肺癌细胞中GTSE1与细胞周期的关系及潜在调控机制

细胞周期的调控对于维持细胞正常功能至关重要,尤其在肺癌等疾病的发展中。细胞周期由四个主要阶段组成(G1、S、G2和M期),这些阶段通过一系列精确的分子事件来确保细胞正确增殖和分裂。在肺癌细胞中,细胞周期失调可导致癌细胞无序增殖和侵袭能力增强。G2和S期表达-1(G2and S-phase expressed 1,GTSE1)是一种在细胞质中发现的调节蛋白,它在多种癌细胞的细胞周期分布中起着关键作用,并参与了细胞增殖和凋亡等过程。GTSE1通过与细胞周期蛋白依赖激酶抑制因子1A(cyclin-dependent kinase inhibitor 1A,p21)的相互作用,维持p21的稳定性,进而抑制细胞周期蛋白依赖性激酶1/2(cyclin-dependent kinase 1/2,CDK1/2)的活性,影响细胞周期的进程。此外,GTSE1还参与肿瘤蛋白53(tumor protein 53,p53)信号通路的调控。在双微体同源基因2(mouse double minute 2 homolog,MDM2)的协助下,GTSE1能够将p53从细胞核转运至胞质,并促进其泛素化降解,从而影响细胞周期和细胞死亡相关信号通路。本文综述了GTSE1在肺癌细胞中的表达情况和对肺癌的影响,以及其参与细胞周期调控的潜在机制。

Identification of tumor-suppressor genes in lung squamous cell carcinoma through integrated bioinformatics analyses

Lung cancer is a prevalent malignancy,and fatalities of the disease exceed 400,000 cases worldwide.Lung squamous cell carcinoma(LUSC)has been recognized as the most common pathological form of lung cancer.The comprehensive understanding of molecular features related to LUSC progression has great significance in LUSC prognosis assessment and clinical management.In this study,we aim to identify a panel of signature genes closely associated with LUSC,which can provide novel insights into the progression of LUSC.Gene expression profiles were retrieved from public resources including gene expression omnibus(GEO)and the cancer genome atlas(TCGA)database.Differentially expressed genes(DEGs)between LUSC specimens and normal lung tissues were identified by bioinformatics analyses.A total of 66 DEGs were identified based on two cohorts of data.CytoHubba plugin of Cytoscape software was utilized for the further analyses of the top 10 candidate hub genes including OGN,ABI3BP,MAMDC2,FGF7,FAM107A,SPARCL1,DCN,COL14A1,and MFAP4 and CHRDL1,which showed significant downregulation in LUSC.Two LUSC cell lines were used to validate the functions of CHRDL1 and FAM107A through overexpression experiment.Together,our data revealed novel candidate tumor-suppressor genes in LUSC,suggesting previously unappreciated mechanisms in the progression of LUSC.

中国肺癌低剂量螺旋CT筛查指南(2018年版)

背景与目的肺癌是导致中国癌症死亡的首要原因。已有的研究证明低剂量螺旋CT在肺癌高危人群进行肺癌筛查能降低20%的肺癌死亡。本研究的目的是建立适合中国国情的肺癌筛查指南。方法由国家卫计委任命的中国肺癌早诊早治专家组专家及部分非专家组专家,包括:4名胸外科专家、4名胸部影像学专家、2名肿瘤学专家、2名肺内科专家、2名病理学专家和2名流行病学专家,共同参与了本指南的制定工作。专家们在系统评价了美国NLST和中国农村肺癌LDCT筛查结果及经验,并达成共识的基础上,共同推荐了本肺癌筛查指南。结果本指南推荐的肺癌高危人群为:年龄50岁-74岁;吸烟20包/年,或者戒烟5年。参与肺癌LDCT筛查前,需要获得筛查者的知情同意。肺癌筛查需与健康教育结合,向患者宣传吸烟对健康的危害。因此,健康教育应该整合到肺癌筛查全过程,以便帮助患者戒烟。结论 LDCT筛查能降低肺癌死亡率,本指南推荐中国肺癌高危人群进行LDCT筛查。但是,未来需要进行更多的研究,包括LDCT联合生物标志物用于肺癌筛查的研究,以优化肺癌LDCT筛查方法及技术。

