Major advances in respiratory medicine in China

Respiratory disease is the term for diseases of the respiratory system. These diseases range from mild and self-limiting such as the common cold to life-threatening such as bacterial pneumonia or pulmonary embolism. They are common and important causes of illness and death. In the US, people suffer 1 billion colds per year. One out of 7 people in the UK are affected by some kinds of chronic lung diseases, most commonly chronic obstructive pulmonary disease （COPD） and asthma. Respiratory disease accounts for over 10% of hospitalizations and over 16% of deaths in Canada.     

Gene expression profiles of ERCC1, TYMS, RRM1, TUBB3 and EGFR in tumor tissue from non-small cell lung cancer patients

Background Personalized medicine becomes essential in lung cancer treatment, however lung-cancer-related gene expression profiles in Chinese patients remain unknown. In this study, the correlation of gene expression profiles and clinical characteristics in non-small-cell lung cancer （NSCLC） was investigated. Methods Seventy-six Chinese patients with NSCLC were enrolled in the study to investigate mRNA expression profiles of excision repair cross complement group 1 （ERCC1）, thymidylate synthetase （TYMS）, ribonucleotide reductase （RRM1）, class Ill 13-tubulin （TUBB3）, and epidermal growth factor receptor （EGFR） genes and their correlation with patient clinical characteristics. A novel liquidchip technology was used to detect mRNA expression levels in formalin fixed paraffin embedded tumor pathology samples. The relationships between gene expression and clinical characteristics were assessed using the Mann-Whitney test. Results ERCC1 mRNA levels were higher in tumors from patients with metastatic disease than patients with non- metastatic disease （P=-0.021）, and higher in adenocarcinomas than squamous cell carcinomas （P=0.006）. Increased TUBB3 mRNA expression levels were found in patients with performance status （PS） 1 in comparison with PS 0 （P=0.049）, with poorly differentiated tumors in comparison with tumors that were moderately and well differentiated （P 〈0.000 1）, and with advanced stage in comparison with early stage disease （P 〈0.000 1）. Conclusions ERCC1 mRNA levels were higher in metastatic adenocarcinoma NSCLC; TUBB3 mRNA levels were significantly higher in poorly differentiated tumors and in advanced stage NSCLC, which indicates the poor prognosis.     

Effects of resolvin D1 on inflammatory responses and oxidative stress of lipopolysaccharide-induced acute lung injury in mice

Background A variety of inflammatory mediators and effector cells participate together in acute lung injury,and lead to secondary injury that is due to an inflammatory cascade and secondary diffuse lung parenchyma injury.Inflammation is associated with an oxidative stress reaction,which is produced in the development of airway inflammation,and which has positive feedback on inflammation itself.Resolvin D1 can reduce the infiltration of neutrophils,regulate cytokine levels and reduce the inflammation reaction,and thereby promote the resolution of inflammation.The purpose of this study is to investigate the effects of resolvin D1 on an inflammatory response and oxidative stress during lipopolysaccharide （LPS）-induced acute lung injury.Methods LPS （3 mg/kg） was used to induce the acute lung injury model.Pretreatment resolvin D1 （100 ng/mouse） was given to mice 30 minutes before inducing acute lung injury.Mice were observed at 6 hours,12 hours,1 day,2 days,3 days,4 days and 7 days after LPS was administrated,then they were humanely sacrificed.We collected bronchoalveolar lavage fluid （BALF） and the lung tissues for further analysis.Paraffin section and HE staining of the lung tissues were made for histopathology observations.Parts of the lung tissues were evaluated for wet-to-dry （W/D） weight ratio.tumor necrosis factor （TNF）-α,inter leukin （IL）-1β,IL-10 and myeloperoxidase （MPO） were detected by enzyme-linked immunosorbent assay （ELISA）.A lipid peroxidation malondialdehyde （MDA） assay kit was used to detect MDA.A total superoxide dismutase assay kit with WST-1 was used to analyze superoxide dismutase （SOD）.We determined the apoptosis of neutrophils by Flow Cytometry.A real-time quantitative PCR Detecting System detected the expression of mRNA for heme oxygenase （HO）-1.Results Pretreatment with resolvin D1 reduced the pathological damage in the lung,decreased the recruitment of neutrophils and stimulated their apoptosis.It markedly decreased the expressions of TNF-α,IL-1β and increased the expressions of IL-10,and decreased the production of MDA and increased the expressions of SOD.The mRNA expression of HO-1 was also significantly increased.Conclusions Resolvin D1 displays potent anti-inflammatory actions by regulating cytokines,inhibiting aberrant neutrophil recruitment and stimulating apoptosis of neutrophils.Resolvin D1 can also relieve the injury due to oxidative stress.The mechanisms might be related to increase HO-1 expression.     

