Noncoding RNAs play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). In this study, we investigated the roles of hsa_circ_0016070, miR-942, and CCND1 in PAH. circRNA microarray was used to search circRNAs involved in PAH, whereas real-time PCR and western blot analysis were performed to detect miR-942 and CCND1 expression in different groups. In addition, the effect of miR-942 on CCND1 expression, as well as the effect of hsa_circ_0016070 on the expression of miR-942 and CCND1, was also studied using real-time PCR and western blot analysis. Moreover, MTT assay and flow cytometry were used to detect the effect of hsa _circ_0016070 on cell proliferation and cell cycle. According to the results of circRNA microarray analysis, hsa _circ_0016070 was identified to be associated with the risk of PAH in chronic obstructive pulmonary disease (COPD) patients. The miR-942 level in the COPD(+) PAH(+) group was much lower than that in the COPD(+) PAH(−) group, while the CCND1 level in the COPD(+) PAH(+) group was much higher. CCND1 was identified as a candidate target gene of miR-942, and the luciferase assay showed that the luciferase activity of wild-type CCND1 3′ UTR was inhibited by miR-942 mimics. In addition, hsa _circ_0016070 reduced miR-942 expression and enhanced CCND1 expression. Furthermore, hsa _circ_0016070 evidently increased cell viability and decreased the number of cells arrested in the G1/G0 phase. In summary, the results of this study suggested that hsa_circ_0016070 was associated with vascular remodeling in PAH by promoting the proliferation of pulmonary artery smooth muscle cells (PASMCs) via the miR-942/CCND1. Accordingly, has_circ_0016070 might be used as a novel biomarker in the diagnosis and treatment of PAH.

ObjectivesThis study aimed to evaluate the correlation between positive PD-L1 expression and driver gene mutations in NSCLC and to seek preliminary evidence in favor of the strategy of PD-L1 inhibitors plus targeted agents.ResultsThe overall analyses revealed that positive PD-L1 expression had a significant relationship with KRAS status (RR = 1.26; 95% CI, 1.06−1.50, P = 0.010), but no correlation with clinical characteristics (gender, smoking status, histological types), driver gene status (EGFR, ALK) and overall survival (OS): male versus female (RR = 1.16; 95% CI, 0.95−1.42; P = 0.15), never smoking versus former/current smoking (RR = 0.79; 95% CI, 0.56−1.11; P = 0.17), adenocarcinoma versus non-adenocarcinoma (RR = 0.94; 95% CI, 0.63−1.41; P = 0.77), EGFR mutation versus EGFR wild type (RR = 0.74; 95% CI, 0.52−1.06; P = 0.10), ALK positive versus ALK negative (RR = 1.02; 95% CI, 0.75−1.38; P = 0.91), OS of positive PD-L1 expression versus that of negative PD-L1 expression (HR = 1.31, 95% CI, 0.90−1.90; P = 0.15), respectively. Noteworthily, subgroup analyses exhibited that in Chinese cohort studies, positive PD-L1 expression was significantly correlated with OS (HR = 1.75, 95% CI, 1.36−2.24, P < 0.0001); and in the studies using PD-L1 monoclonal antibodies (McAbs), positive PD-L1 expression was significantly correlated with KRAS mutation (RR = 1.32, 95% CI, 1.06−1.65, P = 0.01) and EGFR mutation (RR = 0.51, 95% CI, 0.28−0.93, P = 0.03).Materials and MethodsAfter thoroughly searching PubMed, EMBASE and Cochrane Library databases, 11 relevant studies incorporating 3128 cases were identified. The pooled data were analyzed via Review manager 5.3 software.ConclusionsPD-L1 inhibitors probably was a potential promising option to manage advanced NSCLC harboring KRAS mutation.

Non-coding RNAs play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). The aim of this study was to characterize the therapeutic role of melatonin as well as the underlying molecular mechanism (its effects on the expression of H19 and its downstream signaling pathways) in the treatment of PAH. Real-time PCR and western blot analysis were performed to evaluate the expression of H19, miR-200a, miR-675, insulin-like growth factor-1 receptor (IGF1R), and programmed cell death 4 (PDCD4). The value of systolic pulmonary artery pressure (SPAP) and the ratio of medial thickening in the monocrotaline (MCT) group were increased, whereas the melatonin treatment could decrease these values to some extent. The weights of RV (right ventricle), LV (left ventricle) + IVS (interventricular septal), and RV/(LV + IVS) in the MCT group were much higher than those in the MCT + melatonin and control groups. In addition, the expression of H19, miR-675, IGF1R mRNA, and IGF1R protein in the MCT group was the highest, whereas their expression in the control group was the lowest. The expression of miR-200, PDCD4 mRNA, and PDCD4 protein in the MCT group was the lowest, whereas their expression in the control group was the highest. Furthermore, H19 directly suppressed the expression of miR-200a, whereas miR-675-3p and miR-200a directly inhibited the expression of IGF1R and PDCD4, respectively. Finally, melatonin treatment inhibited cell proliferation; upregulated the expression of H19, miR-675-3p, and PDCD4; and downregulated the expression of miR-200a and IGF1R. This study demonstrated the role of H19-miR-675-3p-IGF1R- and H19-miR-200a-PDCD4-signaling pathways in the melatonin treatment of PAH.

Our purpose was to explore potential genetic models for systemic lupus erythematosus (SLE) and analyze genetic epidemiologic characteristics of SLE in a Chinese population. Data for 695 patients with SLE were obtained by using a uniform questionnaire. Patients, clinical characteristics and their family history were analyzed using software. A complex segregation analysis was conducted to propose potential genetic models for SLE. The mean +/- SD age of onset were 30.2 +/- 10.5 years and mean time to progression to SLE was 32.5 +/- 44.4 months. The most frequent initial manifestations were malar rash (61.3%). During the evolution of the disease, the main clinical features were arthritis in 73.6% of our patients, followed by malar rash (68.1%), and renal involvement (56.7%). As the first symptom, the late-onset group (onset of disease beyond the age of 50 years) less often showed malar rash (45% vs. 63.4% in the early-onset group; p = 0.001). There were no significant differences in the other cumulative clinical symptoms between late-onset and early-onset group, except for a lower prevalence of malar rash, photosensitivity and alopecia and a higher prevalence of mucosal ulcers in the late-onset group. A positive family history of SLE was obtained in 50 patients (7.2%). There were no statistical differences in clinical characteristics between familial SLE and sporadic SLE patients. The heritability of SLE was 43.6%, the genetic model of SLE could be polygenetic model and major gene mode is the best fitted one. SLE could be a multifactorial disease with polygenetic model.

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SummaryTo study the clinical and epidemiological profile of Pityriasis versicolor (PV) and to determine the possible genetic model for PV in Chinese Han, we investigated 503 patients with PV who were recruited by a questionnaire method. Statistical analysis, heritability and complex segregation analysis were performed using EPI INFO 6.0, SPSS 10.0, the Falconer method and the SAGE-REGTL programs. In the total 503 PV patients, the mean age of onset was 22.85 ± 10.36 years. For male and female patients, the peak ages of initial onset were both 20-29 years. A total of 106 (21.1%) patients were reported to have a positive family history of PV. The mean age of onset in males with positive family history was earlier than those with negative family history (t = 3.58, P < 0.01). Higher rate of recurrence and longer duration were seen in the patients with positive family history than those with negative family history. The heritability of PV in first-, second-and third-degree relatives was 48.13%, 40.11% and 27.20% respectively. Based on the REGTL results, the best model was a polygenic additive model for PV.

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Cigarette smoking contributes to the development of pulmonary hypertension (PH) complicated with chronic obstructive pulmonary disease (COPD), and the pulmonary vascular remodeling, the structural basis of PH, could be attributed to abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs).In this study, morphometrical analysis showed that the pulmonary vessel wall thickness in smoker group and COPD group was significantly greater than in nonsmokers. In addition, we determined the expression patterns of connective tissue growth factor (CTGF) and cyclin D1 in PASMCs harvested from smokers with normal lung function or mild to moderate COPD, finding that the expression levels of CTGF and cyclin D1 were significantly increased in smoker group and COPD group. In vitro experiment showed that the expression of CTGF, cyclin D1 and E2F were significantly increased in human PASMCs (HPASMCs) treated with 2% cigarette smoke extract (CSE), and two CTGF siRNAs with different mRNA hits successfully attenuated the upregulated cyclin D1 and E2F, and significantly restored the CSE-induced proliferation of HPASMCs by causing cell cycle arrest in G0. These findings suggest that CTGF may contribute to the pathogenesis of abnormal proliferation of HPASMCs by promoting the expression of its downstream effectors in smokers with or without COPD.