Circular RNA Expression of Peripheral Blood Mononuclear Cells Associated with Risk of Acute Exacerbation in Smoking Chronic Obstructive Pulmonary Disease.

Purpose: Circular RNAs (circRNAs) are newly identified endogenous non-coding RNAs that function as crucial gene modulators in the development of several diseases. By assessing the expression levels of circRNAs in peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD), this study attempted to find new biomarkers for COPD screening. Patients and Methods: We confirmed altered circRNA expression in PBMCs of COPD (n=41) vs controls (n=29). Further analysis focused on the highest and lowest circRNA expression levels. The T-test is used to assess the statistical variances in circRNAs among COPD patients in the smoking and non-smoking cohorts. Additionally, among smokers, the Spearman correlation test assesses the association between circRNAs and clinical indicators. Results: Two circRNAs, hsa_circ_0042590 and hsa_circ_0049875, that were highly upregulated and downregulated in PBMCs from COPD patients were identified and verified. Smokers with COPD had lower hsa_circ_0042590 and higher hsa_circ_0049875, in comparison to non-smokers. There was a significant correlation (r=0.52, P<0.01) between the number of acute exacerbations (AEs) that smokers with COPD experienced in the previous year and the following year (r=0.67, P<0.001). Moreover, hsa_circ_0049875 was connected to the quantity of AEs in the year prior (r=0.68, P<0.0001) as well as the year after (r=0.72, P<0.0001). AUC: 0.79, 95% CI: 0.1210-0.3209, P<0.0001) for hsa_circ_0049875 showed a strong diagnostic value for COPD, according to ROC curve analysis. Hsa_circ_0042590 showed a close second with an AUC of 0.83 and 95% CI: -0.1972--0.0739 (P <0.0001). Conclusion: This research identified a strong correlation between smoking and hsa_circ_0049875 and hsa_circ_0042590 in COPD PBMCs. The number of AEs in the preceding and succeeding years was substantially linked with the existence of hsa_circ_0042590 and hsa_circ_0049875 in COPD patients who smoke. Additionally, according to our research, hsa_circ_0049875 and hsa_circ_0042590 may be valuable biomarkers for COPD diagnosis.

Comparison of operation time, efficacy and safety between through-the-scope stent and over-the-while stent in malignant central airway obstruction: a multi-center randomized control trial.

Background: Self-expandable metallic (SEM) airway stents are an important approach to treating malignant central airway obstruction (CAO). Standard over-the-while (OTW) stent needs the guidance of a guide-wire. It should be implanted under flouroscopy or the guidance of bronchoscope visualization. In this study, we evaluated the operation time and safety between OTW stent and a novel through-the-scope (TTS) SEM airway stent. Methods: In this multi-center, randomized, parallel-group superiority study, malignant CAO patients were enrolled randomly assigned (2:1) to the TTS stent implantation group (TTS group) or the standard OTW stent group (OTW group) in six sites across China. The entire process of all surgical procedures was recorded by video. Primary endpoint was the operation time of the airway stent implantation and secondary endpoint was the success rate of the stent implantation as well as its efficacy and safety. Results: From May 15, 2017, to December 30, 2018, 148 patients were enrolled from the six sites. We analyzed 134 patients (including 91 patients from the TTS group and 43 patients from the OTW group) according to the per-protocol set. There were no significant differences in the ages, genders, underlying diseases, and stenosis sites between the two groups. The operation time in the TTS group was significantly shorter than that in the OTW group (104±68 vs. 252±111 seconds, P<0.001). Compared to the OTW group, the efficacy of stent implantation (97.80% vs. 90.70%, P=0.093) and rate of first-time successful stent implantation (78.02% vs. 74.42%, P=0.668) were higher in the TTS group, but did not reach statistically significance. The rates of granulation (28.57% vs. 41.86%, P=0.128) and restenosis (15.38% vs. 30.23%, P=0.064) in the TTS group were slightly lower as compared with the OTW group without achieving statistical significance. Conclusions: The TTS stent implantation procedure time was significantly shorter than that of the OTW airway stent with similar efficacy and complications, which might reduce the risk and flexibility of stent implantation. Trial Registration: Chinese Clinical Trial Registry ChiCTR-IOR-17011431.