Antithrombin-III without concomitant heparin improves endotoxin-induced acute lung injury rats by inhibiting the activation of mitogen-activated protein kinase

Background Antithrombin-Ⅲ （AT-Ⅲ）, the major inhibitor of thrombin in plasma, also has anti-inflammation property and might have positive effect on sepsis. The present study aimed to investigate the effects of AT-Ⅲ on inflammatory reaction and pulmonary protection in endotoxin-induced acute lung injury （ALI） rat. Methods Sixty male Sprague-Dawley rats were randomly assigned equally to normal control group, ALl group, AT-Ⅲ treatment group, AT-Ⅲ＋heparin treatment group, and heparin treatment group. The pulmonary vascular permeability index （PVPI） was measured by single nuclide tracer technique. The activity of AT-Ⅲ in plasma was determined by the method of synthetic chromogenic substrata. Tumor necrosis factor-a （TNF-a） and interleukin-6 （IL-6） levels in serum were determined by enzyme-linked immunosorbent assay. The expressions of lung tissue mitogen-activated protein kinases （ERK1/2, P38 and JNK MAPK） were determined by Western blotting. Results Rats had significantly improved lung histopathology in the AT-Ⅲ treatment group and heparin treatment group compared with the ALl group, The PVPI of the ALl group was 0.38±0.04, significantly higher than that of the normal control group （0.20±0.02, P 〈0.01）, AT-Ⅲ treatment group （0.30±0.04, P 〈0.01） and heparin treatment group （0.28±0.04, P 〈0.01） respectively. There were no significant differences of PVPI in the ALl group and AT-Ⅲ＋heparin treatment group. The activity of AT-Ⅲ in plasma in the ALl group was （76±8）%, significantly lower than that of the normal control group （（96±11）%, P 〈0.05） and AT-Ⅲ treatment group （（105±17）%, P 〈0.05） respectively. The serum levels of TNF-α and I L-6 of the ALl group were （2.770±0.373） μg/L and （1.615±0.128） ng/ml respectively, significantly higher than those of the normal control group （0.506±0.093） μg/L and （0.233±0.047） ng/ml respectively, all P 〈0.01）, AT-Ⅲ treatment group （（1.774±0.218） pg/L and （1.140±0145） ng/ml respectively, all P 〈0.01） and heparin treatment group （（1.924±0.349） μg/L and （1.223±0.127） ng/ml respectively, all P 〈0.01）. The lung tissue levels of phospho-ERK1/2 and phospho-P38 MAPK expressions were markedly higher in the ALl group than in the normal control group, AT-Ⅲ treatment group and heparin treatment group respectively. Conclusions AT-Ⅲ without concomitant heparin inhibited the activation of ERK1/2 and P38 MAPK, down-regulated the levels of downstream cytokines TNF-a and IL-6, relieved endothelial permeability, and improved the ALl in endotoxin-induced rats. It might be helpful to administrate AT-Ⅲ alone, not with concomitant heparin, to those patients with ALl and sepsis.     

