MiR-183-5p promotes the progression of non-small cell lung cancer through targeted regulation of FOXO1

Objective To investigate miR-183-5p targeting to forkhead box protein O1(FOXO1)and its corresponding effect on the proliferation,migration,invasion,and epithelial-mesenchymal transition(EMT)of non-small cell lung cancer(NSCLC)cells.Methods NSCLC tissues and adjacent normal tissues from 60 patients with NSCLC adenocarcinoma were obtained via pathological biopsy or intraoperative resection.Several cell lines were cultured in vitro,including the human normal lung epithelial cell line BEAS-2B and human NSCLC cell lines A549,SPCA-1,PC-9,and 95-D.miR-183-5p and FOXO1 mRNA expression in tissues and cells were detected by qRT-PCR;the corresponding correlations in NSCLC tissues were analyzed using the Pearson test,and the relationship between miR-183-5p expression and clinicopathological parameters was analyzed.The miR-183-5p-mediated regulation of FOXO1 was verified by bioinformatics prediction alongside double luciferase,RNA-binding protein immunoprecipitation(RIP)assay,and pull-down experiments.A549 cells were divided into control,anti-miR-NC,anti-miR-183-5p,miR-NC,miR-183-5p,miR-183-5p+pcDNA3.1,and miR-183-5p+pcDNA3.1-FOXO1 groups.Cell proliferation,invasion,migration,apoptosis,and cell cycle distribution were detected using an MTT assay,clone formation assay,Transwell assay,scratch test,and flow cytometry,respectively.The expression of EMT-related proteins in the cells was analyzed by western blotting.The effect of miR-185-3p silencing on the development of transplanted tumors was detected by analyzing tumor formation in nude mice.Results miR-183-5p expression was significantly higher in NSCLC tissues and cells than in adjacent normal tissues,whereas FOXO1 mRNA expression was significantly down-regulated.There was a significant negative correlation between miR-183-5p and FOXO1 mRNA in NSCLC tissues(P<0.05).Additionally,the expression of miR-183-5p was significantly correlated with tumor size,tumor differentiation,and tumor-node-metastasis stage in patients with NSCLC(P<0.05).miR-183-5p targeted and inhibited FOXO1 expression.Compared to the anti-miR-NC group,the cell proliferation,scratch healing rate,N-cadherin and vimentin protein expression,and the proportion of S phase cells were significantly lower in the anti-miR-183-5p group,whereas the protein expression of E-cadherin andα-catenin and the proportion of G0/G1 phase cells were significantly higher;additionally,the frequency of colony formation and invasion were significantly lower in the anti-miR-183-5p group(P<0.05).Compared to the miR-NC group,the cell proliferation,scratch healing rate,N-cadherin and vimentin protein expression,and the proportion of S phase cells in the miR-183-5p group were significantly higher,whereas the E-cadherin andα-catenin protein expression and the proportion of G0/G1 phase cells were significantly lower;furthermore,the frequency of colony formation and invasion were significantly higher in the miR-183-5p group(P<0.05).Compared with the miR-183-5p+pcDNA3.1 group,the OD value,scratch healing rate,N-cadherin and vimentin protein expression,and the proportion of S phase cells were significantly lower in the miR-183-5p+pcDNA3.1-FOXO1 group,whereas E-cadherin andα-catenin protein expression and the proportion of G0/G1 phase cells were significantly higher;additionally,the frequency of colony formation and invasion was significantly lower in the miR-183-5p+pcDNA3.1-FOXO1 group(P<0.05).Overall,silencing miR-185-3p inhibited the growth of transplanted tumors and promoted FOXO1 expression.Conclusion Overexpression of miR-183-5p can inhibit apoptosis and promote the proliferation,migration,invasion,and EMT,of NSCLC cells by down-regulating FOXO1 expression.

