Comprehensive analysis of the ErbB receptor family in pediatric nervous system tumors and rhabdomyosarcoma

Background: There is a paucity of knowledge regarding pediatric biomarkers, including the relevance of ErbB pathway aberrations in pediatric tumors. We investigated the occurrence of ErbB receptor aberrations across different pediatric malignancies, to identify patterns of ErbB dysregulation and define biomarkers suitable for patient enrichment in clinical studies. / Procedure: Tissue samples from 297 patients with nervous system tumors and rhabdomyosarcoma were analyzed for immunohistochemical expression or gene amplification of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Exploratory analyses of HER3/HER4 expression, and mRNA expression of ErbB receptors/ligands (NanoString) were performed. Assay validation followed general procedures, with additional validation to address Clinical Laboratory Improvement Amendments (CLIA) requirements. / Results: In most tumor types, samples with high ErbB receptor expression were found with heterogeneous distribution. We considered increased/aberrant ErbB pathway activation when greater than or equal to two EGFR/HER2 markers were simultaneously upregulated. ErbB pathway dysregulation was identified in ∼20%–30% of samples for most tumor types (medulloblastoma/primitive neuroectodermal tumors 31.1%, high-grade glioma 27.1%, neuroblastoma 22.7%, rhabdomyosarcoma 23.1%, ependymoma 18.8%), 4.2% of diffuse intrinsic pontine gliomas, and no recurrent or refractory low-grade astrocytomas. In medulloblastoma/primitive neuroectodermal tumors and neuroblastoma, this was attributed mainly to high EGFR polysomy/HER2 amplification, whereas EGFR gene amplification was observed in some high-grade glioma samples. EGFR/HER2 overexpression was most prevalent in ependymoma. / Conclusions: Overexpression and/or amplification of EGFR/HER2 were identified as potential enrichment biomarkers for clinical trials of ErbB-targeted drugs

New Alzheimer Amyloid β Responsive Genes Identified in Human Neuroblastoma Cells by Hierarchical Clustering

Alzheimer's disease (AD) is characterized by neuronal degeneration and cell loss. Aβ42, in contrast to Aβ40, is thought to be the pathogenic form triggering the pathological cascade in AD. In order to unravel overall gene regulation we monitored the transcriptomic responses to increased or decreased Aβ40 and Aβ42 levels, generated and derived from its precursor C99 (C-terminal fragment of APP comprising 99 amino acids) in human neuroblastoma cells. We identified fourteen differentially expressed transcripts by hierarchical clustering and discussed their involvement in AD. These fourteen transcripts were grouped into two main clusters each showing distinct differential expression patterns depending on Aβ40 and Aβ42 levels. Among these transcripts we discovered an unexpected inverse and strong differential expression of neurogenin 2 (NEUROG2) and KIAA0125 in all examined cell clones. C99-overexpression had a similar effect on NEUROG2 and KIAA0125 expression as a decreased Aβ42/Aβ40 ratio. Importantly however, an increased Aβ42/Aβ40 ratio, which is typical of AD, had an inverse expression pattern of NEUROG2 and KIAA0125: An increased Aβ42/Aβ40 ratio up-regulated NEUROG2, but down-regulated KIAA0125, whereas the opposite regulation pattern was observed for a decreased Aβ42/Aβ40 ratio. We discuss the possibilities that the so far uncharacterized KIAA0125 might be a counter player of NEUROG2 and that KIAA0125 could be involved in neurogenesis, due to the involvement of NEUROG2 in developmental neural processes

RNAi screen for NRF2 inducers identifies targets that rescue primary lung epithelial cells from cigarette smoke induced radical stress

Chronic Obstructive Pulmonary Disease (COPD) is a highly prevalent condition characterized by inflammation and progressive obstruction of the airways. At present, there is no treatment that suppresses the chronic inflammation of the disease, and COPD patients often succumb to the condition. Excessive oxidative stress caused by smoke inhalation is a major driving force of the disease. The transcription factor NRF2 is a critical player in the battle against oxidative stress and its function is impaired in COPD. Increasing NRF2 activity may therefore be a viable therapeutic option for COPD treatment. We show that down regulation of KEAP1, a NRF2 inhibitor, protects primary human lung epithelial cells from cigarette-smoke-extract (CSE) induced cell death in an established in vitro model of radical stress. To identify new potential drug targets with a similar effect, we performed a siRNA screen of the 'druggable' genome using a NRF2 transcriptional reporter cell line. This screen identified multiple genes that when down regulated increased NRF2 transcriptional activity and provided a survival benefit in the in vitro model. Our results suggest that inhibiting components of the ubiquitin-proteasome system will have the strongest effects on NRF2 transcriptional activity by increasing NRF2 levels. We also find that down regulation of the small GTPase Rab28 or the Estrogen Receptor ESRRA provide a survival benefit. Rab28 knockdown increased NRF2 protein levels, indicating that Rab28 may regulate NRF2 proteolysis. Conversely ESRRA down regulation increased NRF2 transcriptional activity without affecting NRF2 levels, suggesting a proteasome-independent mechanism

