BRD4 is involved in viral exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Our previous studies have suggested that bromodomain protein 4 (BRD4) is increased in the lung of stable chronic obstructive pulmonary disease (COPD) patients, which has been shown to be involved in inflammatory responses. We investigated its role in the viral exacerbation of COPD. METHODS: BRD4, interleukin (IL)-6 and IL-8 were measured in the blood and sputum of stable COPD patients and patients with viral exacerbation. Mice were exposed to cigarette smoke (CS) and/or infected with influenza virus as an in vivo model. BRD4, IL-6 and keratinocyte-derived chemokine (KC) were measured in the lung. BEAS-2B cells were treated with CS extract and/or influenza virus as an in vitro model. BRD4, IL-6 and IL-8 were measured in the cells and/or culture supernatant. RESULTS: BRD4 was increased in COPD patients with viral exacerbation compared with those in stable condition and its expression was correlated with IL-6 and IL-8 expression. Inflammatory cells, IL-6, KC and BRD4 were synergistically induced in the lung of mice by viral infection and CS exposure, and the former three were decreased by JQ1 (BRD4 inhibitor) treatment. IL-6, IL-8 and BRD4 were significantly induced by CS extract and influenza virus in bronchial epithelial cells, and this upregulation was suppressed by knockdown of BRD4 expression. CONCLUSIONS: Our findings indicate that CS and viruses may synergistically induce IL-6 and IL-8 expression through their synergistic induction of BRD4 expression, which might contribute to the enhanced inflammatory response in the viral exacerbation of COPD.

Evaluation of Blood Markers at Admission for Predicting Community Acquired Pneumonia in Chronic Obstructive Pulmonary Disease.

Acute exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) and community acquired pneumonia (CAP) are two common acute attacks in COPD patients and it is not always easy to determine whether a COPD patient at admission has parenchymal infection or bronchial infection. Comprehensive comparison between AECOPD patients and CAP patients with COPD (COPD + CAP) can help us understand them better. We retrospectively collected the medical records of AECOPD and COPD + CAP patients. Systemic inflammation, eosinophilic inflammation, damage to other organs, common chronic comorbidities, structural changes, phenotype and endotype distributions and coagulation functions between two groups were compared and correlations of these characteristics in total subjects, AECOPD patients and COPD + CAP patients were analyzed. Logistic regression analysis was performed to select helpful biomarkers for distinguishing between them. Receiver operator characteristic (ROC) curve was plotted to assess the diagnostic value of selected biomarkers and their combination. A nomogram was established for the differential diagnosis of AECOPD and COPD + CAP. A total of 206 patients were included into our analysis. In these subjects, 104 patients were classified as AECOPD group and 102 patients were considered to have COPD + CAP mainly based on their chest CT scan results. The counts of eosinophils (EOS), basophils (BAS) and lymphocytes (LYM) and percentage of total white blood cell count, hemoglobin and hematocrit were increased in AECOPD patients compared with COPD + CAP patients. The counts of neutrophils (NEU) and percentage of total white blood cell count, C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR), fibrinogen, D-dimer and N-Terminal pro-brain natriuretic peptide (NT-proBNP) levels were increased in COPD + CAP patients. After logistic regression analysis, EOS < 0.5 × 109/L, ESR ≥ 8 mm/H and NT-proBNP ≥ 100 pg/mL were selected as helpful biomarkers for diagnosis of COPD + CAP instead of AECOPD. Area under the ROC curve (AUC) of the combination of selected biomarkers was 0.764(0.698-0.829). A nomogram was established and the calibration curve suggested that fitting efficiency of the nomogram was good. AECOPD and COPD + CAP are markedly different, mainly reflected in eosinophilic inflammation, systemic inflammation and coagulation function. Correlations between some common inflammatory biomarkers are also different in the two groups. A nomogram was established to offer help to clinicians for differential diagnosis of these two diseases.

The effects of BAFF on T lymphocytes in chronic obstructive pulmonary disease.

