BACKGROUND Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor-α), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR. METHODS We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons. RESULTS NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O6-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease. CONCLUSIONS Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.

Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae present an ever-growing burden in the hospital and community settings, across all ages and demographics. Infections due to ESBL-containing pathogens continue to be associated with significant morbidity and mortality worldwide. With widespread empiric broad-spectrum β-lactam use creating selective pressure, and the resultant emergence of stable, rapidly proliferating ESBL-producing clones with continued horizontal gene transfer across genera, addressing this issue remains imperative. Although well characterized in adults, the epidemiology, risk factors, outcomes, therapies, and control measures for ESBL-producing bacteria are less appreciated in children. This analysis provides a brief summary of ESBL-producing Enterobacteriaceae in children, with a focus on recent clinical and molecular data regarding colonization and infection in nonoutbreak settings.

We present a novel methodology combining traditional fluorescent in situ hybridization with an in situ protein detection technology called proximity ligation assay. This method has potential to perform a detailed analysis of the relationship between gene status and corresponding protein expression in cells and tissues. We demonstrate that the fluorescent in situ gene protein assay methodology is capable of resolving gene and protein patterns simultaneously on a cell-by-cell basis.

Introduction: Aberrant activation of the Epidermal Growth Factor Receptor (EGFR) oncoprotein is a molecular hallmark of glioblastomas. Two-thirds of tumors with excessive EGFR activation show alteration of the EGFR gene. The mechanism of deregulation of EGFR in the other third remains poorly understood. Nuclear factor of κB inhibitor alpha (NFKBIA) is a potential tumor suppressor. Methods: Multidimensional molecular profiles for NFKBIA and EGFR and clinical profiles of 732 malignant glioma patients from multiple academic institutions, The Cancer Genome Atlas Pilot Project, the Repository of Molecular Brain Neoplasia Data, and a randomized phase III trial of temozolomide. NFKBIA mutational and functional analyses in a glioblastoma cell model. Results: We found that about 25% of glioblastomas harbor heterozygous NFKBIA gene deletions at chromosome 14q13. NFKBIA functions as a haploinsufficient tumor suppressor in glioblastomas by terminating EGFR signaling. Tumors with NFKBIA deletion lacked EGFR amplifications, indicating functional redundancy of both genetic events in glioblastoma pathogenesis. Loss of NFKBIA gene dosage was significantly associated with briefer patient survival. Patients with low NFKBIA expression had a significantly worse outcome than patients with intact NFKBIA expression. NFKBIA expression was also significantly associated with patient survival in subsets of tumors with unmethylated promoter of the O6-methylguanine DNA methyltransferase (MGMT) gene. A combined outcome predictor model of NFKBIA and MGMT proved highly predictive of duration of survival. Conclusion: Deletion of NFKBIA is an alternative mechanism for tumorigenic increase in EGFR signaling in glioblastomas. NFKBIA inactivation is associated with shorter survival of patients with malignant gliomas. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1789.