吸烟和肺癌的遗传易感性

1951年．英国所有男医生都收到了来自Doll的邀请,共计40710人加入了一项为期5年的吸烟和非吸烟人群肺癌发病率的队列研究,1957年,英国医学研究委员会宣布：世纪初肺癌激增的始作俑者是吸烟,从而使“吸烟有害健康”写上了烟盒：1963年,Tokuhata等首次展示了遗传与肺癌休戚与共的关系,肺癌患者一级亲属增高2．5倍的肺癌发病率和吸烟无关。从此,吸烟、基因与肺癌的三角关系一直扑朔迷离。而近来一系列革命性的研究正在形成一句话“肺癌在本质上是一种基因病”。     

Edaravone rescues the lung by inhibiting lipid peroxidation and pro-inflammatory cytokines in a rat model

Acute lung injury/acute respiratory distress syndrome （ALI/ARDS） is a frequent complication in critically ill patients and cause significant mortality.1 Effects of reactive oxygen species （ROS） on alveolar epithelial cells are involved in the pathophysiology of ALI/ARDS.ROS can provoke DNA damage,lipid peroxidation,and activation of various genes coding for proteins involved in inflammation and cell damage.     

Utilization of LCM Technique in Sample Preparation for Proteomics Study of Lung Cancer Tissue

Objective Protein-based study plays a very important role in exploring tumor pathogenesis in the post-genomic era. However, tissue heterogeneity presents a major problem in the proteomics study of lung cancer. The aim of this study was to explore the methods of sample preparation for protein-based study of lung cancer tissue using laser capture microdissection （LCM） technique. Methods Six patients with lung squamous cell carcinoma （SQCC）, six patients with lung adenocarcinoma （AD） and six normal lung tissues including 2 cases matched with SQCC and 4 cases matched with AD （from at least 5 cm away the edge of the tumors were included in this study. Tissue sample firstly were cut with a cryostat sections and stained with the improved hematoxylin and eosin （H ＆ E）. LCM using the Arcturus PixCell II system was performed to enrich specific cell populations. The protein was quantitated by Bradford assay after protein extraction from LCM cells. One-way analysis of variance （ANOVA） was used to compare the differences of cell number and protein quantity among three groups. Results We found that fresh frozen material was more desirable in protein-based studies. The improved H＆ E was a feasible staining methods for recognizing cells of interest under light microscope. 56, 60, 63 LCM caps in lung SQCC, lung AD and normal lung were respectively collected. Cell number of normal lung tissue was significantly less than that of lung SQCC and lung AD under visual field of microscope （P〈0.05）. Total protein of lung SQCC, lung AD and normal lung group were respectively 248.20 μg, 261.64 μg and 183.88 p.g. Conclusion The results indicated LCM was a powerful tool in facilitating the molecular biology analysis of lung cancer tissue. It could effectively overcome the heterogeneous problem of lung cancer tissue and provide a more meaningful insight into tumor pathogenesis.     

A （H1N1） Influenza Pneumonia with Acute Disseminated Encephalomyelitis： A Case Report

INTRODUCTION
A 56-year-old Chinese female patient with A （H1N1） influenza pneumonia accompanied by acute disseminated encephalomyelitis （ADEM） of the Central Nervous System （CNS） is described in this article. The patient had typical clinical manifestation, and the diagnosis was reached after MRI and other examinations. From this case, we can conclude that the virus of A （H1N1） influenza can infect CNS, and we should pay more attention to patients of A （H1N1） influenza pneumonia with neurological complications.     

广泛期小细胞肺癌中顺铂联合伊立替康与顺铂联合依托泊苷的比较

3背景 ·小细胞肺癌在肺癌中约占10％-15％．且大多数患者就诊时已处于广泛期,预后差。目前的标准治疗方案是依托泊苷联合顺铂或卡铂。     

吉非替尼/厄洛替尼联合同期放疗治疗晚期肺癌

1文献来源 Chang CC, Chi KK, Kao SJ, et al. Upfront Gefitinib/Erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer： A mono- institutional experience [J]. Lung Cancer, 2011,73 （2） ： 189-194. 2 证据水平     

Acute myocardial infarction mimicking squamous cell lung cancer with bone metastases due to hypercalcemia: a case report

Acute myocardial infarction （AMI）, the most severe .coronary artery disease, is one of the most frequent cardiac emergencies, and early diagnosis and treatment are very important to decrease the subsequent cardiac adverse events such as malignant arrhythmia and sudden cardiac death. But in fact, lots of diseases are similar to AMI in clinical practice, of which the most common are myocarditis, pulmonary embolism in department of cardiology. Here we report a case of AMI-like squamous cell lung cancer with bone metastases.     

