Integrated Multiomics Analyses Revealing Different Molecular Profiles Between Early- and Late-Stage Lung Adenocarcinoma.

The molecular differences in genetic and epigenetic profiling between early-stage (ES) and late-stage (LS) lung adenocarcinoma (LUAD), which might help to understand cancer progression and biomarker guided precision treatment, need further be investigated. In this study, we performed comprehensive analysis using multi-omics next-generation sequencing (NGS) on tissue samples from 7 ES (stage I) and 10 LS (stage III/IV) LUAD patients to study molecular characteristics between the two groups. Characterization of the genomic and transcriptomic profiles showed stage-specific somatic mutations, copy number variations (CNVs) and differentially expressed genes (DEGs). LS samples tend to have more TP53, ERBB2 and CHD4 mutations. Gene copy number loss occurs in immune-related gene pathways in the late stage of LUAD. ATAC-seq analysis showed that LS samples harbored more open chromatin peaks around promoter regions and transcription start sites (TSS) than ES samples. We then identified the known transcription factor (TF) binding motifs for the differentially abundant ATAC-seq peaks between the ES and LS samples and found distinct regulatory mechanisms related to each stage. Furthermore, integrative analysis of ATAC-seq with WGS and RNA-seq data showed that the degree of chromatin accessibility is related to copy number changes, and the open chromatin regions could directly regulate the expression of some DEGs. In conclusion, we performed a comprehensive multi-omics analysis of the early and late stages of LUAD and highlighted some important molecular differences in regulatory mechanisms during cancer progression. Those findings help to further understand mechanism and biomarker related targeted therapy.

Perioperative management of a morbidly obese patient undergoing right upper lobectomy with poor pulmonary function: a case report.

The incidence and prevalence of obesity is drastically increasing worldwide. Clinical surgeons treating cancer patients often encounter obese patients. However, cases of surgical lung cancer patients with morbid obesity and poor pulmonary function undergoing lobectomy have not been reported. A 75-year-old woman was referred to our hospital on June 25, 2014 with a cough with blood in phlegm for 1 week. Staging positron emission tomography revealed an abnormal lesion indicating malignancy under the pleura of the upper lobe of the right lung. As the patient had chronic obstructive pulmonary disease (COPD) and was morbidly obese [body mass index (BMI): 40.1 kg/m2], she had preoperative poor pulmonary function with a forced expiratory volume in 1s (FEV1) of 1.06l and diffusing lung capacity for carbon monoxide of 52.2. After 2 weeks of rehabilitation and treatment, respiratory function improved before surgery. The patient required thoracotomy so that right upper lobectomy with lymph node dissection under general anesthesia could be performed. However, on postoperative day 3, the patient was diagnosed with postoperative severe pneumonia with respiratory failure and cardiac insufficiency, and was transferred to the intensive care unit (ICU). After 72 postoperative days, the patient was discharged from hospital. The pathological diagnosis was invasive adenocarcinoma. Although the patient experienced severe postoperative complications, this case is useful for surgeons treating cancer patients because there are few reports discussing the perioperative management of morbidly obese patients with poor pulmonary function undergoing lung cancer radical resection. Further studies on lobectomy for morbidly obese lung cancer patients with poor pulmonary function are warranted to improve the treatment methods of these patients.

The distribution of refraction by age and gender in a non-myopic Chinese children population aged 6-12 years.