云南宣威、富源地区非吸烟女性肺癌生存分析

背景与目的云南东部农村地区宣威市、富源县女性居民主要从事农业生产和家务工作,基本不吸烟,但肺癌死亡率却是世界上最高的,而且发病、死亡年龄提前。本研究对宣威、富源非吸烟女性肺癌生存状况及其影响因素进行分析。方法以2006年-2010年被当地省、市、县9家医院新诊断、并纳入"非吸烟女性肺癌病例对照研究项目"的常住户籍女性肺癌病例为研究对象随访至2016年末。通过Life-table法进行全部病例生存分析,评估人群相对生存率和年龄别标化相对生存率。应用Kaplan-Meier法和Cox比例风险模型分别进行单因素生存分析、分层分析和多因素分析。结果随访的1,250例病例中,死亡1,075例,删失175例,随访中位时间为69个月(95%CI:61.9-76.0)。病例平均年龄(54.8±10.9)岁,I期、II期、III期、IV期和未知分期分别占3.5%、8.7%、20.7%、29.7%和37.4%;手术、非手术治疗和未治疗分别占17. 2%、39.0%和43. 8%,组织学、细胞学诊断占51.6%。中位生存时间13.2个月,5年观察生存率、相对生存率、年龄标化相对生存率分别为8.9%(95%CI:7.0-10.6)、9.4%(95%CI:7.6-11.5)和10.1%(95%CI:3.7-20.5)。I期、II期、III期、IV期、未分期5年生存率分别为41.1%、22.4%、5. 3%、1. 3%、11.2%;手术治疗、非手术治疗、未治疗分别为34.8%和3.2%、4.7%;腺癌、鳞癌分别为17.9%和5.6%。省级医院治疗、X线胸部筛查、非农民职业、城镇居住、65岁以下年龄等因素有利于提高生存率,而市县级医院治疗、农民职业、乡村居住、65岁以上年龄等则生存率较低。分层分析显示,任意原发灶-淋巴结-远处转移(tumornode-met a st a si s,T N M)分期,无论腺癌或鳞癌患者,行手术治疗的生存率明显高于非手术治疗;与未治疗病例相比非手术治疗仅在III期显示差异;腺癌生存率大于鳞癌不仅仅因为早期和手术病例较多,在III期、未分期也显示明显生存优势。不同级别医院治疗疗效有明显差异,省级医院治疗的IV期、鳞癌的生存预后明显优于市、县级医院。Cox分析显示治疗方法、TNM分期、治疗医院级别、X线胸部筛查是独立预后因素,其中TNM分期、手术治疗对肺癌患者生存影响较大,而治疗医院级别、X胸部筛查相对较弱。结论宣威、富源非吸烟女性肺癌生存率较低,主要与其诊断时早期病例和手术、综合治疗较少、而未治疗病例较多有关,其次较差的农村社会经济、健康保障等也是生存预后的不利因素。

