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Objective To investigate the correlation of neutrophil-to-lymphocyte ratios (NLR) with prognosis of stage I non-small cell lung cancer (NSCLC). Methods. Clinical data from 567 stage I NSCLC patients who received surgical treatment in our hospital from May 2007 to May 2014 were analyzed retrospectively. According to preoperative peripheral blood NLR values, patients were divided into low- and high-NLR groups. Univariate and multivariate survival analyses were performed to evaluate the correlation of preoperative NLRs with postoperative survival. Results. NLRs ranged from 0.48 to 47.25 (median 2.19). The five-year survival for patients in the high-NLR (NLR > 2.19) and low-NLR (NLR

Tumor-infiltrating immune cells have been implicated in the tumorigenesis and progression of esophageal squamous cell carcinoma (ESCC). However, the functionalities and clinical significance of immune cells remain largely unveiled. In this study, the gene expression data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were extracted. The relative infiltrating levels were estimated by single-sample gene set enrichment analysis. Some cytotoxic immune cells were attenuated, and resting cytotoxic immune cells were accumulated in ESCC. Remarkably, we also observed that infiltrating levels of macrophage M2 and resting natural killer (NK) cells were increased in nonresponders of CRT, and T cells that had anticancer activities such as activated memory CD4 and T helper 2 (Th2) cells were significantly reduced in ESCC tissues of the nonresponders. Moreover, the high infiltrations of the resting natural killer (NK) and dendritic cell (DC) were observed to result in a shorter overall survival in ESCC. Consistently, high expression of immune checkpoint genes, CTLA4 and HAVCR2, was associated with poor prognosis. Furthermore, STAT5B, a key transcription factor, as well as its target genes, involved in the regulation of T cells, was significantly downregulated in ESCC, especially subgroup I, indicating that downregulation of STAT5B might be associated with reduced T cell-mediated anticancer activity. In conclusion, the present study significantly improved our understanding of the regulatory roles of immune cells in ESCC.

Background Lung cancer is one of the most common cancers in the word. However, the underlying mechanism remains largely unknown. ACOT11 encodes enzymes hydrolyzing the fatty acyl-CoA esters into free fatty acids and CoA. Besides from its role in fatty acid metabolism, the other aspects regarding its function in the progression of lung cancer have not been revealed. Methods We first explored the clinical profile of ACOT11 in tumor samples. Next, we combined gene knockdown in vitro and in vivo and microarray gene profiling analysis to decipher the unknown regulatory role of ACOT11 in lung cancer carcinoma. Furthermore, we explored the potential molecular mechanisms of ACOT11 with immunoprecipitation. Results We found high expression of ACOT11 in tumor samples. High expression of ACOT11 showed significantly poor prognosis in lung squamous carcinoma (LUSC) patients. Knocking down of ACOT11 inhibited the cell proliferation, migration as well as invasion in vitro and in vivo. It also promoted the cell apoptosis and cell cycle arrest via multiple signaling pathways. Additionally, ACOT11 could bind with CSE1L, which was proved to be an oncogene in lung cancer and speculated to be a potential target of ACOT11. Conclusions The results revealed that ACOT11 regulates proliferation, migration and invasion of lung cancer carcinoma via multiple signaling pathways, indicating its potential value in molecular therapy.

SARS-CoV-2, a β-coronavirus, has rapidly spread across the world, highlighting its high transmissibility, but the underlying morphogenesis and pathogenesis remain poorly understood. Here, we characterize the replication dynamics, cell tropism and morphogenesis of SARS-CoV-2 in organotypic human airway epithelial (HAE) cultures. SARS-CoV-2 replicates efficiently and infects both ciliated and secretory cells in HAE cultures. In comparison, HCoV-NL63 replicates to lower titers and is only detected in ciliated cells. SARS-CoV-2 shows a similar morphogenetic process as other coronaviruses but causes plaque-like cytopathic effects in HAE cultures. Cell fusion, apoptosis, destruction of epithelium integrity, cilium shrinking and beaded changes are observed in the plaque regions. Taken together, our results provide important insights into SARS-CoV-2 cell tropism, replication and morphogenesis., Here, the authors characterize replication of SARS-CoV-2 in human airway epithelial (HAE) cultures and show that it can infect ciliated and secretory cells, affects transepithelial electrical resistance and causes plaque-like cytopathic effects associated with apoptosis.