吉非替尼与标准化疗对EGFR突变的晚期非小细胞肺癌患者疗效和安全性的比较

1文献来源 Makoto M, Akira I, Kunihiko K, et al. Gefitinib or chemotherapy for non-small cell lung cancerwith mutated EGFR [J]. N Engl J Med, 2010, 362（25） ： 2380-2388.     

Diffusion-weighted magnetic resonance imaging with short T1 inversion recovery-echo planar imaging combined with dual-head coincidence single photon emission computed tomography for diagnosing solitary pulmonary nodule

Positron emission tomography （PET） using 18F-fluorodeoxyglucose （FDG） has not been widely used in China for expensive cost （$1200）. Dual-head coincidence single photon emission computed tomography （DHC-SPECT） can depict many of the lesions depicted with a PET scanner in the lungs, which is used in place of PET-CT for discriminating malignant from benign pulmonary nodules in many studies. However, DHC-SPECT has inevitable false-negative results because the sensitivity for small lesions less than 2.0 cm is limited, and has high false-positive rate for active inflammatory nodules. Furthermore,DHC-SPECT also has a considerably higher cost （$300 in China） than other imaging examination.     

Detection of cytokine expression patterns in the peripheral blood of patients with acute leukemia by antibody microarray analysis

The cytokines of acute leukemia （AL） patients have certain expression patterns, forming a complex network involved in diagnosis, progression, and prognosis. We collected the serum of different AL patients before and after complete remission （CR） for detection of cytokines by using an antibody chip. The expression patterns of cytokines were determined by using bioinformatics computational analysis. The results showed that there were significant differences in the cytokine expression patterns between AL patients and normal controls, as well as between acute myeloid leukemia （AML） and acute lymphoblastic leukemia （ALL）. In confirmatory test, ELISA revealed the expression of uPAR in AL. Moreover, the bioinformatic analysis showed that the differentially expressed cytokines among the AL groups were involved in different biological behaviors and were closely related with the development of the disease. It was concluded that the cytokine expression pattern of AL patients is significantly different from that of healthy volunteers. Also, differences of cytokine expression patterns exist between AML and ALL, and between before and after CR in the same subtype of AL, which holds important clinical significance for revealing disease progression.     

Chemotherapy in conjunction with traditional Chinese medicine for survival of elderly patients with advanced non-small-cell lung cancer： protocol for a randomized double-blind controlled trial

BACKGROUND： Traditional Chinese medicine （TCM） is considered an important complementary therapy with beneficial effects for cancer patients. Elderly patients with non-small-cell lung cancer （NSCLC） are a complex patient group with increasing co-morbidity and shrinking physiological reserve, and may derive substantial benefit from the supportive aspects of TCM Researchers from Shanghai Longhua Hospital found that qi and yin deficiency is a common syndrome in patients with stage III or IV lung cancer. This project was designed to study the combination of single-agent chemotherapy with TCM methods of benefiting qi and yin in elderly patients with advanced NSCLC. METHODS AND DESIGN： This is a double-blind controlled, multi-center, and prospective study with randomly selected participants from elderly NSCLC patients in China. Seventy-six patients who meet the inclusion criteria will be allocated into two groups, which will receive treatments of 3-week single-agent chemotherapy with TCM or placebo for four cycles Progression-free survival （PFS） is the primary end point, and the secondary end points are overall survival, objective response rate, time-to-progression, and quality of life （EORTC QLQ-LC43, and TCM syndrome score） Meanwhile, other end points such as toxicity, side effects and safety of the treatments will be assessed. DISCUSSION： Results from this study may provide evidence on the effectiveness, and parameters for the usage of single-agent chemotherapy combined with or without TCM on PFS of elderly patients with NSCLC.     