Maintaining clarity:Review of maintenance therapy in nonsmall cell lung cancer

The purpose of this article is to review the role of maintenance therapy in the treatment of advanced nonsmall cell lung cancer(NSCLC). A brief overview about induction chemotherapy and its primary function in NSCLC is provided to address the basis of maintenance therapies foundation. The development of how maintenance therapy is utilized in this population is discussed and current guidelines for maintenance therapy are reviewed. Benefits and potential pitfalls of maintenance therapy are addressed, allowing a comprehensive review of the achieved clinical benefit that maintenance therapy may or may not have on NSCLC patient population. A review of current literature was conducted and a table is provided comparing the results of various maintenance therapy clinical trials. The table includes geographical location of each study, the number of patients enrolled, progression free survival and overall survival statistics, post-treatment regimens and if molecular testing was conducted. The role of molecular testing in relation to therapeutic treatment options foradvanced NSCLC patients is discussed. A treatment algorithm clearly depicts first line and second line treatment for management of NSCLC and includes molecular testing, maintenance therapy and the role clinical trials have in treatment of NSCLC. This treatment algorithm has been specifically tailored and developed to assist clinicians in the management of advanced NSCLC.

Treatment of Esthesioneuroblastoma and Nonsmall Cell Lung Cancer with Phenylbutyrate

Esthesioneuroblastoma is a malignant tumor, arising in the upper nasal cavity, that could spread to the frontal lobe of the brain as well as metastasize to the lymph nodes. Due to the low incidence of this tumor, FDA-approved treatment modalities do not exist and clinical trials have not been performed. We present an interesting case of a 66-year-old female, diagnosed with Kadish stage B esthesioneuroblastoma and stage IIA nonsmall cell carcinoma of the lung, who benefited from our treatment. Both malignancies were diagnosed in 2002 at which time the patient consented to undergo left upper lobectomy for her lung cancer, but she refused the craniofacial resection and radiation therapy recommended for treatment of her esthesioneuroblastoma. From 2003 to 2004 she received treatment at the Burzynski Clinic with oral sodium phenylbutyrate (0.2 g/kg/day). She tolerated the treatment very well without significant adverse events. Gradual reduction in her tumor size was confirmed by repeat MRIs. From treatment start in March 2003 to December 2003 her tumor decreased by 40%. Subsequent MRI from March 2004 revealed increased tumor size, which, however, was still a 13% reduction from the baseline MRI. What is important to mention is that in addition to shrinkage of the esthesioneuroblastoma, the patient obtained the clinical benefit of 3.5-years longer survival than was predicted for her lung cancer—whereas the median survival for a patient with stage IIA adenocarcinoma of the left upper lobe of the lung is approximately two years, our patient survived more than five and a half years. The effect of phenylbutyrate (PB) and its metabolite phenylacetate on neuroblastoma and lung cancer is documented by numerous preclinical studies and is also evident in this case. It is proposed that the activity of these two compounds is mediated through increased expression of the p21 tumor suppressor gene. p21 is a strong inhibitor of cyclin-D and cyclin-dependent kinase 4, which contribute to undifferentiated phenotype in neuroblastoma and are instrumental in cell cycle progression from G1 to S phase. It is hoped that future research and combination of PB with other chemotherapeutic and targeted agents will provide better control of esthesioneuroblastoma and lung cancer.

Bevacizumab Combined with Icotinib Overcomes Osimertinib Resistance in a Patient of Non-Small Cell Lung Cancer

A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor(EGFR)19 del mutation positive.Treatment with icotinib was given,but her disease progressed after 6 months remission.CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis,and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction(ARMS-PCR)confirmed EGFR T790M mutation.Treatment with osimertinib was initiated.After 2 months remission,the disease progressed.Re-biopsy was performed for the tumor in the inferior lobe of left lung,and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del.Icotinib was re-challenged,but disease progressed continuously.Bevacizumab was added,and partial response was achieved after 2-cycle of combination therapy.The non-small cell lung cancer(NSCLC)in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment.This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.

Shenqi Fuzheng injection combined with GP chemotherapy in the treatment of advanced non-small cell lung cancer： a meta-analysis