BACKGROUND: The Prevalence of myopia is increasing in China. This study aimed to explore the distribution of spherical equivalent (SE) and its association with age, body mass index (BMI), gender in a non-myopic Chinese children population aged 6 to 12 years. METHODS: A total of 6362 students were recruited for ophthalmological investigation. Demographic and myopia related behavioral information was collected. SE value was measured by the Topcon RM-8900 or KR-800autorefractors. Potential independent risk factors were determined with Odds Ratio (OR) and 95% Confidence Interval (CI) by logistic regression analysis. We further constructed the nomogram model to predict future onset of myopia. RESULTS: Among the study population, 3900 (61.3%) were non-myopic. The prevalence of myopia is 38.0% for boys and 39.5% for girls. The average SE values were 0.50 ± 0.70 D for boys and 0.60 ± 0.80 D for girls. The mean SE values decreased with age, and the value of height and BMI took on a stable trend. Threshold values for myopia varied across age groups and gender. Paternal myopia (OR: 1.22, 95%CI: 1.01-1.48), near-work activities on weekends (2.56, 1.17-5.61), and outdoor activities (0.68, 0.54-0.86) were associated with potential myopic in students. CONCLUSION: A series of age-gender based SE threshold values were established to predict myopia in Chinese children aged 6 to 12 years. High risk factors for myopia included paternal myopia, near-work activities on weekends, and outdoor activities. Countermeasures are encouraged to reverse the increasing trend of myopia in children.

Genomic characteristics in Chinese non-small cell lung cancer patients and its value in prediction of postoperative prognosis.

BACKGROUND: The genomic profile of non-small cell lung cancer (NSCLC) in Asians is distinct from that of Caucasians, but comprehensive genetic profiling reports have been limited for Asian patients. We aimed to elucidate genomic characteristics of Chinese NSCLC patients and develop potential model including genomic characteristics to predict postoperative prognosis. METHODS: Resected tumor samples from 511 patients with stage I-IV lung cancer were subjected to targeted sequencing using a panel of 295 cancer-related genes. Based on the molecular profiles and clinical features, we established nomogram models with predictors consisting of integrated clinical and genomic characteristics to provide post-operative risk stratification. RESULTS: Compared to the TCGA population (mainly Caucasians), there was a significantly higher frequency of EGFR (53.7% vs. 14.4%) and NOTCH3 (8.4% vs. 1.3%) mutations and less mutated KRAS (11.0% vs. 32.6%), KEAP1 (4.4% vs. 17.4%) and LRP1B (16.3% vs. 29.6%) in Chinese lung adenocarcinomas (LUAD). Distinct patterns of mutually exclusive and co-occurring mutations were identified between LUAD and lung squamous cell carcinoma (LUSC), indicating the unique histology-specific tumorigenesis mechanism of each subtype. We observed alterations in pathways correlated with clinical characteristics. Additionally, we constructed nomogram model with predictors consisting of clinical and genomic characteristics, which were more accurate than models with clinical characteristics or TNM staging only both in stage I-IIIA patients and T1-2N0M0 sub-cohort. CONCLUSIONS: This study revealed Chinese NSCLC patients have unique genomic profile. Furthermore, the nomogram model combining clinical features with genomic characteristics could improve risk stratification in early-stage NSCLC.

Epidemiological characteristics of elevated blood pressure among middle and high school students aged 12-17 years: a cross-sectional study in Jiangsu Province, China, 2017-2018.

OBJECTIVE: In this study, we aimed to present the epidemiological characteristics of elevated blood pressure among middle and high school students aged 12-17 years in Jiangsu Province. SETTING: Hypertension, which is considered a rare disease in children, is an important early precursor to long-term cardiovascular damage, and elevated blood pressure in childhood is a strong predictor of hypertension in adulthood. PARTICIPANTS: Physical examination and questionnaire investigation among children aged 12-17 years in Jiangsu Province were conducted from 2017 to 2018. MAIN OUTCOME MEASURES: Physical measurements included height, weight, blood pressure and history of menarche/first spermatorrhoea. Questionnaire investigation included family type, delivery mode, lifestyle habits and psychological test. RESULTS: In our study we investigated 17 791 middle and high school students, consisting of 8701 female students and 9090 male students. The prevalence of screening elevated blood pressure among students aged 12-17 years was 20.0% (95% CI 19.2% to 20.9%) for female students and 22.3% (95% CI 21.5% to 23.2%) for male students. The prevalence of screening elevated blood pressure for urban male middle and high school students was higher than that of elevated blood pressure for rural male middle and high school students. However, similar phenomenon cannot be observed among female students. For both male and female students, body mass index (BMI), obesity/overweight and menarche/first spermatorrhoea can be a risk factor contributing to elevated blood pressure, and sleep time and regional distribution might be important factors that need to be investigated in depth. CONCLUSION: We found a relatively high prevalence of screening elevated blood pressure among students aged 12-17 years for both female and male students in Jiangsu Province. The risk factors can be BMI, obesity/overweight and menarche/first spermatorrhoea.

