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9516 Background: An increased prevalence of high-risk disease and worse outcome are observed in children with neuroblastoma who self-report as black versus white. We sought to determine whether genetic variation would explain this racial disparity. Methods: After quality control, we analyzed 511,836 germline genetic variants in 2,709 ethnically diverse children with neuroblastoma enrolled on Children’s Oncology Group study ANBL00B1 from 2001 to 2009. Genetic variation was summarized by conducting principal components analysis. The first principal component (PC1) separated patients with African ancestry from all others. PC1 was used as a continuous variable for ordinal regression with risk group and a Cox proportional hazard model of EFS. To identify genetic mechanisms for the observed disparities, we developed a method using genome-wide variation data applied to high-risk versus non-high risk samples. We identified a comprehensive list of loci with significant divergence between the ancestral populations. We then tested each such locus for association with high-risk phenotype using logistic regression with the proportion of African ancestry estimated by ADMIXTURE as covariate. Finally, top SNPs were added to multivariate models of both risk and event-free survival to determine if any top associations could abrogate observed disparities. Results: PC1 was associated with both risk (p = 0.007) and EFS (p = 0.037). We identified 72 population-divergent SNPs nominally associated with high-risk disease (p < 0.001). The risk allele for one of the top SNPs: rs9295536 (p = 9.2x10-8) was more common in the African ancestral population, was associated with high-risk phenotype and poor outcome in all patients and validated in a Caucasian-only subanalysis. In multivariate testing, this SNP abrogated the PC1 association with EFS (p = 0.18). Conclusions: A SNP with high divergence between ancestral populations on chromosome 6p22 accounts for the observed racial disparity in survival and is also a common genetic variant associated with survival in patients derived from either European or African ancestry (Bonferroni adjusted p < 0.05). Studies to elucidate the function of this SNP are underway.

Background In a cohort of 3539 children with neuroblastoma, we have previously reported that self-reported black race is significantly associated with high-risk disease (p < 0.001) and late relapse or death (p = 0.04). To investigate if the component of genomic variation that co-segregates with African ancestry is associated with risk group and survival in neuroblastoma, we interrogated genome-wide single nucleotide polymorphism (SNP) genotypes against those phenotypes in 2790 neuroblastoma patients. Methods Genome-wide SNP genotypes from 3404 children with neuroblastoma were obtained from 3 Illumina platforms: HumanHap550 v1, HumanHap550 v3 and HumanQuad 610. Quality filtering removed 17 patients who were genotyped twice, 15 patients with ambiguous sex, 72 patients with some degree of relatedness, 120 patients with poor genotype call rates (defined as >5% total SNPs interrogated without a genotype call) and 390 patients with missing clinical data. Genotypes from the remaining 2790 patients were included in the analysis. Using SNPs common to each of the genotyping platforms, ancestral reference populations from the International HapMap Project (Caucasian - CEU, African - YRI and Asian - CHB/JPT) and the EIGENSTRAT method, a principal components analysis was performed and an ancestry map of all patients was created. Principal Component 1 (PC1), which separated black neuroblastoma patients and the YRI HapMap samples from all other ethnic groups, was tested as a continuous variable in a Cox Proportional Hazard Regression model of event-free survival (EFS) and in an ordinal logistic regression of risk group. Using a k-means clustering algorithm, patients were grouped into 1 of 5 ethnic clusters;EFS of clusters was compared using a log-rank test, and Kaplan-Meier curves were plotted. Results PC1 was correlated with neuroblastoma risk group classification (p=0.0063). PC1 was also correlated with EFS (p=0.044). Compared to Caucasian patients, patients with African ancestry had the poorest EFS (log rank p = 0.0257). Discussion Here we show that the component of genomic variation that co-segregates with African ancestry is associated with high-risk disease and event-free survival. Patients with African ancestry had inferior outcomes to patients of Caucasian ancestry. We hypothesize that germline genetic variants associated with both the development of high-risk neuroblastoma and event-free survival after chemotherapy will have different allelic frequencies in Caucasian and African populations and that patients of African ancestry may also harbor unique genetic variants associated with high-risk disease and event-free survival not found in Caucasian patients. Efforts to identify these genetic variants are underway. These results underscore the need to perform association studies from a variety of ancestries, as each group may yield novel associations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2486. doi:1538-7445.AM2012-2486

Disruptions in tokamak reactors are still of serious concern and present a potential obstacle for successful operation and reliable design. Erosion of plasma-facing materials due to thermal energy dump during a disruption can severely limit the lifetime of these components, therefore diminishing the economic feasibility of the reactor. A comprehensive disruption erosion model which takes into account the interplay of major physical processes during plasma-material interaction has been developed. The initial burst of energy delivered to facing-material surfaces from direct impact of plasma particles causes sudden ablation of these materials. As a result, a vapor cloud is formed in front of the incident plasma particles. Shortly thereafter, the plasma particles are stopped in the vapor cloud, heating and ionizing it. The energy transmitted to the material surfaces is then dominated by photon radiation. It is the dynamics and the evolution of this vapor cloud that finally determines the net erosion rate and, consequently, the component lifetime. The model integrates with sufficient detail and in a self-consistent way, material thermal evolution response, plasma-vapor interaction physics, vapor hydrodynamics, and radiation transport in order to realistically simulate the effects of a plasma disruption on plasma-facing components. Candidate materials such as beryllium and carbon more » have been analyzed. The dependence of the net erosion rate on disruption physics and various parameters was analyzed and is discussed. « less

