An Investigation of the Effects of B7-H4 Gene rs10754339 and miR-125a Gene rs12976445 on Cancer Susceptibility.

Objective: To investigate the effects of the B7-H4 gene rs10754339 and miR-125a gene rs12976445 on cancer susceptibility through a case-control study and meta-analysis. Methods: A total of 1,490 cancer patients (lung/gastric/liver/: 550/460/480) and 800 controls were recruited in this case-control study. The meta-analysis was performed by pooling the data from previous related studies and the present study. Results: The results of this study showed that in the Hubei Han Chinese population, the rs10754339 gene was significantly associated with the risk of lung and gastric cancer but not liver cancer, and the rs12976445 gene was significantly associated with the risk of lung cancer but not liver or gastric cancer. The meta-analysis results indicated that rs10754339 and rs12976445 contributed to cancer susceptibility in the Chinese population and also revealed a significant association between rs10754339 and breast cancer risk, as well as between rs12976445 and lung cancer risk. Conclusion: The B7-H4 gene rs10754339 and miR-125a gene rs12976445 may be the potential genetic markers for cancer susceptibility in the Chinese population, which should be validated in future studies with larger sample sizes in other ethnic populations.

Stem cell therapy for chronic obstructive pulmonary disease.

ABSTRACT: Chronic obstructive pulmonary disease (COPD), characterized by persistent and not fully reversible airflow restrictions, is currently one of the most widespread chronic lung diseases in the world. The most common symptoms of COPD are cough, expectoration, and exertional dyspnea. Although various strategies have been developed during the last few decades, current medical treatment for COPD only focuses on the relief of symptoms, and the reversal of lung function deterioration and improvement in patient's quality of life are very limited. Consequently, development of novel effective therapeutic strategies for COPD is urgently needed. Stem cells were known to differentiate into a variety of cell types and used to regenerate lung parenchyma and airway structures. Stem cell therapy is a promising therapeutic strategy that has the potential to restore the lung function and improve the quality of life in patients with COPD. This review summarizes the current state of knowledge regarding the clinical research on the treatment of COPD with mesenchymal stem cells (MSCs) and aims to update the understanding of the role of MSCs in COPD treatment, which may be helpful for developing effective therapeutic strategies in clinical settings.

Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice.

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.

Retraction Note: Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

The authors have retracted the article [Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma, Cell Death & Disease volume 7, page e2388 (2016), doi 10.1038/cddis.2016.260] because it has recently come to their attention that the A549 cells used in this research were contaminated with Hela cells, which may have altered the outcome of their experiment. The conclusions of this article are therefore unreliable. All authors agree to this retraction.

Correction to: Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

Following publication of their article, the authors noticed that there were minor errors in Figs. 3, 7 and S5. The errors had no effect on the scientific content or conclusions. The rectified figures are given below.

Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

This corrects the article DOI: 10.1038/cddis.2016.260.

Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

Our previous study revealed that Ku80 was overexpressed in lung cancer tissues and hsa-miR-623 regulated the Ku80 expression; however, the detailed function of hsa-miR-623 in lung cancer was unclear. We identified that hsa-miR-623 bound to the 3'-UTR of Ku80 mRNA, thus significantly decreasing Ku80 expression in lung adenocarcinoma cells. Hsa-miR-623 was downregulated in lung adenocarcinoma tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Downregulation of hsa-miR-623 was associated with poor clinical outcomes of lung adenocarcinoma patients. Hsa-miR-623 suppressed lung adenocarcinoma cell proliferation, clonogenicity, migration and invasion in vitro. Hsa-miR-623 inhibited xenografts growth and metastasis of lung adenocarcinoma in vivo. Ku80 knockdown in lung adenocarcinoma cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-623 overexpression. Further, hsa-miR-623 overexpression decreased matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels, with decreased ERK/JNK phosphorylation. Inhibition of hsa-miR-623 or overexpression of Ku80 promoted lung adenocarcinoma cell invasion, activated ERK/JNK phosphorylation and increased MMP-2/9 expressions, which could be reversed by ERK kinase inhibitor or JNK kinase inhibitor. In summary, our results showed that hsa-miR-623 was downregulated in lung adenocarcinoma and suppressed the invasion and metastasis targeting Ku80 through ERK/JNK inactivation mediated downregulation of MMP-2/9. These findings reveal that hsa-miR-623 may serve as an important therapeutic target in lung cancer therapy.

Impact of village-based health education of tobacco control on the current smoking rate in Chinese rural areas.

