Effect of superoxide dismutase on early radiation injury of lungs in the rat

Early responses of lungs to a single radiation dose of 30 Gy were marked by an inflammatory reaction and the onset of pneumonitis within 4 weeks following hemithorax radiation in the rat. Superoxide dismutase reduced the severity of radiation lesions in lungs.     

Serum interleukin-17 as a diagnostic and prognostic marker for non-small cell lung cancer

Abstract

Objective: The aim of this study was to explore the clinical role of serum interleukin (IL)-17 in patients with non-small-cell lung cancer (NSCLC).

Materials and method: Serum specimens from 128 patients with NSCLC and 60 healthy controls were collected. The concentrations of IL-17 were measured using enzyme-linked immunosorbent assay.

Results: Serum IL-17 levels were higher in the NSCLC group in comparison with the control group (p?<?0.01). With a cut-off value of 16?pg/ml, IL-17 showed a good diagnostic performance for NSCLC. Multivariate survival analysis indicated that IL-17 was an independent prognostic factor in NSCLC.

Conclusion: Measurement of IL-17 might be a useful diagnostic and prognostic value for patients with NSCLC.     

Finding biomarkers for non-small cell lung cancer diagnosis and prognosis

Despite of several decades of efforts,lung cancer remains one of most deadly diseases,with a 5-year survival rate approximately 15％ worldwide.In China,the situation is even worse.Although there is no o...     

Dosimetric accuracy of three dose calculation algorithms for radiation therapy of in situ non-small cell lung carcinoma

BackgroundStudy determines differences in calculated dose distributions for non-small cell lung carcinoma (NSC LC) patients. NSC LC cases were investigated, being the most common lung cancer treated by radiotherapy in our clinical practice.Materials and methodsA retrospective study of 15 NSCLC patient dose distributions originally calculated using standard superposition (SS) and recalculated using collapsed cone (CC ) and Monte Carlo (MC) based algorithm expressed as dose to medium in medium (MCD_m) and dose to water in medium (MCD_w,) was performed so that prescribed dose covers at least 99% of the gross target volume (GTV). Statistical analysis was performed for differences of conformity index (CI), heterogeneity index (HI), gradient index (GI), dose delivered to 2% of the volume (D_2%), mean dose (D_mean) and percentage of volumes covered by prescribed dose (V_70Gy). For organs at risk (OARs), D_mean and percentage of volume receiving 20 Gy and 5Gy (V_20Gy, V_5Gy) were analysed.ResultsStatistically significant difference for GTVs was observed between MCD_w and SS algorithm in mean dose only. For planning target volumes (PTVs), statistically significant differences were observed in prescribed dose coverage for CC, MCD_m and MCD_w. The differences in mean CI value for the CC algorithm and mean HI value for MCD_m and MCD_w were statistically significant. There is a statistically significant difference in the number of MUs for MCD_m and MCD_w compared to SS.ConclusionAll investigated algorithms succeed in managing the restrictive conditions of the clinical goals. This study shows the drawbacks of the CC algorithm compared to other algorithms used.     

MiRNA调控非小细胞肺癌转移的研究进展

微小RNA是内源性的非编码小RNA分子,通过与靶mRNA的结合在转录后水平调控基因的表达,从而参与众多生命活动的调控。NSCLC是严重威胁人类健康的恶性肿瘤,侵袭转移是其主要特征,也是其治疗失败和死亡的主要原因。miRNA可以通过促进上皮-间质转化、金属基质蛋白酶表达,以及血管生成来促进NSCLC转移,而且miRNA在调节肺癌干细胞特性中也发挥着重要作用。转移相关的miRNA已成为肺癌靶向治疗的新靶点。     

非小细胞肺癌靶向治疗的临床前研究进展

针对表皮生长因子受体（EGFR）和血管生成（angiogenesis）信号通路的靶向治疗已经在晚期非小细胞肺癌的治疗上取得成功,但由于抗药性的存在,大多数晚期患者的生存时间仍然提高有限。继发性的EGFR T790M突变和原癌基因肝细胞生长因子受体（MET）的扩增被鉴定为两种主要的抗药机制。最近转化生长因子-β（TGF-β）/白介素-6信号通路被报道能介导选择性和适应性地对erlotinib的抗药。另一方面,Kras突变所致肺癌的靶向治疗方面也取得了一些进展。双重抑制磷脂酰肌醇3-激酶（PI3K）和促分裂素原活化蛋白激酶激酶（MEK）信号通路可导致Kras突变肿瘤的显著消退,联合抑制SRC、PI3K和MEK可使丝氨酸/苏氨酸蛋白激酶11（Lkb1）缺失,Kras突变的肺癌小鼠的肿瘤明显消退,抑制核因子-κB（NF-κB）信号通路导致p53缺失,Kras突变的肿瘤发展显著减慢。这些发现都为发展非小细胞肺癌患者的靶向治疗提供了有力的支持。     