Objective： To evaluate the clinical efficacy of Shenqi Fuzheng injection combined with gemcitabine plus cisplatin（GP） in the treatment of advanced non-small cell lung cancer （NSCLC）. Methods： we performed a systematicsearch in the electronic databases such as Cochrane Library, Pubmed, Embase, Chinese Journal Full-text Database,Chinese Biomedical Literature Database, Chinese Science and Technology Periodical Full-text Database andWanfang Database up to 30 January 2017. Randomized controlled trials （RCT） of Shenqi Fuzheng Injectioncombined with GP chemotherapy in the treatment of advanced NSCLC were searched, and all the RCTs wereconducted on methodological quality assessment. Data extraction and data analysis were according to standards ofCochrane systematic review. Results： Eight trials were included including a total of 701 patients. Meta-analysisresults： Shenqi Fuzheng injection combined with GP chemotherapy could significantly improve the functionalstatus of patients with NSCLC （OR = 3.44, 95% CI [2.26, 5.25], P 〈 0.0001） and clinical treatment efficacy （OR =（OR = 0.31, 95%CI [0.20, 0.47], P 〈 0.0001. The rate of leukopenia （OR = .31, 95%CI [0.20,0.47], P 〈 0.0001）,thrombocytopenia （OR = 0.58, 95%CI [0.37, 0.91], P = 0.020）, hemoglobin decline （（OR = 0.31, 95%CI [0.16,0.59], P = 0.0004） and incidence of gastrointestinal reactions （OR = 0.58,P 〈 0.05） could be reduced. Conclusion：Shenqi Fuzheng injection combined with GP chemotherapy in the treatment of advanced NSCLC obtainedsignificantly clinical efficacy. The quality of the literature incorporated is low, the conclusion requires high-qualityresearch to further prove.

Circular RNA circFOXM1 triggers the tumorigenesis of non-small cell lung cancer through miR-132-3p/TMEM14A axis

Farlier studies indicated that circular RNAs(circRNAs)were found in various cancer clls,and circFOXM1 was reported to act as an oncogane in non-small cell lung cancer(NSCLC).However,the function of circFOXM1 in NSCLC remains undear.The epression lewels of genes were measured using quantative real-time polymerase chain reactions(qRT-PCR).Cell prolferation and apoptosis were determined by 3-(4,5 dimethylthiazol-2-yl)-25 dipbenyletrazolium bromide solution(MTT)and flow cytometry assay.The rdative protein expression was assed by westen blot Moreower,transwell assays were employed to examine ell migration and invasion.The targeted relationship was confirmed by dual-luciferase reporter assay.The expression of circFOXMI was up-regulated in NSCIC tissues and cell lines.The depletion of circFOXM1 decreased the prolferation,migration,invasion,and induced cell apoptosis of NSCLC cells.MicroRNA-132-3p(MiR-1323p)was idenified as a target of dircFOXMl.The expression level of miR-132-3p was decrased in NSCLC tssues and cell lines and inversely corrdated with circFOXM1 expression.Furthermore,the efects of drdOXMl down regulation on NSCLC cell progression were abolished by mR-1323p inhibitor.Transmembrane protein 14A(TMEM14A)was verifed as a target gene of miR-132-3p.The efects of circFOXM1 depletion on NSCLC cell proliferation,apoptosis,migration,and invasion were reversed by TMEMI4A overexpression.Our study demonstrated that knodkdown of circFOXM1 suppressed NSCLC progression through rqgulating miR-132-3p/TMEMI4A axis,sugesting the drFOXM/miR-132-3p/TMEM14A axis may serve as the novd target for NSCLC diagnosis and therapy.

Serum levels of CA19-9 may be as an indicator for metastases in patients with non-small cell lung cancer

Objective:The aim of our study was to evaluate the serum levels of CA19-9 in patients with non-small cell lung cancer(NSCLC)and to analyze the relationship between serum levels of CA19-9 and metastasis.Methods:Serum levels of CA19-9 in 1200 NSCLC patients from February 2006 to August 2011 were evaluated retrospectively.The relationship between serum levels of CA19-9 and sites of metastasis were analyzed.Results:Of the 1200 patients,528 were stage IV and the positive rate of CA19-9 was 32%(169 cases)and 288 stage III,positive rate 20%(58 cases);144 stage II,positive rate 12%(17 cases);240 stage I,positive rate 3%(7 cases).There were statistical differences from stage I to stage IV(P<0.01).The total positive rate in the 1200 cases was 21%.Furthermore,of the 528 stage IV cases,350 had bone metastasis and the positive rate of CA19-9 was 43%(150 cases)in bone metastatic cases.In turn,in CA19-9 positive patients(169 cases)of stage IV, the positive rate of bone metastasis was 89%(150/169).There was no statistical difference of positive rate of CA19-9 between adenocarcinoma and squamous carcinoma(P>0.05).Conclusion:Positive rate of CA19-9 increases accordingly from stage I to stage IV.The serum levels of CA19-9 may be as an indicator for metastases in patients with NSCLC,especially for bone metastasis in stage IV diseases.