BACKGROUND: It has been reported that B cell activating factor belonging to the tumor necrosis factor family (BAFF) expression is increased in chronic obstructive pulmonary disease (COPD). However its role in this chronic inflammatory disease is not fully understood. Previous studies have suggested that BAFF also affects T cell function. We therefore investigated the effects of BAFF on T lymphocytes in COPD. METHODS: BAFF was detected in the cells of sputum and the plasma. Peripheral blood mononuclear cells (PBMCs) were isolated from COPD patients and treated with BAFF or BAFF plus BR3-Fc (BAFF antagonist). The apoptosis of CD4+ cells and CD8+ cells was analyzed by flow cytometry. CD4+ cells and CD8+ cells were isolated from peripheral blood of COPD patients respectively and treated with BAFF or BAFF plus BR3-Fc. Interferon-γ (IFN-γ) and interleukin-4 (IL-4) were detected in the CD4+ cells, and perforin and granzyme B were detected in the CD8+ cells. RESULTS: BAFF expression was increased in the cells of sputum and the plasma from COPD patients compared with control subjects. The plasma BAFF levels were inversely correlated with FEV1 percentage of predicted in patients with COPD. BAFF did not significantly alter the apoptosis of CD4+ cells, however it significantly inhibited the apoptosis of CD8+ cells from COPD patients. BAFF increased IFN-γ expression in the CD4+ cells from COPD patients, while it did not significantly alter the expresson of IL-4 in these cells. BAFF increased the expression of perforin and granzyme B in the CD8+ cells from COPD patients. CONCLUSIONS: Our findings indicate that BAFF may be involved in the inflammatory response in COPD via affecting T lymphocytes, suggesting a possible role of BAFF in the pathogenesis of COPD.

Pentraxin 3 promotes airway inflammation in experimental asthma.

BACKGROUND: Pentraxin 3 (PTX3) regulates multiple aspects of innate immunity and tissue inflammation. Recently, it has been reported that PTX3 deficiency enhances interleukin (IL)-17A-dominant pulmonary inflammation in an ovalbumin (OVA)-induced mouse asthma model. However, whether PTX3 treatment would provide protection against allergic airway inflammation has not been clearly elucidated. The goal of this study was to further investigate the effect of recombinant PTX3 administration on the phenotype of asthma. METHODS: C57BL/6 J mice were sensitized and challenged with OVA to induce eosinophilic asthma model, as well as sensitized with OVA plus LPS and challenged with OVA to induce neutrophilic asthma model. We evaluated effect of recombinant PTX3 on asthma phenotype through both asthma models. The bronchoalveolar lavage fluid (BALF) inflammatory cells and cytokines, airway hyperresponsiveness, and pathological alterations of the lung tissues were assessed. RESULTS: In both eosinophilic and neutrophilic asthma models, PTX3 treatment provoked airway hyperresponsiveness, concomitant with increased inflammatory cytokines IL-4, IL-17, eotaxin, and transforming growth factor (TGF)-ß1 and aggravated airway accumulation of inflammatory cells, especially eosinophils and neutrophils. In histological analysis of the lung tissue, administration of PTX3 promoted inflammatory cells infiltration, mucus production, and collagen deposition. In addition, PTX3 also significantly enhanced STAT3 phosphorylation in lung tissue. CONCLUSION: Our results show that exogenous PTX3 can exacerbate multiple asthmatic features by promoting both eosinophils and neutrophils lung infiltration and provide new evidence to better understand the complex role of PTX3 in allergic airway inflammation.

Decreased miR-29b expression is associated with airway inflammation in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common chronic airway inflammatory disease. MicroRNAs are shown to be involved in the regulation of inflammation. We investigated the role of microRNA-29b (miR-29b) in the airway inflammation in COPD. The expression of miR-29b in the lung and plasma was examined. The target of miR-29b, bromodomain protein 4 (BRD4), was predicted by online algorithms and verified in human bronchial epithelial (HBE) cells. The expression of BRD4, interleukin (IL)-8, and IL-6 in the lung was also examined. The role of miR-29b in the inflammatory cytokine expression of airway epithelial cells was studied using an in vitro model system. In total, 60 subjects were recruited, including 10 nonsmokers, 24 smokers, and 26 patients with COPD. Both lung and plasma miR-29b are decreased in patients with COPD, and miR-29b expression levels are correlated with pulmonary function and inflammation. BRD4 is increased in the lung of patients with COPD and is correlated with miR-29b and IL-8 expression. miR-29b regulates cigarette smoke extract (CSE)-induced IL-8 expression by targeting BRD4 in HBE cells. The antioxidant N-acetylcysteine prevents CSE-induced miR-29b downregulation and BRD4 and IL-8 upregulation. Our findings indicate that miR-29b may participate in the airway inflammation in COPD by regulating inflammatory cytokine expression through targeting BRD4, plasma miR-29b may serve as a biomarker for disease severity in COPD, and oxidative stress may contribute to the decrease of miR-29b induced by cigarette smoke.