Background Neuron-specific enolase (NSE) has become a widely used and easily attainable laboratory assay of small cell lung cancer (SCLC). However, the prognostic value of NSE for SCLC patients remains controversial. The aim of the study was to evaluate the correlation between elevated serum NSE before therapy and survival of SCLC patients. Methods We performed a systematic review and meta-analysis. A systematic literature search was conducted in PubMed, Embase, and the Cochrane Central Register from the inception dates to December 2019. Eligible articles were included according to inclusion and exclusion criteria; then, data extraction and quality assessment were performed. The primary outcome was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Results We identified 18 studies comprising 2981 patients. Pooled results revealed that elevated NSE was associated with worse OS (HR = 1.78, 95% CI 1.55–2.06, p < 0.001) and PFS (HR = 1.50, 95% CI 1.16–1.93, p = 0.002). In subgroup analysis, elevated NSE did not predict worse OS in patients who received only chemotherapy (HR 1.22, 95% CI 0.96–1.55, p = 0.10) or part of whom received surgical resection before chemotherapy and radiotherapy (HR = 2.16, 95% CI 0.82–5.69, p = 0.12). Conclusion Elevated serum NSE before any therapy of SCLC patients may be a negative prognostic factor for OS and PFS. The prognostic value of NSE for OS was particularly observed in patients treated by standard management.

Current evidence has unveiled that long non-coding RNAs (lncRNAs) are pivotal regulators in the development of cancers. This study aimed to investigate the potential mechanisms of LINC01224 in esophageal squamous cell carcinoma (ESCC) cells. RT-qPCR analysis was done to test LINC01224 expression in ESCC cells. Functional assays were conducted to assess the influences of LINC01224 on ESCC cell functions. Mechanism assays were carried out to detect the regulatory mechanisms of LINC01224 at post-transcriptional and transcriptional levels. Briefly, LINC01224 expression was remarkably high in ESCC cells. LINC01224 silence restricted the proliferative, migratory, and invasive capabilities of ESCC cells. Moreover, LINC01224 could combine with miR-6884-5p by acting as a ceRNA. Further, DVL3 was proved to be targeted by miR-6884-5p. Importantly, LINC01224 could switch on Wnt/β-catenin signaling pathway by via enhancing DVL3 expression. Additionally, E2F1 could serve as a transcription factor to stimulate LINC01224 transcription. In summary, our study elucidated that E2F1-activated LINC01224 regulated miR-6884-5p/DVL3 to actuate the Wnt/β-catenin signaling pathway, which facilitates multiple phenotype of ESCC cells, including proliferation, migration, and invasion. Our findings might offer potential therapeutic targets for ESCC treatment.

Background Actin-like protein 8 (ACTL8) is a member of the CTA family, and it is expressed in various types of cancer, including glioblastoma and breast cancer. However, whether ACTL8 is involved in the development of lung adenocarcinoma (LUAD) remains unknown. Here, we try to demonstrate the role of ACTL8 in human LUAD A549 cells. Methods First, the high expression of ACTL8 was observed in patients with LUAD via immunohistochemistry (IHC) staining. Second, cell proliferation was significantly inhibited in ACTL8 knockdown A549 cells. Third, a global gene expression analysis was performed to discover the potential genes and signal pathways modulated by ACTL8 in A549 cells. Results A total of 504 differentially expressed genes (DEGs) (146 up-regulated, and 358 down-regulated) were found in the ACTL8 knockdown A549 cells compared with the mock-transfected cells. Ingenuity pathway analysis (IPA) revealed that canonical pathways such as cyclins and cell cycle regulation and estrogen-mediated S-phase entry were significantly inhibited, while pathways such as cell cycle: G2/M DNA damage checkpoint regulation and HMGB1 signaling were significantly activated by ACTL8 knockdown. Disease and functions enrichment analysis revealed that processes associated with “cell death” and “apoptosis” were significantly activated. Upstream regulator analysis showed that NUPR1 was the most activated, while CSF2 was the most inhibited. Lastly, a qRT-PCR and Western blot analysis further confirmed that the expression levels of FOXM1, STMN1, PLK1, and BIRC5 were markedly reduced in ACTL8 knockdown of A549 cells. Conclusions In summary, these results suggest that a knockdown of ACTL8 inhibits cell proliferation in human LUAD A549 cells by regulating FOXM1, STMN1, PLK1, and BIRC5.