DNA-PKcs participated in hypoxic pulmonary hypertension.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a common complication of chronic lung disease, which severely affects the survival and prognosis of patients. Several recent reports have shown that DNA damage and repair plays a crucial role in pathogenesis of pulmonary arterial hypertension. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a part of DNA-PK is a molecular sensor for DNA damage that enhances DSB repair. This study aimed to demonstrate the expression and potential mechanism of DNA-PKcs on the pathogenesis of HPH. METHODS: Levels of DNA-PKcs and other proteins in explants of human and rats pulmonary artery from lung tissues and pulmonary artery smooth muscle cells (PASMC) were measured by immunohistochemistry and western blot analysis. The mRNA expression levels of DNA-PKcs and NOR1 in PASMCs were quantified with qRT-PCR. Meanwhile, the interaction among proteins were detected by Co-immunoprecipitation (Co-IP) assays. Cell proliferation and apoptosis was assessed by cell counting kit-8 assay(CCK-8), EdU incorporation and flow cytometry. Rat models of HPH were constructed to verify the role of DNA-PKcs in pulmonary vascular remodeling in vivo. RESULTS: DNA-PKcs protein levels were both significantly up-regulated in explants of pulmonary artery from HPH models and lung tissues of patients with hypoxemia. In human PASMCs, hypoxia up-regulated DNA-PKcs in a time-dependent manner. Downregulation of DNA-PKcs by targeted siRNA or small-molecule inhibitor NU7026 both induced cell proliferation inhibition and cell cycle arrest. DNA-PKcs affected proliferation by regulating NOR1 protein synthesis followed by the expression of cyclin D1. Co-immunoprecipitation of NOR1 with DNA-PKcs was severely increased in hypoxia. Meanwhile, hypoxia promoted G2 + S phase, whereas the down-regulation of DNA-PKcs and NOR1 attenuated the effects of hypoxia. In vivo, inhibition of DNA-PKcs reverses hypoxic pulmonary vascular remodeling and prevented HPH. CONCLUSIONS: Our study indicated the potential mechanism of DNA-PKcs in the development of HPH. It might provide insights into new therapeutic targets for pulmonary vascular remodeling and pulmonary hypertension.

Long Intergenic Non-protein Coding RNA 511 in Cancers.

Background: Long intergenic non-protein coding RNA 511 (LINC00511) is upregulated in diverse cancers and involved in prognosis. This study aimed to evaluate the prognostic profile of LINC00511 in cancer patients. Methods: Published studies evaluating the prognosis of LINC00511 in patients with different cancers were identified from Medline, Embase, and Web of Science. Analysis of the association between LINC00511 and clinicopathological characteristics was conducted. GEPIA was used to validation and functional analysis and LnCeVar was used to get genomic variations. Results: We eventually included 9 studies, and the combined results showed LINC00511 was significantly associated with decreased OS (HR = 3.18, 95% CI = 2.29 ~ 4.42, P < 0.001) albeit with mild heterogeneity (I 2 = 58.1%, P h = 0.014), similarly in cancer type subgroups: breast cancer, digestive system cancer, and cervical cancer (all P < 0.001). There is no publication bias and meta-regression indicated follow-up time maybe heterogeneity of the results (P = 0.008). Additionally, LINC00511 appeared to be correlated with age, clinical stage, tumor size, and lymph node metastasis. Those findings were confirmed in GEPIA. Through LnCeVars, gene ontology and functional pathways were enriched, and dysregulated hallmarks and related ceRNA network of LINC00511 were disturbed. Conclusions: LINC00511 could be predictive of poor OS and lymph node metastasis in multiple cancers, in another word, LINC00511 serves as an unfavorable prognostic factor, and its mechanism is related to ceRNA.

The roles of MASPIN expression and subcellular localization in non-small cell lung cancer.

Accumulating studies have confirmed that mammary serine protease inhibitor (MASPIN) plays an essential role in non-small cell lung cancer (NSCLC). However, results are still controversial or inconsistent. In the present study, we attempted to identify the clinical significance of MASPIN and its potential molecular roles in NSCLC. The correlation of MASPIN with prognosis and clinicopathological characteristics was assessed by meta-analysis. Additionally, the potential molecular mechanisms of MASPIN in NSCLC was also investigated through several online databases. A total of 2220 NSCLC patients from 12 high quality studies were included and the results indicated that up-regulated MASPIN nucleus and cytoplasm expression was associated with poor overall survival (OS) (hazard ratio (HR) = 1.43, 95% confidence interval (CI) = 1.01-2.04, P<0.05), elevated MASPIN cytoplasm expression was associated with poor OS (HR = 1.45, 95% CI = 1.01-2.07, P<0.05), disease-free survival (DFS) (HR = 1.95, 95% CI = 1.31-2.88, P=0.001), and disease-specific survival (DSS) (HR = 2.17, 95% CI = 1.18-3.99, P=0.013). MASPIN both nucleus and cytoplasm location were associated with clinicopathological characteristics. Bioinformatics analysis validated the above results and suggested that human serpin family B member 5 (SERPINB5) hypomethylated levels were negatively correlated with its mRNA expression. Bioinformatics analysis also revealed the 85 most frequently altered neighboring genes of SERPINB5, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed 20 GO terms and 3 KEGG pathways with statistical significance. MASPIN had a statistically negative correlation with NSCLC prognosis, functioning as an oncoprotein by hypomethylation and influencing specific pathways involving the 85 genes identified herein. MASPIN might be a promising prognostic signature in NSCLC.