Pentraxin levels in non-eosinophilic versus eosinophilic asthma.

BACKGROUND: Innate immunity has been thought to be involved in asthma pathogenesis. Pentraxins, acting as soluble pattern recognition molecules, play an important role in humoral innate immunity. Asthma is a heterogeneous inflammatory disease of airways and can be classified as eosinophilic or non-eosinophilic asthma. OBJECTIVE: To investigate whether pentraxin levels differ in subjects with eosinophilic versus non-eosinophilic asthma. Furthermore, to access the predictive performance of pentraxin levels for discriminating asthma inflammatory phenotypes. METHODS: A total of 80 asthmatic patients and 24 healthy control subjects underwent sputum induction at study inclusion. Differential leucocyte counts were performed on selected sputum. Plasma C-reactive protein (CRP), serum amyloid P (SAP), pentraxin 3 (PTX3), and sputum SAP, PTX3, IL-8 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Subjects with non-eosinophilic asthma had significantly increased pentraxin levels compared with those with eosinophilic asthma and healthy controls, with median (interquartile range) plasma CRP levels of 0.86 (0.28-2.07), 0.26 (0.14-0.85), and 0.15 (0.09-0.45)mg/L (P < .001), respectively, plasma SAP levels of 33.69 (19.79-58.39), 19.76 (16.11-30.58), and 20.06 (15.68-31.11)mg/L (P = .003), respectively, and sputum PTX3 levels of 4.9 (1.35-18.72), 0.87 (0.30-2.07), and 1.08 (0.31-4.32)ng/mL (P < .001), respectively. Conversely, sputum SAP concentrations of eosinophilic asthmatics (median, 21.49 ng/mL; IQR, 6.86-38.79 ng/mL) were significantly higher than those of non-eosinophilic patients (median, 8.15 ng/mL; IQR, 2.82-18.01 ng/mL) and healthy controls (median, 8.79 ng/mL; IQR, 2.00-16.18 ng/mL). Asthma patients with high plasma CRP (P = .004), SAP (P = .005) and sputum PTX3 levels (P < 0.001) also had significantly lower sputum eosinophil percentages. Sputum PTX3 levels had the best power (11.18-fold, P < .001) to predict non-eosinophilic airway inflammation in asthma patients. CONCLUSION AND CLINICAL RELEVANCE: Pentraxin levels differed significantly between patients with non-eosinophilic asthma and those with eosinophilic asthma. Furthermore, elevated pentraxin expressions may predict non-eosinophilic airway inflammation in asthmatic patients.

Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1ß and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia.

