Two plasma microRNA panels for diagnosis and subtype discrimination of lung cancer.

OBJECTIVES: Early and accurate diagnosis of lung cancer is crucial for effective treatment. This study aimed to identify plasma microRNAs for diagnosis of lung cancer and for further discrimination of small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Plasma microRNA expression was investigated using three independent cohorts including 1132 participants recruited between October 2008 and September 2014 from five medical centers. The subjects were healthy individuals and patients with NSCLC or SCLC. Microarrays were used to screen 723 human microRNAs in 106 plasma samples for candidate selection. Quantitative reverse-transcriptase PCR was applied to evaluate the expression of selected microRNAs. Two logistic regression models were constructed based on a training cohort (n = 565) and then validated using an independent cohort (n = 461). The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. RESULTS: Plasma panel A with six microRNAs (miR-17, miR-190b, miR-19a, miR-19b, miR-26b, and miR-375) provided high diagnostic accuracy in discriminating lung cancer patients from healthy individuals (AUC 0.873 and 0.868 for training and validation cohort, respectively). Moreover, plasma panel B with three microRNAs (miR-17, miR-190b, and miR-375) demonstrated high diagnostic accuracy in discriminating SCLC from NSCLC (AUC 0.878 and 0.869 for training and validation cohort, respectively). CONCLUSION: We constructed and validated two plasma microRNA panels that have considerable clinical value in diagnosis of lung cancer, and could play an important role in determining optimal treatment strategies based on discrimination between SCLC and NSCLC.

The optimum timing to wean invasive ventilation for patients with AECOPD or COPD with pulmonary infection.

COPD is characterized by a progressive decline in lung function and mental and physical comorbidities. It is a significant burden worldwide due to its growing prevalence, comorbidities, and mortality. Complication by bronchial-pulmonary infection causes 50%-90% of acute exacerbations of COPD (AECOPD), which may lead to the aggregation of COPD symptoms and the development of acute respiratory failure. Non-invasive or invasive ventilation (IV) is usually implemented to treat acute respiratory failure. However, ventilatory support (mainly IV) should be discarded as soon as possible to prevent the onset of time-dependent complications. To withdraw IV, an optimum timing has to be selected based on weaning assessment and spontaneous breathing trial or replacement of IV by non-IV at pulmonary infection control window. The former method is more suitable for patients with AECOPD without significant bronchial-pulmonary infection while the latter method is more suitable for patients with AECOPD with acute significant bronchial-pulmonary infection.

Metabonomic characteristics and biomarker research of human lung cancer tissues by HR1H NMR spectroscopy.

BACKGROUND: The combination of NMR spectroscopy and multivariate data analysis (MVDA), such as orthogonal partial least squares-discriminant analysis (OPLS-DA), has been collectively acknowledged as an excellent tool to investigate tissue metabolism and provide metabolite information for the diagnosis of disease, and become an important metabonomic platform for studies in biological tissues so far. METHODS: Both ex vivo high resolution magic-angle spinning1H NMR and in vitro1H NMR spectroscopy technique were synchronously employed to analyze the metabonomic characteristics of 102 lung tissues from 34 patients with lung cancer in hope to identify potential diagnostic biomarkers for malignancy detection in lung tissues. RESULTS: Significant elevations in the levels of lipids and lactate and significant reductions in the levels of myo-inositol and valine in the cancer tissues had been identified when compared with the adjacent non-involved tissues. Furthermore, the OPLSDA models calculated by two1H NMR spectra provided for relatively high sensitivity, specificity and good prediction accuracy in the identification of class membership regardless of the number of metabolites involved. CONCLUSIONS: MVDA in combination with1H NMR spectra highlighted the potential of metabonomics in clinical settings so that the techniques might be further exploited for future lung cancer biomarker research or identification.

Increased Lung Ischemia-Reperfusion Injury in Aquaporin 1-Null Mice Is Mediated via Decreased Hypoxia-Inducible Factor 2α Stability.