Regeneration des verbliebenen Lebergewebes bei Spendern nach Leberlebendspende: Langzeitverlaufskontrollen mittels CT und MRT

Purpose: To assess liver remnant volume regeneration and maintenance, and complications in the long-time follow-up of donors after living donor liver transplantation using CT and MRI. Materials and Methods: 47 donors with a mean age of 33.5 years who donated liver tissue for transplantation and who were available for follow-up imaging were included in this retrospective study. Contrast-enhanced CT and MR studies were acquired for routine follow-up. Two observers evaluated pre- and postoperative images regarding anatomy and pathological findings. Volumes were manually measured on contrast-enhanced images in the portal venous phase, and potential postoperative complications were documented. Pre- and postoperative liver volumes were compared for evaluating liver remnant regeneration. Results: 47 preoperative and 89 follow-up studies covered a period of 22.4 months (range: 1 - 84). After right liver lobe (RLL) donation, the mean liver remnant volume was 522.0 ml (± 144.0; 36.1 %; n = 18), after left lateral section (LLS) donation 1,121.7 ml (± 212.8; 79.9 %; n = 24), and after left liver lobe (LLL) donation 1,181.5 ml (± 279.5; 72.0 %; n = 5). Twelve months after donation, the liver remnant volume were 87.3 % (RLL; ± 11.8; n = 11), 95.0 % (LS; ± 11.6; n = 18), and 80.1 % (LLL; ± 2.0; n = 2 LLL) of the preoperative total liver volume. Rapid initial regeneration and maintenance at 80 % of the preoperative liver volume were observed over the total follow-up period. Minor postoperative complications were found early in 4 patients. No severe or late complications or mortality occurred. Conclusion: Rapid regeneration of liver remnant volumes in all donors and volume maintenance over the long-term follow-up period of up to 84 months without severe or late complications are important observations for assessing the safety of LDLT donors. Key Points: Liver remnant volumes of LDLT donors rapidly regenerated after donation and volumes were maintained over the long-term follow-up period of up to 84 months without severe or late complications.Ziel: Das Ziel dieser Studie war, die Regeneration und die Aufrechterhaltung des verbliebenen Lebervolumens sowie das Auftreten von Komplikationen im Langzeitverlauf bei Spendern nach Leberlebendspende mittels CT und MRT zu überprüfen. Material und Methoden: In die retrospektive Studie wurden 47 Personen mit einem mittleren Alter von 33,5 Jahren eingeschlossen, die Lebergewebe gespendet hatten und für die Verlaufsbildgebung zur Verfügung standen. Kontrastverstärkte CT- und MRT-Untersuchungen wurden im Rahmen der Routinenachsorge angefertigt. Die prä- und postoperativen Bilder wurden durch zwei Beobachter im Hinblick auf die präoperative Anatomie und pathologische Befunde evaluiert. Organvolumina wurden manuell anhand kontrastverstärkter Bilder in portalvenöser Phase gemessen, und potentielle postoperatove Komplikationen wurden dokumentiert. Die Regeneration des verbliebenen Lebergewebes wurde durch Vergleich der prä- und postoperativen Volumina evaluiert. Ergebnisse: Die Verlaufskontrollen erfolgten über einen mittleren Zeitraum von 22,4 Monaten (1 – 84 Monate), wobei 47 präoperative und 89 Verlaufsuntersuchungen zur Verfügung standen. Die Volumina des verbliebenen Lebergewebes betrugen nach Spende des rechten Leberlappens (RLL) 522,0 ml (± 144,0; 36,1 %; n = 18), nach links-lateraler Sektion (LLS) 1121,7 ml (± 212,8; 79,9 %; n = 24) und nach Spende des linken Leberlappens (LLL) 1181,5 ml (± 279,5; 72,0 %; n = 5). Nach 12 Monaten betrugen die verbliebenen Lebervolumina 87,3 % (RLL; ± 11,8; n = 11), 95,0 % (LS; ± 11,6; n = 18) und 80,1 % (LLL; ± 2,0; n = 2) der präoperativen Volumina. Das verbliebene Lebergewebes regenerierte zügig, wobei ein Volumenanteil von 80 % des präoperativen Volumens über den gesamten Nachsorgezeitraum beobachtet wurde. Leichtgradige Komplikationen wurden frühzeitig bei 4 Patienten festgestellt. Es wurden jedoch keine schwergradigen oder spät auftretenden Komplikationen gefunden. Schlussfolgerung: Die zügige Regeneration des verbliebenen Lebervolumens bei Leberlebendspendern, dessen Aufrechterhaltung über den gesamten Nachsorgezeitraum von max. 84 Monaten und das Ausbleiben schwerer oder später Komplikationen sind wichtige Beobachtungen, um die Sicherheit potentieller Leberlebendspender abzuschätzen. Kernaussage: Bei Leberlebendspendern regenerierte das verbliebene Lebergewebe zügig, wobei die Organvolumnia über den gesamten Nachsorgezeitraum von bis zu 84 Monaten aufrecht erhalten wurden und keine schwerwiegenden oder späten Komplikationen auftraten