云南省肿瘤医院2005年-2014年肺癌流行病学特征变化趋势分析

背景与目的云南省是全国乃至世界肺癌的高发区,其发病率和死亡率仍处于不断上升趋势。随着生活方式及环境因素的改变,肺癌的临床流行病学特征在发生改变。但近10年来云南省肺癌临床特征的变化趋势未见报道,需进一步研究。本研究旨在探讨2005年-2014年云南地区肺癌临床特征及其变化趋势,为本地区的肺癌防治提供理论依据。方法采用回顾性调查研究方法,通过简单随机抽样抽取本院2005年-2014年的肺癌住院患者,应用统一、规范的调查问卷提取患者的社会人口学及临床病理特征,并进行数据统计分析。结果共纳入1,000例肺癌患者,平均年龄(58.1±10.1)岁,男女比例3.08/1.00。男性患者比例从2005年的75.0%下降至2014年的66.0%,而女性患者从25.0%增加到34.0%(P=0.007)。年龄≥60岁患者比例从2005年的30.0%增加到2014年的39.0%,60岁以下患者占比有所下降,但无统计学差异(P=0.532)。受教育水平较低(小学或初中)患者的比例从36.0%增加到66.0%(P<0.001)。吸烟患者占比从71.0%下降至47.0%,不吸烟人群从29.0%上升至52.0%(P=0.003)。晚期肺癌(IIIb期-IV期)患者从20.0%上升至54.0%,而II期-IIIa期比例从62.0%下降至24.0%(P=0.002)。腺癌占比从36.0%增加至61.0%,而鳞状细胞癌从32.0%下降至27.0%(P<0.001)。胸部X射线应用从91.0%下降到58.0%(P<0.001),而胸部计算机断层扫描(computed tomography, CT)使用率从46.0%增加到89.0%(P<0.001)。头部磁共振成像(magnetic resonance imaging,MRI)使用率由1.0%上升至15.0%(P<0.001)。骨扫描从35.0%上升至78.0%(P<0.001)。高成本的正电子发射计算机断层显像(positron emission tomography-CT, PET-CT)检查技术从0.0%显著上升至17.0%。化疗(P=0.67)和手术(P=0.78)是最常用的治疗方式,且在过去10年间治疗方式不变。结论女性患者比例增加、临床分期较晚、病理类型转变等是目前云南地区肺癌防治面临的重要趋势。尽管社会人口学及临床病理特征发生较大变化,但主要治疗方式的选择仍未发生改变,需进一步研究。

云南省昆明市城市癌症早诊早治项目:肺癌高危人群评估及筛查效果分析

背景与目的肺癌是最常见的恶性肿瘤,预后较差,5年生存率较低,早期筛查是肺癌防治的重要措施。目前,不同国家和地区发布了相应的肺癌筛查指南,但我国仍缺乏基于中国人群研究的指南。因此,国家癌症中心在全国启动了多中心的城市癌症早诊早治项目研究。本研究分析了城市癌症早诊早治项目中云南省单中心的肺癌高危人群评估模型及临床筛查应用效果,为探索适合我国国情的肺癌高危人群评估模型及制定和更新中国人群肺癌筛查指南提供一定的参考依据。方法采取整群抽样的方法,于2015年1月-2019年12月对云南省昆明市4个主城区36个街道办事处165,337人进行问卷调查及肺癌风险评估,评估为高风险者进行胸部低剂量计算机断层扫描(low-dose computed tomography,LDCT)筛查。同时对所有参与者进行主动随访和被动随访,获得详细的临床结局,进行统计分析。结果整体人群5年间经病理确诊肺癌患者264例,总体肺癌发生率为0.16%(264/165,337),高风险组(0.31%,116/37,914)高于非高风险组(0.12%,148/127,423),差异有统计学意义(P<0.001)。不同性别和不同年龄的亚组分析显示高风险组肺癌发生率均高于非高风险组,均有统计学差异(P<0.001),但在未进行LDCT筛查组无统计学差异(P=0.73)。肺癌高危人群评估模型的敏感性为43.94%(116/264),特异性为77.10%(127,275/165,073)。筛查组早诊率为72.97%(54/74),明显高于非筛查组的28.48%(43/151)。结论国家重大公共卫生服务项目城市癌症筛查项目肺癌高危人群评估模型能有效检出高风险人群,提高肺癌早诊率。

Identification of a potential tumor suppressor gene, UBL3, in non-small cell lung cancer