Pseudomonas aeruginosa causes hospital-acquired pneumonia and is associated with high mortality. An effective response to such an infection includes efficient clearance of pathogenic organisms while limiting collateral damage from the host inflammatory response, known as host resistance and host tolerance, respectively. P. aeruginosa expresses a type III secretion system (T3SS) needle complex that induces NLRC4 (NOD-like receptor C4) activation, interleukin-1ß (IL-1ß) production, and host tissue damage. Chitinase 3-like-1 (Chil1) is expressed during infection and binds to its receptor, IL-13 receptor α2 (IL-13Rα2), to regulate the pathogen-host response during Streptococcus pneumoniae infection, but the role Chil1 plays in balancing the host resistance and host tolerance during P. aeruginosa pneumonia is not known. We conducted experiments using C57BL/6 mice with or without a genetic deficiency of Chil1 and demonstrated that Chil1-deficient mice succumb to P. aeruginosa infection more rapidly than the wild type (WT). The decreased survival time in infected Chil1-deficient mice is associated with more neutrophils recruited to the airways, more lung parenchymal damage, and increased pulmonary consolidation while maintaining equivalent bacterial killing compared to WT mice. Infected Chil1-deficient mice and bone marrow-derived macrophages (BMDMs) from Chil1-deficient mice have increased production of tumor necrosis factor alpha (TNF-α) and IL-1ß compared to infected WT mice and macrophages. Infection of Chil1-deficient BMDMs with non-NLRC4-triggering P. aeruginosa, which is deficient in the T3SS needle complex, did not alter the excessive IL-1ß production compared to BMDMs from WT mice. The addition of recombinant Chil1 decreases the excessive IL-1ß production but only partially rescues stimulated BMDMs from IL-13Rα2-deficient mice. Our data provide mechanistic insights into how Chil1 regulates P. aeruginosa-induced host responses.

MBL2 polymorphisms and the risk of asthma: A meta-analysis.

BACKGROUND: The association between MBL2 gene polymorphisms and the risk of asthma has been evaluated in multiple studies; however, the results are inconsistent. OBJECTIVE: To perform a meta-analysis to explore whether MBL2 gene polymorphisms were associated with the risk of asthma. METHODS: We searched PubMed, Web of Science, and Cochrane Library to find relevant articles published up to March 2016. Nine studies, including 2066 cases and 2183 controls, were included in the meta-analysis. The strength of association was evaluated by odds ratio (OR) with 95% confidence interval (CI). RESULTS: The results reveal that MBL2 gene polymorphisms (codon 54 A/B, -550 H/L or -221 X/Y) were not associated with the risk of asthma (codon 54 A/B: BB+AB vs AA: OR, 1.02; 95% CI, 0.85-1.23; -550 H/L: LL+HL vs HH: OR, 0.81; 95% CI, 0.63-1.03; -221 X/Y: XX+YX vs YY: OR, 0.85; 95% CI, 0.69-1.04). Subgroup analysis by ethnicity implied that the MBL2 codon 54 A/B polymorphism was not significantly associated with the risk of asthma in Asians (BB+AB vs AA: OR, 0.95; 95% CI, 0.70-1.29) or whites (BB+AB vs AA: OR, 1.07; 95% CI, 0.84-1.35). CONCLUSION: The results indicated that MBL2 gene polymorphisms (codon 54 A/B, -550 H/L or -221 X/Y) may be not associated with the risk of asthma.

Regulation of Retinoic Acid Receptor Beta by Interleukin-15 in the Lung during Cigarette Smoking and Influenza Virus Infection.

Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. IL-15 is critical in antiviral immune responses. Retinoic acid (RA) signaling plays an important role in tissue maintenance and repair, particularly in the lung. We studied RA signaling and its relation to IL-15 in the lung during cigarette smoke (CS) exposure and influenza virus infection. In vivo studies show that RA signaling is diminished by long-term CS exposure or influenza virus infection alone, which is further attenuated during infection after CS exposure. RA receptor ß (RARß) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RARß is found in these mice compared with wild-type (WT) mice after infection. RARß is increased in IL-15 knockout (IL-15KO) mice compared with WT mice after infection, and the additive effect of CS and virus on RARß down-regulation is diminished in IL-15KO mice. IL-15 receptor α (IL-15Rα) is increased and RARß is significantly decreased in lung interstitial macrophages from IL-15Tg mice compared with WT mice. In vitro studies show that IL-15 down-regulates RARß in macrophages via IL-15Rα signaling during influenza virus infection. These studies suggest that RA signaling is significantly diminished in the lung by CS exposure and influenza virus infection. IL-15 specifically down-regulates RARß expression, and RARß may play a protective role in lung injury caused by CS exposure and viral infections.

