Yong-Long Xiao

Meta-Analysis of the Adverse Effects of Long-Term Azithromycin Use in Patients with Chronic Lung Diseases

ABSTRACT The adverse effects of azithromycin on the treatment of patients with chronic lung diseases (CLD) were evaluated in the present study. MEDLINE and other databases were searched for relevant articles published until August 2013. Randomized controlled trials that enrolled patients with chronic lung diseases who received long-term azithromycin treatment were selected, and data on microbiological studies and azithromycin-related adverse events were abstracted from articles and analyzed. Six studies were included in the meta-analysis. The risk of bacterial resistance in patients receiving long-term azithromycin treatment was increased 2.7-fold (risk ratio [RR], 2.69 [95% confidence interval {95% CI}, 1.249, 5.211]) compared with the risk in patients receiving placebo treatment. On the other hand, the risk of bacterial colonization decreased in patients receiving azithromycin treatment (RR, 0.551 [95% CI, 0.460, 0.658]). Patients receiving long-term azithromycin therapy were at risk of increased impairment of hearing (RR, 1.168 [95% CI, 1.030, 1.325]). This analysis provides evidence supporting the idea that bacterial resistance can develop with long-term azithromycin treatment. Besides the increasingly recognized anti-inflammatory role of azithromycin used in treating chronic lung diseases, we should be aware of the potential for adverse events with its long-term use.

Loss of long noncoding RNA FOXF1-AS1 regulates epithelial-mesenchymal transition, stemness and metastasis of non-small cell lung cancer cells.

Although recent evidence shows that long noncoding RNAs (lncRNAs) are involved in the regulation of gene expression and cancer progression, the understanding of the role of lncRNAs in lung cancer metastasis is still limited. To identify novel lncRNAs in non-small cell lung cancer (NSCLC), we profile NSCLC tumor and matched normal samples using GeneChip® Human Gene 2.0 ST Array, which provides the most accurate, sensitive, and comprehensive measurement of protein coding and lncRNA transcripts. We identified a panel of key factors dysregulated in lung cancer. Among them, the expression of FOXF1-AS1 was significantly downregulated in lung cancer. Stable overexpression of FOXF1-AS1 inhibits lung cancer cell migration and invasion by regulating EMT. Meanwhile, loss of FOXF1-AS1 mediates stem-like properties of lung cancer cells. Interestingly, we found that FOXF1-AS1 physically associates with PRC2 components EZH2 and loss of FOXF1-AS1 mediates cell migration and stem-like properties require EZH2. Loss of FOXF1-AS1 is also correlated with downregulation of FOXF1 in lung cancer. These results suggested that FOXF1-AS1 might regulate EMT, stemness and metastasis of NSCLC cells via EZH2, indicating it as a therapeutic target for future treatment of NSCLC.

Elevated Platelets Enhance Cancer Cell Migration, Promote Hematogenous Metastasis and Associate with a Poor Prognosis in Advanced Non-small Cell Lung Cancer Cases

Although correlations between platelets and lung cancer has been recognized, effects on non-small cell lung cancer (NSCLC) metastasis remain to be determined in detail. In the present study, wound healing assays revealed a role of platelets in NSCLC cell migration . Thus the mean migration rate of lung adenocarcinoma A549 cells was significantly elevated after co-culture with platelets (81.7±0.45% vs 41.0±3.50%, P<0.01). Expression of GAPDH was examined by reverse transcription-polymerase chain reaction to study the effect of platelets on NSCLC cell proliferation. The result showed that the proliferation of A549 and SPC-A1 cells was not affected. Mouse models were established by transfusing A549 cells and SPC-A1 cells into mice lateral tail veins. We found tumor metastasis nodules in lungs to be increased significantly after co-transfusion with platelets (in A549, 4.33±0.33 vs 0.33±0.33, P=0.01; in SPC-A1, 2.67±0.33 vs 0.00±0.00, P=0.01). In addition, consecutive inoperable patients with newly diagnosed NSCLC (TNM stage III or IV) between January 2009 and December 2011 were retrospectively reviewed. Using the Kaplan-Meier method, NSCLC patients with a high platelet counts demonstrated a significantly shorter progression free survival compared with those with a low platelet count (>200x109/L, 3 months versus ≤200x109/L, 5 months, P=0.001). An elevated platelet count was also identified as an independent prognostic factor by Cox regression analysis for prgression free survival (adjusted hazard ratio: 1.69; 95% CI: 1.16, 2.46; P=0.006). This study suggested that platelets might contribute to the hematogenous metastatic process by promoting cancer cell migration, which eventually affects the prognosis of NSCLC.

