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.

The role of tracheal wall injury in the development of benign airway stenosis in rabbits.

To investigate the role of tracheal wall injury in the development of benign airway stenosis in rabbits. Prospective study. We injured the tracheal walls of 28 New Zealand white rabbits using four different methods. Experimental group: Group A (n = 7, mild injury of tracheal mucosa by ordinary brush under bronchoscopy); Group B (n = 7, severe injury of tracheal mucosa by nylon brush under tracheotomy); Group C (n = 7, tracheal cartilage was injured by vascular clamp after tracheotomy); Group D (n = 7, the tracheal cartilage was injured with vascular forceps and the tracheal mucosa was injured with a nylon brush after tracheotomy). Bronchoscopy was performed on each experimental rabbit at 1, 2, 3 and 4 weeks after operation. High-resolution computed tomography (HRCT) and endobronchial optical coherence tomography (EB-OCT) were performed at 4 weeks, and the rabbits were sacrificed after the examination. Their gross and histological findings were comparatively determined whether the experimental rabbit stenosis was established. No airway stenosis was observed in group A. In group B, 28.57% of experimental rabbits developed tracheal stenosis (granulation tissue proliferation was observed in rabbits No. 2 and No. 6 at 1, 2 and 3 weeks after operation, and the tracheal scar contracture was observed in No.6 rabbit at 4 weeks after operation). Fourteen rabbits in group C and group D had tracheal stenosis caused by granulation tissue proliferation at 1, 2 and 3 weeks after operation. At the fourth week after operation, 71.43% of experimental rabbits had tracheal stenosis due to granulation tissue hyperplasia, 7.14% of experimental rabbits had tracheal stenosis due to scar contracture and granulation hyperplasia, and 21.43% of experimental rabbits had tracheal stenosis due to scar contracture. EB-OCT scan showed that the cartilage layer with low signal reflection band was discontinuous. The injury of cartilage is the key factor of benign airway stenosis. Acute injury of airway mucosa alone is unlikely to cause airway stenosis, but combined with cartilage injury may aggravate airway stenosis. EB-OCT can clearly identify the airway layers of rabbits, which is helpful to evaluate the damage of tracheal cartilage and mucosa. The diagnostic potential of this technique makes EB-OCT a promising approach for the study and monitoring of airway diseases.

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.