Non-small-cell lung cancer with epidermal growth factor receptor L861Q-L833F compound mutation benefits from both afatinib and osimertinib: A case report

BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the two common mutations exon 19 deletion and L858R,which together comprise approximately 85%of EGFR mutations in NSCLC,rare EGFR mutations also exist,including point mutations,deletions,and insertions spanning EGFR exons 18-25.However,the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest.CASE SUMMARY Herein,we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis.The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo.After afatinib failure,the patient received multiple line treatments with chemotherapy.Upon disease progression,the heavily pretreated patient was treated with osimertinib and bevacizumab,and both lung lesion and brain metastases were stable for more than 3 mo.He had an overall survival of 25 mo.CONCLUSION Our case revealed that both afatinib and the osimertinib+bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833FL861Q compound mutation.The results provide more therapeutic options for patients with rare compound mutations.

CYFRA 21-1 as an early predictor of first line chemotherapy response in advanced non small cell lung cancer

Objective： In an era of ever evolving, promising new therapies for advanced non small cell lung cancer （NSCLC）, early predictors of response to therapy, are needed. We evaluated early variations in CYFRA 21-1 serum levels of patients with advanced NSCLC receiving first line chemotherapy and correlated the results with objective tumor response. Methods： 29 consecutive, previously untreated, patients of advanced non small cell lung cancer, with measurable disease on CT scan were evaluated. All patients were treated with conventional systemic chemotherapy, although the choice of chemotherapy was left to the discretion of the treating physicians. Serum samples were obtained immediately before the start of 1st and 2nd cycles of chemotherapy. CYFRA 21-1 was measured with an electrochemiluminescense immunoassay on an automatic analyzer （Elecsys 2000; Roche Diagnostics）. Response was evaluated using Response evaluation criteria in solid tumors （RECIST） criteria. Results： 10 patients had partial response, 9 patients had stable disease and 9 had progressive disease. None of the patients had complete response. 21/29 （72%） patients had an elevated baseline value of CYFRA 21-1.62% patients （18/29） had a decrease in CYFRA 21-1 after 1 cycle of chemotherapy. The average reduction in the 2nd reading was irrespective of whether baseline value was normal or not. The average reduction was statistically significant （P = 0.002; 95% CI, from 0.8369 to 3.49464; t test）. 8 out of 10 （80%） patients with partial response had a reduction in their 2nd reading of. CYFRA （P = 0.019; 95% CI, from 0.81965 to 7.20035; t test） which was significant. We also observed that 6/9 （66%） patients whose disease remains stable also had a decrease in their subsequent reading （P = 0.0106; 95% CI, from -0.44942 to 3.82720; t test）, though it was not significant statistically. Although 5 out of 9 （55%） patients, who had an increase in their CYFRA 21-1 level, had progressive disease, but it was not statistically significant （P = 0.537; 95% CI, from -1.20021 to 2.13354; ttest）. 14 out of 19 （73%） who either had partial response or had stable disease, had a reduction in their 2nd value of CYFRA 21-1 and was significant statistically （P = 0.004; 95% CI, from 0.74792 to 3.50208; t test）. We also observed that except for 1 patient, all patients who had a decrease of 42% or more in their subsequent CYFRA 21-1 level, were those who had either responded to chemotherapy or had stable disease （P = 0.001）, which was statistically significant. Conclusion： We can conclude that monitoring of serum marker CYFRA 21-1, early dudng first-line chemotherapy may be a useful prognostic tool for evaluation of early tumor response in patients with advanced NSCLC.

Effect of TCM Combined with Chemotherapy on Immune Function and Quality of Life of Patients with Non-small Cell Lung Cancer inStage Ⅲ-Ⅳ

Objective: To observe and compare the effect of traditional Chinese medicine (TCM) combined with chemotherapy (CT) on immune function and quality of life (QOL)of patients with non-small cell lung cancer (NSCLC) in stage Ⅲ-Ⅳ. Methods: One hundred cases with stage Ⅲ-Ⅳ NSCLC were randomly divided into two groups. The treated group (n=50) received CT combined with TCM, and the control group received CT alone. The percentage of T lymphocyte subset in peripheral blood and the change of natural killer (NK) cell count were observed after treatment. The QOL and tolerance of CT were also compared between the two groups after treatment. Results: In the treated group, CD3 cell count, CD4 cell count, CD4/ CDg ratio and NK cell activity were higher than those in control group, while CD8 cell count in the treated group was lower than that in the control group (P<0.05), and QOL and tolerance of CT in the treated group were also better (P<0.05). Conclusion: TCM combined with CT could raise the patients' ability in tolerating CT in stage Ⅲ-ⅣNSCLC.

