Molecular determinants of lung development.

Ann Am Thorac Soc. 2013 Apr;10(2):S12-6

Authors: Morrisey EE, Cardoso WV, Lane RH, Rabinovitch M, Abman SH, Ai X, Albertine KH, Bland RD, Chapman HA, Checkley W, Epstein JA, Kintner CR, Kumar M, Minoo P, Mariani TJ, McDonald DM, Mukouyama YS, Prince LS, Reese J, Rossant J, Shi W, Sun X, Werb Z, Whitsett JA, Gail D, Blaisdell CJ, Lin QS

Abstract
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.

PMID: 23607856 [PubMed - in process]

Prognostic value of K-RAS mutations in patients with non-small cell lung cancer: A systematic review with meta-analysis.

Lung Cancer. 2013 Apr 19;

Authors: Meng D, Yuan M, Li X, Chen L, Yang J, Zhao X, Ma W, Xin J

Abstract
K-RAS gene mutations have been found in 20-30% of non-small cell lung cancer and occur most commonly in adenocarcinoma, however, there was no definitive conclusion about the prognostic role of K-RAS mutations in NSCLC. Herein we performed a systematic review of the literatures with meta-analysis to assess K-RAS mutations' prognostic value in NSCLC. After a methodological assessment, survival data from published studies were aggregated. Combined hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated in terms of overall survival. 41 trials (6939 patients) were included in the analysis, the overall HR was 1.45 (95% CI: 1.29-1.62), showing that K-RAS mutations have an unfavorable impact on survival of patients with NSCLC. Then a subgroup analysis was performed about ethnicity, the combined HR was 1.97 (95% CI: 1.58-2.44) for Asians, and 1.37 (95% CI: 1.25-1.5) for non-Asians. In subgroup analysis of histology, the HR was 1.39 (95% CI: 1.24-1.55) for adenocarcinoma, suggesting that K-RAS mutations were correlated with shortened survival for adenocarcinoma. When the subgroup analysis was conducted according to disease stage, K-RAS mutations were poor prognostic factors in early stages: stage I (1.81; 95% CI: 1.36-2.39) and stage I-IIIa (1.68; 95% CI: 1.11-2.55), but not in advanced stage (IIIb-IV) (1.3; 95% CI: 0.99-1.71). At last, in subgroup analysis about test methods, all of the four methods: PCR-MSOP (1.73; 95% CI: 1.35-2.2), PCR-DGGE (1.27; 95% CI: 1.01-1.62), PCR-RFLP (1.88; 95% CI: 1.42-2.49) and PCR-seq (1.34; 95% CI: 1.14-1.58) showed statistically significant impact on survival of NSCLC patients. In conclusion, this meta-analysis suggests that K-RAS mutations are associated with a worse overall survival in patients with NSCLC, especially in patients with adenocarcinoma and early stage.

PMID: 23608713 [PubMed - as supplied by publisher]

Results of T4 Surgical Cases in the Japanese Lung Cancer Registry Study: Should Mediastinal Fat Tissue Invasion Really be Included in the T4 Category?

J Thorac Oncol. 2013 Apr 19;

Authors: Watanabe SI, Asamura H, Miyaoka E, Okumura M, Yoshino I, Fujii Y, Nakanishi Y, Eguchi K, Mori M, Sawabata N, Yokoi K, for the Japanese Joint Committee of Lung Cancer Registry

Abstract
INTRODUCTION:: T4 lung cancer is a heterogeneous group of locally advanced disease. We hypothesized that patients in whom T4 lung cancer invaded only mediastinal fat tissue would show better prognosis after surgery than patients in whom T4 disease invaded other organs. The present study aimed to investigate how different invasive features of T4 disease impacted prognosis, and what types of patients with T4 disease could benefit most from surgical treatment. METHODS:: A nationwide registry study on lung cancer surgical cases during 2004 was conducted by the Japanese Joint Committee of Lung Cancer Registry, including registries of 11,663 cases within Japan. The present study analyzed 215 of these cases involving T4 structures or with ipsilateral nonprimary lobe pulmonary metastasis (PM). RESULTS:: Reasons for T4 classification included invasion of only mediastinal tissue in 32 cases (15%), invasion of other structures in 96 cases (45%), and ipsilateral different lobe PM in 87 cases (40%); among these three groups, there were no significant differences in survival, nodal status, and patterns of first recurrence. Multivariate analysis showed an age of 70 years or above (p = 0.022) and nodal status (p = 0.004) to be significant prognostic factors. T4N0 patients less than 70 years of age showed significantly better prognosis than those who were T4N1-2 and 70 years of age or older (p = 0.0001; 5-year survival rate 50.3 versus 19.9%). CONCLUSIONS:: There was no significant difference in survival between T4 patients with only mediastinal fat invasion and those with other T4 organ invasion and ipsilateral different lobe PM, demonstrating appropriateness of the T4 category definition in the current tumor, node, metastasis staging system. Age and nodal status were significant independent prognostic factors in T4 patients, and the best surgical candidates were shown to be T4N0 patients who were less than 70 years of age and had a 5-year survival rate of more than 50%.

PMID: 23608818 [PubMed - as supplied by publisher]

Inflammatory Responses of Airway Smooth Muscle Cells and Effects of Endothelin Receptor Antagonism.

Am J Respir Cell Mol Biol. 2013 Apr 3;

Authors: Knobloch J, Lin Y, Konradi J, Jungck D, Behr J, Strauch J, Stoelben E, Koch A

Abstract
Endothelin receptor antagonists (ETRAs), authorized for pulmonary hypertension, have failed to prove their utility in chronic lung diseases with corticosteroid-resistant airway inflammation when applied at late disease stages with emphysema/fibrosis. Earlier administration might prove effective by targeting the interaction between airway inflammation and tissue remodeling. Hypothesis: human airway smooth muscle cells (HASMCs) participate in linking inflammation with remodeling; associated genes become differentially suppressed by ambrisentan (A-receptor selective ETRA) and bosentan (non-selective/dual ETRA). Inflammatory responses of ex-vivo-cultivated HASMCs to TNFα were investigated by whole-genome-microarray analyses. qRT-PCR and ELISA were used to test inflammatory and remodeling genes for sensitivity to bosentan and ambrisentan and to investigate differential sensitivities mechanistically. ETRA and corticosteroid effects were compared in HASMCs from patients with COPD. TNFα induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in (severe/corticosteroid-insensitive) asthma, COPD, IPF and/or pulmonary hypertension. 13 cytokines/chemokines, MMP13 and WISP1 were suppressed by ETRAs. Eight genes had differential sensitivity to bosentan and ambrisentan depending on the endothelin-B-receptor impact on transcriptional regulation and mRNA stabilization. CCL2, CCL5, GM-CSF and MMP13 had increased sensitivity to bosentan or bosentan/dexamethasone combination versus dexamethasone alone. Suppression of cytokine and remodeling gene expression by ETRAs was confirmed in TNFα-activated human bronchial epithelial cells (HBECs). HASMCs and HBECs participate in the interaction of inflammation and tissue remodeling. This interaction is targeted differentially by selective and non-selective ETRAs, which could be utilized in therapies of chronic lung diseases with corticosteroid-resistant airway inflammation at early disease stages in order to attenuate inflammation-induced airway remodeling.

PMID: 23590298 [PubMed - as supplied by publisher]