Target volume definition for staple line recurrences of non-small cell lung cancer

BackgroundStaple line (SL) recurrences of non-small cell lung cancer (NSCLC) are commonly treated with radiotherapy (RT), but the target volume definition — whole SL versus focused on recurrence — is unclear. The aim of the study was to determine the appropriate target volume for RT of SL recurrences.Materials and methodsTwenty-two consecutive patients (20 stage I, 2 stage II) treated with salvage RT for SL recurrences were retrospectively analyzed. Imaging features at the time of SL recurrence were evaluated to guide target volume definition.ResultsSurgeryAll patients had complete tumor resection (wedge resection in 10 (45%) and lobectomy in 12 (55%) patients). 14 (64%) patients had risk factors for recurrence, including surgical margins ≤ 2 cm, angiolymphatic and visceral pleural invasion.Salvage RTAfter a median 26 months (9–67), all 22 patients developed SL recurrence which was metabolically active on PET in all and biopsy-confirmed in 18/22 (82%) patients. All patients underwent RT targeting the location of the SL recurrence only. 13/22 (59%) patients had additional PE T-negative nodular or linear SL changes that were not included in the irradiated volume.Recurrence after RTAfter a median 17 months (9–34) 10/22 (45%) patients recurred either regionally 6/10 (60%), in the lungs 4/10 (40%) or distally 3/10 (30%). No patient recurred at the SL. Two-year overall and disease-free survival rates after RT were 71% and 65%, respectively.ConclusionRT to SL recurrences alone results in excellent local control. Additional treatment to reduce regional and distant recurrences should be considered.     

非小细胞肺癌患者肠道微生物特征分析

[目的]分析非小细胞肺癌患者与肺部良性病变患者肠道微生物的构成差异,探究特异肠道菌群对非小细胞肺癌发生发展的影响.[方法]收集63例患者粪便样本,非小细胞肺癌患者39例,其中肺腺癌(ADC) 32例,肺鳞癌(SCC)7例,肺部良性病变患者24例,进行16S rDNA测序.[结果]毛螺菌属(Lachnospira)、瘤胃...     

自噬通路基因多态性与晚期非小细胞肺癌含铂化疗疗效的相关性分析

对晚期非小细胞肺癌患者采用含铂化疗是肺癌临床治疗中非常重要的方法,然而不同患者对含铂化疗的敏感性却存在着明显的个体差异,这提示发现潜在的分子标志物对预测临床中含铂化疗疗效具有关键作用。本研究旨在探索自噬通路基因多态性与晚期非小细胞肺癌含铂化疗疗效之间的相关性,以期寻找可能影响含铂化疗药物敏感性的分子标记。本研究纳入了1004例接受含铂化疗的晚期非小细胞肺癌患者,分析了自噬通路中13个基因上的99个SNP位点与含铂化疗临床获益、无疾病进展时间及总生存时间之间的相关性。研究发现,位于ULK1基因的位点rs7953348(G>A) (P=0.017, OR:0.67, 95%CI:0.49~0.93)和rs12303764(A>C) (P=0.009, OR:0.63, 95%CI:0.45-0.89)及位于ATG14基因上的位点rs17742719(C>A) (P=0.002, OR:1.83, 95%CI:1.26~2.66)、rs8003279(A>G) (P=0.006, OR:1.65, 95%CI:1.16~2.35)和rs1009647(G>A) (P=0.002, OR:1.70, 95%CI:1.22~2.37)与临床获益存在显著关联,位于DRAM基因上的位点rs7955890(G>A) (P=0.004, HR:0.63; 95%CI:0.46~0.86)和rs17032060(G>A) (P=0.006, HR:0.65, 95%CI:0.48~0.88)及位于ATG3基因上的位点rs13082005(G>A) (P=0.012, HR:1.27,95%CI:1.05~1.53)与含铂化疗的无疾病进展时间显著相关,位于ULK1基因的位点rs7953348(G>A) (P=0.011, HR:0.74, 95%CI:0.58~0.93)和位于ATG10基因上的位点rs1864183(G>A) (P=0.016, HR:0.42, 95%CI:0.21~0.85)对含铂化疗的总生存时间有着显著影响。研究结果提示自噬通路在含铂化疗敏感性中发挥着重要作用,自噬通路基因多态性可能是预测含铂化疗疗效的潜在分子标志物,这可能为临床上肺癌的个体化医疗提供一定的理论基础。     

