung adenocarcinoma,LUAD)中,微乳头(micropapillary,MPP)成分尤其常见,且通常表现出高侵袭性,其与早期转移、淋巴浸润的风险以及患者的5年生存率显著相关。本研究旨在探究以磨玻璃影(ground-glass opacities,GGOs)为特征的早期LUAD中MPP成分和非MPP成分的异同,寻找MPP成分所特有的突变特征,并分析锌指蛋白家族的ZNF469基因与早期LUAD预后以及免疫浸润的关系。方法收集31例LUAD恶性肺结节,采用显微解剖法将其分为成对的MPP和非MPP成分。对早期恶性肺结节组分进行全外显子组测序(whole-exome sequencing,WES),利用maftools、非负矩阵分解(Nonnegative Matrix Factorization,NMF)法、Sigminer等方法进行突变特征分析,以揭示侵袭性LUAD中MPP组分相比于其他肿瘤组织所特有的基因组突变特征。利用癌症基因组图谱(The Cancer Genome Atlas,TCGA)的LUAD数据库中ZNF469的表达情况,探讨其与肺癌预后的关系;利用GeneMANIA数据库以及基因本体(Gene Ontology,GO)、京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析探索LUAD中与ZNF469相关基因的互作网络及信号通路;利用TIMER和TISIDB数据库分析ZNF469表达与LUAD中免疫细胞浸润水平的相关性。结果MPP成分具有较多的基因组变异,相比于非MPP成分的肿瘤组织,癌症体细胞突变目录(Catalogue of Somatic Mutations in Cancer,COSMIC)的13号突变特征(胞苷脱氨酶家族,APOBEC)是MPP成分所特有的,这提示其参与了MPP成分对LUAD早期侵袭过程的促进作用;并且APOBEC特征高的MPP样本具有更高的肿瘤突变负荷(tumor mutational burden,TMB),提示这些患者更能从免疫治疗中获益。LUAD中突变ZNF469的表达高于正常组织,与LUAD患者的不良预后有关。基因互作网络分析以及GO和KEGG富集分析发现,COL6A1、COL1A1、COL1A2、TGFB2、MMP2、COL8A2、C2CD4C等与ZNF469具有相互作用,且主要与编码胶原蛋白、参与细胞外基质构成有关。ZNF469表达与肿瘤的免疫浸润呈正相关。结论本研究揭示了中国人群侵袭性LUAD中MPP成分的特有突变特征,并发现突变ZNF469的高表达影响LUAD预后与免疫浸润,推测ZNF469可作为LUAD潜在的诊断及预后生物标志物。