Background. The competitive endogenous RNA (ceRNA) mechanism has been discovered recently and regulating cancer-related gene expressions. The ceRNA network participates in multiple processes, such as cell proliferation and metastasis, and potentially drives the progression of cancer. In this study, we focus on the ceRNA networks of esophageal squamous cell carcinoma and discovered a novel biomarker panel for cancer prognosis. Methods. RNA expression data of esophageal carcinoma from the TCGA database were achieved and constructed ceRNA network in esophageal carcinoma using R packages. Results. Four miRNAs were discovered as the core of the ceRNA model, including miR-93, miR-191, miR-99b, and miR-3615. Moreover, we constructed a ceRNA network in esophageal carcinoma, which included 4 miRNAs and 6 lncRNAs. After ceRNA network modeling, we investigated six lncRNAs which could be taken together as a panel for prognosis prediction of esophageal cancer, including LINC02575, LINC01087, LINC01816, AL136162.1, AC012073.1, and AC117402.1. Finally, we tested the predictive power of the panel in all TCGA samples. Conclusions. Our study discovered a new biomarker panel which may have potential values in the prediction of prognosis of esophageal carcinoma.

The aim of the present study was to investigate the association between histopathological subtypes, epidermal growth factor receptor (EGFR) mutations and 18F-fluorodeoxyglucose (FDG) uptake in patients with lung adenocarcinoma (ADC). The cases of 97 patients with lung ADC who underwent 18F-FDG positron emission tomography-computed tomography prior to surgical resection were retrospectively reviewed. The patients were stratified according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification, and graded using a histopathological scoring system. EGFR mutations were identified. Clinicopathological characteristics associated with EGFR mutation status were evaluated using univariate and multivariate analyses. EGFR mutation was identified in 45.4% of the patients and was associated with gender, smoking history, maximum standardized uptake value (SUVmax) and histopathological score. ADC patients with a low SUVmax were more likely to exhibit EGFR mutations compared with patients with a high SUVmax (P=0.018). Patients with a lower histopathological score possessed a significantly lower SUVmax compared with patients with a higher score (P

Background: Clinical trials of anti-CCR4 antibody for solid cancers with or without other immune-modulating agents including immune checkpoint blockade therapy are currently underway. However, little is known about the roles of CCR4 + lymphocytes and their prognostic impact in lung cancer. We hypothesized that high CCR4 expression in the tumor microenvironment would be associated with a poor prognosis and would act as a biomarker in lung adenocarcinoma. Methods: First, the prognostic impact of CCR4 gene expression was explored using pooled data from public transcriptomic databases with online survival analysis software. Second, tissue microarrays (TMAs) were constructed from resected lung adenocarcinoma specimens from tumors up to 3 cm in size. The density of CCR4 + lymphocytes infiltrating the tumor was then assessed by immunohistochemistry and related to survival. Confounding factors were controlled for by multivariate analysis using the Cox proportional hazards model. Results: Higher than median expression of the CCR4 gene was identified as an independent poor prognostic factor for overall survival (OS) by multivariate analysis of 720 lung adenocarcinoma patients in the public databases [HR =1.55 (95% CI: 1.03–2.35), P=0.037]. Consistent with this, high CCR4 + tumor-infiltrating lymphocyte (TIL) density was found to be an independent poor prognostic factor for both OS [HR =2.24 (1.01–5.34), P=0.049] and recurrence-free survival (RFS) [HR =2.20 (1.16–4.39), P=0.017] in the patients from whom TMA were obtained (n=180). Age, male gender, predominantly non-lepidic histological subtype, nodal involvement, and low CD8 + TIL density were also independent poor prognostic factors. However, FOXP3 gene expression and Foxp3 + lymphocyte infiltration did not possess any prognostic value in either study. Conclusions: High CCR4 expression in the tumor microenvironment may be a poor prognostic factor in lung adenocarcinoma. Patients with high CCR4 + lymphocyte infiltration may have a poor prognosis and thus be suitable candidates for clinical trials of anti-CCR4 antibody treatment.