Mechanism of lncRNA SNHG19 miR-299-5p MAPK6 signaling axis promoting metastasis of non-small cell lung cancer cells

Objective The aim of this study was to explore the mechanism behind lncRNA small nucleolar RNA host gene 19(lncRNA SNHG19)/microrNA-299-5P(miR-299-5p)/mitogen-activated protein kinase 6(MAPK6)signaling axis promoting metastasis of non-small cell lung cancer(NSCLC).Methods To analyze the abnormal expression of lncRNAs in NSCLC,50 surgically resected NSCLC and adjacent tissue samples were collected from August 2021 to August 2022.The mRNA expression levels of lncRNA SNHG19,Mir-299-5p,and MAPK6 were detected by qRT-PCR.The functions of lncRNA SNHG19,Mir-299-5p and MAPK6 were investigated by CCK-8,clone formation,EdU,scratch,Transwell western blotting(WB)and in vivo xenograft assay.RNA fluorescence in-situ hybridization(FISH),RNA pull-down,dual luciferase reporter,and RNA co-immunoprecipitation assays were used to explore the mechanism of action between lncRNA SNHG19,miR-299-5p,and MAPK6.Results High expression of lncRNA SNHG19 was correlated with poor prognosis,tumor size,lymph node metastasis,and TNM stage in NSCLC patients(P<0.05).Cell function experiments showed that lncRNA SNHG19 could improve the proliferation,clone formation,migration,and invasion ability of A549 cells both in vitro and in vivo(all P<0.05)and increased the relative expression levels of vimentin and MAPK6(P<0.05).The relative expression level of E-cadherin was decreased(P<0.05).lncRNA SNHG19 can interact with Mir-299-5p and regulate the expression level of MAPK6.Conclusion lncRNA SNHG19 is upregulated in NSCLC tissues and cells,and its high expression is associated with tumor progression and poor survival.Moreover,it can act as a molecular sponge for Mir-299-5p to regulate MAPK6 expression and promote the proliferation and metastasis of A549 cells.

Selective targeting p53^(WT) lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

OBJECTIVE To explored the potential of pharmacological stabilization and reactivation of p53 for targeted cancer therapies.METHODS The cytotoxicity of a potent Cyclophilin A(CypA)inhibitor HL001 was tasted against a panel of cancer cell lines.The genotypes and activation of p53 were compared with the cytotoxicity profile of HL001.Two-dimensional(2D)PAGE analysis was performed to investigate differentially expressed proteins that involves in the anti-proliferation effects of HL001.Pull-down and Co-IP were used to confirmed the new identified PPI between CypA and G3BP1 and orthotopic animal model of lung cancer was used to tested the anti-tumor activity of HL001 in vivo.RESULTS We identify a novel CypA small molecule inhibitor HL001 that induces non-small cell lung cancer(NSCLC)cell cycle arrest and apoptosis via restoring p53 expression.We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination.Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of reactive oxygen species and DNA damage by HL001 contribute to p53 stabilization.Surprisingly,HL001 selectively suppresses tumor growth in p53wildtype NSCLC harboring Arg72 homozygous alleles(p53-72R)through disrupting interaction between MDM2 and p53-72R in a CypA dependent manner.Moreover,combining HL001 with cisplatin synergistically enhance tumor regression in orthotopic NSCLC mouse model.CONCLUSION Pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.