肺腺癌中免疫微环境特征与EGFR突变状态的相关性研究

背景与目的在全球范围内肺癌发病率和死亡率一直居高不下,而肺腺癌是其中最主要的一个组织亚型,表皮生长因子受体(epidermal growth factor receptor,EGFR)突变是肺腺癌的一个重要驱动基因突变。近年来以程序性死亡受体1(programmed cell death 1,PD-1)及程序性死亡配体1(programmed cell death ligand 1,PD-L1)抑制剂为代表的免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)治疗在部分肺癌患者中疗效显著。有研究表明EGFR突变的患者对免疫治疗的获益程度有限,本研究旨在讨论肺腺癌患者中EGFR突变状态与各类免疫细胞浸润数量、空间分布的关系。方法本研究纳入62例接受手术的肺腺癌患者。通过对手术切除的肿瘤组织进行不同区域多点采样,最终获取了223份肿瘤组织样本。通过基因检测获取了每份肿瘤组织的EGFR突变情况,包括突变丰度(variant allele frequency,VAF)以及突变亚型等信息。对肿瘤组织进行苏木精-伊红(hematoxylin-eosin,HE)染色、免疫组化染色、多重荧光免疫组化染色,并通过计算免疫组化评分获取各类免疫细胞在肿瘤组织中的浸润情况以及三级淋巴结构(tertiary lymphoid structure,TLS)的分布情况。结果与野生型患者相比,EGFR突变肺腺癌患者肿瘤组织中CD68^(+)巨噬细胞以及组织相容性复合物(major histocompatibility complex,MHC)II类抗原呈递细胞浸润更多,且MHC II类抗原呈递细胞空间分布的异质性较大,而CD56^(+)自然杀伤细胞以及CD8^(+)T细胞等浸润更低。EGFR VAF高的肿瘤组织与更低的CD3^(+)T细胞、CD20^(+)B细胞、CD56^(+)自然杀伤细胞、CD68^(+)巨噬细胞、CD8^(+)T细胞等细胞浸润相关,其中只有CD3^(+)T细胞分布的空间异质性较小。对于中国人群常见的两种EGFR突变亚型,EGFR外显子19缺失突变相较于EGFR外显子21 L858R突变肿瘤组织中有更低的免疫细胞浸润,但CD3^(+)T细胞、CD56^(+)自然杀伤细胞、CD68^(+)巨噬细胞以及CD8^(+)T细胞等免疫细胞分布的空间异质性更高。预后分析发现,CD3^(+)T细胞、CD20^(+)B细胞浸润程度高、TLS形成数量多以及CD8^(+)T细胞高分布异质性的EGFR突变患者拥有更长的无病生存期。结论EGFR突变肺腺癌具有独特的低免疫细胞浸润的“非炎性”肿瘤微环境,不同突变亚型以及VAF的肿瘤微环境之间也表现出异质性,这些差异不仅体现在免疫细胞的浸润数量上,也体现在免疫细胞的空间分布情况。因此对EGFR突变肺腺癌的免疫微环境进行进一步更深入的研究对未来提高EGFR突变肺腺癌患者的免疫治疗疗效具有重大意义。

Cerium Methacrylate Assisted Preparation of Highly Thermally Conductive and Anticorrosive Multifunctional Coatings for Heat Conduction Metals Protection

Preparing polymeric coatings with well corrosion resistance and high thermal conductivity(TC)to prolong operational life and ensure service reliability of heat conductive metallic materials has long been a substantive and urgent need while a difficult task.Here we report a multifunctional epoxy composite coating(F-CB/CEP)by synthesizing cerium methacrylate and ingeniously using it as a novel curing agent with corrosion inhibit for epoxy resin and modifier for boron nitride through"cation-π"interaction.The prepared F-CB/CEP coating presents a high TC of 4.29 W m^(−1)K^(−1),which is much higher than other reported anti-corrosion polymer coatings and thereby endowing metal materials coated by this coating with outstanding thermal management performance compared with those coated by pure epoxy coating.Meanwhile,the low-frequency impedance remains at 5.1×10^(11)Ωcm^(2)even after 181 days of immersion in 3.5 wt%NaCl solution.Besides,the coating also exhibits well hydrophobicity,self-cleaning properties,temperature resistance and adhesion.This work provides valuable insights for the preparation of high-performance composite coatings with potential to be used as advanced multifunctional thermal management materials,especially for heat conduction metals protection.

Empowering highway network:Optimal deployment and strategy for dynamic wireless charging lanes

Amid escalating energy crises and environmental pressures,electric vehicles(EVs)have emerged as an effective measure to reduce reliance on fossil fuels,combat climate change,uphold sustainable energy and environmental development,and strive towards carbon peaking and neutrality goals.This study introduces a nonlinear integer programming model for the deployment of dynamic wireless charging lanes(DWCLs)and EV charging strategy joint optimization in highway networks.Taking into account established charging resources in highway service areas(HSAs),the nonlinear charging characteristics of EV batteries,and the traffic capacity constraints of DWCLs.The model identifies the deployment of charging facilities and the EV charging strategy as the decision-making variables and aims to minimize both the DWCL construction and user charging costs.By ensuring that EVs maintain an acceptable state of charge(SoC),the model combines highway EV charging demand and highway EV charging strategy to optimize the DWCL deployment,thus reducing the construction cost of wireless charging facilities and user charging expenses.The efficacy and universality of the model are demonstrated using the classical Nguyen-Dupius network as a numerical example and a real-world highway network in Guangdong Province,China.Finally,a sensitivity analysis is conducted to corroborate the stability of the model.The results show that the operating speed of EVs on DWCLs has the largest impact on total cost,while battery capacity has the smallest.This comprehensive study offers vital insights into the strategic deployment of DWCLs,promoting the sustainable and efficient use of EVs in highway networks.