BACKGROUND: Tumor recurrence is the most common cause of treatment failure, especially after complete resection of pathological stage N2 non-small cell lung cancer (NSCLC). In this study, we investigated the clinicopathological characteristics in order to identify independent risk factors for postoperative recurrence. METHODS: Between January 2001 and December 2013, 96 patients who underwent surgical resection for pathological N2 NSCLC were retrospectively reviewed. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method to explore risk factors, while the Cox proportional hazard model was used to assess independent predictors. RESULTS: The median and five-year RFS rates were 15 months and 27.4%, respectively. Univariate analysis showed a significantly poorer prognosis for non-regional N2 metastasis, more than three metastatic N2 lymph nodes, multiple N2 station, and multiple N2 zone involvement. Multivariate analysis demonstrated that non-regional N2 metastasis (hazard ratio [HR] 1.857, 95% confidence interval [CI] 1.061-3.249, P = 0.030) and more than three metastatic N2 lymph nodes (HR 2.555, 95% CI 1.164-5.606, P = 0.019) were independent risk factors for RFS. Additionally, the incidence of non-regional N2 metastasis was higher in patients with a primary tumor in the left lower (57.1%) or right lower lobe (48.1%), followed by left upper (31.8%), right middle (14.3%) and right upper lobe (7.7%). CONCLUSION: The combination of the distribution and number of metastatic N2 lymph nodes provides a more accurate prediction for N2 NSCLC regarding recurrence. Non-regional N2 metastasis could occur with a primary tumor in any lobe, but occurs more frequently in the lower lobe.

Background: Lung cancer is the leading cause of cancer-related death worldwide, and the number of elderly patients with nonsmall-cell lung cancer (NSCLC) has risen with increasing life-expectancy. Aims: To evaluate safety and efficacy of thoracoscopic lobectomy for NSCLC patients above 75 years old. Patients and Methods: We reviewed the data of 795 consecutive patients with NSCLC, who underwent video-assisted thoracoscopic lobectomy from January 2006 to December 2013. Patients were divided into two groups: The elderly group aged at least 75 years old (n = 54), the contrast group aged

Guangliang Qiang, Chaoyang Liang, Fei Xiao, Qiduo Yu, Huanshun Wen, Zhiyi Song, Yanchu Tian, Bin Shi, Yongqing Guo, Deruo Liu Department of Thoracic Surgery, China–Japan Friendship Hospital, Beijing, People’s Republic of China Background: The platelet-to-lymphocyte ratio (PLR) is a useful predictive factor in several cancers. However, the prognostic value of PLR in patients with non-small-cell lung cancer (NSCLC) is still indistinct. Therefore, it was necessary for us to perform a meta-analysis to assess the prognostic value of PLR in patients with NSCLC. Methods: A systematic literature search was performed by using PubMed, EMBASE, and Web of Science databases for relevant studies until May 2015. Published studies investigating the association between PLR and overall survival (OS) and disease-free survival (DFS) were selected. Data from each eligible study were extracted. A meta-analysis was performed to analyze the prognostic value of PLR by using the hazard ratio (HR) and 95% confidence intervals (95% CI). Results: A total of seven studies involving 1,554 patients were included in our meta-analysis. Our pooled results demonstrated that high PLR was associated with poor OS (HR: 1.60, 95% CI: 1.34–1.90, I2=22.3%, Pheterogeneity =0.259) and DFS (HR: 1.38, 95% CI: 1.11–1.73, I2=0%, Pheterogeneity =0.482). Subgroup analysis between PLR and OS was performed in a further investigation. When the patients were segregated according to ethnicity, sample size, cutoff value, stage, and treatment modality, high PLR was also significantly correlated with OS. There was no significant heterogeneity among included studies. Conclusion: High PLR is associated with poor prognosis in patients with NSCLC. PLR may be a significant predictive biomarker in patients with NSCLC. Keywords: non-small cell lung cancer, platelet-to-lymphocyte ratio, prognosis, meta-analysis, overall survival, disease-free survival