晚期非小细胞肺癌EGFR-TKI治疗失败的临床模型及其后续治疗

1文献来源 Yang JJ, Chen HJ, Yan HH, et al. Clinicalmodes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer[J]. Lung Cancer, 2013,79（ 1 ）： 33-39. 2 证据水平     

Expression of nerve growth factor and hypoxia inducible factor-1α and its correlation with angiogenesis in non-small cell lung cancer

Summary： In order to investigate the expression of nerve growth factor （NGF） and hypoxia inducible factor-1α （HIF-1α） and its correlation with angiogenesis in non-small cell lung cancer （NSCLC）, paraffin-embedded tissue blocks from 20 patients with NSCLC were examined. Twenty corresponding para-cancerous lung tissue specimens were obtained to serve as a control. The expression of NGF, HIF-1α, and vascular endothelial growth factor （VEGF） in the NSCLC tissues was detected by using immunohistochemistry. The microvascular density （MVD） was determined by CD31 staining. The resuits showed that the expression levels ofNGF, HIF-1α and VEGF in the NSCLC tissues were remarkably higher than those in the para-cancerous lung tissues （P〈0.05）. There was significant difference in the MVD between the NSCLC tissues （9.19±1.43） and para-cancerous lung tissues （2.23±1.19） （P〈0.05）. There were positive correlations between NGF and VEGF, between HIF-1α and VEGF, and between NGF and HIF-1α in NSCLC tissues, with the spearman correlation coefficient being 0.588, 0.519 and 0.588, respectively. In NSCLC tissues, the MVD had a positive correlation with the three factors （P〈0.05）. Theses results suggest that NGF and HIF-1α are synergically involved in the angiogenesis of NSCLC.     

Deaths of obstructive lung disease in the Yangpu district of Shanghai from 2003 through 2011: a multiple cause analysis

Background Obstructive lung disease （OLD, chronic obstructive pulmonary disease or asthma） is an important cause of death in older people. There has been no exhaustive population-based mortality study of this subject in Shanghai. The objective of this study was to use a multiple cause of death methodology in the analysis of OLD mortality trends in the Yangpu district of Shanghai, from 2003 through 2011. Methods We analyzed death data from the Shanghai Yangpu District Center for Disease Control and Prevention for Medical Cause of Death database, selecting all death certificates for individuals 40 years or older on which OLD was listed as a cause of death. Results From 2003 to 2011, there were 8 775 deaths with OLD listed, of which 6 005 （68%） were identified as the underlying cause of death. For the entire period, a significantly decreasing trend of age standardized rates of death from OLD was observed in men （-6.2% per year） and in women （-5.7% per year）, similar trends were observed in deaths with OLD. The mean annual rates of deaths from OLD per 100 000 were 161.2 for men and 80.8 for women from 2003 to 2011. While, as the underlying cause of death, the main associated causes of death were as follows： cardiovascular diseases （70.7%）, carebrovascular diseases （13.3%）, diabetes （8.6%）, and cancer （4.3%）. The associated causes and the principal overall underlying causes of death were cardiovascular diseases （37.0%）, cancer （30.3%）, and cerebrovascular disease （15.3%）. A significant seasonal variation, with the highest frequency in winter, occurred in deaths identified with underlying causes of chronic bronchitis, other obstructive pulmonary diseases, and asthma. Conclusions Multiple cause mortality analysis provides a more accurate picture than underlying cause of total mortality attributed on death certificates to OLD. The major comorbidities associated with OLD were cardiovascular disease, cancer, and cerebrovascular disease. From 2003 to 2011, the mortality rate from OLD decreased substantially in the Yangpu district of Shanghai.     

Radiological features of lung changes caused by avian influenza subtype A H5N1 virus: report of two severe adult cases with regular follow-up

Several subtypes of avian influenza A have been shown to cross the species barrier and infect humans, leadingto human cases of avian influenza） Till June 2, 2009, globally there were 433 confirmed human cases of avian influenza caused by H5N1 virus, with a death rate of 60.5%.3 This is far higher than the reported 11% death rate of severe acute respiratory syndrome （SARS）.4 The epidemiologic features of human case of influenza A subtype H5N1 virus infection consist of high incidence rate in cold weather, high susceptibility in population of younger age associated with rapid onset of the disease and devastating illness in humans.12＇5＇6 H5N1 virus is mostly transmitted to humans directly through contact with infected birds or their secretions and the patients present with an influenza type illness with fever, cough, sore throat, malaise, and gastrointestinal symptoms; which can result in a rapidly progressive primary viral pneumonia and respiratory failure.2 Patients above the age of 5 years are likely to have an adverse course of disease.5