Elevated exhalation of hydrogen peroxide in patients with non-small cell lung cancer is not affected by chemotherapy

Objectives: Reactive oxygen species, which are implicated in the process of carcinogenesis, are also responsible for cell death during chemotherapy (CHT). Therefore, the aim of the study was to evaluate exhaled H₂O₂ levels in non-small cell lung cancer (NSCLC) patients before and after CHT.

Methods: Thirty patients (age 61.3?±?9.3 years) with advanced NSCLC (stage IIIB–IV) and 15 age-matched healthy cigarette smokers were enrolled into the study. Patients received four cycles of cisplatin or carboplatin with vinorelbine every three weeks. Before and after the first, second, and fourth cycle, the concentration of H₂O₂ in exhaled breath condensate was measured with respect to treatment response.

Results: At the baseline, NSCLC patients exhaled 3.8 times more H₂O₂ than the control group (0.49?±?0.14 vs. 0.13?±?0.03?µmol/L, P?2O₂ levels independent of the treatment response (partial remission vs. progressive disease). Pre- and post-CHT cycles of H₂O₂ levels generally correlated positively.

Discussion: The study demonstrated the occurrence of oxidative stress in the airways of advanced NSCLC patients. Exhaled H₂O₂ level was not affected by CHT and independent of treatment results and changes in the number of circulating neutrophils.     

Lymphokine-activated killer cell susceptibility in epirubicin-resistant and parental human non-small cell lung cancer (NSCLC)

The aim of this study was to evaluate that: (i) epirubicin-HCl (EPI) and lymphokine-activated killer (LAK) cells cytotoxicity may be mediated by free radical generation; and (ii) resistant H1299 cells may be more sensitive to combined treatment of LAK cells plus EPI than the LAK or EPI treatment alone. Viability of H1299 cells treated with EPI, LAK and LAK plus EPI was measured using the MTT test. Amount of glutathione (GSH), protein content and enzymatic activity were measured by spectrophotometer. Glutathione S-transferase (GST)-pi expression in the cells was determined by western blot analysis. LAK plus EPI combined treatment increased susceptibility of H1299 WT and H1299 EPI(R) (300-fold EPI resistant) cells to LAK cell cytotoxicity. The resistance of H1299 EPI(R) cells to EPI appears to be associated with a developed tolerance to free radicals, most likely because of a 2-fold increase in NADPH-dependent-cytochrome-P450 reductase (NADPH-CYP reductase) activity, 11-fold GST activity and 11-and 7-fold augmented selenium dependent and independent glutathione peroxidase (GSH-Px) activity, respectively. Amount of GST-pi in H1299 EPI(R) cells is statistically different from negative control and H1299 WT (p < 0.01). It is proposed that production of reactive oxygen species and hydrogen peroxide by the treatment of EPI and LAK cells can cause cytotoxicity of H1299 WT and H1299 EPI(R) cells. Superoxide dismutase, catalase, GSH-Px, GST, NADPH-CYP reductase and GSH must be considered as part of the intracellular antioxidant defense mechanism of H1299 WT and H1299 EPI(R) cells against reactive oxygen species. Combined treatment of EPI plus LAK cells caused the increasing cytotoxicity on the H1299 EPI(R) cells.     