Aquaporin (AQP) 1, a water channel protein expressed widely in vascular endothelia, has been shown to regulate cell migration, angiogenesis, and organ regeneration. Even though its role in the pathogenesis of lung ischemia-reperfusion (IR) injury has been defined, the functional role of AQP1 during long-term IR resolution remains to be clarified. Here, we found that AQP1 expression was increased at late time points (7-14 d) after IR and colocalized with endothelial cell (EC) marker CD31. Compared with IR in wild-type mice, IR in Aqp1(-/-) mice had significantly enhanced leukocyte infiltration, collagen deposition, and microvascular permeability, as well as inhibited angiogenic factor expression. AQP1 knockdown repressed hypoxia-inducible factor (HIF)-2α protein stability. HIF-2α overexpression rescued the angiogenic factor expression in pulmonary microvascular ECs with AQP1 knockdown exposed to hypoxia-reoxygenation. Furthermore, AQP1 knockdown suppressed cellular viability and capillary tube formation, and enhanced permeability in pulmonary microvascular ECs, which were partly rescued by HIF-2α overexpression. Thus, this study demonstrates that AQP1 deficiency delays long-term IR resolution, partly through repressing angiogenesis mediated by destabilizing HIF-2α. These results suggest that AQP1 participates in long-term IR resolution, at least in part by promoting angiogenesis.

Role of a serum-based biomarker panel in the early diagnosis of lung cancer for a cohort of high-risk patients.

BACKGROUND: This study applied a combined cancer biomarker panel to clinically identify small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) in a high-risk population. METHODS: The serum levels of 4 biomarkers (progastrin-releasing peptide [ProGRP], carcinoembryonic antigen [CEA], squamous cell carcinoma antigen [SCC], and cytokeratin 19 fragment [CYFRA21-1]) were determined in 153 patients with a high risk of lung cancer (12 with a new diagnosis of SCLC, 52 with NSCLC, and 89 without lung cancer). Information about diagnosis delays was collected through interviews of all participants. RESULTS: Significantly higher serum levels of ProGRP (P < .0001) were found among the SCLC patients versus the rest of the population. A receiver operating characteristic curve analysis established the cutoff values of ProGRP, CEA, SCC, and CYFRA21-1 as 300 pg/mL, 7.3 ng/mL, 3 ng/mL, and 6.5 ng/mL, respectively. The sensitivity and specificity of ProGRP in diagnosing SCLC were 75% and 100%, respectively. Among the 14 lung cancer patients with a false-negative computed tomography (CT) result, the diagnostic panel detected 8 additional cancers. CONCLUSIONS: This panel increased the diagnostic specificity for high-risk subjects (those with renal failure being excluded), and auxiliary to a CT scan, it increased the sensitivity for patients with lung cancer. These results might be applied to shorten the diagnosis delay at health care institutions in China.

Autophagy protects against ischemia/reperfusion-induced lung injury through alleviating blood-air barrier damage.

BACKGROUND: Understanding the role and underlying regulation mechanism of autophagy in ischemia/reperfusion (I/R)-induced lung injury may provide potentially new pharmacologic targets for treatment of acute lung injury. The aim of this study was to adjust autophagy with pharmacologic agents to determine its functional significance in I/R-induced lung injury. METHODS: Human pulmonary microvascular endothelial cells (HPMVECs) and mice were pre-conditioned with autophagy inhibitor chloroquine or promoter rapamycin before they were challenged with oxygen-glucose deprivation/oxygen-glucose restoration (OGD) and lung I/R, respectively. Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 was pre-injected into I/R-induced mice to test the role of ERK1/2 in regulating autophagy. RESULTS: OGD caused tight conjunction damage and cell death in HPMVECs, which was further aggravated by blocking autophagy, yet ameliorated through promoting autophagy. On a consistent basis, inhibiting autophagy aggravated I/R-induced lung edema and tissue inflammation, which was significantly alleviated by promoting autophagy with rapamycin. In addition, inhibition of ERK1/2 increased expression of active mammalian target-of-rapamycin and thus decreased I/R-induced autophagy. CONCLUSIONS: It appears that autophagy plays a protective role in I/R-induced lung injury and this effect may be enhanced by moderately improving autophagy level. Meanwhile, the ERK1/2 signal pathway has a positively regulating role in lung I/R-induced autophagy.

Prognosis of 18 H7N9 avian influenza patients in Shanghai.

PURPOSE: To provide prognosis of an 18 patient cohort who were confirmed to have H7N9 lung infection in Shanghai. METHODS: Patients' history, clinical manifestation, laboratory test, treatment strategy and mortality were followed and recorded for data analysis. RESULTS: A total of 18 patients had been admitted into Shanghai Public Health Clinical Center from April 8th to July 29, 2013. 22.2% of the patients were found to have live poultry contact history and 80% were aged male patients with multiple co-morbidities including diabetes, hypertension and/or chronic obstructive pulmonary disease (COPD). This group of patients was admitted to the clinical center around 10 days after disease onset. According to laboratory examinations, increased C reactive protein (CRP), Procalcitonin (PCT), Plasma thromboplastin antecedent (PTA) and virus positive time (days) were indicative of patients' mortality. After multivariate analysis, only CRP level showed significant prediction of mortality (P = 0.013) while results of prothrombin time (PT) analysis almost reached statistical significance (P = 0.056). CONCLUSIONS: H7N9 infection induced pneumonia of different severity ranging from mild to severe pneumonia or acute lung injury/acute respiratory distress syndrome to multiple organ failure. Certain laboratory parameters such as plasma CRP, PCT, PTA and virus positive days predicted mortality of H7N9 infection and plasma CRP is an independent predictor of mortality in these patients.