Circulating tumor DNA detection is correlated to histologic types in patients with early-stage non-small-cell lung cancer.

OBJECTIVES: Circulating tumor DNA (ctDNA) testing in plasma in patients with non-small-cell lung cancer (NSCLC) has the potential to be a supplemental or surrogate tool for tissue biopsy. Detection of genomic abnormalities in ctDNA and their association with clinical characteristics in early-stage NSCLC need to be clarified. MATERIALS AND METHODS: Here, we comprehensively analyzed gene variations of 48 tumor tissues and 48 matched preoperative (pre-op) plasma and 25 postoperative (post-op) plasma from early-stage NSCLC patients using a targeted 546 genes capture-based next generation sequencing (NGS) assay. RESULTS: In early-stage NSCLC, the average mutation allele frequency (MAF) in pre-op plasma ctDNA was lower than that in tissue DNA (tDNA). The concordant gene variations between pre-op ctDNA and tDNA were difficult to detect. However, we found the tissue- pre-op plasma concordant ctDNA mutation detection ratio in lung squamous cell carcinoma (LUSC) was much higher than that in lung adenocarcinoma (LUAD). We also established a LUSC-LUAD classification model by a least absolute shrinkage and selection operator (LASSO) based approach to help separate LUAD from LUSC based on ctDNA profiling. This model included 14 gene mutations and extracted an accuracy of 89.2% in the training set and 91.5% in the testing set. Correlation analysis showed tDNA-ctDNA concordant ratio was related to histologic subtype, gene mutations and tumor size in early-stage NSCLC. CONCLUSION: This study suggests histology subtype and gene mutations could affect ctDNA detection in early-stage NSCLC. NGS-based ctDNA profile has the potential utility in LUSC-LUAD classification.

Driving anger among motor vehicle drivers in China: A cross-sectional survey.

Objective: Driving anger is a common emotion while driving and has been associated with traffic crashes. This study aimed to investigate situations that increase driving anger among Chinese drivers. Methods: A cross-sectional study was conducted among 3,101 drivers in southern China. The translated version of the 33-item Driving Anger Scale (DAS) was used to measure driving anger. Data were collected by face-to-face interviews between June 2016 and September 2016. Results: Confirmatory factor analysis showed that the fit of the original 6-factor model (discourtesy, traffic obstacles, hostile gestures, slow driving, illegal driving, and police presence) was satisfactory, after removing 2 items and allowing 5 error pairs to covary. The model showed satisfactory fit: goodness of fit index (GFI) = 0.90, incremental fit index (IFI) = 0.90, root mean square error of approximation (RMSEA) = 0.06, 90% confidence interval (CI) = 0.061-0.064. Driving anger among Chinese drivers was lower than that in some Western countries. Compared to older and experienced drivers, younger and new drivers were more likely to report driving anger. There was no difference in total reported driving anger between males and females. Additionally, the higher the driver's anger level was, the more likely he or she was to have had a traffic crash. Conclusion: Driving anger is a common emotion among Chinese drivers and has a strong correlation with aggressive driving behavior and traffic crashes.

TPP1 OB-fold domain protein suppresses cell proliferation and induces cell apoptosis by inhibiting telomerase recruitment to telomeres in human lung cancer cells.