淋巴细胞/单核细胞比值及其动态变化与PD-1抑制剂治疗晚期非小细胞肺癌的疗效分析

目的:探讨PD-1抑制剂治疗前外周血淋巴细胞和单核细胞比值(lymphocyte-to-monocytes ratios,LMR)及治疗后的动态变化与PD-1抑制剂治疗晚期非小细胞肺癌患者(non-small cell lung cancer,NSCLC)疗效及预后的关系。方法:回顾性分析芜湖市第二人民医院肿瘤内科、肿瘤放疗科及肿瘤介入科自2019年6月至2022年7月收治的83例晚期NSCLC患者的临床病例资料。收集所有患者治疗前及治疗后的血常规LMR数值,根据ROC曲线计算临界值,并将LMR分为治疗前和治疗后高低两组。分析比较各组患者的客观缓解率(ORR)、疾病控制率(DCR),以及无进展生存期(progression-free survival,PFS)、总生存期(overall survival,OS)的差异,分析LMR值及治疗后的动态变化对PD-1抑制剂治疗NSCLC患者疗效及预后的价值。结果:根据ROC曲线计算LMR临界值为1.8,将LMR分为基线低LMR组(LMRB/S<1.8)、高LMR组(LMRB/S≥1.8)及治疗后低LMR组(LMRafter<1.8)、治疗后高LMR组(LMR_(after)≥1.8)。治疗前高LMRB/S组免疫治疗后的ORR和DCR均高于低LMRB/S组(P=0.037;P=0.0025)。治疗前低LMRB/S患者中,在治疗后LMRafter≥1.8组的DCR优于LMR_(after)<1.8组(P=0.005)。治疗前高LMR患者中,治疗后LMR_(after)≥1.8组的DCR优于LMR_(after)<1.8组(P=0.034)。Kaplan-Meier分析显示,治疗前高LMRB/S组的PFS、OS均比低LMRB/S组延长;且在治疗前低LMRB/S组中,治疗后LMRafter≥1.8的患者PFS、OS均比LMR_(after)<1.8的患者延长(P=0.047;P=0.007)。多因素Cox回归模型分析显示,治疗前高LMRB/S值是影响NSCLC患者PFS和OS的独立危险因素(P=0.006;P=0.033)。结论:免疫治疗前患者高LMR值可能提高PD-1抑制剂的疗效,改善患者预后,延长生存时间;且治疗后LMR值的升高可能会增加治疗前低LMR患者的疗效,改善患者的预后。

Defining lung cancer stem cells exosomal payload of miRNAs in clinical perspective

Since the first publication regarding the existence of stem cells in cancer[cancer stem cells(CSCs)]in 1994,many studies have been published providing in-depth information about their biology and function.This research has paved the way in terms of appreciating the role of CSCs in tumour aggressiveness,progression,recurrence and resistance to cancer therapy.Targeting CSCs for cancer therapy has still not progressed to a sufficient degree,particularly in terms of exploring the mechanism of dynamic interconversion between CSCs and non-CSCs.Besides the CSC scenario,the problem of cancer dissemination has been analyzed indepth with the identification and isolation of microRNAs(miRs),which are now considered to be compelling molecular markers in the diagnosis and prognosis of tumours in general and specifically in patients with non-small cell lung cancer.Paracrine release of miRs via“exosomes”(small membrane vesicles(30-100 nm),the derivation of which lies in the luminal membranes of multi-vesicular bodies)released by fusion with the cell membrane is gaining popularity.Whether exosomes play a significant role in maintaining a dynamic equilibrium state between CSCs and non-CSCs and their mechanism of activity is as yet unknown.Future studies on CSC-related exosomes will provide new perspectives for precision-targeted treatment strategies.

A Matched Comparison Study of Uniportal Versus Triportal Thoracoscopic Lobectomy and Sublobectomy for Early-stage Nonsmall Cell Lung Cancer

Background： Both uniportal and triportal thoracoscopic lobectomy and sublobectomy are feasible for early-stage non-small cell lung cancer （NSCLC）. The aim of this study was to compare the perioperative outcomes of uniportal and triportal thoracoscopic Iobectomy and sublobectomy for early-stage NSCLC. Methods： A total of 405 patients with lung lesions underwent thoracoscopic lobectomy or sublobectomy through a uniportal or triportal procedure in approximately 7-month period （From November 2014 to May 2015）. A propensity-matched analysis, incorporating preoperative variables, was used to compare the short-term outcomes of patients who received uniportal or triportal thoracoscopic lobectomy and sublobectomy. Results： Fifty-eight patients underwent uniportal and 347 patients underwent triportal pulmonary resection. The conversion rate for uniportal and triportal procedure was 3.4% （2/58） and 2.3% （8/347）, respectively. The complication rate for uniportal and triportal procedure was 10.3% and 9.5%, respectively. There was no perioperative death in either group. Most patients had early-stage NSCLC in both groups （uniportal： 45/47, 96%; triportal： 313/343, 91%）. Propensity score-matching analysis demonstrated no significant differences in operation time, intraoperative blood loss, numbers of dissected lymph nodes, number of stations of lymph node dissected, duration of chest tube, and complication rate between uniportal and triportal group for early-stage NSCLC. However, the duration of postoperative hospitalization was longer in the uniportal group （6.83 ± 4.17 vs. 5.42 ± 1.86 d, P = 0.036） compared with the triportal group. Conclusions： Uniportal thoracoscopic lobectomy and sublobectomy is safe and feasible, with comparable short-term outcomes with triportal thoracoscopic pulmonary resection. Uniportal lobectomy and sublobectomy lead to similar cure rate as triportal Iobectomy and sublobectomy for early NSCLC.