Inhibition of cell growth by overexpression of manganese superoxide dismutase (MnSOD) in human pancreatic carcinoma

Manganese superoxide dismutase (MnSOD) levels have been found to be low in human pancreatic cancer [Pancreas26, (2003), 23] and human pancreatic cancer cell lines [Cancer Res.63, (2003), 1297] when compared to normal human pancreas. We hypothesized that stable overexpression of pancreatic cancer cells with MnSOD cDNA would alter the malignant phenotype. MIA PaCa-2 cells were stably transfected with a pcDNA3 plasmid containing sense human MnSOD cDNA or containing no MnSOD insert by using the lipofectAMINE method. G418-resistant colonies were isolated, grown and maintained. Overexpression of MnSOD was confirmed in two selected clones with a 2-4-fold increase in MnSOD immunoreactive protein. Compared with the parental and neo control cells, the MnSOD-overexpressing clones had decreased growth rates, growth in soft agar and plating efficiency in vitro, while in vivo, the MnSOD-overexpressing clones had slower growth in nude mice. These results suggest that MnSOD may be a tumor suppressor gene in human pancreatic cancer.     

Methylation of TMEFF2 gene in tissue and serum DNA from patients with non-small cell lung cancer

Lung cancer remains a global health problem with a high mortality rate. CpG island methylation is a common aberration frequently associated with gene silencing in multiple tumor types, emerging as a highly promising biomarker. The transmembrane protein with a single EGF-like and two follistatin domains (TMEFF2) is epigenetically silenced in numerous tumor types, suggesting a potential role as a potential tumor suppressor. However, the role of TMEFF2 in lung cancer remains to be fully elucidated. We explored the methylation status of TMEFF2 gene in 139 patients with non-small cell lung cancer (NSCLC) and the feasibility of detecting circulating methylated DNA as a screening tool for NSCLC using methylation-specific PCR in 316 patients and 50 age-matched health controls. TMEFF2 methylation in tumor tissues was found in 73 of the 139 NSCLCs (52.5%) and was related to gene expression. The frequency of TMEFF2 methylation was higher in females and never-smokers than in males and smokers with borderline significance (65.8% vs 47.8%, p = 0.06; 65.7% vs 48.1%, p = 0.07). Notably, in adenocarcinomas, TMEFF2 methylation was significantly more frequent in tumors without EGFR mutation than those with EGFR mutation (adjusted odds ratio = 7.13, 95% confidence interval = 2.05-24.83, P = 0.002). Furthermore, TMEFF2 methylation was exclusively detected in the serum of NSCLC patients at a frequency of 9.2% (29/316). These findings suggest that methylation-associated down-regulation of TMEFF2 gene may be involved in lung tumorigenesis and TMEFF2 methylation can serve as a specific blood-based biomarker for NSCLC.     

Peroxiredoxin-I is an autoimmunogenic tumor antigen in non-small cell lung cancer

In eukaryotic cells, peroxiredoxins are both antioxidants and regulators of H(2)O(2)-mediated signaling. We previously found that peroxiredoxin-I (Prx-I) was overexpressed in non-small cell lung cancer (NSCLC) tissue. Since overexpressed protein can induce a humoral immune response, we examined whether serum from NSCLC patients exhibited immunoreactivity against Prx-I using Western blotting. We found that 25 (47%) of 53 NSCLC patients tested had autoantibodies against Prx-I in their sera, whereas such activity was detected in 4 (8%) sera from 50 healthy subjects. Prx-I itself was detected in the sera from 18 (34%) of 53 NSCLC patients but in only 1 (2%) serum from 50 controls. Moreover, 17% of NSCLC sera were positive to both Prx-I antibody and antigen but none in control sera. The data indicate both Prx-I autoantibody and circulating antigen are potential biomarkers for use in serological diagnosis of NSCLC. Interestingly enough, we found that Prx-I was secreted by lung adenocarcinoma cells (A549) but not by non-cancer lung cells (BEAS 2B) or breast cancer cells (MCF7). This cell culture study suggests the possibility of Prx-I secretion from NSCLC tumor tissues.     

Knockdown of LncRNAZFAS1 suppresses cell proliferation and metastasis in non-small cell lung cancer