PURPOSE: Maintaining telomeres by recruiting telomerase-to-chromosome ends is essential for cancer cell survival. Inhibiting telomerase recruitment to telomeres represents a novel strategy for telomere-based lung cancer therapy. However, approaches for interrupting telomerase recruitment for cancer therapy still need to be explored. METHODS: The telomere-binding protein TPP1 is responsible for recruiting telomerase to telomeres and synthesizing telomeres through the association between the oligosaccharide/oligonucleotide-binding (OB)-fold domain of TPP1 and telomerase reverse transcriptase. We overexpressed the TPP1 OB domain (TPP1-OB) by lentivirus infection in lung cancer cells. Telomere length was examined by Southern blot analysis of terminal restriction fragments. The effects of TPP1-OB on cell proliferation, the cell cycle, apoptosis, chemosensitivity, and tumor growth were evaluated in vitro and in vivo. RESULT: TPP1-OB inhibited the recruitment of telomerase to telomeres and shortened telomere length by acting as a dominant-negative mutant of TPP1. TPP1-OB resulted in reduced cell proliferation, G1 cell cycle arrest, and increased cell apoptosis in lung cancer cells. Cell apoptosis occurred mainly through the caspase-3-dependent signaling pathway. TPP1-OB also suppressed anchorage-independent growth and tumor growth in vivo. Moreover, we demonstrated that TPP1-OB enhances the sensitivity of lung cancer cells to the chemotherapeutic drug paclitaxel. CONCLUSION: Our results suggest that inhibiting TPP1-mediated telomerase recruitment by expressing the TPP1-OB domain is a potential novel strategy for telomere-targeted lung cancer therapy.

Preoperative albumin-to-globulin ratio predicts survival in patients with non-small-cell lung cancer after surgery.

The prognostic value of the preoperative albumin-to-globulin ratio (AGR) has not been investigated in non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the clinical applicability of the preoperative AGR to predict the prognosis in patients with NSCLC. We retrospectively enrolled 545 patients with stage I/II/III NSCLC who underwent surgery at our institution. The cutoff value for preoperative AGR was calculated by using a receiver operating characteristic curve analysis. A low AGR was associated with several clinicopathological variables related to tumor progression. In the multivariate analyses, the preoperative AGR was identified as an independent prognostic factor for disease-free survival (DFS; P = 0.003) and overall survival (OS; P = 0.005). For patients with stage II and III with a preoperative AGR ≤ 1.43, the surgery plus chemotherapy group had a significantly longer DFS and OS than the surgery alone group (P = 0.002 and P = 0.001, respectively); however, a significant difference in DFS and OS between these two groups was not observed in patients with stage II and III with an AGR > 1.43 (P = 0.808 and P = 0.842, respectively). The preoperative AGR is an independent, significant predictor of DFS and OS in patients with NSCLC. Our results also demonstrate that the preoperative AGR might be a predictive marker of the therapeutic effect of postoperative chemotherapy in patients with stage II and III NSCLC.

Prevalence of overweight and obesity among primary school-aged children in Jiangsu Province, China, 2014-2017.

BACKGROUND: Data was limited on prevalence of overweight and obesity among primary school-aged children in Jiangsu Province. We aimed to present the current situation of obesity in Jiangsu Province and explore the relationship between obesity and other common diseases in children. METHODS: Physical examination among children aged 7 to 14 years in Jiangsu Province was conducted since 2014, and more than one third primary schools were covered annually. The physical measurements included body height, weight, blood pressure, vision, sex, age, and so on. RESULTS: The prevalence of overweight and obesity among primary school children was 15.2% (18.7% for male students and 11.0% for female students), and 11.7% (14.5% for male students and 8.2% for female students) respectively. Obesity/overweight prevalence varied by regions. Among them the lowest prevalence was found in the southern region of Jiangsu Province, where residents had the highest average income level. Obesity group had elevated blood pressure comparing with the normal group, and obesity group especially in the male children aged 7 to 12 years had a higher prevalence of uncorrected visual acuity (UCVA) than that of normal group. CONCLUSION: This study found that obesity/overweight prevalence differed by sex, age, and regions in Jiangsu Province. In addition, obese children were closely associated with other common disease. Further studies are needed to explore the basis of biological and statistical theories.

A novel long non-coding RNATCONS_00001798 is downregulated and predicts survival in patients with non-small cell lung cancer.