Macrophage Inhibitory Cytokine-1 as a Novel Diagnostic and Prognostic Biomarker in Stage I and II Nonsmall Cell Lung Cancer

Background： Increased level of serum macrophage inhibitory cytokine- 1 （MIC- 1 ）, a member oftransfonning growth thctor-β superfamily, was found in patients with epithelial tumors. This study aimed to evaluate whether serum level of MIC-I can be a candidate diagnostic and prognostic indicator for early-stage nonsmall cell lung cancer （NSCLC）. Methods： A prospective study enrolled 152 patients with Stage I-II NSCLC, who were followed up after surgical resection. Forty-eight patients with benign pulmonary disease （BPD） and 105 healthy controls were also included in the study. Serum M IC- 1 levels were measured using an enzyme-linked immunosorbent assay, and the association with clinical and prognostic features was analyzed. Results： In patients with NSCLC, serum protein levels of M IC-I were significantly increased compared with healthy controls and BPD patients （all P 〈 0.001 ）. A threshold of 1000 pg/ml ofM IC-1 was found in patients with early-stage （Stage 1 and II） NSCLC, with sensitivity and specificity of 70.4% and 99.0%, respectively. The serum levels ofMIC- ] were associated with age （P = 0.001 ）, gender （P = 0.030）, and T stage （P = 0.022）. Serum MIC-1 threshold of 1465 pg/ml was found in patients with poor early outcome, with sensitivity and specificity of 72.2% and 66.1%, respectively. The overall 3-year survival rate of NSCLC patients with high serum levels of MIC-1 （〉I 465 pg/ml） was lower than that of NSCLC patients with low serum MIC-1 levels （77.6% vs. 94.8%）. Multivariate Cox regression survival analysis showed that a high serum level ofMIC- 1 was an independent risk factor lbr reduced overall survival （hazard ratio - 3.37, 95% confidential interval： 1.09-10.42, P = 0.035）. Conclusion： The present study suggested that serum M1C-I may be a potential diagnostic and prognostic biomarker ~cbr patients with early-stage NSCLC.

A Model Predicting Lymph Node Status for Patients with Clinical Stage TlaNO-2MO Nonsmall Cell Lung Cancer

Background： Lymph node status of patients with early-stage nonsmall cell lung cancer has an influence on the choice of surgery. To assess the lymph node status more correspondingly and accurately, we evaluated the relationship between the preoperative clinical variables and lymph node status and developed one model for predicting lymph node involvement. Methods： We collected clinical and dissected lymph node information of 474 patients with clinical stage TlaN0-2M0 nonsmall cell lung cancer （NSCLC）. Logistic regression analysis of clinical characteristics was used to estimate independent predictors of lymph node metastasis. The prediction model was validated by another group. Results： Eighty-two patients were diagnosed with positive lymph nodes （17.3%）, and four independent predictors of lymph node disease were identified： larger consolidation size （odds ratio [OR] = 2.356, 95% confidence interval [CI]： 1.517-3.658, P 〈 0.001）, central tumor location （OR = 2.810, 95% CI： 1.545-5.109, P = 0.001 ）, abnormal status of tumor marker （OR = 3.190, 95% CI： 1.797-5.661, P 〈 0.001 ）, and clinical N1-N2 stage （OR = 6.518, 95% CI： 3.242-11.697, P 〈 0.001）. The model showed good calibration （Hosmer-Lemeshow goodness-of-fit, P 〈 0.766） with an area under the receiver operating characteristics curve （AUC） of 0.842 （95% [CI]： 0.797-0.886）. For the validation group, the AUC was 0.810 （95% CI： 0.731-0.889）. Conclusions： The model can assess the lymph node status of patients with clinical stage TlaN0-2M0 NSCLC, enable surgeons perform an individualized prediction preoperatively, and assist the clinical decision-making procedure.