Plasma Leptin Is Elevated in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Background. The natural history of idiopathic pulmonary fibrosis (IPF) is very complex and unpredictable. Some patients will experience acute exacerbation (AE) and fatal outcomes. Methods. The study included 30 AE-IPF patients, 32 stable IPF (S-IPF) patients, and 12 healthy controls. We measured the plasma concentrations of leptin and KL-6. Simple correlation was used to assess associations between leptin and other variables. Plasma leptin levels were compared between AE-IPF and S-IPF subjects, decedents, and survivors. Kaplan-Meier curves were used to display survival and Cox proportional hazards regression was used to examine risk factors for survival. Results. In subjects with AE-IPF, plasma leptin was significantly greater than in subjects with S-IPF (p = 0.0003) or healthy controls (p < 0.0001). Plasma leptin was correlated with BMI, KL-6, LDH, CRP, and PaO2/FiO2 (p = 0.007; p = 0.005; p = 0.003; p = 0.033; and p = 0.032, resp.). Plasma leptin was significantly greater in 33 decedents than in the 23 survivors (p = 0.007). Multivariate Cox regression analysis showed leptin (>13.79 ng/mL) was an independent predictor of survival (p = 0.004). Conclusions. Leptin could be a promising plasma biomarker of AE-IPF occurrence and predictor of survival in IPF patients.

Occupational inhalational exposure and serum GM-CSF autoantibody in pulmonary alveolar proteinosis

Objectives Although the serum granulocyte-macrophage colony stimulating factor autoantibody (GMAb) levels have been recognised as a diagnostic marker in primary pulmonary alveolar proteinosis (PAP), their role in PAP with occupational inhalational exposure (PAPo) remains unclear. Methods Forty-five consecutive patients with PAP were enrolled. Each patient with PAP was assessed for baseline clinical characteristics, chest high-resolution CT (HRCT), serum GMAb and occupational exposure. Fifty healthy controls were included to define normal ranges for GMAb levels. Ninety-seven hospital controls with other respiratory diseases were included to establish prevalence of a history of occupational inhalation exposure. Results According to the serum GMAb cut-off value of 2.39 μg/mL, 84.4% of the recruited patients with PAP had positive serum GMAb with a median level of 28.7 μg/mL, defined as autoimmune PAP, and the remaining 15.6% had negative serum GMAb with a median level of 0.16 μg/mL, defined as non-autoimmune PAP. Also, 34.2% of patients with autoimmune PAP had a history of occupational inhalational exposure, which was not significantly higher than that of hospital controls (34.2% vs 19.6%, p=0.072). Four patients with PAPo showed negative GMAb. Their arterial oxygen tension, pulmonary function parameters and chest HRCT features were significantly different when compared with patients with autoimmune PAP (p<0.05). These four non-autoimmune occupational lung disease cases culminated in 3 deaths and a lung transplant. Conclusions A number of patients with PAP who may have occupational inhalational exposure and negative serum GMAb represent a high possibility of silicoproteinosis and very poor survival.