ABSTRACT

To evaluate the effects of LncRNAZFAS1 on cell proliferation and tumor metastasis in non-small cell lung cancer (NSCLC), we detected the expression level of LncRNAZFAS1 in NSCLC-related tissues and cells. qRT-PCR results revealed that LncRNAZFAS1 in tumor tissues was significantly higher than that in normal lung tissue, especially significantly up-regulated in stage III / IV and in metastatic NSCLC tissues. LncRNAZFAS1 expression was dramatically up-regulated in 4 NSCLC-related cells (A549, SPC-A1, SK-MES-1, and NCI-H1299), with having the highest expression level in A549 cells. Furthermore, we implemented a knockdown of LncRNAZFAS1 in A549 cells, and the results of CCK8 and Transwell assays suggested that knockdown of LncRNAZFAS1 significantly inhibited NSCLC cell proliferation and metastasis. Next, we constructed a tumor xenograft model to evaluate the effect of LncRNAZFAS1 on the NSCLC cell proliferation in vivo. The results indicated that knockdown of LncRNAZFAS1 dramatically inhibited A549 cells proliferation and repressed tumor growth. Additionally, knockdown of LncRNAZFAS1 drastically weakened the expressions of MMP2, MMP9 and Bcl-2 proteins, whereas noticeably strengthened the expression of BAX protein. Our results altogether suggest that knockdown of LncRNAZFAS1 has a negative effect on the proliferation and metastasis of NSCLC cell, which implying LncRNAZFAS1 is a potential unfavorable biomarker in patients with NSCLC.     

MiR-491在非小细胞肺癌发生发展过程中的作用机制研究

人类miR-491 (has-miR-491)是一段长度为84 bp的微小RNA,可以通过与靶mRNA的3'端非翻译区(3'-untranslated region,3'-UTR)结合,降解靶mRNA或抑制其翻译,在转录后水平对肿瘤细胞基因表达进行调控,影响肿瘤发展进程.非小细胞肺癌(non-small lang ca...     

Orally active microtubule-targeting agent,MPT0B271, for the treatment of human non-small cell lung cancer,alone and in combination with erlotinib

Microtubule-binding agents, such as taxanes and vinca alkaloids, are used in the treatment of cancer. The limitations of these treatments, such as resistance to therapy and the need for intravenous administration, have encouraged the development of new agents. MPT0B271 (N-[1-(4-Methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-1-oxy-isonicotinamide), an orally active microtubule-targeting agent, is a completely synthetic compound that possesses potent anticancer effects in vitro and in vivo. Tubulin polymerization assay and immunofluorescence experiment showed that MPT0B271 caused depolymerization of tubulin at both molecular and cellular levels. MPT0B271 reduced cell growth and viability at nanomolar concentrations in numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES. Further studies indicated that MPT0B271 is not a substrate of P-glycoprotein (P-gp), as determined by flow cytometric analysis of rhodamine-123 (Rh-123) dye efflux and the calcein acetoxymethyl ester (calcein AM) assay. MPT0B271 also caused G2/M cell-cycle arrest, accompanied by the up-regulation of cyclin B1, p-Thr161 Cdc2/p34, serine/threonine kinases polo-like kinase 1, aurora kinase A and B and the downregulation of Cdc25C and p-Tyr15 Cdc2/p34 protein levels. The appearance of MPM2 and the nuclear translocation of cyclin B1 denoted M phase arrest in MPT0B271-treated cells. Moreover, MPT0B271 induced cell apoptosis in a concentration-dependent manner; it also reduced the expression of Bcl-2, Bcl-xL, and Mcl-1 and increased the cleavage of caspase-3 and -7 and poly (ADP-ribose) polymerase (PARP). Finally, this study demonstrated that MPT0B271 in combination with erlotinib significantly inhibits the growth of the human non-small cell lung cancer A549 cells as compared with erlotinib treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new tubulin-binding compound for the treatment of various cancers.     

Resveratrol alters microRNA expression profiles in A549 human non-small cell lung cancer cells

Resveratrol is a plant phenolic phytoalexin that has been reported to have antitumor properties in several types of cancers. In particular, several studies have suggested that resveratrol exerts antiproliferative effects against A549 human non-small cell lung cancer cells; however, its mechanism of action remains incompletely understood. Deregulation of microRNAs (miRNAs), a class of small, noncoding, regulatory RNA molecules involved in gene expression, is strongly correlated with lung cancer. In this study, we demonstrated that resveratrol treatment altered miRNA expression in A549 cells. Using microarray analysis, we identified 71 miRNAs exhibiting greater than 2-fold expression changes in resveratrol-treated cells relative to their expression levels in untreated cells. Furthermore, we identified target genes related to apoptosis, cell cycle regulation, cell proliferation, and differentiation using a miRNA target-prediction program. In conclusion, our data demonstrate that resveratrol induces considerable changes in the miRNA expression profiles of A549 cells, suggesting a novel approach for studying the anticancer mechanisms of resveratrol.