Increased IL-33 expression in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by inflammatory cell activation and the release of inflammatory mediators. Interleukin-33 (IL-33) plays a critical role in various inflammatory and immunological pathologies, but evidence for its role in COPD is lacking. This study aimed to investigate the expression of IL-33 in COPD and to determine whether IL-33 participates in the initiation and progression of COPD. Levels of serum IL-33 and its receptors were measured by ELISA, and serum levels of IL-33, ST2, and IL-1 receptor accessory protein were elevated in patients with COPD compared with control subjects. Flow cytometry analysis further demonstrated an increase in peripheral blood lymphocytes (PBLs) expressing IL-33 in patients with COPD. Immunofluorescence analysis revealed that the main cellular source of IL-33 in lung tissue was human bronchial epithelial cells (HBEs). Cigarette smoke extract and lipopolysaccharide could enhance the ability of PBLs and HBEs to express IL-33. Furthermore, PBLs from patients with COPD showed greater IL-33 release in response to the stimulus. Collectively, these findings suggest that IL-33 expression levels are increased in COPD and related to airway and systemic inflammation. Therefore, IL-33 might contribute to the pathogenesis and progression of this disease.

Cigarette smoke inhibits BAFF expression and mucosal immunoglobulin A responses in the lung during influenza virus infection.

BACKGROUND: It is incompletely understood how cigarette smoke (CS) exposure affects lung mucosal immune responses during viral respiratory infections. B cell activating factor belonging to the tumor necrosis factor family (BAFF) plays an important role in the induction of secretory immunoglobulin A (S-IgA) which is the main effector of the mucosal immune system. We therefore investigated the effects of CS exposure on BAFF expression and S-IgA responses in the lung during influenza virus infection. METHODS: Mice were exposed to CS and/or infected with influenza virus. Bronchoalveolar lavage fluid and lung compartments were analyzed for BAFF expression, influenza-specific S-IgA level and histological changes. Lung B cells were isolated and the activation-induced cytidine deaminase (Aicda) expression was determined. BEAS-2B cells were treated with CS extract (CSE), influenza virus, interferon beta or N-acetylcysteine and BAFF expression was measured. RESULTS: CS inhibited BAFF expression in the lung, particularly after long-term exposure. BAFF and S-IgA levels were increased during influenza virus infection. Three-month CS exposure prior to influenza virus infection resulted in reduced BAFF and S-IgA levels in the lung as well as augmented pulmonary inflammation on day 7 after infection. Prior CS exposure also caused decreased Aicda expression in lung B cells during infection. Neutralization of BAFF in the lung resulted in reduced S-IgA levels during influenza virus infection. CSE inhibited virus-mediated BAFF induction in a dose-dependent manner in BEAS-2B cells, while this inhibition of BAFF by CSE was prevented by pretreatment with the antioxidant N-acetylcysteine. CONCLUSIONS: Our findings indicate that CS may hinder early mucosal IgA responses in the lung during influenza virus infection through oxidative inhibition of BAFF, which might contribute to the increased incidence and severity of viral infections in smokers.

Gene susceptibility identification in a longitudinal study confirms new loci in the development of chronic obstructive pulmonary disease and influences lung function decline.

BACKGROUND: To identify COPD associated gene susceptibility and lung function in a longitudinal cohort including COPD and subjects who were at risk for developing COPD, and to replicate this in two cross-sectional and longitudinal populations in Chinese Han population. METHODS: Three cohorts were recruited in this study, including an 18-year follow-up population (306 COPD and 743 control subjects) in one village in 1992 and it changed to 409 COPD and 611 controls in 2010, a 2 year follow-up study in another village (374 COPD and 377 controls) and another 2 year follow-up one in a city (541 COPD and 560 controls) in 2010. Sixteen candidate single nucleotide polymorphisms (SNPs) were selected for genotyping. Among them, 5SNPs in or near HHIP, 1SNP in IREB2 and 1SNP in FAM13A were previously reported to be associated with COPD susceptibility or lung function decline. And another 9SNPs were selected from HapMap website as HHIP tags. In 2010, totaling 1,324 COPD patients and 1,548 healthy controls were finally included in our genetic susceptibility analyses. RESULTS: We identified two new regions showing an association with COPD susceptibility in the Human Hedgehog interacting protein (HHIP) rs11100865 and rs7654947, and we confirmed that the family with sequence similarity 13 member A gene (FAM13A) rs7671167 was associated with the development of COPD in Chinese Han population. And the HHIP rs7654947 and FAM13A rs7671167 were associated with lung function decline, and this result was replicated in other two populations. CONCLUSIONS: These results suggest an important role of the HHIP and FAM13A regions as genetic risk factors for COPD development and lung function decline in Chinese Han population. Future research on these genes should focus on the molecular mechanisms of these genes on developing COPD and creating therapies to alleviate reduced lung function.