The overexpression of glypican-5 promotes cancer cell migration and is associated with shorter overall survival in non-small cell lung cancer

Although the correlation between glypican-5 (GPC5) and lung cancer is well known, the effect of GPC5 expression on non-small cell lung cancer (NSCLC) survival remains to be determined. In the present study, GPC5 expression in A549, H3255, and SPC-A1 NSCLC cell lines was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. GPC5 mRNA and protein expression levels were found to be higher in A549 and H3255 cells compared with SPC-A1 cells. The role of GPC5 in NSCLC cell migration was evaluated in vitro by shRNA-mediated knockdown or the overexpression of GPC5 through scratch and transwell assays. The mean migration rates of cancer cells transfected with pRNAT-shRNA-GPC5-1 were reduced compared with the controls in A549 (P<0.001) and H3255 (P=0.001), while the migration rate of SPC-A1 with GPC5 overexpression was higher than that of the control (P=0.001). The downregulation of GPC5 impeded the transmigration of A549 and H3255 while the upregulation of GPC5 expression promoted the transmembrane invasion of SPC-A1. Furthermore, a panel of formalin-fixed paraffin-embedded NSCLC tissues from 127 patients undergoing curative resection (stages I, II and III) between January, 2003 and December, 2008 were obtained in order to investigate the correlation between GPC5 expression and clinicopathological factors using immunohistochemical methods. The results demonstrated that high GPC5 expression levels in NSCLC were associated with respiratory symptoms in lung cancer diagnosis, poor differentiation, vascular invasion, regional lymph node metastasis and a higher TNM stage. Using the Kaplan-Meier method, NSCLC patients with high levels of GPC5 expression demonstrated a significantly shorter overall survival time compared with those with low GPC5 expression levels (median postsurgical survival time: 14.0 months vs. 59.0 months, P=0.001). GPC5 expression was also identified as an independent prognostic factor by Cox regression analysis [adjusted hazard ratio: 2.18; 95% confidence interval (CI): 1.35–3.52; P=0.001]. This study suggested that increased levels of GPC5 expression are a poor prognostic marker for NSCLC.

Clinical and Radiological Profile of Acute Fibrinous and Organizing Pneumonia: A Retrospective Study

Background: Acute fibrinous and organizing pneumonia (AFOP) is a unique pathological entity with intra-alveolar fibrin in the form of “fibrin balls” and organizing pneumonia. It was divided into rare idiopathic interstitial pneumonia according to the classification notified by American Thoracic Society/European Respiratory Society in 2013. As a rare pathological entity, it is still not well known and recognized by clinicians. We reviewed the clinical features of 20 patients with AFOP diagnosed in a teaching hospital. Methods: The medical records of 20 patients with biopsy-proven diagnosis of AFOP were retrospectively reviewed. The patients’ symptoms, duration of the disease, comorbidities, clinical laboratory data, pulmonary function testing, radiographic studies, and the response to treatment were extracted and analyzed. Results: Fever was the most common symptom and was manifested in 90% of AFOP patients. For clinical laboratory findings, systematic inflammatory indicators, including C-reactive protein and erythrocyte sedimentation rate, were significantly higher than normal in AFOP patients. In accordance with this increased indicators, injured liver functions were common in AFOP patients. Inversely, AFOP patients had worse clinical conditions including anemia and hypoalbuminemia. For pulmonary function testing, AFOP patients showed the pattern of restrictive mixed with obstructive ventilation dysfunction. For high-resolution computerized tomography (HRCT) findings, the most common pattern for AFOP patients was lobar consolidation which was very similar to pneumonia. However, unlike pneumonia, AFOP patients responded well to glucocorticoids. Conclusion: Patients with AFOP manifest as acute inflammatory-like clinical laboratory parameters and lobar consolidation on HRCT, but respond well to steroid.

Hypoxia Induced High Expression of Thioredoxin Interacting Protein (TXNIP) in Non-small Cell Lung Cancer and its Prognostic Effect