Inhibition of Nonsmall Cell Lung Cancer Cell Migration by Protein Arginine Methyltransferase 1-small Hairpin RNA Through Inhibiting Epithelial-mesenchymal Transition,Extracellular Matrix Degradation, and Src Phosphorylation In Vitro

Background：Protein arginine methyltransferases 1 （PRMT1） is over-expressed in a variety of cancers,including lung cancer,and is correlated with a poor prognosis of tumor development.This study aimed to investigate the role of PRMT1 in nonsmall cell lung cancer （NSCLC） migration in vitro.Methods：In this study,PRMT1 expression in the NSCLC cell line A549 was silenced using lentiviral vector-mediated short hairpin RNAs.Cell migration was measured using both scratch wound healing and transwell cell migration assays.The mRNA expression levels of matrix metalloproteinase 2 （MMP-2） and tissue inhibitor ofmetalloproteinase 1,2 （TIMP l,2） were measured using quantitative real-time reverse transcription-polymerase chain reaction.The expression levels of protein markers for epithelial-mesenchymal transition （EMT） （E-cadherin,N-cadherin）,focal adhesion kinase （FAK）,Src,AKT,and their corresponding phosphorylated states were detected by Western blot.Results：Cell migration was significantly inhibited in the PRMT1 silenced group compared to the control group.The mRNA expression of MMP-2 decreased while TIMP 1 and TIMP2 increased significantly.E-cadherin mRNA expression also increased while N-cadherin decreased.Only phosphorylated Src levels decreased in the silenced group while FAK or AKT remained unchanged.Conclusions：PRMT1-small hairpin RNA inhibits the migration abilities of NSCLC A549 cells by inhibiting EMT,extracellular matrix degradation,and Src phosphorylation in vitro.

Updates in the management of brain(leptomeningeal) metastasis of lung cancer

Brain(leptomeningeal) metastasis is one of the most common and severe complications of lung cancer. This article interprets expert consensus on the treatment advice for brain(leptomeningeal) metastasis of lung cancer, expounding on its epidemiology, diagnostic standards, efficacy assessment, treatment advice, and other aspects.

Evaluation of Three Small Molecular Drugs for Targeted Therapy to Treat Nonsmall Cell Lung Cancer

Objective： To guide the optimal selection among first-generation epidermal growth factor receptor-tyrosine kinase inhibitors （EGFR-TKIs） in clinical practice.This review attempted to provide a thorough comparison among three first-generation EGFR-TKIs, namely icotinib,erlotinib, and gefitinib, with regard to their molecular structure, pharmacokinetic parameters, clinical data, adverse reactions, and contraindications.Data Sources： An electronic literature search of the PubMed database and Google Scholar for all the available articles regarding gefitinib,icotinib, and erlotinib in the English language from January 2005 to December 2014 was used.Study Selection： The search terms or keywords included but not limited to ＆quot;lung cancer＆quot;, ＆quot;nonsmall cell lung cancer （NSCLC）＆quot;,＆quot;epidemiology＆quot;, ＆quot;EGFR＆quot;, ＆quot;TKIs＆quot;, and ＆quot;optimal selection＆quot;.Results： As suggested by this review, even though the three first-generation EGFR-TKIs share the quinazoline structure, erlotinib had the strongest apoptosis induction activity because of its use of a different side-chain.The pharmacokinetic parameters indicated that both erlotinib and icotinib are affected by food.The therapeutic window of erlotinib is narrow, and the recommended dosage is close to the maximum tolerable dosage.Icotinib enjoys a wider therapeutic window, and its concentration in the blood is within a safe dosage range even if it is administered with food.Based on multiple large-scale clinical trials, erlotinib is universally applied as the first-line treatment.In marked contrast, icotinib is available only in China as the second-or third-line therapeutic approach for treating advanced lung cancer.In addition, it exhibits a similar efficacy but better safety profile than gefitinib.Conclusions： Although there is a paucity of literature regarding whether icotinib is superior to erlotinib, its superior toxicity profile, noninferior efficacy, and lower cost indicate that it is a better alternative for Chinese patients living with advanced NSCLC.