Objective: Oncogenes have been shown to be drivers of non-small cell lung cancer(NSCLC), yet the tumor suppressing genes involved in lung carcinogenesis remain to be systematically investigated. This study aimed to identify tumor suppressing ubiquitin pathway genes(UPGs) that were critical to lung tumorigenesis.Methods: The 696 UPGs were silenced by an siRNA screening in NSCLC cells;the potential tumor suppressing UPGs were analyzed, and their clinical significance was investigated.Results: We reported that silencing of 11 UPGs resulted in enhanced proliferation of NSCLC cells, and four UPGs(UBL3, TRIM22, UBE2 G2, and MARCH1) were significantly downregulated in tumor samples compared to that in normal lung tissues and their expression levels were positively associated with overall survival(OS) of NSCLC patients. Among these genes, UBL3 was the most significant one. UBL3 expression was decreased in tumor samples compared to that in paired normal lung tissues in 59/86(68.6%) NSCLCs, was correlated with TNM stage and sex of NSCLC patients, and was significantly higher in non-smoking patients than in smoking patients. Silencing UBL3 accelerated cell proliferation and ectopic expression of UBL3 suppressed NSCLC in vitro and in vivo.Conclusions: These results showed that UBL3 represented a tumor suppressor in NSCLC and may have potential for use in therapeutics and for the prediction of clinical outcome of patients.

Therapeutic Effect Observation of Tiotropium Bromide in the Treatment of Overlap Syndrome

Objective:To study the M receptor blocker on inhalation in patients with overlap syndrome(chronic obstructive pulmonary disease and Obstructive sleep apnea syndrome)curative effect analysis.Methods:25 patients with overlap syndrome as the experimental group,chronic obstructive pulmonary disease patients(30)as control group,patients with overlap syndrome use inhaled tiotropium powder treat 30 days,to observe the changes of pulmonary function,polysomnography,and other indicators after treatment.Results:Overlap syndrome were treated by tiotropium bromide inhalation powder,has improved the pulmonary function,the sleep apnea index and lowest nocturnal oxygen saturation after treatment.Conclusion:tiotropium bromide has a preferable effective in treatment of overlap syndrome,COPD and OSAHS are interacting with each other.

Application of Blocking Unilateral Main Pulmonary Artery in Pulmonary Lobectomy of Lung Cancer

OBJECTIVE To explore the application of blocking the unilateralmain pulmonary artery (MPA) in pulmonary lobectomy (PL) forpatients with stage Ⅱ and Ⅲ lung cancer, and to retrospectivelyanalyze the methods of surgery for blocking the unilateral mainpulmonary artery, perioperative indications, intraoperativeconcerns and postoperative cardio-pulmonary complications.METHODS During a period from January 2006 to January 2008,intra-pericardial, or extra-pericardial separation and blockade ofthe left or right MPA followed by completion of various PLs wereconducted for 30 lung cancer patients in stage-Ⅱ to Ⅲ with ill-defined anatomic structure of the pulmonary hilum and difficultpulmonary angiodiastasis.RESULTS In the 30 patients, 5 were diagnosed as stage-Ⅱb, 11stage-Ⅲa, and 14 stage-Ⅲb. During the surgery, giant tumors atthe superior pulmonary lobe, with a diameter of over 10 cm, wereseen in 13 cases, in which tumor invasion in the extra-pericardiacpulmonary artery was found in 5 cases. Hilar lymphadenectasiswith severe tumor adhesion to pulmonary blood vessel couldbe seen in 20 cases and partial tumorous invasion in thepericardium in 7. In most of the cases, adhesions existed aroundthe tumor, aorta, superior vena, and azygous vein. Invasion ofthe laryngeal and vagus nerves on the left side was found in 3cases. Of the 30 patients, simple PL was conducted in 12, andsleeve lobectomy combined with a pulmonary arterioplasty in18 cases. With a blockade of unilateral MPA, no intraoperativehemorrhea of pulmonary blood vessels occurred during surgery,when there was a clear surgical field of vision. Both PL andlymphadenectomy were smoothly completed in the 30 patients.The healthy pulmonary lobes with normal function were keptand total pneumonectomy was avoided. The time of blocking thepulmonary artery ranged from 10 to 30 min, and intraoperativeblood loss was from 200 to 300 ml. Postoperative complicatedacute pulmonary edema occurred in 5 patients and tachycardia in7 cases. Nevertheless, all patients recovered and left the hospitalafter treatment. No severe cardiopulmonary complications werefound in all patients of the group.CONCLUSION Blocking the unilateral MPA is effective todecrease the risk of intraoperative hemorrhea in the PL. It canshorten the time of surgery, improve the excision rate of lungcancer, and cut down on the rate of total pneumonectomy.

The expression of Sox4 in female lung cancer patients and its clinical significance

Objective:To investigate the expression level of sex-determining region Y-related high mobility group box 4(Sox4)in female lung cancer patients and its clinical significance.Methods:213cases of female lung cancer patients who presented in the third affiliated hospital of Kunming medical university were selected for this study.Patients were performed radical surgery of lung cancer;the tumor and adjacent normal tissues were collected.The expression of Sox4 were determined by real-time PCR and immunohistochemical staining.The correlation between Sox4 expression and clinicopathological characteristics was analyzed.Results:The mRNA level of Sox4 was significantly higher in tumor tissues than that in adjacent normal tissues(P <0.05).The positive expression rate of SOX4 in carcinoma tissues was 54.46%,which was significantly higher than that in adjacent normal tissues(23.47%)(P <0.05).The positive expression rate of Sox4 in stageⅢ was 89.47%,which was significantly higher than that in stageⅠ-Ⅱ(P <0.05).The positive expression rate of SOX4 in lung cancer patients with lymph node metastasis was 90.91%,which was significantly higher than that in patients without lymph node metastasis(P <0.05).The positive expression rates of Sox4 in low,middle and high differentiation tissues were 69.05%,32.88% and 23.21% respectively,suggesting that the expression of Sox4 in female lung cancer tissues decreased with the increase of pathological differentiation grades.Conclusion:In female lung cancer,SOX4expression was significantly higher in tumor tissue than that of adjacent normal tissues and was correlated with clinical stage,lymph node metastasis and pathological differentiation.Sox4 expression detection may help determine the prognosis of women with lung cancer and provide a theoretical basis for molecular targeted therapy of lung cancer in women.

中国人群伤残权重测量:聚焦癌症,量化评估伤残权重对癌症疾病负担估计的影响

伤残权重对于量化评估非死亡相关健康损失至关重要.全球范围看,目前仅有少数国家或地区对伤残权重进行了评估,且极少有肿瘤特异性的伤残权重结果报道.本研究基于大样本人群估计中国人群肿瘤特异性伤残权重,并比较不同伤残权重对量化评估肿瘤疾病负担的影响.基于开放式网络调查,采用配对比较的方法进行伤残权重的测量.伤残寿命损失年(YLDs)估计为不同瘤种各时期肿瘤的患病人数与其对应时期的伤残权重乘积之和.研究共收集到44,069份有效调查问卷,估计了包含18类恶性肿瘤在内的254个健康状态的残疾权重.其中,诊断和初始治疗阶段的肿瘤特异性伤残权差异较大,脑瘤的伤残权重最高为0.619(95%不确定性区间(UI):0.606~0.632),口咽癌伤残权重最低,为0.167(95%UI:0.158~0.176).不同肿瘤伤残权重对YLDs估计影响较大,所有肿瘤合计的YLDs差异超过30%.本研究提供的肿瘤特异性伤残权重可以为精确估计肿瘤疾病负担提供重要的数据支持.

EphA2:A promising therapeutic target in breast cancer

Ephrin type-A receptor 2(EphA2),a receptor tyrosine kinase,is overexpressed in human breast cancers often linked to poor patient prognosis.Accumulating evidence demonstrates that EphA2 plays important roles in several critical processes associated with malignant breast progression,such as proliferation,survival,migration,invasion,drug resistance,metastasis,and angiogenesis.As its inhibition through multiple approaches can inhibit the growth of breast cancer and restore drug sensitivity,EphA2 has become a promising therapeutic target for breast cancer treatment.Here,we summarize the expression,functions,mechanisms of action,and regulation of EphA2 in breast cancer.We also list the potential therapeutic strategies targeting EphA2.Furthermore,we discuss the future directions of studying EphA2 in breast cancer.