Background: In a cohort of 3539 children with neuroblastoma, we have previously reported that self-reported black race is significantly associated with high-risk disease (p < 0.001) and late relapse or death (p = 0.04) [1]. To investigate if the component of genomic variation that co-segregates with African ancestry is associated with risk group and survival in neuroblastoma, we interrogated genome-wide SNP genotypes against those phenotypes in 3180 neuroblastoma patients. Methods: Genome-wide SNP genotypes from 3404 children with neuroblastoma were obtained from 3 Illumina platforms: HumanHap550 v1, HumanHap550 v3 and HumanQuad 610. Quality filtering removed 17 patients who were genotyped twice, 15 patients with ambiguous sex, 72 patients with some degree of relatedness and 120 patients with poor genotype call rates (defined as >5% total SNPs interrogated without a genotype call). Genotypes from the remaining 3180 patients were included in the analysis. Using ancestral reference populations from the International HapMap Project (Caucasian - CEU, African - YRI and Asian – CHB/JPT) and the EIGENSTRAT method, a principal components analysis for each of the three genotyping platforms was performed and an ancestry map of all patients was created. Pricincipal Component 2 (PC2), which separated black neuroblastoma patients and the YRI HapMap samples from all other ethnic groups, was used as a continuous variable for linear regressions with both event-free survival and risk group. Results: PC2 was correlated with event-free survival in patients with intermediate- and high-risk neuroblastoma (those patients that receive chemotherapy), showing that degree of African ancestry was associated poorer outcome (p = 0.047). Furthermore, linear regression of PC2 versus risk group classification showed that degree of African ancestry was associated with high-risk disease (p = 0.05). Discussion: Here we show that the component of genomic variation that co-segregates with African ancestry is associated with high-risk disease and a poorer event-free survival. We hypothesize that germline genetic variants associated with both high-risk neuroblastoma and event-free survival after chemotherapy will have different allelic frequencies in Caucasian and African populations and that patients of African ancestry may also harbor unique genetic variants associated with high-risk disease and event-free survival not found in Caucasian patients. Efforts to identify these genetic variants are underway. These results underscore the need to perform association studies from a variety of ancestries, as each group may yield novel associations. Reference: 1. Henderson, T. O., Bhatia, S., Pinto, N., London, W. B., McGrady, P., Crotty, C., Sun, C. L. & Cohn, S. L. Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children's Oncology Group study. J Clin Oncol, 2011, 29, 76–82. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A46.

Dense hydrogen plasma streams from plasma guns are often used for studying the behaviour of divertor materials under simulated tokamak disruption conditions. In such experiments rather high target plasma temperatures are observed. To understand this the interaction of an intense high density hot plasma stream with a target material was modeled. During beam deposition a vapor cloud is formed. Its density can decrease below 1017cm−3due to the vapor expansion. In this case a pure beam plasma layer can be formed in front of the vapor cloud having comparable density. The impinging plasma beam is converted into thermal energy of this layer, resulting in a rather high temperature of the layer. The energy is transported into the target vapor cloud by electron heat conduction. Such a process can play an important role in modeling the stream target interaction by a dense plasma flow. Results for a simplified analytical model and results of first numerical calculations using the particle-in-cell method are presented.

In a next generation tokamak energy densities of up to 12 MJ/m2are estimated to be dumped to the divertor during the thermal quench phase of a disruption event. In the course of the plasma dumping a series of complex processes develops, starting with sudden evaporation of a very thin layer of the divertor plate material. The plasma beam energy then is deposited completely into the vapor cloud. There it is converted into ionization, kinetic energy, heating and radiation. The paper gives a description of the physical and numerical modeling of these complex processes at KfK and TRINITl. A plasma beam energy of 10 keV was assumed for simulation. First results show that a fraction of up to 90 % of the beam energy is converted into radiation. Up to 95 % of this radiation is back-radiated into the cavity. The radiative energy transport to the target decreases with time and after about 50 μs becomes negligible for the TRINITI modeling but continues for the KfK modeling at a very low value. At later times the energy transfer to the target due to free streaming or collisional energy transport from the dense but rather cold plasma to the target could become important.

