Expression Signatures of Metastatic Capacity in a Genetic Mouse Model of Lung Adenocarcinoma

Background: Non-small cell lung cancer (NSCLC) is the foremost cause of cancer-related death in Western countries, which is due partly to the propensity of NSCLC cells to metastasize. The biologic basis for NSCLC metastasis is not well understood. Methodology/Principal Findings: Here we addressed this deficiency by transcriptionally profiling tumors from a genetic mouse model of human lung adenocarcinoma that develops metastatic disease owing to the expression of K-rasG12D and p53R172H. We identified 2,209 genes that were differentially expressed in distant metastases relative to matched lung tumors. Mining of publicly available data bases revealed this expression signature in a subset of NSCLC patients who had a poorer prognosis than those without the signature. Conclusions/Significance: These findings provide evidence that K-rasG12D; p53R172H mice recapitulate features of human NSCLC metastasis and will provide a useful platform on which to study the biologic basis for lung adenocarcinom

ZEB1 Is a Transcription Factor That Is Prognostic and Predictive in Diffuse Gliomas

Objective: To address the unmet medical need to better prognosticate patients with diffuse gliomas and to predict responses to chemotherapy regimens.Methods: ZEB1 alterations were retrospectively identified from a cohort of 1,160 diffuse glioma patients. Epigenome-wide association scans (EWAS) were performed on available data. We determined the utility of ZEB1 as a prognostic indicator of patient survival in diffuse gliomas and assessed the value of ZEB1 to predict the efficacy of treating diffuse glioma patients with procarbazine, CCNU, and vincristine along with radiation at diagnosis. Decision curve analysis (DCA) was used to determine if ZEB1 added benefit to clinical decision-making over and above conventional methods.Results: Fifteen percent of diffuse glioma patients had a ZEB1 deletion. ZEB1 deletion was associated with poor overall survival (OS) with and without adjustment for age and tumor grade (adjusted HR: 4.25; 95% CI: 2.35 to 7.66; P < 0.001). Decision curve analysis confirmed that ZEB1 status with or without IDH1 was more beneficial to clinical decision making than conventional information such as age and tumor grade. We showed that ZEB1 regulates TERT expression, and patients with ZEB1 deletions likely subsume patients with mutant TERT expression in diffuse gliomas. ZEB1 influenced clinical decision making to initiate procarbazine, CCNU, and vincristine treatment.Conclusion: We demonstrate the prognostic value of ZEB1 in diffuse glioma patients. We further determine ZEB1 to be a vital and influential molecular marker in clinical decisions that exceed conventional methods regarding whether to treat or not treat patients with diffuse glioma

Late onset of necrotizing enterocolitis in the full-term infant is associated with increased mortality: Results from a two-center analysis

Purpose: The effect of timing of onset of necrotizing enterocolitis (NEC) on outcomes has not been determined for the full-term infant. In this study we aimed to characterize the full-term NEC population and to evaluate onset of NEC. Methods: We performed a two-center retrospective review of all full-term infants (≥ 37 weeks) with a diagnosis of NEC between 1990 and 2012. Patients were identified by ICD-9 and age. Early onset for NEC was ≤ 7 days and late onset after 7 days of life. Demographics, comorbidities, maternal factors, clinical factors, surgical intervention, complications, and mortality were evaluated. Wilcoxon's test was performed on continuous variables and Fisher's exact test on categorical data. A p-value b 0.05 was considered significant. Univariate outcomes with a p-value b 0.1 were selected for multivariable analysis. Results: Thirty-nine patients (24 boys, 15 girls) with median EGA of 39 weeks were identified. Overall mortality was 18%. Univariate predictors of mortality included congenital heart disease and placement of an umbilical artery (UA) catheter. Multivariate analysis revealed late onset of NEC to be an independent predictor of mortality (OR 90.8, 95% CI 2.6-3121). Conclusion: Full-term infants who develop NEC after 7 days of life, have congenital heart disease, and/or need UA catheterization have increased mortality. © 2014 Elsevier Inc. All rights reserved. The pathogenesis of necrotizing enterocolitis (NEC) in infants remains incompletely understood. Most commonly, NEC occurs in the premature infant, with less than 10% occurring in full-term neonates It is not known whether the underlying pathophysiology of NEC in the term infant is distinctly different from that in the premature infant. In addition to the frequent presence of significant co-morbidities, term infants are frequently reported to present with NEC earlier in postnatal life Methods Patient Population We performed a two-center retrospective review of all full-term infants (≥ 37 weeks) with a diagnosis of NEC between 1990 and 2012. Charts were identified by including ICD-9 codes (777.5-777.6) and were reviewed to verify diagnosis of NEC and gestational age. Term infants determined to have Bell's stage 2 or 3 NEC were included. Term infants with possible Bell's stage I NEC were excluded from analysis. Infants who had an estimated gestational age less than 37 weeks were also excluded from the study. The subject met inclusion criteria for NEC if he/she had evidence of Bell's stage II or greater and had diagnosis of NEC documented in the chart with signs and symptoms that included temperature instability, apnea, bradycardia, lethargy, pneumatosis, metabolic acidosis, peritonitis, and/or pneumoperitoneum Similar to a previous publication, early-onset NEC was defined as development of NEC during the 1st week of life (≤ 7 days) and lateonset NEC as any time after day 7 of lif

Late onset of necrotizing enterocolitis in the full-term infant is associated with increased mortality: Results from a two-center analysis

The effect of timing of onset of necrotizing enterocolitis (NEC) on outcomes has not been determined for the full-term infant. In this study we aimed to characterize the full-term NEC population and to evaluate onset of NEC. We performed a two-center retrospective review of all full-term infants (≥ 37weeks) with a diagnosis of NEC between 1990 and 2012. Patients were identified by ICD-9 and age. Early onset for NEC was ≤7days and late onset after 7days of life. Demographics, comorbidities, maternal factors, clinical factors, surgical intervention, complications, and mortality were evaluated. Wilcoxon’s test was performed on continuous variables and Fisher’s exact test on categorical data. A p-value<0.05 was considered significant. Univariate outcomes with a p-value<0.1 were selected for multivariable analysis. Thirty-nine patients (24 boys, 15 girls) with median EGA of 39weeks were identified. Overall mortality was 18%. Univariate predictors of mortality included congenital heart disease and placement of an umbilical artery (UA) catheter. Multivariate analysis revealed late onset of NEC to be an independent predictor of mortality (OR 90.8, 95% CI 2.6–3121). Full-term infants who develop NEC after 7days of life, have congenital heart disease, and/or need UA catheterization have increased mortality