Loss of a FYN-regulated differentiation and growth arrest pathway in advanced stage neuroblastoma

AbstractTumor stage, age of patient, and amplification of MYCN predict disease outcome in neuroblastoma. To gain insight into the underlying molecular pathways, we have obtained expression profiles from 94 primary neuroblastoma specimens. Advanced tumor stages show a characteristic expression profile that includes downregulation of multiple genes involved in signal transduction through Fyn and the actin cytoskeleton. High expression of Fyn and high Fyn kinase activity are restricted to low-stage tumors. In culture, expression of active Fyn kinase induces differentiation and growth arrest of neuroblastoma cells. Expression of Fyn predicts long-term survival independently of MYCN amplification. Amplification of MYCN correlates with deregulation of a distinct set of genes, many of which are target genes of Myc. Our data demonstrate a causal role for Fyn kinase in the genesis of neuroblastoma

Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

Differences in MYCN/c-MYC target gene expression are associated with distinct neuroblastoma subtypes and clinical outcome

cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma

BACKGROUND: Recurrent non-random genomic alterations are the hallmarks of cancer and the characterization of these imbalances is critical to our understanding of tumorigenesis and cancer progression. RESULTS: We performed array-comparative genomic hybridization (A-CGH) on cDNA microarrays containing 42,000 elements in neuroblastoma (NB). We found that only two chromosomes (2p and 12q) had gene amplifications and all were in the MYCN amplified samples. There were 6 independent non-contiguous amplicons (10.4–69.4 Mb) on chromosome 2, and the largest contiguous region was 1.7 Mb bounded by NAG and an EST (clone: 757451); the smallest region was 27 Kb including an EST (clone: 241343), NCYM, and MYCN. Using a probabilistic approach to identify single copy number changes, we systemically investigated the genomic alterations occurring in Stage 1 and Stage 4 NBs with and without MYCN amplification (stage 1-, 4-, and 4+). We have not found genomic alterations universally present in all (100%) three subgroups of NBs. However we identified both common and unique patterns of genomic imbalance in NB including gain of 7q32, 17q21, 17q23-24 and loss of 3p21 were common to all three categories. Finally we confirm that the most frequent specific changes in Stage 4+ tumors were the loss of 1p36 with gain of 2p24-25 and they had fewer genomic alterations compared to either stage 1 or 4-, indicating that for this subgroup of poor risk NB requires a smaller number of genomic changes are required to develop the malignant phenotype. CONCLUSIONS: cDNA A-CGH analysis is an efficient method for the detection and characterization of amplicons. Furthermore we were able to detect single copy number changes using our probabilistic approach and identified genomic alterations specific to stage and MYCN amplification

Application of Developed APCVD Transparent Conducting Oxides and Undercoat Technologies for Economical OLED Lighting

Economics is a key factor for application of organic light emitting diodes (OLED) in general lighting relative to OLED flat panel displays that can handle high cost materials such as indium tin oxide (ITO) or Indium zinc oxide (IZO) as the transparent conducting oxide (TCO) on display glass. However, for OLED lighting to penetrate into general illumination, economics and sustainable materials are critical. The issues with ITO have been documented at the DOE SSL R&D and Manufacturing workshops for the last 5 years and the issue is being exacerbated by export controls from China (one of the major sources of elemental indium). Therefore, ITO is not sustainable because of the fluctuating costs and the United States (US) dependency on other nations such as China. Numerous alternatives to ITO/IZO are being evaluated such as Ag nanoparticles/nanowires, carbon nanotubes, graphene, and other metal oxides. Of these other metal oxides, doped zinc oxide has attracted a lot of attention over the last 10 years. The volume of zinc mined is a factor of 80,000 greater than indium and the US has significant volumes of zinc mined domestically, resulting in the ability for the US to be self-sufficient for this element that can be used in optoelectronic applications. The costs of elemental zinc is over 2 orders of magnitude less than indium, reflecting the relative abundance and availability of the elements. Arkema Inc. and an international primary glass manufacturing company, which is located in the United States, have developed doped zinc oxide technology for solar control windows. The genesis of this DOE SSL project was to determine if doped zinc oxide technology can be taken from the commodity based window market and translate the technology to OLED lighting. Thus, Arkema Inc. sought out experts, Philips Lighting, Pacific Northwest National Laboratories (PNNL) and National Renewable Research Laboratories (NREL), in OLED devices and brought them into the project. This project had a clear focus on economics and the work plan focused both on doped ZnO process and OLED device structure that would be consistent with the new TCO. The team successfully made 6 inch OLEDs with a serial construction. More process development is required to optimize commercial OLED structures. Feasibility was demonstrated on two different light extraction technologies: 1/4 lambda refractive index matching and high-low-high band pass filter. Process development was also completed on the key precursors for the TCO, which are ready for pilot-plant scale-up. Subsequently, Arkema has developed a cost of ownership model that is consistent with DOE SSL R&D Manufacturing targets as outlined in the DOE SSL R&D Manufacturing 2010 report. The overall outcome of this project was the demonstration that doped zinc oxide can be used for OLED devices without a drop-off in performance while gaining the economic and sustainable benefits of a more readily available TCO. The broad impact of this project, is the facilitation of OLED lighting market penetration into general illumination, resulting in significant energy savings, decreased greenhouse emissions, with no environmental impact issues such as mercury found in Fluorescent technology. The primary objective of this project was to develop a commercially viable process for 'Substrates' (Substrate/ undercoat/ TCO topcoat) to be used in production of OLED devices (lamps/luminaries/modules). This project focused on using Arkema's recently developed doped ZnO technology for the Fenestration industry and applying the technology to the OLED lighting industry. The secondary objective was the use of undercoat technology to improve light extraction from the OLED device. In optical fields and window applications, technology has been developed to mitigate reflection losses by selecting appropriate thicknesses and refractive indices of coatings applied either below or above the functional layer of interest. This technology has been proven and implemented in the fenestration industry for more than 15 years. Successful completion of this project would provide doped ZnO coated on inexpensive soda lime glass resulting in a significantly lower cost relative to the current ITO coated Flat Panel Display Glass substrates. Additional benefits will be a more consistent TCO that does not need an activation step with better optical performance. Clearly, this will serve to enhance penetration of OLED technologies into the lighting market