儿童文学翻译中的叙事转换与认知等效

因诗学传统、文化背景等方面的不同,源语和目标语儿童读者在认知框架上存在固有差异。为缩小认知差距,使目标语读者充分吸收原文含义,实现或者无限趋近目标语读者与源语读者的认知等效,译者可根据读者认知框架,适当转换原文本叙事结构,实现译文阅读效果最大化与最优化。本文以《狗狗的世界》的汉译实践为例,以目标语儿童读者与源语儿童读者的认知等效为目的,以叙事学“二分法”为研究视角,探究译者在翻译过程中可采取的叙事转化策略,试图为以认知等效为指导的儿童文学作品的翻译策略提供理论支持和方法论参考,进一步提升儿童文学作品的翻译质量并优化阅读效果,促进文化传播与交流。

LncRNA LINC00525 suppresses p21 expression viamRNA decay and triplex-mediated changes in chromatin structure in lung adenocarcinoma

Background:Emerging evidence suggests that long noncoding RNAs(lncRNAs)play crucial roles in various cancers.In the present study,we aim to investigate the function and molecular mechanism of an up-regulated and survivalassociated lncRNA,LINC00525,in lung adenocarcinoma(LUAD).Methods:The expression level of LINC00525 in tissueswas determined by quantitative reverse transcription polymerase chain reaction(RT-qPCR)and in situ hybridization(ISH).The functional role of LINC00525 in LUAD was investigated using gain-and loss-of-function approaches,both in vivo and in vitro.RNA pull-down,RNA immunoprecipitation(RIP),chromatin immunoprecipitation(ChIP),triplex-capture assay,dual-luciferase assay,gene expression microarray,and bioinformatics analysis were used to investigate the potential underlying mechanisms involved.Results:LINC00525 is highly expressed in LUAD cells and tissues.Survival analysis indicated that upregulation of LINC00525 was associated with poor prognosis in patients with LUAD patients.Knockdown of LINC00525 inhibited cell proliferation and cell cycle progression in vitro.In xenograft models,LINC00525 knockdown suppressed tumor growth and tumorigenesis of tumorbearing mice.Mechanistically,LINC00525 epigenetically suppressed p21 transcription by guiding Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit(EZH2)to the p21 promoter through an formation of RNA-DNA triplex with the p21 promoter,leading to increased trimethylation of lysine 27 on histone 3(H3K27me3)of the p21 promoter.In addition,LINC00525 repressed p21 expression post-transcriptionally by enhancing p21mRNA decay.LINC00525 promoted p21mRNAdecay by competitively binding toRNABindingMotif Single Stranded Interacting Protein 2(RBMS2).Conclusion:Our findings demonstrate that LINC00525 promotes the progression of LUAD by reducing the transcription and stability of p21 mRNA in concert with EZH2 and RBMS2,thus suggesting that LINC00525 may be a potential therapeutic target for clinical intervention in LUAD.

Meiotic nuclear divisions 1(MND1)fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma

Background:Considering the increase in the proportion of lung adenocarcinoma(LUAD)cases among all lung cancers and its considerable contribution to cancer-related deaths worldwide,we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD.Methods:The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus(GEO)datasets and The Cancer Genome Atlas(TCGA)data were combined,and a promising risk biomarker called meiotic nuclear divisions 1(MND1)was selectively acquired.Cell viability assays and subcutaneous xenograftmodelswere used to validate the oncogenic role ofMND1 in LUADcell proliferation and tumor growth.Aseries of assays,including mass spectrometry,co-immunoprecipitation(Co-IP),and chromatin immunoprecipitation(ChIP),were performed to explore the underlying mechanism.Results:MND1 up-regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis.In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle.The results of the Co-IP,ChIP and dual-luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel-like factor 6(KLF6),and thereby protecting E2F transcription factor 1(E2F1)from KLF6-induced transcriptional repression.Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner.Conclusions:MND1,KLF6,and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD.MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients.