Combination therapy with long-acting bronchodilators and the risk of major adverse cardiovascular events in patients with COPD: a systematic review and meta-analysis.

INTRODUCTION: Accumulated high-quality data from randomised controlled trials (RCTs) indicate that long-acting muscarinic antagonist (LAMA)/long-acting ß2 agonist (LABA) combination therapy significantly improves clinical symptoms and health status in patients with chronic obstructive pulmonary disease (COPD) and reduces exacerbation risk. However, there is a growing concern that LAMA/LABA therapy may increase the risk of cardiovascular disease in patients with COPD. The aim of this paper is to determine whether the use of LAMA/LABA combination therapy modifies the risk of cardiovascular disease in patients with COPD. METHODS: Two reviewers independently searched Embase, PubMed and Cochrane Library to identify relevant RCTs of LAMA/LABA or LABA/LAMA/inhaled corticosteroids (ICS) for the management of patients with COPD that reported on cardiovascular end-points. The primary outcome was major adverse cardiovascular events (MACE), which was a composite of cardiovascular death, myocardial infarction or stroke. RESULTS: A total of 51 RCTs enrolling 91 021 subjects were analysed. Both dual LAMA/LABA (1.6% versus 1.3%; relative risk 1.42, 95% CI 1.11-1.81) and triple therapy (1.6% versus 1.4%; relative risk 1.29, 95% CI 1.03-1.61) significantly increased the risk of MACE compared with ICS/LABA. The excess risk was most evident in RCTs in which the average underlying baseline risk for MACE was >1% per year. Compared with LAMA only, LABA only or placebo, dual LAMA/LABA therapy did not significantly increase the risk of MACE, though these comparisons may have lacked sufficient statistical power. CONCLUSION: Compared with ICS/LABA, dual LAMA/LABA or triple therapy increases cardiovascular risk in patients with COPD. This should be considered in the context of the incremental benefits of these therapies for symptoms and exacerbation rates in patients with COPD, especially in those with a MACE risk of >1% per year.

Prognostic nomograms for lung neuroendocrine carcinomas based on lymph node ratio: a SEER database analysis.

OBJECTIVE: The current study aimed to explore the prognostic value of the lymph node ratio (LNR) in patients with lung neuroendocrine carcinomas (LNECs). METHODS: Data for 1564 elderly patients with LNECs between 1998 and 2016 were obtained from the Surveillance, Epidemiology, and End Results database. The cases were assigned randomly to training (n = 1086) and internal validation (n = 478) sets. The association between LNR and survival was investigated by Cox regression. RESULTS: Multivariate analyses identified age, tumor grade, summary stage, M stage, surgery, and LNR as independent prognostic factors for both overall survival (OS) and lung cancer-specific survival (LCSS). Tumor size was also a prognostic determinant for LCSS. Prognostic nomograms combining LNR with other informative variables showed good discrimination and calibration abilities in both the training and validation sets. In addition, the C-index of the nomograms was statistically superior to the American Joint Committee on Cancer (AJCC) staging system in both the training and validation cohorts. CONCLUSIONS: These nomograms, based on LNR, showed superior prognostic predictive accuracy compared with the AJCC staging system for predicting OS and LCSS in patients with LNECs.

Pedigree analysis of the EGFR p.V1010M germline mutation in a family with a family history of non-small-cell lung cancer.

Background: Tumors can be caused by genetic or environmental factors, but previous studies have shown that genetic factors contribute less to lung cancer than environmental factors. The epidermal growth factor receptor (EGFR) is the most common driver gene in non-small-cell lung cancer (NSCLC), but most variations are somatic. In this study, we reported on the pedigree of the EGFR p.V1010M germline mutation for the first time, and explored the correlation between the V1010M and the occurrence of NSCLC. Further, the effect of the V1010M on the treatment of the EGFR-tyrosine kinase inhibitors (TKIs) was investigated through the treatment of the proband with the simultaneous somatic mutation of the EGFR p.L858R. Methods: The family members were screened using next-generation sequencing (NGS) and Sanger sequencing, and the pedigree was analyzed to examine the relationship between the EGFR p.V1010M and the occurrence of NSCLC. Schrodinger software was used to predict the structural function of the mutant amino acid sequence proteins. Results: A total of 10 blood samples were collected from 4 generations of family members, many of whom had suffered from lung cancer. Six carriers of the EGFR p.V1010M were detected. The pedigree analysis showed that there was still no evidence of a correlation between the EGFR p.V1010M and disease occurrence. Additionally, the proband had the EGFR p.L858R somatic mutation, and the response after the treatment of gifitinib was stable disease (SD), which turned to progressive disease (PD) some 4 months later. Schrodinger software showed that the 1010th amino acid valine was located near the C terminal, and the variation to methionine had little effect on the structure of the EGFR dimer. Conclusions: This study is the first report on pedigree with the EGFR p.V1010M germline mutation. Further research needs to be conducted to determine whether this mutation is pathogenic, but it is likely related to EGFR-TKI resistance in NSCLC.

Albumin corrected anion gap for predicting in-hospital mortality among intensive care patients with sepsis: A retrospective propensity score matching analysis.

BACKGROUND: The relationship between albumin corrected anion gap (ACAG) and in-hospital mortality of intensive care sepsis patients is currently inconclusive. METHODS: The baseline data, concentration of albumin, anion gap (AG), ACAG and in-hospital prognosis of intensive care patients with sepsis were retrieved from the Medical Information Mart for Intensive Care IV database. Propensity score matching (PSM) analysis was performed to reduce bias. Receiver operating characteristic curves were drawn for albumin, AG, and ACAG, and comparisons between the areas under the ROC curves were conducted. Decision curve analysis (DCA) was performed to determine the net benefit of ACAG. RESULTS: ACAG was related to in-hospital mortality in intensive care patients with sepsis. The AUCs of ACAG were 0.689 (before PSM) and 0.644 (after PSM), which were significantly higher than that of albumin or AG. The Youden's index of ACAG was the highest, and the net benefit range of ACAG was also the largest according to the DCA. CONCLUSIONS: ACAG has the highest predictive value for in-hospital mortality of intensive care patients with sepsis, which is better than albumin and AG. Using ACAG to predict the in-hospital mortality to guide clinical applications may obtain the highest net benefit.

The association between four scoring systems and 30-day mortality among intensive care patients with sepsis: a cohort study.

Several commonly used scoring systems (SOFA, SAPS II, LODS, and SIRS) are currently lacking large sample data to confirm the predictive value of 30-day mortality from sepsis, and their clinical net benefits of predicting mortality are still inconclusive. The baseline data, LODS score, SAPS II score, SIRS score, SOFA score, and 30-day prognosis of patients who met the diagnostic criteria of sepsis were retrieved from the Medical Information Mart for Intensive Care III (MIMIC-III) intensive care unit (ICU) database. Receiver operating characteristic (ROC) curves and comparisons between the areas under the ROC curves (AUC) were conducted. Decision curve analysis (DCA) was performed to determine the net benefits between the four scoring systems and 30-day mortality of sepsis. For all cases in the cohort study, the AUC of LODS, SAPS II, SIRS, SOFA were 0.733, 0.787, 0.597, and 0.688, respectively. The differences between the scoring systems were statistically significant (all P-values < 0.0001), and stratified analyses (the elderly and non-elderly) also showed the superiority of SAPS II among the four systems. According to the DCA, the net benefit ranges in descending order were SAPS II, LODS, SOFA, and SIRS. For stratified analyses of the elderly or non-elderly groups, the results also showed that SAPS II had the most net benefit. Among the four commonly used scoring systems, the SAPS II score has the highest predictive value for 30-day mortality from sepsis, which is better than LODS, SIRS, and SOFA. The results of the DCA curves show that using the SAPS II score to predict the 30-day mortality of intensive care patients with sepsis to guide clinical applications may obtain the highest net benefit.

Diagnostic management of inpatients with a positive D-dimer test: developing a new clinical decision-making rule for pulmonary embolism.

BACKGROUND: A positive D-dimer test has high sensitivity but relatively poor specificity for the diagnosis of pulmonary embolism, causing difficulty for clinicians unskilled in pulmonary embolism diagnosis in determining whether a patient with a positive D-dimer test needs to undergo computed tomographic pulmonary angiography. OBJECTIVES: We sought to develop a new clinical decision-making rule based on a positive D-dimer result to predict the probability of pulmonary embolism and to guide clinicians in making decisions regarding the need for computed tomographic pulmonary angiography. METHODS: We conducted a prospective, multicenter study in three hospitals in China. A total of 3014 inpatients with positive D-dimer results were included. In the derivation group, we built a multivariate logistic regression model and deduced a regression equation from which our score was derived. Finally, we validated the score in an independent cohort. RESULTS: Our score included nine variables (points): chest pain (1.4), chest tightness (2.3), shortness of breath (3.6), hemoptysis (3.4), heart rate ≥100 beats/min (3.6), blood gas analysis (2.9), electrocardiogram presenting a typical S1Q3T3 pattern (4.1), electrocardiogram findings (2.4), and ultrasonic cardiogram findings (3.7). The sensitivities and specificities were 100% and 86.94%, respectively, in the derivation group and 100% and 90.82%, respectively, in the validation group. Additionally, the observed and predicted proportions of patients who underwent computed tomographic pulmonary angiography were 16.82% and 10.76%, respectively, in the derivation group and 18.72% and 11.40%, respectively, in the validation group. CONCLUSIONS: The new score can categorize inpatients with a positive D-dimer test as pulmonary embolism-likely or pulmonary embolism-unlikely, thus reducing unnecessary computed tomographic pulmonary angiography examinations.

Plasma YKL-40 and NGAL are useful in distinguishing ACO from asthma and COPD.

BACKGROUND: Asthma-chronic obstructive pulmonary disorder (COPD) overlap (ACO) is characterized by the coexistence of features of both asthma and COPD and is associated with rapid progress and a poor prognosis. Thus, the early recognition of ACO is crucial. OBJECTIVES: We sought to explore the plasma levels of biomarkers associated with asthma (periostin, TSLP and YKL-40), COPD (NGAL) and their possible correlation with lung function, the bronchodilator response and radiographic imaging in patients with asthma, COPD and with features of ACO. METHODS: We enrolled 423 subjects from 6 clinical centers. All participants underwent blood collection, lung function measurements, bronchodilator response tests and high-resolution CT. Correlations of the plasma biomarkers with lung function, the bronchodilator response and percentemphysema were calculated by Spearman's rank correlation and multivariate stepwise regressionanalysis. RESULTS: 1) Patients with features of ACO had lower plasma YKL-40 than COPD patients and a moderate elevated plasma level of NGAL compared with asthma patients. 2) Patients with features of ACO had an intermediate degree of airflow obstruction, the bronchodilator response and emphysema between patients with COPD and asthma. 3) Plasma YKL-40 was negatively correlated with lung function and with the bronchodilator response, and plasma NGAL was positively correlated with the extent of emphysema. CONCLUSIONS: Plasma YKL-40 is a promising candidate for distinguishing between patients with features of ACO and COPD patients, while plasma NGAL may be a valuable biomarker for differentiating between patients with features of ACO and asthma patients. CLINICAL TRIAL REGISTRATION: ChiCTR-OOC-16009221.

Interleukin-13 stimulates MUC5AC expression via a STAT6-TMEM16A-ERK1/2 pathway in human airway epithelial cells.

Transmembrane protein 16A (TMEM16A), a channel underlying the calcium-activated chloride channel (CaCC) currents, has been shown to be a key regulator of mucus overproduction in airway epithelial cells. However, the precise molecular mechanism involved in the TMEM16A-mediated mucus secretion remains unclear. In the present study, we inquired into a novel signaling mechanism for TMEM16A driving mucin 5AC (MUC5AC) production in human airway epithelial cells. Following treatment for 24-48h with type 13 interleukin (IL-13), an upregulation of TMEM16A expression in both mRNA and protein levels was observed in human bronchial epithelial cell line (HBE16), while signal transducer and activator of transcription 6 (STAT6) inhibition could decrease this elevated expression, suggesting that the regulation of TMEM16A expression by IL-13 was via a STAT6-based transcriptional mechanism. Further investigation of the HBE16 cells revealed that TMEM16A knockdown or specific chloride channel inhibitor T16Ainh-A01 could suppress the CaCC currents and consequently reduce the extracellular regulated kinase (ERK1/2) phosphorylation, accompanying a dramatical decrease in MUC5AC expression. Moreover, pretreated with PD98059, an inhibitor of ERK1/2, the HB16 cells showed a remarkable diminution in TMEM16A-mediated MUC5AC expression. Altogether, STAT6-TMEM16A-ERK1/2 signal pathway and TMEM16A channel activity are required for the IL-13-induced TMEM16A mediated mucus production.

Functional Effects of WNT1-Inducible Signaling Pathway Protein-1 on Bronchial Smooth Muscle Cell Migration and Proliferation in OVA-Induced Airway Remodeling.

Upregulation of WISP1 has been demonstrated in lung remodeling. Moreover, it has been recently found that some signaling components of WNT pathway can activate GSK3ß signaling to mediate remodeling of airway smooth muscle (ASM) in asthma. Therefore, we hypothesized that WISP1, a signaling molecule downstream of the WNT signaling pathway, is involved in PI3K/GSK3ß signaling to mediate ASM remodeling in asthma. Our results showed that WISP1 depletion partly suppressed OVA-induced ASM hypertrophy in vivo. In vitro, WISP1 could induce hBSMC hypertrophy and proliferation, accompanied by upregulation of levels of PI3K, p-Akt, p-GSK3ß, and its own expression. TGF-ß treatment could increase expression of PI3K, p-Akt, p-GSK3ß, and WISP1. SH-5 treatment could partly suppress TGF-ß-induced hypertrophy and proliferation of hBSMC, and depress expression of p-GSK3ß and WISP1. In conclusion, WISP1 may be a potential inducer of ASM proliferation and hypertrophy in asthma. The pro-remodeling effect of WISP1 is likely due to be involved in PI3K-GSK3ß-dependent noncanonical TGF-ß signaling.

TMEM16A mediates the hypersecretion of mucus induced by Interleukin-13.

Previous studies showed that the Ca(2+)-activated Cl(-) channel (CaCC) was involved in the pathogenesis of mucus hypersecretion induced by Interleukin-13 (IL-13). However, the mechanisms underlying the process were unknown. Recently, transmembrane protein 16A (TMEM16A) was identified as the channel underlying the CaCC current. The aim of the current study was to investigate whether the TMEM16A channel is part of the mechanism underlying IL-13-induced mucus hypersecretion. We observed that both TMEM16A mRNA and protein expression were significantly up-regulated after treatment with IL-13 in human bronchial epithelial 16 (HBE 16) cells, which correlated with an increase in mucus production. Additionally, mucus hypersecretion in rat airways was induced by intratracheal instillation of IL-13 and similar increases were observed in the expression of TMEM16A mRNA and protein in the bronchial epithelium. Niflumic acid (NA), a selective antagonist of CaCC, markedly blocked IL-13-induced mucin (MUC) 5AC mRNA and protein production in vivo and in vitro. Further investigation with HBE16 cells revealed that TMEM16A overexpression clearly promoted mucus production, IκBα phosphorylation, and p65 accumulation in the nucleus. The loss of TMEM16A resulted in inhibition of mucus production, and the TMEM16A-mediated production of MUC5AC was significantly blocked by a nuclear factor-kappa B (NF-κB) inhibitor. Therefore, the TMEM16A channel acts upstream of NF-κB in the regulation of mucus production. This is the first demonstration that the TMEM16A-NF-κB pathway is positively involved in IL-13-induced mucus production, which provides novel insight into the molecular mechanism of mucin overproduction.

A role for WNT1-inducible signaling protein-1 in airway remodeling in a rat asthma model.

Over-expression of WISP1 has been described in multi-organ fibrosis and tissue remodeling. Moreover, it has recently been found that polymorphism of WISP1 gene is related with the change of lung function in asthmatic subjects. Therefore, we hypothesized that WISP1 might be closely linked to occurrence and development of asthmatic airway remodeling. Aim of this study was to examine the roles of WISP1 in an asthmatic model with airway remodeling and assess the specific effects of WISP1 on human lung fibroblast in vitro. Animal models were developed by challenged with ovalbumin. The levels of WISP1 expression in animal models were assessed by real-time PCR and immunohistochemistry. To examine the specific effects of WISP1 on airway remodeling, WISP1 was depleted by neutralizing α-WISP1 antibodies in vivo. Moreover, human lung fibroblast (HFL-1) was challenged with WISP1 in the presence and absence of SH-5 in vitro. Our study showed that OVA exposure increased the levels of WISP1 expression in a rat asthma model. WISP1 depletion could partially inhibit OVA-induced airway remodeling. In vitro, WISP1-treated HFL-1 cells presented abnormal proliferation and over-expression of Col1a1 and Fn1. However, WISP1-induced collagen release from HFL-1 cells could be attenuated by pretreatment with an Akt inhibitor. Moreover, the levels of p-Akt and p-GSK-3ß in WISP1-treated HFL-1 cells were also significantly elevated. In summary, WISP1 might initiate and perpetuate the pathological remodeling of asthma by inducing fibroblast proliferation and ECM deposition. The specific effects of WISP1 were likely due to activation of pulmonary Akt/GSK-3ß signaling.