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关键词： Diseases  

摘要： Circulating tumor DNA (ctDNA)-based mutation detection is promising to change the clinical practice of genotype-directed therapy for cancer. A growing number of non-invasive tests for cancer screening and monitoring that involve the detection of ctDNA have been commercialized. Primary reference measurement procedures (PRMPs) and reference materials (RMs) are urgently needed to assess the non-invasive tests. In this study, a PRMP based on digital PCR (dPCR) and ctDNA RMs for quantification of the frequently occurring variant in epidermal growth factor receptor (EGFR L858R, T790M, and 19Del) in non-small cell lung cancer (NSCLC) were established. The candidate dPCR PRMP showed high specificity (false positive rate 0-0.003%), good repeatability (coefficient of variance (CV), 2-3% for 10(4) copies/reaction), and high interlaboratory reproducibility (3-10%). A good linearity (0.97 < slope < 1.03, R-2 >= 0.9999) between the measured mutant (MU) value and prepared value was observed for all assays over the fractional abundance (FA) range, between 25% and 0.05%. The limit of quantification (LoQ) was determined to be 34 L858R, 23 T790M, and 34 19Del copies/reaction, corresponding to a FA of 0.2%. An inter-laboratory study of using the EGFR ctDNA RMs and dPCR assays demonstrated that the participating laboratories produced consistent concentrations of MU and wild-type (WT), as well as FA. This study demonstrates that dPCR can act as a potential PRMP for EGFR mutation for validation of NSCLC genotyping tests and ctDNA quantitative tests. The PRMP and RMs established here could improve interlaboratory repeatability and reproducibility, which supports rapid translation and application of non-invasive tests into clinical practice.

关键词： chemogenomic profiling   marine natural products   mechanism of action   membrane interactions  

摘要： Amantelide A, a polyhydroxylated macrolide isolated from a marine cyanobacterium, displays broad-spectrum activity against mammalian cells, bacterial pathogens, and marine fungi. We conducted comprehensive mechanistic studies to identify the molecular targets and pathways affected by amantelide A. Our investigations relied on chemical structure similarities with compounds of known mechanisms, yeast knockout mutants, yeast chemogenomic profiling, and direct biochemical and biophysical methods. We established that amantelide A exerts its antifungal action by binding to ergosterol-containing membranes followed by pore formation and cell death, a mechanism partially shared with polyene antifungals. Binding assays demonstrated that amantelide A also binds to membranes containing epicholesterol or mammalian cholesterol, thus suggesting that the cytotoxicity to mammalian cells might be due to its affinity to cholesterol-containing membranes. However, membrane interactions were not completely dependent on sterols. Yeast chemogenomic profiling suggested additional direct or indirect effects on actin. Accordingly, we performed actin polymerization assays, which suggested that amantelide A also promotes actin polymerization in cell-free systems. However, the C-33 acetoxy derivative amantelide B showed a similar effect on actin dynamics in vitro but no significant activity against yeast. Overall, these studies suggest that the membrane effects are the most functionally relevant for amantelide A mechanism of action.

关键词： 市政桥梁工程   伸缩缝   施工技术  

摘要： 近年来对于市政桥梁工程中出现的问题,需要进行格外的重视,使相关技术得到充分的提高。避免在进行使用的过程中,出现更多的问题,从而影响人们的生活的便利。为避免出现因为桥梁问题给百姓们的日常生活带来影响,为了提高百姓们的生活质量,我们应加强技术,使桥梁工程更加安全、坚固、可靠。基于此,本篇文章对市政桥梁工程伸缩缝施工技术进行研究,以供相关人士参考。

关键词： 桥梁施工   伸缩缝   施工质量  

摘要： 伴随社会的持续发展与进步,桥梁项目就得到了极大的改善和发展。但桥梁建设内的桥梁伸缩缝就会存在问题,所以也就应该积极的研究并响应,以推动桥梁建设的稳定进行,保护中国工程建设的健康发展,并在桥梁建设阶段中增强伸缩缝施工研究,提升施工效率及品质。本篇文章就分析了桥梁伸缩缝设计的质量管理,并提出了桥梁建设阶段中伸缩缝施工中具有的问题,提出对应的应对方法,希望能够为桥梁施工技术的改进做出一定的贡献。