Multiplexed imaging of tumor immune microenvironmental markers in locally advanced or metastatic non-small-cell lung cancer characterizes the features of response to PD-1 blockade plus chemotherapy

Background:Although programmed cell death 1(PD-1)blockade plus chemotherapy can significantly prolong the progression-free survival(PFS)and overall survival(OS)in first-line settings in patients with driver-negative advanced non-small-cell lung cancer(NSCLC),the predictive biomarkers remain undetermined.Here,we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD-1 blockade plus chemotherapy.Methods:Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone.Tumor immune microenvironmental markers,including PD-1 ligand(PDL1),CD8,CD68,CD4 and forkhead box P3,were assessed using multiplex immunofluorescence(mIF)assays.Kaplan-Meier curveswere used to determine treatment outcome differences according to their expression status.Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations.Results:Responders had significantly higher CD8/PD-L1(P=0.015)or CD68/PD-L1 co-expression levels(P=0.021)than non-responders in the camrelizumab plus chemotherapy group,while no difference was observed in the chemotherapy group.Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression level was associated with significantly longer PFS(P=0.002,P=0.024;respectively)and OS(P=0.006,P=0.026;respectively)than those with low co-expression in camrelizumab plus chemotherapy group.When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD-L1 co-expression stratification,significantly better PFS(P=0.003)and OS(P=0.032)were observed in high co-expression subgroups.The predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression remained statistically significant for PFS and OS when adjusting clinicopathological features.Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD-L1 or CD68/PD-L1 co-expression,the positive groups had a significantly higher proportion of TP53/KRAS co-mutations than the negative groups(both 13.0%vs.0.0%,P=0.023).Notably,enriched PI3K(P=0.012)and cell cycle pathway(P=0.021)were found in the CD8/PD-L1 co-expression group.Conclusion:Tumor immune microenvironmental marker expression,especially CD8/PD-L1 or CD68/PD-L1 co-expression,was associated with the efficacy of PD-1 blockade plus chemotherapy as first-line treatment in patients with advanced NSCLC.

LSD1 is required for euchromatic origin firing and replication timing

The chromatin-based rule governing the selection and activation of replication origins remains to be elucidated.It is believed that DNA replication initiates from open chromatin domains;thus,replication origins reside in open and active chromatin.However,we report here that lysine-specific demethylase 1(LSD1),which biochemically catalyzes H3K4me1/2 demethylation favoring chromatin condensation,interacts with the DNA replication machinery in human cells.We find that LSD1 level peaks in early S phase.

Temporal trend of mortality from major cancers in Xuanwei, China

Although a number of studies have examined the etiology of lung cancer in Xuanwei County, China, other types of cancer in this county have not been reported systematically. This study aimed to investigate the temporal trend of eight major cancers in Xuanwei County using data from three mortality surveys （1973-1975, 1990-1992, and 2004-2005）. The Chinese population in 1990 was used as a standard population to calculate age- standardized mortality rates. Cancers of lung, liver, breast, brain, esophagus, leukemia, rectum, and stomach were identified as the leading cancers in this county in terms of mortality rate. During the three time periods, lung cancer remained as the most common type of cancer. The mortality rates for all other types of cancer were lower than those of the national average, but an increasing trend was observed for all the cancers, particularly from 1990-1992 to 2004-2005. The temporal trend could be party explained by changes in risk factors, but it also may be due to the improvement in cancer diagnosis and screening. Further epidemiological studies are warranted to systematically examine the underlying reasons for the temporal trend of the major cancers in Xuanwei County.

The existence of a nonclassical TCA cycle in the nucleus that wires the metabolic-epigenetic circuitry

The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid(TCA)cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus.We report here the identification of a nonclassical TCA cycle in the nucleus(nTCA cycle).We found that all the TCA cycle-associated enzymes including citrate synthase(CS),aconitase 2(ACO2),isocitrate dehydrogenase 3(IDH3),oxoglutarate dehydrogenase(OGDH),succinyl-CoA synthetase(SCS),fumarate hydratase(FH),and malate dehydrogenase 2(MDH2),except for succinate dehydrogenase(SDH),a component of electron transport chain for generating ATP,exist in the nucleus.We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria.We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates,not for energy production.We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation.Together,our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.