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关键词： Bladder cancer   Circulating tumor cells   Mutation   LUNG-CANCER   HETEROGENEITY   RECURRENCE   SIGNATURES  

摘要： BackgroundWhile circulating tumor cells may serve as minimally invasive cancer markers for bladder cancers, the relationship between primary bladder cancers and circulating tumor cells in terms of somatic mutations is largely unknown. Genome sequencing of bladder tumor and circulating tumor cells is highlighted to identify the somatic mutations of primary bladder *** cancer tissue was collected by transurethral resection of the bladder and preserved by snap-freezing. Circulating tumor cells were Isolated from the blood obtained before treatment. We performed whole exome sequencing of 20 matched pairs of primary bladder cancers and circulating tumor cells to identify and compare somatic mutations of these two different genomic *** observed that mutation abundances of primary bladder cancers and circulating tumor cells were highly variable. The mutation abundance was not significantly correlated between matched pairs. Of note, the mutation concordance between two resources was only 3-24% across 20 pairs examined, suggesting that the circulating tumor cell genomes of bladder cancer patients might be genetically distinct from primary bladder cancers. A relative enrichment of mutations belonging to APOBEC-related signature and a depletion of C-to-G transversions were observed for primary- and circulating tumor cells specific mutations, respectively, suggesting that distinct mutation forces might have been operative in respective lesions during *** observed discrepancy of mutation abundance and low concordance level of mutations between genomes of primary bladder cancers and circulating tumor cells should be taken into account when evaluating clinical utility of circulating tumor cells for treatments and follow-up of bladder *** registrationPatients were selected and registered retrospectively, and medical records were evaluated.

关键词： Molecular docking   Structure-activity relationship   Quinolinium iodide   Anticancer agents   Antibacterial agents  

摘要： The structural modification of quinolone derivatives has been a hot spot in recent years, especially the modification of the N-1 position, which is the part that this article focuses on. In this paper, series of synthesized quinoline quaternary ammonium salts with odd and even carbon number alkyl groups in N-1 position were used to explain the influence of the alkyl side chain on activity. With respect to all the recently synthesized twenty products, the biological activity results exhibited significant antitumor and antibacterial activity with obvious differences in the target alkyliodine substituted compounds and the antibacterial activities apparently had the prominent odd-carbon number predominance. Compound 8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dioxolo[4,5-g]quinolin-5-ium (4d) was found to be the most potent derivative with IC50 values of 4 +/- 0.88, 4 +/- 0.42, 14 +/- 1.96, and 32 +/- 3.66 against A-549, Hela, SGC-7901, and L-02 cells, respectively, stronger than the positive control 5-FU and MTX. Furthermore, it had the most potent bacterial inhibitory activity of MIC value against E. coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739) at 3.125 nmol mL(-1). With respect to molecular simulations, in order to illustrate the possible mechanism of the difference between the series of compounds in the even or odd carbon chain alkyliodine substitution, this paper simulated the conceivable mode and explained the main interactions. Finally, we could find that the position and proportion of hydrogen bonds and other interactions in each series were regarded as the main reasons for this difference in activity. (C) 2020 Elsevier B.V. All rights reserved.

关键词： Non-small-cell lung cancer   Enhancer of zeste homolog 2 (EZH2)   EZH2 inhibitor   EGFR-TKIs   ZESTE HOMOLOG 2   HISTONE METHYLATION   EXPRESSION   SURVIVAL   ENHANCER   CISPLATIN   ONCOGENE  

摘要： BackgroundLung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC *** RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western ***2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell prol

关键词： type III secretion system   sorting platform   basal body   PscK/SctK   PscD/SctD   PROTEIN-STRUCTURE   MODEL   REFINEMENT   DOMAIN   CELLS   TOOL  

摘要： Many Gram-negative bacterial pathogens use type III secretion systems (T3SS) to inject proteins into eukaryotic cells to subvert normal cellular functions. The T3SS apparatus (injectisome) shares a common architecture in all systems studied thus far, comprising three major components - the cytoplasmic sorting platform, envelope-spanning basal body and external needle with tip complex. The sorting platform consists of an ATPase (SctN) connected to "pods" (SctQ) having six-fold symmetry via radial spokes (SctL). These pods interface with the 24-fold symmetric SctD inner membrane ring (IR) via an adaptor protein (SctK). Here we report the first high-resolution structure of a SctK protein family member, PscK from Pseudomonas aeruginosa, as well as the structure of its interacting partner, the cytoplasmic domain of PscD (SctD). The cytoplasmic domain of PscD forms a forkhead-associated (FHA) fold, like that of its homologues from other T3SS. PscK, on the other hand, forms a helix-rich structure that does not resemble any known protein fold. Based on these structural findings, we present the first model for an interaction between proteins from the sorting platform and the IR. We also test the importance of the PscD residues predicted to mediate this electrostatic interaction using a two-hybrid analysis. The functional need for these residues in vivo was then confirmed by monitoring secretion of the effector ExoU. These structures will contribute to the development of atomic-resolution models of the entire sorting platform and to our understanding of the mechanistic interface between the sorting platform and the basal body of the injectisome. (C) 2020 Elsevier Ltd. All rights reserved.

