Overexpression of miR-199a-5p decreases esophageal cancer cell proliferation through repression of mitogen-activated protein kinase kinase kinase-11 (MAP3K11).

Studies examining the oncogenic or tumor suppressive functions of dysregulated microRNAs (miRs) in cancer cells may also identify novel miR targets, which can themselves serve as therapeutic targets. Using array analysis, we have previously determined that miR-199a-5p was the most downregulated miR in two esophageal cancer cell lines compared to esophageal epithelial cells. MiR-199a-5p is predicted to bind mitogen-activated protein kinase kinase kinase 11 (MAP3K11) mRNA with high affinity. In this study, we observed that MAP3K11 is markedly overexpressed in esophageal cancer cell lines. Forced expression of miR-199a-5p in these cells leads to a decrease in the mRNA and protein levels of MAP3K11, due to decreased MAP3K11 mRNA stability. A direct binding interaction between miR-199a-5p and MAP3K11 mRNA is demonstrated using biotin pull-down assays and heterologous luciferase reporter constructs and confirmed by mutational analysis. Finally, forced expression of miR-199a-5p decreases proliferation of esophageal cancer cells by inducing G2/M arrest. This effect is mediated, in part, by decreased transcription of cyclin D1, due to reduced MAP3K11-mediated phosphorylation of c-Jun. These findings suggest that miR-199a-5p acts as a tumor suppressor in esophageal cancer cells and that its downregulation contributes to enhanced cellular proliferation by targeting MAP3K11.

Long-Term Venovenous Extracorporeal Membrane Oxygenation Support for Acute Respiratory Distress Syndrome.

BACKGROUND: Given substantial advances in venovenous extracorporeal membrane oxygenation (ECMO) technology, long-term support is increasingly feasible. Although the benefits of short-term ECMO as a bridge to recovery in acute respiratory distress syndrome (ARDS) are well described, the utility and outcomes of long-term support remain unclear. METHODS: Patients requiring ECMO for ARDS between January 2009 and November 2012 were retrospectively reviewed and analyzed separately for those requiring ECMO support for less than 3 weeks or for 3 weeks or longer. Demographic factors, ECMO variables, and outcomes were assessed. RESULTS: Fifty-five patients with ARDS received ECMO during the study period, with 11 patients requiring long-term ECMO support and a median duration of 36 (interquartile range: 24 to 68) days. Recovery was the initial goal in all patients. Pre-ECMO mechanical ventilatory support, indices of disease severity, and the ECMO cannulation strategy were similar between the two groups. Eight (73%) patients receiving long-term support were bridged to recovery, and 1 patient was bridged to transplantation after a refractory course. Eight (73%) patients receiving long-term support and 25 (57%) patients receiving short-term support survived to 30 days and hospital discharge. CONCLUSIONS: Previously, long-term ECMO support was thought to be associated with unfavorable outcomes. This study, however, may provide support for the efficacy of ECMO support even for 3 weeks or more as a bridge to recovery or transplantation.

Class III Obesity is Not a Contraindication to Venovenous Extracorporeal Membrane Oxygenation Support.

BACKGROUND: The use of venovenous extracorporeal membrane oxygenation (ECMO) has increased as a bridge to recovery for acute respiratory distress syndrome (ARDS) refractory to conventional support. Morbid obesity can pose a significant challenge to obtaining indexed flows, and outcomes in this population are not well described. METHODS: Patients requiring ECMO for ARDS between January 2009 and November 2012 were retrospectively reviewed. Demographics, ECMO variables, and outcomes were assessed. Morbid obesity and super obesity were defined as a body mass index (BMI) greater than 40 kg/m(2) and greater than 50 kg/m(2), respectively. RESULTS: Fifty-five patients with ARDS were placed on ECMO during the study period. Twelve were morbidly obese with a BMI of 49.0 kg/m(2) (interquartile range [IQR]: 45.4-57.3 kg/m(2)). Pre-ECMO mechanical ventilatory support and indices of disease severity were similar between the 2 groups, as were cannulation strategy and duration of ECMO support. Nine (75%) morbidly obese patients and 27 (63%) non-morbidly obese patients were successfully weaned from ECMO support, and patient survival to time of discharge was 67% and 58%, respectively. In the subset of super obese patients (n = 6; BMI, 57.3 kg/m(2) [IQR: 51.3-66.5 kg/m(2)]), recovery and midterm survival was 100%. CONCLUSIONS: In this review, class III obesity was not associated with poorer outcomes, and based on these data, ECMO support should not be withheld from this patient population.