[Value of low-dose spiral computed tomography in lung cancer screening].

OBJECTIVE: To explore the application value of low-dose spiral computed tomography (LDCT) in lung cancer screening. METHODS: A total of 2251 asymptomatic subjects undergoing chest LDCT scan at Center of Physical Examination, Affiliated Zhongshan Hospital, Fudan University between June 2011 and December 2012 were prospectively enrolled. The incidence rates of lung nodule and lung cancer were analyzed to compare the value of LDCT screening in subjects with smoking-related high, medium and low risks of lung cancer. The value of serum tumor biomarker in the reduction of false positive of LDCT was also discussed. RESULTS: Among all subjects, 9.9% (222/2251) displayed at least 1 non-calcified nodule with a diameter ≥ 4 mm. Two subjects were diagnosed with lung cancer and 1 of them received surgical resection. Other subjects with lung nodules were followed. There was no statistical difference in the incidence rates of lung nodule between the high, medium and low-risk groups of lung cancer associated with smoking (8.8%, 9.5% and 10.1%, P = 0.864). The incidence rates of lung nodule in subjects ≥ 55 years old were higher than that of those <55 years old (12.7% vs 9.1%, P = 0.034). Female gender had a high risk of ground glass opacity (GGO) or ground glass nodule (GGN) (P = 0.015). The independent or combined increase of serum tumor biomarkers of carcinoembryonic antigen (CEA), neuron specific enolase (NSE), cytokeratin fragment 21-1 (Cyfra211) and squamous cell carcinoma antigen (SCC) might not predicate the incidence of lung nodule. CONCLUSION: LDCT screening is highly valuable in lung cancer screening.

Does prohibitin expression regulate sperm mitochondrial membrane potential, sperm motility, and male fertility?

Prohibitin (PHB) is a highly conserved major sperm mitochondrial membrane protein whose absence in somatic cells is associated with mitochondrial membrane depolarization and increased generation of reactive oxygen species (ROS). Our recent findings suggest that high levels of oxidants in human semen may contribute to male infertility and that sperm motility could be the earliest and most sensitive indicator of oxidative damage. Based on PHB's roles in mitochondrial sub-compartmentalization and respiratory chain assembly, we examine sperm PHB expression and mitochondrial membrane potential (MITO) in infertile men with poor sperm motility (asthenospermia, A) and/or low sperm concentrations (oligoasthenospermia, OA). Here, we demonstrate that MITO is significantly lower in sperm from A and OA subjects than in normospermic (N) subjects; the decrease is more severe for OA than for A subjects. PHB expression is also significantly lower in sperm from A and OA subjects. Significantly positive correlations are found among PHB expression, MITO, and sperm motility in normospermic, asthenospermic, and oligoasthenospermic subjects. Collectively, our observations lead to the hypothesis that PHB expression is an indicator of sperm quality in infertile men, and that it regulates sperm motility via an alteration in MITO and increased ROS levels.

Tobacco smoking in China: prevalence, disease burden, challenges and future strategies.

About one-third of the world's tobacco is produced and consumed in China. Despite existing tobacco control policies and activities, the prevalence of smoking in China remains high with 350 million smokers and 740 million passive smokers. Furthermore, smoking rates in the young population and in females are increasing. The number of deaths attributed to tobacco use has reached 1.2 million per year, whereas the death toll is expected to rise to 2 million annually by 2025. Sociocultural factors favouring smoking initiation, lack of awareness among the public about the hazards of smoking, weak support from the government and strong resistance from the tobacco industry are major reasons for the lack of effectiveness of current tobacco control measures. Effective intervention efforts are urgently required. Commitments from the government are crucial in tobacco control. Firm action should be taken on tobacco control issues at multiple levels including a reduction in tobacco supply, increased tobacco taxation, increased education, tobacco advertising limitations, decreased second-hand smoke exposure and smoking cessation support. The health-care community should also play a leading role in anti-tobacco campaigns and take a more active role in smoking cessation programmes.