The morbidity and mortality rates of patients with non-small cell lung cancer (NSCLC) are increasing worldwide. Previous studies have demonstrated that long non-coding RNAs (lncRNAs) may serve critical roles in oncogenesis and cancer progression. The present study aimed to investigate the expression of lncRNA TCONS_00001798 and the clinicopathological factors and prognosis of patients with NSCLC. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of TCONS_00001798 in 118 paired NSCLC and adjacent non-tumor tissues. The association between TCONS_00001798 expression and patient clinicopathological factors and survival rates was subsequently analyzed. The results demonstrated that the expression of TCONS_00001798 was significantly downregulated in NSCLC tissues compared with adjacent non-tumor tissues (P<0.001). Additionally, the expression of TCONS_00001798 was negatively associated with lymph node metastasis (P<0.001) and an advanced pathological stage (P=0.003). A Kaplan-Meier analysis demonstrated that decreased TCONS_00001798 expression was significantly associated with shorter overall survival (OS) and disease-free survival (DFS) rates (each P<0.001). Furthermore, the results of multivariate analyses revealed that TCONS_00001798 expression may serve as an independent predictor for OS and DFS rates (each P=0.001). Therefore, the present study demonstrated that TCONS_00001798 may be involved in the oncogenesis and progression of NSCLC and that TCONS_00001798 may be a potential diagnostic and therapeutic target in patients with NSCLC.

Claudin-3 Inhibits Lung Squamous Cell Carcinoma Cell Epithelial-mesenchymal Transition and Invasion via Suppression of the Wnt/ß-catenin Signaling Pathway.

Altered expression of claudin-3 (CLDN3), a key cytoskeletal structural protein of the tight junctions in the epithelium, is associated with the development and metastasis of various human cancers. CLDN3 expression has been shown to be significantly associated with the prognosis of lung squamous cell carcinoma (SqCC). This study investigated the role of CLDN3 in inhibiting lung SqCC cell migration and invasion as well as the underlying molecular mechanisms. The CLDN3 levels were assessed between 20 paired lung SqCC tissues and adjacent normal tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The ectopic CLDN3 overexpression or knockdown was generated by using a plasmid carrying CLDN3 cDNA or shRNA, respectively. CLDN3 expression was significantly reduced in lung SqCC tissues vs. the adjacent normal tissues. The ectopic CLDN3 overexpression markedly inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of lung cancer H520 cells, whereas CLDN3 knockdown had an inverse effect on SK-MES-1 cells. However, cell viability and plate colony formation assays showed that both CLDN3 knockdown and overexpression did not affect SqCC cell proliferation. Both tissue and cell data revealed that CLDN3 expression was significantly associated with the expression of the EMT biomarkers E-cadherin and Vimentin. Furthermore, CLDN3-modulated EMT and expression of the EMT markers were through regulation of the Wnt/ß-catenin signaling pathway. In conclusion, this study identified reduced CLDN3 expression in lung SqCC tissues, which was associated with the progression and metastasis of lung SqCC and was attributed to EMT by activation of the Wnt pathway. Thus, CLDN3 could be further evaluated as a novel biomarker for predicting the prognosis of lung SqCC and as a target for the treatment of lung SqCC in the future.

B3GNT3 overexpression is associated with unfavourable survival in non-small cell lung cancer.

OBJECTIVE: The aim of this study was to evaluate the expression of beta-1,3-N-acetylglucosaminyltransferase-3 (B3GNT3) in non-small cell lung cancer (NSCLC) patients and to investigate the relevance of B3GNT3 expression in tumour prognosis. METHODS: In this study, B3GNT3 expression was examined in five pairs of resectable NSCLC tissue by Western blot and in 42 pairs of resectable NSCLC tissue by quantitative real-time PCR (qRT-PCR). Immunohistochemistry and statistical analysis were performed to assess the relationship between B3GNT3 expression scores and clinicopathological parameters, as well as clinical prognosis in a retrospective cohort of 176 NSCLC patients. RESULTS: Both B3GNT3 mRNA and protein expression levels were significantly higher in NSCLC tissue than in adjacent normal tissue. In the 176 NSCLC cases, a high B3GNT3 expression level was positively correlated with lymph node metastasis (P<0.001) and advanced TNM stage (P=0.043). Kaplan-Meier analysis indicated that patients with high B3GNT3 expression had significantly lower disease-free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001) than those with low B3GNT3 expression. Moreover, in the multivariate analyses, B3GNT3 expression was an independent prognostic factor for DFS (HR 0.329, 95% CI 0.213 to 0.508, P<0.001) and OS (HR 0.383, 95% CI 0.249 to 0.588, P<0.001). CONCLUSIONS: Our study demonstrated that high expression of B3GNT3 was associated with unfavourable DFS and OS in NSCLC patients, suggesting that B3GNT3 might be a potential prognostic biomarker for NSCLC.

