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Elevated CO(2) levels cause mitochondrial dysfunction and impair cell proliferation.

Elevated CO(2) concentrations (hypercapnia) occur in patients with severe lung diseases. Here, we provide evidence that high CO(2) levels decrease O(2) consumption and ATP production and impair cell proliferation independently of acidosis and hypoxia in fibroblasts (N12) and alveolar epithelial cells (A549). Cells exposed to elevated CO(2) died in galactose medium as well as when glucose-6-phosphate isomerase was knocked down, suggesting mitochondrial dysfunction.

High CO(2) levels led to increased levels of microRNA-183 (miR-183), which in turn decreased expression of IDH2 (isocitrate dehydrogenase 2). The high CO(2)-induced decrease in cell proliferation was rescued by α-ketoglutarate and overexpression of IDH2, whereas proliferation decreased in normocapnic cells transfected with siRNA for IDH2. Also, overexpression of miR-183 decreased IDH2 (mRNA and protein) as well as cell proliferation under normocapnic conditions, whereas inhibition of miR-183 rescued the normal proliferation phenotype in cells exposed to elevated levels of CO(2).

Accordingly, we provide evidence that high CO(2) induces miR-183, which down-regulates IDH2, thus impairing mitochondrial function and cell proliferation. These results are of relevance to patients with hypercapnia such as those with chronic obstructive pulmonary disease, asthma, cystic fibrosis, bronchopulmonary dysplasia, and muscular dystrophies.

The combined treatment of CT-guided percutaneous 125I seed implantation and chemotherapy for non-small-cell lung cancer.

PURPOSE: Gemcitabine plus cisplatin (GP) is a first-line treatment for advanced non-small-cell lung cancer (NSCLC). In this study, we evaluated the efficacy and safety of a combined treatment consisting of CT-guided percutaneous (125)I seed implantation with GP chemotherapy for advanced NSCLC.

METHODS: Fifty-three patients with advanced NSCLC were enrolled in a nonrandomized, two-armed clinical trial. Of these patients, 24 received a combination treatment of CT-guided percutaneous (125) I seed implantation and GP (the combo group), while 29 were treated with GP only (the control group).

RESULTS: Patients in the combo group received (125)I seed implantation with prescription dose of 100-140 Gy and a total of 55 cycles of GP, and patients in the control group received a total of 73 cycles of GP. The overall response rate was 79.2% in the combo group and 41.4% in the control group. The median overall survival time was 13.5 ± 1.5 months in the combo group and 9.0 ± 1.8 months in the control group. The progression-free survival time was 8.0 ± 1.2 months in the combo group and 5.0 ± 0.8 months in the control group. The 1- and 2-year survival rates were 62.5 and 16.7% in the combo group, respectively, and 41.4 and 13.8% in the control group. The interventional complications in the combo group included 5 cases of pneumothorax and 4 cases of hemoptysis. There were no complications due to radiation pneumonia or radiation esophagitis in the combo group, and no patients had lethal hemoptysis or esophagotracheal fistula. Chemotherapy treatment-related toxicities, including Grade 3/4 myelosuppression and Grade 3 gastrointestinal toxicity, were similar in both groups.

CONCLUSIONS: Our initial experience showed that combined CT-guided (125)I radioactive seed implantation and GP chemotherapy are effective and safe for treating advanced NCSLC.

Endothelial progenitor cells are associated with response to chemotherapy in human non-small-cell lung cancer.

PURPOSE: Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in angiogenesis and tumor growth. However, the clinical relevance of EPCs in non-small-cell lung cancer (NSCLC) remains unclear. Recently, some reports suggested that EPCs correlate with clinical behavior of cancer patients. We assessed the hypothesis that EPCs correlate with efficient of therapy, prognosis, and clinicopathological factors, and EPCs may offer a possible biomarker for treatment outcome in NSCLC.

METHODS: EPCs labeled with CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR-2) antibodies were counted by flow cytometry in the peripheral blood of 31 NSCLC patients. We categorized two groups of NSCLC patients according to circulating EPC numbers. We examined age, pathological stage, histological type, Fluoro-D: -glucose Positron emission tomography (FDG-PET), response to therapy, progression-free survival, and tumor size of NSCLC patients and investigated whether these factors correlate with EPC counts.

RESULTS: Circulating EPC numbers before antitumor therapy were increased in NSCLC patients compared with healthy controls (P < 0.05). In NSCLC patients, therapy was significantly effective in low circulating EPC group compared with that of high (P < 0.05). Furthermore, the low EPC group showed significantly longer progression-free survival times than that of high (P < 0.05). However, no significant associations with age, gender, histological type, pathological stage, or FDG-PET were detected.

CONCLUSION: Peripheral blood levels of bone marrow-derived EPCs are significantly increased in patients with NSCLC and correlate with response to chemotherapy. EPCs may offer a possible biomarker for efficient of treatment and prognosis.

Advances in the diagnosis of pulmonary tuberculosis in HIV-infected and HIV-uninfected children.

The identification of improved diagnostic tests for tuberculosis has been identified as a global research priority. Over the past decade, there has been renewed interest in the development and validation of novel diagnostic tools for pulmonary tuberculosis that are applicable to resource-poor settings. These techniques are aimed primarily at improving detection of the organism or a specific host immune response.

Although most studies have focused on determining the accuracy of novel tests in adults, it is likely they will also have the capacity to significantly improve the diagnosis of childhood tuberculosis. Improving the quality of clinical samples obtained from children with suspected tuberculosis remains an important research priority while awaiting validation of novel diagnostic tests. This review will focus on a number of recent developments for the diagnosis of tuberculosis, with a specific emphasis on the application of these new tests to children in settings where tuberculosis is endemic.

Recommendations for epidemiological studies on COPD.

The prevalence of chronic obstructive pulmonary disease (COPD) has been extensively studied, especially in Western Europe and North America. Few of these data are directly comparable because of differences between the surveys regarding composition of study populations, diagnostic criteria of the disease and definitions of the risk factors. Few community studies have examined phenotypes of COPD and included other ways of characterising the disease beyond that of spirometry.

The objective of the present Task Force report is to present recommendations for the performance of general population studies in COPD in order to facilitate comparable and valid estimates on COPD prevalence by various risk factors. Diagnostic criteria in epidemiological settings, and standardised methods to examine the disease and its potential risk factors are discussed.

The paper also offers practical advice for planning and performing an epidemiological study on COPD. The main message of the paper is that thorough planning is worth half the study. It is crucial to stick to standardised methods and good quality control during sampling.

We recommend collecting biological markers, depending on the specific objectives of the study. Finally, studies of COPD in the population at large should assess various phenotypes of the disease.

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