Although associations between thioredoxin interacting protein (TXNIP) and cancers have been recognized, the effects of TXNIP on non-small cell lung cancer (NSCLC) prognosis remained to be determined in detail. In addition, while hypoxia is a key characteristic of tumor cell growth microenvironment, the effect of hypoxia on TXNIP expression is controversial. In this study, formaldehyde fixed and paraffin embedded (FFPE) samples of 70 NSCLC patients who underwent resection between January 2010 and December 2011 were obtained. Evaluation of TXNIP and hypoxia inducible factor-1α (HIF-1α) protein expression in FFPE samples was made by immunohistochemistry. By Kaplan-Meier method, patients with high TXNIP expression demonstrated a significantly shorter progression free survival (PFS) compared with those with low TXNIP expression (18.0 months, 95%CI: 11.7, 24.3 versus 23.0 months, 95%CI: 17.6, 28.4, P=0.02). High TXNIP expression level was also identified as an independent prognostic factor by Cox regression analysis (adjusted hazard ratio: 2.46; 95%CI: 1.08, 5.56; P=0.03). Furthermore, TXNIP expression was found to be significantly correlated with HIF- 1α expression (Spearman correlation=0.67, P=0.000). To further confirm correlations, we established a tumor cell hypoxic culture model. Expression of TXNIP was up-regulated in all three NSCLC cell lines (A549, SPC-A1, and H1299) under hypoxic conditions. This study suggests that hypoxia induces increased TXNIP expression in NSCLC and high TXNIP expression could be a poor prognostic marker.

Lesion with morphologic feature of organizing pneumonia (OP) in CT-guided lung biopsy samples for diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP): a retrospective study of 134 cases in a single center

BACKGROUND Small biopsy samples are generally considered inconclusive for bronchiolitis obliterans organizing pneumonia (BOOP) diagnosis despite their potential to reveal organizing pneumonia (OP) pathologically, necessitating risky invasive tissue biopsy during surgery for reliable confirmation. OBJECTIVE OP by CT-guided lung biopsy was to evaluate the role in the diagnosis of BOOP. METHODS A retrospective review of 134 cases with the OP feature in the CT-guided lung biopsy samples between 2004 and 2011 at a single center was conducted. Diagnostic accuracy of OP by CT-guided lung biopsy and clinical-radiographic data alone were compared. RESULTS After exclusion of 11 cases due to pathology with others besides OP and 15 cases for loss to follow-up, 108 were included. Of these, 95 cases and 13 cases were classified as BOOP and non-BOOP group, respectively. Among BOOP group, only 30 were initially diagnosed as BOOP according to the typical clinical and radiographic features. The other 65 cases with atypical features were diagnosed as BOOP mainly based on OP by CT-guided lung biopsy. Among non-BOOP group, one was misdiagnosed as BOOP, and others were not BOOP according to clinical and radiographic findings. Thus, OP by CT-guided lung biopsy produced a diagnostic accuracy of 87.96% (95/108), much higher than 31.25% (30/96) observed using clinical and radiographic data alone. Combined, these techniques produced diagnostic accuracy of 98.96% (95/96). CONCLUSIONS OP by CT-guided lung biopsy can be effectively used as the pathological evidence for BOOP diagnosis and reducing unnecessary surgery.

Using ROS as a Second Messenger, NADPH Oxidase 2 Mediates Macrophage Senescence via Interaction with NF-κB during Pseudomonas aeruginosa Infection

Pseudomonas aeruginosa (PA) is one of the most prevalent pathogens that cause nosocomial infection in critical patients. However, the mechanisms underlying macrophage growth status and functional changes during PA infection are yet unknown. In the present study, NADPH oxidase, gp91phox (NOX2) mediated macrophage to senescence in a PAO1 colony-dependent manner. gp91phox might regulate the senescence process through mutual interaction with the NF-κB pathway. During infection, the overexpression or downregulation of gp91phox in macrophage could affect the nuclear activity of NF-κB p65, while the downregulation of NF-κB p65 led to a suppressed expression of gp91phox. Reactive oxygen species (ROS) served as the second messenger between both molecules as the ROS inhibitor, N-acetylcysteine (NAC), could partially restore these changes. Consequently, the level of ROS and inflammatory cytokines, including IL-6 and TNFα, elevated during PAO1 infection, and their production altered as a result of the genetic manipulation of gp91phox and NF-κB p65, as well as NAC treatment. Also, the senescent phenotypes, SA-β-gal staining and p16ink4a, changed after genetic manipulation with gp91phox and NF-κB p65 and NAC treatment. The capacity of phagocytosis in macrophages was decreased during senescence. In conclusion, PA directs the macrophage towards senescence, and senescent macrophages exhibit a decreased ability of phagocytosis. This process of senescence was regulated by the interactions between NADPH oxidase gp91phox and NF-κB p65 via ROS as a second messenger.