Guangliang Qiang, Chaoyang Liang, Fei Xiao, Qiduo Yu, Huanshun Wen, Zhiyi Song, Yanchu Tian, Bin Shi, Yongqing Guo, Deruo Liu Department of Thoracic Surgery, China–Japan Friendship Hospital, Beijing, People’s Republic of China Purpose: This study aimed to determine whether the severity of chronic obstructive pulmonary disease (COPD) affects recurrence-free survival in non-small-cell lung cancer (NSCLC) patients after surgical resection.Patients and methods: A retrospective study was performed on 421 consecutive patients who had undergone lobectomy for NSCLC from January 2008 to June 2011. Classification of COPD severity was based on guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Characteristics among the three subgroups were compared and recurrence-free survivals were analyzed.Results: A total of 172 patients were diagnosed with COPD (124 as GOLD-1, 46 as GOLD-2, and two as GOLD-3). The frequencies of recurrence were significantly higher in patients with higher COPD grades (P

To analyze the prognostic impact of preoperative (18)F-fluorodeoxyglucose (FDG) PET-CT on postoperative recurrence in patients with completely resected stage I non-small cell lung cancer (NSCLC).The clinic data of 182 patients with stage I NSCLC who underwent (18)F-FDG PET-CT scan before surgical resection between June 2005 and June 2012 were reviewed retrospectively. There were 121 male and 61 female patients, with an average age of 68 years (range from 34 to 85 years). The pathological stage was I A in 98 patients, I B in 84 patients; the histology were adenocarcinoma in 137 patients, squamous cell carcinoma in 35 patients, and others in 10 patients. Clinicopathological factors including gender, age, smoking history, SUV(max), surgical procedure, pathological features and adjuvant chemotherapy were evaluated to identify the independent factors predicting postoperative recurrences by univariate and multivariate analysis. The survivals were calculated by the Kaplan-Meier method and differences in variables were analyzed by the Log-rank test.The postoperative recurrence rate was 15.9%. The univariate analysis identified that the SUV(max) (t=3.278, P0.001), p-stage (χ² =5.204, P=0.026), blood vessel invasion (χ² =5.333, P=0.027) and visceral pleural invasion (χ² =7.697, P=0.009) are factors for predicting postoperative recurrence. Only SUV(max) was found to be a significant independent factor according to multivariate analysis (HR=1.068, 95%CI: 1.015 to 1.123, P=0.001). The study population was stratified into three groups by SUV(max), patients with SUV(max)5.0 had significantly higher risk of recurrence (23.9%) than those with 2.5SUV(max) ≤ 5.0 (15.0%) and SUV(max) ≤ 2.5 (7.3%) (P=0.043); patients with SUV(max) ≤ 2.5 had significantly better 5-year recurrence-free survival rate (90.9%) than those with 2.5SUV(max) ≤ 5.0 (82.7%) and SUV(max) ≤ 2.5 (71.0%) (P=0.030). There was a trend toward higher probability of blood vessel invasion (χ² =20.267, P0.001), visceral pleural invasion (χ² =6.185, P=0.045) and pathological stage I B (χ² =13.589, P=0.001) with increased SUV(max).Preoperative SUV(max) of primary tumor is a predictor of postoperative relapse for stage I NSCLC after surgical resection. Therefore, it can contribute to the risk stratification for patients with the same pathological stage and selecting the optimal postoperative follow-up and therapeutic strategy.

To explore the patterns of mediastinal lymph node metastases and prognostic factors of recurrence in patients undergoing curative resection of stage IIIA-N2 non-small cell lung cancer (NSCLC).A total of 92 patients underwent curative operation and pathologically diagnosed as stage IIIA-N2 NSCLC were retrospectively reviewed. The clinicopathological data were compared between the recurrence and non-recurrence groups. And the potential prognostic factors were included for multivariate analysis using Cox proportional hazard model.The 3 and 5-year recurrence rates were 61.0% and 70.2% respectively. For univariate analysis, the prognostic factors were number of metastatic lymph nodes, positive lymph node ratio, number of metastatic mediastinal lymph nodes (MLN), positive MLN ratio, number of MLN metastasis3, multiple station metastasis, trans-regional metastasis and multi-zonal metastasis. A multivariate analysis using Cox regression identified 2 independent factors of prognosis: trans-regional MLN metastasis (P = 0.035) and number of MLN metastasis3 (P = 0.045). The recurrence risk of patients with trans-regional MLN metastasis was 2.0 times higher than those with regional MLN metastasis while the recurrence risk of patients with number of MLN metastasis3 was 2.2 times higher than those with number of MLN metastasis of 1-3.Recurrence risk of stage IIIA-N2 non-small cell lung cancer (NSCLC) after curative resection may be estimated by location and number of MLN metastasis. And the subgroup with trans-regional MLN metastasis and number of MLN metastasis3 carries the highest risk of recurrence.