Resveratrol prevented experimental pulmonary vascular remodeling via miR-638 regulating NR4A3/cyclin D1 pathway.

OBJECTIVE: Resveratrol has shown benefit for pulmonary hypertension improvement. Our previous reports showed NR4A3/cyclin D1 pathway promoted pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study tried to explore the mechanism underlying this process, focusing on the role of resveratrol in regulation of miRNA and NR4A3. METHODS: Rats were injected with monocrotaline (MCT) to establish pulmonary hypertension (PH) models. Resveratrol was used to prevent pulmonary vascular remodeling. Primary rat PASMCs were cultured in vitro and stimulated by platelet-derived growth factor (PDGF) with or without resveratrol. Cells proliferation and expression of miR-638 as well as NR4A3 were evaluated. RESULTS: MCT resulted in significant pulmonary vascular remodeling and down-regulation of miR-638, which could be suppressed by resveratrol. Moreover, PDGF-induced PASMC proliferation and miR-638 down-regulation were both significantly prevented by resveratrol treatment in vitro. MiR-638 mimics markedly inhibited PASMC proliferation and percentage of PCNA-positive cells in vitro. But anti-miR-638 could markedly promote cells proliferation and percentage of PCNA-positive cells. The luciferase reporter assay showed that NR4A3 was a direct target of miR-638. The loss-of-function and gain-of-function experiments indicated that NR4A3 promoted proliferation via cyclin D1 pathway. CONCLUSION: Our data indicated that resveratrol prevented MCT-induced pulmonary vascular remodeling via miR-638 regulating NR4A3/cyclin D1 pathway.

Low-dose apatinib monotherapy in advanced chemotherapy-refractory small cell lung cancer: a case series and literature review.

The therapeutic regimen for small cell lung cancer (SCLC) has changed little in the past several decades. Apatinib is a small molecule inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase. Apatinib has demonstrated efficacy against advanced gastric cancer and breast cancer, and recent studies have also reported its successful use in non-SCLC; however, its efficacy in SCLC remains unclear. In this study, we used apatinib as salvage therapy for chemotherapy-refractory SCLC. Five male patients with advanced SCLC were administered oral apatinib (250 mg/day) as 2nd- to 4th-line treatment. One patient showed a partial response to apatinib, one showed stable disease, and three patients showed progressive disease. The progression-free survival durations in the patients with stable disease and partial response were 1.5 and 3 months, respectively. Only three patients showed adverse effects, including mild hypertension, vomiting, and hand-foot syndrome, respectively, all of which were manageable. Apatinib might thus be a salvage option in patients with advanced SCLC after chemotherapy.

Fasting blood glucose levels and prognosis in patients with non-small-cell lung cancer: a prospective cohort study in China.

PURPOSE: Non-small-cell lung cancer (NSCLC) is the most diagnosed lung cancer and is associated with poor prognosis. This study aimed to analyze whether fasting blood glucose (FBG) levels could provide prognostic information in Chinese patients with NSCLC, using the Suzhou Lung Cancer Survival study. PATIENTS AND METHODS: A prospective cohort study of adult patients with primary NSCLC was performed. The patients who were hospitalized between January 2016 and April 2018 in two hospitals affiliated with Soochow University were recruited. Patient information, including lifestyle habits and clinical and laboratory data, were collected through face-to-face interviews and evaluation of medical records. Follow-up was initiated from the date of patient enrollment until May 8, 2018 or until patient death. The long-term survival of patients was assessed every 6 months. Patient vital status was confirmed by using hospital records, telephone interview, or local death registration system. Cox proportional hazards regression was used to estimate hazard ratio and 95% confidence interval (CI) for death, with adjustment for cancer stage, medical treatments, smoking, and other potential confounders. RESULTS: A total of 387 patients were included in the analysis, and the numbers (percentages) of patients with stages I, II, III, and IV NSCLC were 53 (13.7%), 41 (10.6%), 64 (16.5%), and 215 (55.6%), respectively. The median duration of follow-up was 19.1 months. Compared with patients in the second tertile of FBG, the HRs for mortality were 2.16 (95% CI: 1.26-3.73) and 1.87 (95% CI: 1.03-3.42) for those in the lowest one and diabetic group, respectively. Subgroup analysis according to various patient characteristics confirmed these associations. CONCLUSION: Diabetes and low FBG could be important predictors of death in patients with NSCLC. Maintaining appropriate blood glucose levels may improve prognosis in patients with NSCLC.