Comparison of the efficacy and safety of mometasone furoate to other inhaled steroids for asthma: a meta-analysis.

BACKGROUND: It has been of great interest whether mometasone furoate (MF) is better than other inhaled corticosteroids (ICSs) as the controller therapy in patients with moderate or severe asthma who had previously been taking ICSs. OBJECTIVE: The aim of this meta-analysis is to thoroughly compare the efficacy and safety of MF versus other ICSs with equipotent daily doses in those patients. METHODS: Relative databases were searched. Randomised controlled trials of more than or equal to 4 weeks' treatment duration comparing MF with other ICSs were reviewed. RESULTS: Six trials with 1354 randomised patients met the inclusion criteria. Significant differences favouring MF were found in all indices of pulmonary function. MF was superior compared to other ICSs in decreasing the frequency of rescue medication use and morning difficulty breathing score. There was no significant difference between MF and other ICSs therapy in morning wheezing score, cough score and percentage of patients with no nocturnal awakenings due to asthma. For the treatment-related adverse effects (AEs), treatment-related severe AEs, discontinuations due to AEs and some common symptom of AEs, MF was all similar to other ICSs in their incidence. CONCLUSIONS: In adult patients with moderate or severe asthma who had previously been taking ICSs, MF was superior to other ICSs with equipotent daily doses as controller monotherapy in improving pulmonary function and decreasing the frequency of rescue medication use, and was similar to other ICSs in the incidence of AEs. These results demonstrated the priority of MF in asthma therapy.

Mannose-binding lectin two gene polymorphisms and tuberculosis susceptibility in Chinese population: a meta-analysis.

Numerous studies have been done to explore the association between mannose-binding lectin two (MBL2) gene polymorphisms and the risk of tuberculosis (TB). However, the results are inconsistent. We performed a meta-analysis to investigate whether polymorphisms in the MBL2 gene were associated with TB risk. Databases including PubMed, Medline, Chinese Biomedicine Database, China National Knowledge Infrastructure, Wanfang Database, and Weipu Database were searched to find relevant articles published up to 2 October, 2012. Odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of association. All statistical tests were performed by using Revman 5.1 software and STATA 11.0 software. Six case-control studies including 1106 cases and 1190 controls were accepted in the meta-analysis. The results indicated that individuals carrying the MBL2 codon 54 B allele may have an increased risk of TB as compared with AA homozygotes (BB+AB vs. AA: OR=1.52, 95% CI: 1.22-1.88), whereas MBL2 +4 P/Q was possibly not associated with TB susceptibility in Chinese population.

Risk profile of bevacizumab in patients with non-small cell lung cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: Severe adverse events (AEs) have been reported in cancer patients treated with bevacizumab. Currently, safety of bevacizumab in patients with non-small cell lung cancer (NSCLC) is not clear. We conducted a meta-analysis to evaluate the risk profile of bevacizumab in NSCLC patients. METHODS: Relevant trials were identified by searching databases and conference proceedings. Data on treatment-related deaths and grade 3 or 4 AEs were extracted and pooled to calculate relative risks (RRs) with 95% confidence interval (CI) for bevacizumab compared with chemotherapy alone. RESULTS: A total of 2210 patients were included in the analysis. Compared with chemotherapy alone, high-dosage (15 mg/kg) bevacizumab was associated with an increased risk of treatment-related deaths (RR = 2.04, 95% CI = 1.18-3.52), but not for low-dosage (7.5 mg/kg) group (RR = 1.20, 95% CI = 0.60-2.41). In addition, treatment with bevacizumab was associated with several grade 3 or 4 AEs in patients with NSCLC, especially in high-dosage bevacizumab group. CONCLUSION: The use of the bevacizumab increases the risk of treatment-related deaths and several grade 3 or 4 AEs in patient with NSCLC. The risk may be dose-dependent. Close monitoring and adequate management are recommended to decrease severe AEs.