关键词： Non-small cell lung cancer   Adjuvant chemotherapy   Tegafur-uracil   Lymphovascular invasion   Targeted therapy   Phase II study   VESSEL INVASION   PROGNOSTIC IMPACT   SYSTEM   VINORELBINE   METASTASIS   CISPLATIN   SURGERY  

摘要： BackgroundLymphovascular invasion (LVI), which includes vascular or lymphatic invasions, is a representative prognostic factor even in patients with resected stage IA non-small cell lung cancer (NSCLC). Because tegafur-uracil is effective on cancers with LVI, we conducted a multi-center single-arm phase II study to estimate the efficacy of adjuvant tegafur-uracil in patients with LVI-positive stage IA *** with completely resected LVI-positive stage IA NSCLC were registered. LVI was diagnosed by consensus of two of three pathologists. Adjuvant chemotherapy consisted of 2years of oral tegafur-uracil at 250mg/m(2)/day. Fifty-five patients from 7 institutions were enrolled from June 2007 to September *** the 52 eligible patients, 36 (69.2%) completed the treatment course. There were 39 male and 13 female patients. The observation period was calculated as 562 to 3107days using the reverse Kaplan-Meier method. The 5-year overall and relapse free survival rates were 94.2 and 88.5% respectively, which were significantly better than that of any other studies conducted on patients with LVI-positive stage IA NSCLC. Notably, the overall survival rate was 15% better than that of our prior retrospective study. The retrospective analysis of stage IA NSCLC patients who had received an operation in the same period revealed that the 5-year overall survival rate of the LVI positive group was 73.6% when adjuvant chemotherapy was not applied. Among 55 safety analysis sets, 4 cases of grade 3 hepatic function disorder (9.1%) and 5 cases of grade 2 anorexia (10.9%) were most frequently observed. No grade 4 adverse effects were *** 2-year course of oral tegafur-uracil administration is feasible and might have a significant benefit in the adjuvant treatment of LVI-positive stage IA *** registrationUMIN identifier: UMIN000005921; Date of enrolment of the first participant to the trial: 19 June 2007; Date of registration: 5 July 2011

关键词： 伸缩缝   施工技术   市政路桥  

摘要： 市政路桥是城市交通的重要基础设施,其在实际使用过程中,由于的大量的车辆通行而导致荷载增加,并且在温度变化的作用下,很容易引起路桥表面发生涨缩变化。在一定程度上会影响桥梁主体材料的应力发生改变,对其正常运营产生不利作用。而伸缩缝的设置和施工则能够为应力变化提供缓冲区,有效避免出现路桥裂缝和变形等问题。基于此本文主要探讨伸缩缝施工技术在市政路桥施工中的控制措施,并分析其具体技术要点,旨在为相关施工单位提供借鉴和参考。

关键词： 连拱隧道   偏压隧道   无中隔墙   进洞顺序   施工优化   数值分析  

摘要： 浅埋偏压无中隔墙连拱隧道左右洞进洞顺序对围岩和结构的影响不同,通常开挖施工属于不可逆的弹塑性力学响应过程,因此进洞顺序必存在优化方案。以云南华坪至丽江高速公路陆家湾隧道为例,采用有限元数值模拟手段开展浅埋偏压无中隔墙连拱隧道进洞施工顺序优化分析,从围岩稳定和隧道结构安全等角度,探讨了先开挖埋深较浅一侧洞体与先开挖埋深较深一侧洞体两种进洞方案的力学响应特征。研究表明:两种方案对应的衬砌内力、位移等模拟结果的数值差异不大,然而从减少施工对山体扰动和利于围岩稳定方面考虑,先进洞埋深较浅一侧的方案更优。陆家湾隧道现场施工采取了埋深浅一侧先进洞方案,施工过程和监测数据验证了其合理性。

关键词： 后浇带   基础沉降   温度控制   伸缩缝   质量控制  

摘要： 钢筋混凝土施工中采用后浇带技术有利于构筑物的整体稳定和质量控制。构筑物的不同部位,所采用后浇带施工的具体要求也各不相同。文章结合水工建筑物特征,对施工中采用的后浇带作用、结构类型、质量控制要点等分别进行梳理分析,对类似工程的施工具有一定参考作用。

关键词： 景观环境   城区环境   净水站   项目背景   生态恶化   调蓄池   坪山新区   经济和社会  

摘要： 项目背景坪山河位于深圳市东北部坪山新区,发源于梅沙尖,干流从西南至东北纵贯坪山新区全境,河道全长13.5公里。在区域经济和社会高速发展的背景下,坪山河水质下降,生态恶化,给沿河和下游城区环境带来了很大影响。根据坪山河流域水环境综合整治工程的规划,沿河设置净水站、调蓄池和人工湿地以改善坪山河水质,提升沿岸景观环境。