Clinical significance of cripto-1 expression in lung adenocarcinoma.

Cripto-1 can promote tumourigenesis and may be a potential prognostic biomarker in several malignancies, yet little is known about this protein in lung adenocarcinoma (LAC). The aim of this study was to evaluate the prognostic value of cripto-1 expression in a cohort of patients with LAC. Tumours from 290 patients with pathologically confirmed LAC were used for an immunohistochemical analysis of cripto-1 expression. The correlation between cripto-1 expression and the clinicopathological parameters of patients, EGFR-TKI sensitivity was analysed. Significant associations between cripto-1 expression and pT status, pN status, pTNM status, E-cadherin expression and EGFR-TKI sensitivity were identified. Compared with patients with low cripto-1 expression, patients with high cripto-1 expression exhibited significantly poorer progression-free survival (PFS) and overall survival (OS). Moreover, multivariate analyses showed that high cripto-1 expression was an independent predictor of worse survival of patients with LAC. The combination of cripto-1 expression and serum CEA level was correlated with both PFS and OS. In conclusion, cripto-1 may be a potential prognostic biomarker of survival in patients with LAC.

Prognostic value of combination of preoperative platelet count and mean platelet volume in patients with resectable non-small cell lung cancer.

The aim of the present study was to investigate the prognostic value of the combination of preoperative platelet count (PLT) and mean platelet volume (MPV) in patients with primary operable non-small cell lung cancer (NSCLC). We retrospectively analysed data from 546 patients with NSCLC who underwent complete resection at our institution from 2006 to 2010. Patients' clinical characteristics and laboratory test data at initial diagnosis were collected. Both preoperative PLT and MPV (COP-MPV) were calculated on the basis of the data obtained using the recommended cut-off values of 300 × 109 L-1 and 11.0 fL, respectively. Patients with both an elevated PLT (≥300× 109 L-1) and a decreased MPV (<11.0 fL) were assigned a score of 2, and patients showing one or neither were allocated a score of 1 or 0, respectively. Multivariate analysis of the 9 clinical laboratory variables selected by univariate analysis revealed that preoperative COP-MPV was a significantly independent prognostic factor for overall survival (OS) (hazard ratio, 1.775; 95% confidence interval, 1.500-2.101; P< 0.001) and disease-free survival (DFS) (hazard ratio, 1.719; 95% confidence interval, 1.454-2.033; P< 0.001). In subgroup analyses for tumour pathological stage (I/II/IIIA) patients, we found that the level of COP-MPV was significantly associated with OS and DFS in each subgroup (P< 0.001, P< 0.001, P<0.001 for OS and P<0.001, P< 0.001, P=0.001 for DFS, respectively). In conclusion, the preoperative COP-MPV is a promising predictor of postoperative survival in patients with NSCLC and could classify these patients into three independent groups before surgery.

Claudin-3 expression increases the malignant potential of lung adenocarcinoma cells: role of epidermal growth factor receptor activation.