The number of smokers in Chinese rural areas is more than 200 million, which is twice that in cities. It is very significant to carry out tobacco control interventions in rural areas. We performed this community intervention study to evaluate the efficacy of village-based health education of tobacco control on the male current smoking rate in rural areas. The population of this study was the males above 15 years old from 6 villages in rural areas. The villages were randomly assigned to intervention group or control group (3 villages in each group). Self-designed smoking questionnaire was applied. The intervention group received the village-based health education of tobacco control for one year. The primary outcome measurement was the male current smoking rate. In the baseline investigation, completed surveys were returned by 814 male residents from the control group and 831 male residents from the intervention group. The male current smoking rate in the control group and the intervention group was 61.2% and 58.5%, respectively, before intervention. There was no significant difference between these two groups (P>0.05). After one-year intervention, the current smoking rate in the intervention group (51.2%) was significantly lower than that in the control group (62.8%) (P<0.001). Our study suggested that the village-based health education of tobacco control was effective in lowering the male current smoking rate in rural areas, which could be a suitable and feasible way for tobacco control in the Chinese rural areas.

CXCL12 G801A polymorphism and cancer risk: An updated meta-analysis.

Many studies have reported the relationship between CXCL12 G801A polymorphism and cancer risk, with conflicting results. In this study, we tried to clarify the possibility that this polymorphism may increase cancer risk by conducting an updated meta-analysis. PubMed and EMbase were searched for case-control studies regarding the association of the gene polymorphism and cancer risk. Data were extracted and odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of the association. Heterogeneity among articles and publication bias was also assessed. Significantly increased risk for cancer was found (A vs. G: OR=1.26, 95% CI=1.13-1.40, P<0.01; AA+AG vs. GG: OR=1.33, 95% CI=1.16-1.52, P<0.01). In subgroup analysis, statistically elevated cancer risk was found in both Asian and Caucasian populations (for Asian, AA+AG vs. GG: OR=1.74, 95% CI=1.22-2.47, P<0.01; for Caucasian, AA+AG vs. GG: OR=1.24, 95% CI=1.09-1.42, P<0.01). Our result indicated that CXCL12 G801A polymorphism is a risk factor for cancer. To validate the finding, further large-size case-control studies are warranted.

Establishment of surfactant-associated protein A suicide gene system and analysis of its activity.

Alveolar epithelial type II (AT II) cells are essential for lung development and remodeling, as they are precursors for type I cells and also produce other non-repair cells (fibroblasts). Progenitor cells are believed to possess capability of multi-potent transdifferentiation, which is closely related to the niche, suggesting the importance of establishment of a lung progenitor cell niche model. We hypothesized that pulmonary surfactant-associated protein A (SPA) suicide gene system would cause AT II cell to kill itself through apoptosis and leave its niche. In vitro, the recombinant adeno-associated virus vectors-SPA-thymidine kinase (rAAV-SPA-TK) system was established to get targeted apoptotic AT II cells. The apoptosis of AT II cells was detected by using MTT. The results showed that cloned SPA gene promoter had specific transcriptional activity in SPA high expression cells, and SPA high expression cells (H441) transfected with TK gene had higher sensitivity to ganciclovir (GCV) than SPA low expression cells (A549). In vivo, increased apoptosis of AT II cells induced by GCV in rAAV-SPA-TK system was observed by TUNEL. Finally, the successful packaging and application of rAAV-SPA-TK system provide experimental basis to get specific lung progenitor cell (AT II) niche in vitro and in vivo.

Inhibitory effect of dexamethasone on expression of cysteine-rich 61 protein in airway epithelial cells of allergic mouse models.

In order to study whether cysteine-rich 61 protein (cyr61) is involved in the pathogenesis of asthma and its relation to airway inflammation, the effect of dexamethasone (Dxm) on the expression of cyr61 in the lung tissues of asthmatic mice was investigated. Forty BALB/c mice were divided into asthma group (n=15), control group (n=10) and Dxm group (n=15). The asthma group was sensitized and challenged by ovalbumin (OVA). The mice in Dxm group were intraperitoneally administered with Dxm after OVA challenge. The expression of cyr61 in the lung tissues was detected by using immunohistochemistry, and that of eotaxin protein in the bronchoalveolar lavage fluid (BALF) by using enzyme-linked immunosorbent assay (ELISA). The number of inflammatory cells in BALF was also analyzed. The results showed that the cyr61 expression was highest in asthma group (P<0.05), followed by Dxm group (P<0.05) and control group. The cyr61 had a positive correlation with the total nucleated cells (r=0.867, P<0.05), especially eosinophils (r=0.856, P<0.05), and eotaxin level (r=0.983, P<0.05) in the BALF. Our findings suggested that cyr61 is expressed in airway epithelial cells and has a positive correlation with eotaxin and number of airway infiltrating eosinophils.