Background Tumor recurrence is the most common cause of treatment failure, especially after complete resection of pathological stage N2 non-small cell lung cancer (NSCLC). In this study, we investigated the clinicopathological characteristics in order to identify independent risk factors for postoperative recurrence. Methods Between January 2001 and December 2013, 96 patients who underwent surgical resection for pathological N2 NSCLC were retrospectively reviewed. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method to explore risk factors, while the Cox proportional hazard model was used to assess independent predictors. Results The median and five-year RFS rates were 15 months and 27.4%, respectively. Univariate analysis showed a significantly poorer prognosis for non-regional N2 metastasis, more than three metastatic N2 lymph nodes, multiple N2 station, and multiple N2 zone involvement. Multivariate analysis demonstrated that non-regional N2 metastasis (hazard ratio [HR] 1.857, 95% confidence interval [CI] 1.061–3.249, P = 0.030) and more than three metastatic N2 lymph nodes (HR 2.555, 95% CI 1.164–5.606, P = 0.019) were independent risk factors for RFS. Additionally, the incidence of non-regional N2 metastasis was higher in patients with a primary tumor in the left lower (57.1%) or right lower lobe (48.1%), followed by left upper (31.8%), right middle (14.3%) and right upper lobe (7.7%). Conclusion The combination of the distribution and number of metastatic N2 lymph nodes provides a more accurate prediction for N2 NSCLC regarding recurrence. Non-regional N2 metastasis could occur with a primary tumor in any lobe, but occurs more frequently in the lower lobe.

We present the case of a 66-year-old female who had undergone pulmonary wedge resection for diagnosis and followed by a radical lobectomy for the treatment of the primary lung cancer. We performed a left upper lobectomy through Video-Assisted Thoracic Surgery (VATS), we successfully adapted simultaneous stapling technique to division of both pulmonary vein and lobar bronchus which were densely adhered each other because of the previous surgery.

Lung cancer is highly heterogenous and is composed of various subtypes that are in diverse differential stages. The newly identified integrin-interacting proteins Kindlin-1 and Kindlin-2 are the activators of transmembrane receptor integrins that play important roles in cancer progression. In this report we present the expression profiles of Kindlin-1 and Kindlin-2 in lung cancers using patient specimens and established their correlation with lung cancer progression. We found that Kindlin-1 was expressed in epithelia-derived non-small-cell lung cancer, especially in squamous cell lung cancer but expressed at low levels in poorly differentiated large cell lung cancer. However, Kindlin-2 was highly expressed in large cell lung cancer. Both Kindlin-1 and Kindlin-2 were found not expressed or expressed at very low levels in neuroendocrine-derived small cell lung cancer. Importantly, the Kindlin-1 expression level was positively correlated with the differentiation of squamous cell lung cancer. Surprisingly, we found that the very homologous Kindlin family proteins, Kindlin-1 and Kindlin-2, displayed counteracting functional roles in lung cancer cells. Ectopic expression of Kindlin-1 in non-small-cell lung cancer cells inhibited in vitro cell migration and in vivo tumor growth, while Kindlin-2 promoted these functions. Mechanistically, Kindlin-1 prohibited epithelail to mesenchymal transition in non-small-cell lung cancer cells, while Kindlin-2 enhanced epithelail to mesenchymal transition in these cells. Taken together, we demonstrated that Kindlin-1 and Kindlin-2 differentially regulate lung cancer cell progression. Further, the expression levels of Kindlin-1 might be potentially used as a marker for lung cancer differentiation and targeting Kindlin-2 might block the invasive growth of large cell lung cancer.