Claudins are essential for the formation and maintenance of tight junctions (TJ). The altered expression of claudin proteins has been described in a variety of malignancies. However, the alteration of these proteins in lung adenocarcinoma (ADC) are poorly understood. Therefore, we report, based on the protein expression analysis of a total of 275 patient samples, that claudin-3 (CLDN3) expression is significantly increased in ADC tissues and is associated with cancer progression, correlating significantly with the poor survival of ADC patients (p=0.041&0.029). More importantly, forcing CLDN3 expression in ADC cells without endogenous CLDN3 expression resulted in significant increases in the cell proliferation, anchorage-dependent growth, migration and drug-resistance. In addition, epidermal growth factor (EGF) signaling pathway modulates the expression of claudins in a number of solid tumors. However, the mechanism of tight junction regulation by EGF in ADC remains unclear. To investigate this mechanisms, ADC cell lines were treated with EGF and its inhibitor. EGF unregulated CLDN3 expression via the MEK/ERK or PI3K/Akt signaling pathways and was required for the maintenance of baseline CLDN3 expression. Furthermore, downregulation of CLDN3 expression in ADC cell was found to prevent the EGF-induced increase in cell proliferation. In conclusion, our results demonstrate a novel role of CLDN3 overexpression in promoting the malignant potential of lung adenocarcinoma. This function is potentially regulated by the EGF-activated MEK/ERK and PI3K-Akt pathways.

Kras mutations increase telomerase activity and targeting telomerase is a promising therapeutic strategy for Kras-mutant NSCLC.

As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). MEK inhibition led to reduced TERT expression and telomerase activity. Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant Kras-induced long-term proliferation, colony formation and migration capabilities of BEAS-2B and Calu-3 cells. Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. In addition, higher TERT expression was seen in Kras-mutant NSCLC than that with wild-type Kras. Our data suggest that Kras mutations increase telomerase activity and telomere length by activating the RAS/MEK pathway, which contributes to an aggressive phenotype of NSCLC. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC.

Cytokeratin 18 knockdown decreases cell migration and increases chemosensitivity in non-small cell lung cancer.

PURPOSE: Cytokeratin 18 (CK18) is a structural protein that is normally expressed in many single-layer epithelia. Previous studies have indicated that aberrant CK18 expression is associated with cancer progression. However, the functions of CK18 in lung cancer have not been fully elucidated. Here, we investigate the roles of CK18 in non-small cell lung cancer (NSCLC). METHODS: CK18 protein expression was evaluated by immunohistochemistry in a lung cancer tissue microarray containing 129 cancer samples, and correlations between CK18 expression and clinicopathological characteristics and prognosis were analyzed. We then studied the effects of CK18 knockdown on cell motility and chemosensitivity in lung cancer cells. RESULTS: High CK18 expression was detected in 101/129 (78.3 %) lung cancers. CK18 expression was significantly correlated to clinical stage, lymph node metastasis, the number of pathologically positive lymph nodes and recurrence and metastasis. Kaplan-Meier survival analysis showed that CK18 was a prognostic factor for overall survival (P = 0.016) and disease-free survival (P = 0.014). In addition, CK18 knockdown decreased cell migration and enhanced the sensitivity of lung cancer cells to paclitaxel. CONCLUSIONS: These findings indicate that CK18 plays an important role in lung cancer progression and may be a therapeutic target for NSCLC.

Prognostic value of platelet to lymphocyte ratio in non-small cell lung cancer: a systematic review and meta-analysis.

The prognostic value of the platelet-to-lymphocyte ratio (PLR) in non-small cell lung cancer (NSCLC) remains controversial. We therefore conducted a meta-analysis of published studies to determine the prognostic value of PLR in NSCLC. A systematic search was performed in PubMed, Web of Science and Embase for relevant studies. The data and characteristics of each study were extracted, and the hazard ratio (HR) at a 95% confidence interval (CI) was calculated to estimate the effect. We also performed subgroup and meta-regression analyses. A total of 2,889 patients in 12 studies were enrolled in this meta-analysis, and the pooled HR of 1.492 (95% CI: 1.231-1.807, P < 0.001) indicated that patients with an elevated PLR are expected to have a shorter overall survival (OS) after treatment. This meta-analysis indicates that a high PLR might be a predictive factor of poor prognosis in NSCLC. Further large-cohort studies are needed to confirm these findings.