Effect of dexamethasone on expression of AGR2 protein in asthmatic mice.

This study examined the expression of the anterior gradient-2 (AGR2) protein and Muc5ac protein in the lung tissues of asthmatic mice and the effect of dexamethasone, with an attempt to explore the role of AGR2 in the over-secretion of mucus in the airway. Eighteen BALB/c mice were divided into asthma group, control group and dexamethasone group. In dexamethasone group, dexamethasone was intraperitoneally administered. Expression of AGR2 protein and Muc5ac protein in the murine lung tissues was immunohistochemically detected. IL-13 level was determined in the bronchoalveolar lavage fluid (BALF) by ELISA. The results exhibited that the expression of AGR2 protein in asthma group (0.522±0.041) was significantly higher than that in normal controls (0.361±0.047) (P<0.01) and bore a positive linear relationship to the expression of Muc5ac protein (r=0.873, P<0.05) and IL-13 level (r=0.828, P<0.05). Expression of AGR2 protein in the dexamethasone group (0.456±0.049) was significantly lower than that in the asthma group. It was concluded that: (1) the expression of AGR2 protein was significantly higher in asthmatic mice as compared with their normal counterparts; (2) the expression was obviously related to the expression of Muc5ac protein and IL-13; (3) dexamethasone could down-regulate the expression of AGR2 protein. Our findings suggested that AGR2 might be involved in the over-secretion of mucus in the airway in asthma.

Diagnostic value of interleukin 21 and carcinoembryonic antigen levels in malignant pleural effusions.

The aim of this study was to evaluate the diagnostic value of interleukin 21 (IL-21) and carcinoembryonic antigen (CEA) in tuberculous pleural effusions (TPEs) and malignant pleural effusions (MPEs). Pleural effusion samples from 103 patients were classified on the basis of diagnosis as TPE (n=51) and MPE (n=52). The concentration of IL-21 was determined by ELISA. Lactate dehydrogenase (LDH), adenosine dehydrogenase (ADA) and CEA levels were also determined in all patients. A significant difference was observed in the levels of ADA and CEA (P<0.01), but not in the levels of LDH (P>0.05) between TPE and MPE. The concentration of IL-21 in MPE was significantly higher compared to TPE (P<0.01). With a threshold value of 4.32 pg/ml, IL-21 had a sensitivity of 76.9% (40/52) and a specificity of 80.4% (41/51). Combined detection of IL-21 and CEA had a sensitivity of 69.2% (36/52) and a specificity of 92.2% (47/51). These two markers can contribute to the differential diagnosis of MPEs.

Primary pulmonary coccidioidomycosis in China.

Coccidioidomycosis is a fungal infection endemic to south-west USA, north Mexico and parts of Central and South America. We report here a case of primary pulmonary coccidioidomycosis in a previously healthy 14-year-old boy in China, which is considered a non-endemic country. The patient had non-specific symptoms of pulmonary infection, including fever, non-productive cough and night sweats. Both spherules and endospores of Coccidioides immitis were seen histologically following transbronchial biopsy of a cavitary lesion. The patient was treated with amphotericin B and fluconazole. Follow up 6 months post discharge found that the patient made a good recovery.

Plasmid-based short hairpin RNA against cyclin D1 attenuated pulmonary vascular remodeling in smoking rats.

Accumulating evidence indicated that smoking might directly induce pulmonary vascular remodeling at the initial stage of chronic obstructive pulmonary disease (COPD). However, the molecular mechanism underlying this process remains poorly understood. To investigate the role of cyclin D1 in pulmonary vascular remodeling, we constructed a plasmid-based short hairpin RNA (shRNA) to knock down the expression of cyclin D1 in smoking rats. Specific shRNA against cyclin D1 significantly prevented the cyclin D1 expression and the cell proliferation in rat pulmonary artery smooth muscle cells (rPASMCs). Furthermore, the plasmid-based shRNA successfully decreased the cyclin D1 protein in intra-pulmonary arteries of smoking rats and subsequently decreased the wall thickness of pulmonary vessels and the percentage of muscularized vessels. We conclude that the plasmid-based shRNA against cyclin D1 gene attenuated pulmonary vascular remodeling in smoking rats. Cyclin D1 might play a critical role in cigarette smoke-induced pulmonary vascular remodeling via regulating rPASMCs proliferation.