Interleukin-12B rs3212227 polymorphism and cancer risk: a meta-analysis.

IL-12 plays a very important role in the development and progress of cancer. IL-12B rs3212227 polymorphism has been reported and many studies have focused on the role of this polymorphism in various cancers. However, the association between IL-12B rs3212227 polymorphism and cancer risk remains controversial. Therefore, we performed a systematic meta-analysis to estimate the overall cancer risk associated with this gene polymorphism and to quantify any potential between-study heterogeneity. PubMed and Embase databases were searched for case-control studies published up to April 1, 2012 that investigated IL-12B rs3212227 polymorphism and cancer risk. Odds ratios (OR) with 95 % confidence intervals (95 % CI) were used to access the strength of this association. Heterogeneity among articles and publication bias were also verified. Ten studies with 2,954 cancer patients and 3,276 healthy controls were included. This meta-analysis showed that there was a significant association between IL-12B rs3212227 polymorphism and overall cancer risk (CC/AC vs AA: OR = 1.32, 95 % CI = 1.06-1.63). When stratified by cancer type, we found a significant increased risk in cervical and nasopharyngeal cancer (OR = 1.34, 95 % CI = 1.04-1.73; OR = 2.03, 95 % CI = 1.57-2.63, respectively). In the stratified analysis, we also observed a similar association in population-based studies (OR = 1.34, 95 % CI = 1.00-1.80), Asian populations (OR = 1.33, 95 % CI = 1.06-1.67) and European populations (OR = 1.54, 95 % CI = 1.04-2.28). According to the results of our meta-analysis, IL-12B rs3212227 polymorphism probably is associated with a high risk of cancer.

Increased expression of interleukin-18 and its receptor in peripheral blood of patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex systemic disorder characterized by both local pulmonary and systemic inflammation. Many studies suggested that activation of circulating inflammatory cells and increased circulating levels of inflammatory cytokines occur in COPD. Interleukin (IL)-18 is a unique proinflammatory cytokine that mediates its effects by binding to the IL-18 receptor (IL-18R). In the present study, the expression of IL-18 in serum and IL-18R on peripheral blood T lymphocytes was analyzed. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of IL-18 and interferon (IFN)-γ, and high sensitivity C-reactive protein (hsCRP) were measured by chemiluminiscent immunoassay. Expression of IL-18R was examined using a three-color flow cytometry method. In total, 120 subjects were recruited including 32 nonsmokers, 30 current smokers and 58 stable COPD patients. Serum levels of IL-18 and hsCRP were significantly higher in stable COPD patients than those in nonsmokers and current smokers. A significant negative correlation existed between pulmonary function and serum level of IL-18 rather than hsCRP in stable COPD patients. The proportions of IL-18Rα-expressing T lymphocytes and CD8(+) T lymphocytes were significantly higher in stable COPD patients than in nonsmokers and current smokers. The current study extended prior analyses by examining IL-18R expression in peripheral blood. The results suggested that IL-18/IL-18R system was active in peripheral blood of COPD patients.

Comparison of leukotriene receptor antagonists in addition to inhaled corticosteroid and inhaled corticosteroid alone in the treatment of adolescents and adults with bronchial asthma: a meta-analysis.

BACKGROUND: Leukotriene receptor antagonists (LTRA) have been recommended as treatment for persistent asthma. It is not clear whether oral LTRA in combination with inhaled corticosteroids (ICS) confers any additional benefit over ICS alone. OBJECTIVE: This meta-analysis was conducted to review the evidence for the benefits and risks of ICS-LTRA in comparison to ICS alone in bronchial asthma. METHODS: MEDLINE, EMBASE, LILACS, and CINAHL databases were searched for studies published through Aug 20, 2011. Studies comparing ICS-LTRA and ICS and those comparing ICS-LTRA and high-dose ICS were examined separately. Studies were pooled to yield odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs). RESULTS: Eight trials in which ICS-LTRA was compared with the same dose of ICS and five in which ICS-LTRA was compared with high-dose ICS were identified. In adults with mild to moderate asthma, the combination of ICS-LTRA improves the control of asthma when compared with same dose of ICS as monotherapy. The effects of ICS-LTRA therapy are similar to those of high-dose ICS in asthma control, but high-dose ICS is superior to ICS-LTRA with regard to improvement in some pulmonary function indices. CONCLUSIONS: In adults with mild to moderate asthma, though the effects were minimal, the combination of ICS-LTRA is recommended, when comparing its effects with the same dose ICS as monotherapy. The relative merits of ICS-LTRA and high-dose ICS therapy are uncertain and more research is needed.

