Cameron Schlegel

Akt2 Regulates Metastatic Potential in Neuroblastoma

Activation of PI3K/AKT pathway correlates with poor prognosis in patients with neuroblastoma. Our previous studies have demonstrated that PI3K/AKT signaling is critical for the oncogenic transformations induced by gastrin-releasing peptide (GRP) and its receptor, GRP-R, in neuroblastoma. Moreover, PI3K/AKT-dependent oncogenic transformations require N-myc, an extensively studied oncogene in neuroblastoma. Whether AKT directly regulates the expression of N-myc oncogene is yet to be determined. Here, we report a novel finding that of the three AKT isoforms, AKT2 specifically regulated N-myc expression in neuroblastoma cells. We also confirmed that GRP-R is upstream of AKT2 and in turn, regulated N-myc expression via AKT2 in neuroblastoma cells. Functional assays demonstrated that attenuation of AKT2 impaired cell proliferation and anchorage-independent cell growth, and decreased the secretion of angiogenic factor VEGF in vitro. Furthermore, silencing AKT2 inhibited migration and invasion of neuroblastoma cells in vitro. Xenografts established by injecting AKT2 silenced human neuroblastoma cells into murine spleen expressed decreased levels of AKT2 and resulted in fewer liver metastases compared to controls in vivo. Hence, our study highlights the potential molecular mechanism(s) mediating the oncogenic role of GRP/GRP-R and demonstrates a novel role for AKT2 in neuroblastoma tumorigenesis, indicating that targeting the GRP/GRP-R/AKT2 axis may be important for developing novel therapeutics in the treatment of clinically aggressive neuroblastoma.

Congenital lung anomalies: can we postpone resection?

BACKGROUND/PURPOSE The management of asymptomatic congenital lung lesions is controversial. It is unclear whether elective resection provides a significant benefit. We sought to determine whether early vs delayed resection of asymptomatic congenital lung malformations resulted in complications. METHODS Institutional billing records were queried for patients with lung malformations over a 10-year period. Medical records were reviewed for demographics, type of anomaly, symptoms, management, and procedural or disease-related complications. RESULTS Eighty-seven patients were identified. The diagnoses included congenital cystic adenomatoid malformation (41%), bronchogenic cyst (19.3%), sequestration (13.2%), and congenital lobar emphysema (12.0%). Fifty patients were observed for some period. Eleven became symptomatic, and 47 underwent resection at a mean age of 11 months. There was no difference in the type of resection, length of hospitalization, or complication rate between patients who underwent early vs delayed resection. There were no occurrences of malignancy or death. CONCLUSIONS In our series, there was no difference in measurable outcomes between early and delayed resection of congenital lung lesions. These data provide some support for a management strategy that might include observation with delayed resection for asymptomatic patients.

Integrin-linked kinase regulates phosphatase and tensin homologue activity to promote tumorigenesis in neuroblastoma cells

BACKGROUND The phosphatidylinositol 3-kinase (PI3K), a critical intracellular pathway, is negatively regulated by phosphatase and tensin homologue (PTEN). Integrin-linked kinase (ILK) induces phosphorylation of Akt leading to an increase in cell survival. However, a potential interaction between ILK and PTEN activity in neuroblastoma cells is unknown. We sought to examine the relationship between ILK and PTEN in the PI3K/Akt signaling pathway in neuroblastoma tumorigenesis. METHODS The human neuroblastoma cell line, BE(2)-C, was transfected with small interfering or short hairpin RNA to silence ILK expression. A plasmid containing the ILK wild-type (ILK wt) gene was transfected to overexpress ILK. Cell proliferation was assessed, and anchorage independence was measured by soft agar assay. Insulin-like growth factor-1 was used to stimulate the PI3K/Akt pathway. Protein levels were determined by Western blotting. RESULTS Transient silencing of ILK produced correlative decreases in PTEN expression, cell proliferation, and soft agar colony formation. Conversely, stably transfected ILK knockdown cells showed an increase in phospho-Akt levels, leading to cell proliferation. CONCLUSION ILK plays an important role in the regulation of PI3K/Akt pathway via PTEN or an upstream effector of PTEN. The effects of ILK silencing on PTEN expression seem to be critically dependent on duration of ILK dysregulation.

Evolution of a level I pediatric trauma center: Changes in injury mechanisms and improved outcomes

Background: Trauma is the leading cause of mortality among children, underscoring the need for specialized child‐centered care. The impact on presenting mechanisms of injury and outcomes during the evolution of independent pediatric trauma centers is unknown. The aim of this study was to evaluate the impact of our single center transition from an adult to American College of Surgeons–verified pediatric trauma center. Methods: A retrospective analysis was performed of 1,190 children who presented as level I trauma activations between 2005 and 2016. Patients were divided into 3 chronological treatment eras: adult trauma center, early pediatric trauma center, and late pediatric trauma center after American College of Surgeons verification review. Comparisons were made using Pearson χ2, Wilcoxon rank sum, and Kruskal‐Wallis tests. Results: The predominant mechanism of injury was motor vehicle crash, with increases noted in assault/abuse (2% adult trauma center, 11% late pediatric trauma center). A decrease in intensive care admissions was identified during late pediatric trauma center compared with early pediatric trauma center and adult trauma center (51% vs 62.4% vs 67%, P < .001), with concomitant increases in admissions to the floor and immediate operative interventions, but overall mortality was unchanged. Conclusion: Transition to a verified pediatric trauma center maintains the safety expected of the American College of Surgeons certification, but with notable changes identified in mechanism of injury and improvements in resource utilization.