ABSTRACT
Objective This historical cohort study investigated how a shift toward a more conservative approach of awaiting spontaneous closure of the patent ductus arteriosus (PDA) in preterm infants has affected neonatal outcomes and resource utilization. Methods We retrospectively studied very low birth weight infants diagnosed with a PDA by echocardiogram (ECHO) in 2006-2008 (era 1), when medical or surgical PDA management was emphasized, to those born in 2010-2012 (era 2) when conservative PDA management was encouraged. Multiple regression analyses adjusted for gestational age were performed to assess differences in clinical outcomes and resource utilization between eras. Results More infants in era 2 (35/89, 39%) compared with era 1 (22/120, 18%) had conservative PDA management (p < 0.01). Despite no difference in surgical ligation rate, infants in era 2 had ligation later (median 24 vs. 8 days, p < 0.0001). There was no difference in clinical outcomes between eras, while number of ECHOs per patient was the only resource measure that increased in era 2 (median 3 vs. 2 ECHOs, p = 0.003). Conclusion In an era of more conservative PDA management, no increase in adverse clinical outcomes or significant change in resource utilization was found. Conservative PDA management may be a safe alternative for preterm infants.
Subject(s)
Conservative Treatment , Disease Management , Ductus Arteriosus, Patent/therapy , Health Resources/statistics & numerical data , Watchful Waiting , Birth Weight , Cardiovascular Agents/therapeutic use , Ductus Arteriosus, Patent/diagnostic imaging , Ductus Arteriosus, Patent/surgery , Echocardiography , Female , Gestational Age , Humans , Indomethacin/therapeutic use , Infant, Newborn , Infant, Premature , Infant, Very Low Birth Weight , Ligation , Male , Retrospective Studies , Treatment OutcomeABSTRACT
Adenocarcinoma is the most common type of lung cancer. Epithelial-mesenchymal transition (EMT) is required for tumor invasion/metastasis and the components that control this process are potential therapeutic targets. This study we examined the role of Gli in lung adenocarcinoma and whether its activation regulates metastasis through EMT in lung adenocarcinoma. We found that tumors with high Gli expression had significantly lower E-Cadherin expression in two independent cohorts of patients with lung adenocarcinoma that we studied. In vitro up-regulation of SHh resulted in increased cell migration while small molecule inhibitors of Smo or Gli significantly reduced cell mobility both in a wound healing assay and in a 3D cell invasion assay. Inhibition of Gli in vivo decreased tumor growth and induced an increase in E-Cadherin expression. Our results indicate that Gli may be critical for lung adenocarcinoma metastasis and that a novel Gli inhibitor shows promise as a therapeutic agent by preventing cell migration and invasion in vitro and significantly reducing tumor growth and increasing E-Cadherin expression in vivo.
Subject(s)
Adenocarcinoma/metabolism , Epithelial-Mesenchymal Transition , Lung Neoplasms/metabolism , Zinc Finger Protein GLI1/metabolism , A549 Cells , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/secondary , Adenocarcinoma of Lung , Animals , Antigens, CD , Antineoplastic Agents/pharmacology , Cadherins/genetics , Cadherins/metabolism , Cell Movement , Epithelial-Mesenchymal Transition/drug effects , Female , Gene Expression Regulation, Neoplastic , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mice, Nude , Middle Aged , Neoplasm Invasiveness , Signal Transduction , Smoothened Receptor/antagonists & inhibitors , Smoothened Receptor/metabolism , Time Factors , Tumor Burden , Xenograft Model Antitumor Assays , Zinc Finger Protein GLI1/antagonists & inhibitors , Zinc Finger Protein GLI1/geneticsABSTRACT
BACKGROUND: Squamous cell carcinomas (SCC) account for approximately 30% of non-small cell lung cancer. Investigation of the mechanism of invasion and metastasis of lung SCC will be of great help for the development of meaningful targeted therapeutics. This study is intended to understand whether the activation of Hedgehog (Hh) pathway is involved in lung SCC, and whether activated Hh signaling regulates metastasis through epithelial-mesenchymal transition (EMT) in lung SCC. METHODS: Two cohorts of patients with lung SCC were studied. Protein expression was examined by immunohistochemistry, Western blot, or immunofluorescence. Protein expression levels in tissue specimens were scored and correlations were analyzed. Vismodegib and a Gli inhibitor were used to inhibit Shh/Gli activity, and recombinant Shh proteins were used to stimulate the Hh pathway in lung SCC cell lines. Cell migration assay was performed in vitro. RESULTS: Shh/Gli pathway components were aberrantly expressed in lung SCC tissue samples. Gli1 expression was reversely associated with the expression of EMT markers E-Cadherin and ß-Catenin in lung SCC specimens. Inhibition of the Shh/Gli pathway suppressed migration and up-regulated E-Cadherin expression in lung SCC cells. Stimulation of the pathway increased migration and down-regulated E-Cadherin expression in lung SCC cells. CONCLUSIONS: Our results suggested that the Shh/Gli pathway may be critical for lung SCC recurrence, metastasis and resistance to chemotherapy. Inhibition of the Shh/Gli pathway activity/function is a potential therapeutic strategy for the treatment of lung SCC patients.