Increased CAP37 Expression in Stable Chronic Obstructive Pulmonary Disease.

OBJECTIVE: Cationic antimicrobial protein of 37 kDa (CAP37), a neutrophil-derived protein originally identified for its antimicrobial activity, is now known to have many regulatory effects on host cells. However, its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) has not been studied. We therefore investigated the expression of CAP37 in COPD and its effects on airway structural cells, including bronchial epithelial cells, smooth muscle cells, and fibroblasts. METHODS: CAP37 was detected in the lung tissue, sputum, and plasma of COPD patients and the control subjects, as well as in the neutrophils stimulated by cigarette smoke extract (CSE). BEAS-2B cells, human bronchial smooth muscle cells (HBSMCs), and MRC-5 cells were treated with CAP37 or an anti-CAP37 antibody plus CAP37. Interleukin (IL)-6 and IL-8 were detected in the BEAS-2B cells. The cell proliferation was analyzed in the HBSMCs. Collagens were also detected in the MRC-5 cells. RESULTS: The expression of CAP37 was increased in the lung tissue and sputum supernatant of the COPD patients compared with the control subjects. The sputum supernatant CAP37 levels were inversely correlated with the forced expiratory volume in the first second percentage predicted in COPD. CAP37 was induced by CSE stimulation in the peripheral blood neutrophils from healthy non-smokers. CAP37 induced expression of IL-6 and IL-8 in BEAS-2B cells, and collagen expression of lung fibroblasts (MRC-5 cells). However, CAP37 did not significantly alter the proliferation of the HBSMCs. CONCLUSION: Our findings indicated that neutrophil-derived CAP37 may be involved in airway inflammation and fibrosis in COPD via affecting the bronchial epithelial cells, and fibroblasts, thus suggesting a possible role of CAP37 in the development and progression of COPD.

Nurse-Led Motor Function Rehabilitation Program for Acute Ischemic Stroke: A Randomized Pilot Study.

BACKGROUND: Rehabilitation care for patients with stroke in the acute stage must be strengthened. However, the evidence on how to strengthen this care is insufficient. PURPOSE: This article was designed to evaluate the feasibility and effectiveness of implementing a nurse-led motor function rehabilitation program on patients with acute ischemic stroke. METHODS: From January to October 2018, patients with initial acute ischemic stroke were assigned to one of two groups using a pilot randomized controlled trial design, with one group receiving a nurse-led motor function intervention program developed based on Orem's theory (7 consecutive days, twice daily for 30 minutes, experimental group) and the other receiving usual care (control group). The effectiveness measures included changes in the Motor Assessment Scale, the modified Barthel Index, and the National Institutes of Health Stroke Scale. The feasibility measures included patient retention rate, incidence of adverse events, and acceptance of nurses and patients. RESULTS: We assigned 104 patients (male: 55.7%; age: 62.8 ± 13.2 years) to receive either a nurse-led motor function rehabilitation program or usual care. Eighty-eight patients were evaluated after 7 days (87% retention rate), including 43 (83% retention rate) in the experimental group. Patients accepted the intervention well, and no severe adverse events were reported. Nurses had good fidelity and showed high acceptance. The experimental group showed significantly higher postintervention Motor Assessment Scale and modified Barthel Index scores than the control group (p < .001), whereas postintervention National Institutes of Health Stroke Scale scores did not differ significantly between the two groups. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The nurse-led rehabilitation program used in this study was shown to be feasible and effective in improving motor function in patients with acute ischemic stroke. Further study is recommended to determine related clinical recommendations.