Abstract LBA-4 The HNA-3a/b (5b/a) leukocyte alloantigens were identified in 1964 by van Leeuwen et al. as a biallelic system with gene frequencies of 0.82 (HNA-3a) and 0.18 (HNA-3b), respectively. Despite the passage of more than 40 years, the presumptive protein carrier for HNA-3a/b and the molecular composition of the antigens themselves is unknown. The importance of defining the HNA-3a/b antigens more fully has been heightened by the recognition that HNA-3a-specific antibodies are especially prone to cause severe, often fatal, transfusion-related lung acute injury (TRALI), now the single most important cause of transfusion-related mortality. About 4-5% of the general population is HNA-3a-negative and is at risk to produce HNA-3a-specific antibodies. We performed genome-wide single nucleotide polymorphism (SNP) scanning of DNA from 8 HNA-3a-negative (HNA-3b/b) and 107 unrelated normal individuals and found that each of the HNA-3a-negatives, but only 5 of the normal subjects was homozygous (AA) for a SNP (G>A) located at nt542 of the SLC44A2 gene encoding the choline transporter-like protein CTL2 (pA542) in the gene SLC44A2 encoding CTL2.HNA-3-a negative subjects (n = 8)Normal subjects (N = 107)GGGAAAGGGAAA008*64385*p = 2.4 × 10−12 This SNP (rs2288904) is the only one known in SLC44A2 that correlates with the HNA-3a-negative phenotype and predicts an extracellular amino acid substitution (R>Q154) in the mature protein. Gene frequencies of the high and low frequency alleles of SNP rs2288904 are 0.82 and 0.18, respectively, identical to the gene frequencies of HNA-3a and HNA-3b determined by serologic typing. Although HNA-3a is widely considered to be a neutrophil antigen, we found that lymphocytes carry slightly more HNA-3a than neutrophils, and that persons heterozygous for HNA-3a have 50% as much antigen as homozygotes, allowing heterozygotes to be identified by flow cytometry. To validate the SNP analyses, we directly sequenced DNA encoding CTL2 from 4 HNA-3a/a, 4 HNA-3a/b and 8 HNA-3b/b subjects and found that, without exception, nt542G and nt542A correlated with the phenotypes HNA-3a and HNA-3b (determined serologically), respectively. To obtain direct evidence that HNA-3a is carried on CTL2, we sensitized leukocytes with anti-HNA-3a, immunoprecipitated antibody-bound proteins, performed SDS electrophoresis and subjected candidate bands to mass spectrometric analysis. In three independent assays, peptides derived from CTL2 spanning the entire length of the protein were identified (p Disclosures: No relevant conflicts of interest to declare.

Material selection and lifetime issues for extreme ultraviolet (EUV) lithography are of critical importance to the success of this technology for commercial applications. This work reviews current trends in production and use of plasma-facing electrodes, insulators, and wall materials for EUV-type sources. Ideal candidate materials should be able to: withstand high thermal shock from the short pulsed plasma; withstand high thermal loads without structural failure; reduce debris generation during discharge; and be machined accurately. We reviewed the literature on current and proposed fusion plasma-facing materials as well as current experience with plasma gun and other simulation devices. Both fusion and EUV source materials involve issues of surface erosion by particle sputtering and heat-induced evaporation/melting. These materials are either bare structural materials or surface coatings. EUV materials can be divided into four categories: wall, electrode, optical, and insulator materials. For electric discharge sources, all four types are required, whereas laser-produced plasma EUV sources do not require electrode and insulator materials. Several types of candidate alloy and other materials and methods of manufacture are recommended for each component of EUV lithography light sources.

It was shown that specific collisional instability can arise in counter-streaming plasma due to the dependence of frictional force on the velocity of streams. To solve this problem it was necessary to consider the propagation of waves in the medium with time-dependent parameters. Such a problem is similar to that of wave propagation in a stationary inhomogeneous medium, the solution of which can usually be found using the WKB approximation.

The possibility of hot dense plasma creation for the filling of open traps by thermalization of the direct energy of supersonic plasma clusters accelerated by electrodynamic accelerators has been studied theoretically and experimentally. The mean free path of particles in these traps, as a rule, exceeds typical system size, therefore, it is of great interest to study the turbulent mechanisms of counter-streaming plasmas relaxation. A calculation of relaxation length is very important because such turbulent relaxation of counter-streaming plasmas is observed experimentally. Investigation of counter-streaming plasma interaction is of general physical concern. Such situations occur, for example, in astrophysics: the shock wave structure problem, the relaxation of ionosphere plasma flow behind satellites, the spreading of laser-produced plasma in surrounding gas, etc. A detailed discussion is given of the relaxation of counter-streaming plasma due to turbulent mechanisms: the two-stream ion-acoustic instability.

The authors consider the possibility of a self-sustaining thermonuclear reaction in a dense plasma (n 1016 cm3). The pressure of the plasma is contained by walls and the magnetic field only serves to reduce thermal conductivity in a transverse direction. A solution is obtained for the plasma balance equation that makes allowance for radiation losses along the magnetic field, and it is shown that there is no satisfactory solution across a uniform magnetic field. The authors discuss the possibility of a steady-state thermonuclear reaction with a non-uniform magnetic field.

The existence is demonstrated of a steady-state thermonuclear combustion wave in dense plasma. The parameters of the wave are determined by numerical integration of the plasma balance equations. The possibility is examined of constructing a flow reactor incorporating a self-sustaining thermonuclear reaction.