A Pilot Study of a Novel through-the-Scope Self-Expandable Metallic Airway Stents Delivery System in Malignant Central Airway Obstruction.

Objective: Self-expandable metallic (SEM) airway stents are an important approach to malignant central airway obstruction (CAO). SEM airway stent insertions are usually performed under fluoroscopic guidance over a guide wire placed through a flexible bronchoscope often resulting in a longer procedure time and exposure to radiation. In this pilot study, we designed a novel delivery system of the through-the-scope (TTS) SEM airway stent insertion and observed its feasibility. Methods: From Jan 2015 to Sept 2016, 25 consecutive patients with inoperable malignant CAO were enrolled requiring airway stent implantation. All patients were followed up to death or at least 6 months. Results: 36 TTS stents were inserted into 25 patients using a flexible bronchoscope under general anesthesia or local anesthesia. All stents were successfully deployed directly through the working channel (2.8 mm diameter) of the flexible bronchoscope in 91.7% (33/36) of the subjects. The mMRC score and stenosis grade improved significantly after stent implantation. The common stent-related complications were secretion retention (25%, 9/36), development of granulation tissue (13.9%, 5/36), tumor in-growth (13.9%, 5/36), and hemoptysis (8.3%, 3/36). The 6-month overall survival (OS) was 44% (11/25). Conclusion: The novel TTS stent release system was an effective and safe approach in malignant central airway obstruction.

Post-diagnostic C-reactive protein and albumin predict survival in Chinese patients with non-small cell lung cancer: a prospective cohort study.

Non-small cell lung cancer (NSCLC) is the most commonly diagnosed lung cancer and is associated with poor prognosis. This study aimed to analyze if serum C-reactive protein (CRP), albumin (Alb), and CRP/Alb ratio could provide prognostic information in patients with NSCLC. 387 patients with primary NSCLC were included in this analysis. Cox proportional hazards regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI) of death with adjustment for some potential confounders. The multivariate regression analyses revealed the statistically significant associations of decreased survival of patients with NSCLC with elevated CRP, decreased Alb, and elevated CRP/Alb ratio. The HRs of mortality were 1.56 (95% CI: 0.80-3.04) and 2.64 (95% CI: 1.35-5.16) for patients in the second and the highest tertiles of CRP (P-trend = 0.003). For albumin, the HR was 0.50 (95% CI: 0.29-0.85) for the normal group. The CRP/Alb ratio strongly predicted the survival of patients in the highest tertile with a fourfold risk of dying compared with those in the lowest tertile (HR = 4.14, 95% CI: 2.15-7.98). The subgroup analysis according to various patient characteristics confirmed these associations. In conclusion, serum CRP, albumin, and CRP/Alb ratio are predictive of survival for Chinese patients with NSCLC.

Low dosage of apatinib monotherapy as rescue treatment in advanced lung squamous cell carcinoma.

PURPOSE: Platinum-based doublet chemotherapy and radiotherapy are the standard treatment option in advanced squamous cell carcinoma patients. However, few agents could be selected for subsequent post-second-line treatment. As a small molecule inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase, apatinib had been proved in advanced gastric cancer. Here, we showed its efficacy and safety in lung squamous cell carcinoma. METHODS: In this retrospective study, 13 advanced lung squamous cell carcinoma patients were enrolled. They received doublet chemotherapy or docetaxel as the first-line treatment. After disease progressed, all patients were administrated apatinib monotherapy (250-425 mg/day) for second-line or fourth-line therapy. RESULTS: After apatinib monotherapy, two patients achieved partial response, four patients achieved stable disease, and seven patients achieved progression disease. The medium PFS was 3.1 months. The median OS had not yet been reached. The objective remission rate was 15.4% (2/13). The total disease control rate was 46.2% (6/13). The main advert effects were vomiting and hypertension. CONCLUSION: Apatinib might be an option as rescue treatment in advanced lung squamous cell carcinoma.