[Inhibition of NF-kappaB through IkappaBalpha transfection affects invasion of human lung cancer cell line A549].

BACKGROUND & OBJECTIVE: Recent studies have shown that activation of nuclear factor-kappaB(NF-kappaB) can regulate the invasion and metastasis of cancer cells. The present study was to investigate inhibition of NF-kappaB activity on invasion of human lung cancer cell line A549 and the possible mechanism. METHODS: The recombinant plasmid pcDNA3.1(+)/IkappaBalpha, expressing the alpha isoform (IkappaBalpha) of the NF-kappaB inhibitor, was constructed. A549 cells were cultured in vitro and divided into non-transfection group, pcDNA3.1(+) transfected group and pcDNA3.1(+)/IkappaBalpha transfected group. The expression of IkappaBalpha was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The activity of NF-kappaB was determined by electrophoretic mobility shift assay (EMSA). Invasion of A549 cells was assessed by transwell chamber assay. The expression of MMP-2 and MMP-9 was detected by RT-PCR and gelatin zymography. RESULTS: Plasmid pcDNA3.1(+)/IkappaBalpha was successfully constructed and expressed in A549 cells. The activity of NF-kappaB, the number of invasive cells, the activity of MMP-2 and MMP-9 of A549 cells in pcDNA3.1(+)/IkappaBalpha transfected group were significantly lower than those in non-transfection group and pcDNA3.1(+) transfected group (all P<0.05). CONCLUSION: Transfection of IkappaBalpha can inhibit NF-kappaB activity, thus inhibit cell invasion of A549, which may be through the down-regulation of MMP-2 and MMP-9 expressions.

[Liposarcoma of the pleura: clinical characteristics].

OBJECTIVE: Primary liposarcoma of the pleura is extremely rare. The first case report in China was described. METHODS: The clinical data of a case of primary liposarcoma of the pleura diagnosed in this hospital were reported, and the pertinent literature was reviewed. RESULTS: A total of 17 cases of primary liposarcomas of the pleura, including the case reported herein, had been described in international literature. Primary pleural liposarcomas occur predominantly in males and older patients, and the myxoid histological subtype is common. The most common symptoms are chest pain and shortness of breath. Radiographic and surgical evaluation are important for its diagnosis. Surgical resection with adjuvant radiation therapy is recommended for the disease. CONCLUSION: More data are required for the treatment and prognostic evaluation of the primary liposarcoma of the pleura.

[Effects of recombinant adeno-virus vector carrying interleukin-5 antisense on the expression of interleukin-5 mRNA and protein in CD4+ T lymphocytes of asthmatic rats].

OBJECTIVE: To construct recombinant adeno-associated virus vector carrying antisense interleukin-5 (IL-5) gene (rAAV-asIL-5), and to explore the effects of this virus transfection on IL-5 mRNA and protein in CD(4)(+) T lymphocytes of asthmatic rats. METHODS: The eukaryotic antisense IL-5 expressing vector plasmid of recombinant adeno-associated virus (pasIL-5/rAAV) was constructed by gene recombination technique. The rAAV-asIL-5 particles were produced by co-transfection of pasIL-5/rAAV, pXX2, and pXX6 in package cell 293 through phosphate calcium deposit, and the titers of rAAV-asIL-5 were measured by Southern blot. The rAAV-asIL-5 particles were transfected into CD(4)(+) T lymphocytes obtained by gradient of Ficoll and immunomagnetic beads from the peripheral blood of asthmatic rats. Then IL-5 mRNA in T lymphocytes and IL-5 protein in supernatant of cell culture were determined with semi-quantitative RT-PCR and ELISA respectively. RESULTS: (1) The rAAV-asIL-5 was constructed and identified, and the titer of rAAV-asIL-5 was 1.3 x 10(11) virus particles/ml. (2) The relative ratio A of absorbance (IL-5/beta-actin) of rAAV group was 1.0515 +/- 0.1477, which was significantly lower than that of the control group (1.4271 +/- 0.1655) (n = 6, P < 0.01). (3) The protein level of IL-5 in supernatant of culture of rAAV group was (12.0840 +/- 1.4769) ng/L, significantly lower than that of the control group [(15.3590 +/- 1.2685) ng/L, n = 6, P < 0.01]. CONCLUSION: Construction of rAAV-asIL-5 was successful, and transfection of this virus was capable of inhibiting the expression of IL-5 mRNA and protein in CD(4)(+) T lymphocytes of asthmatic rats. The results of this study provide experimental data for further study of gene therapy for asthma.