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Cancer cells are endowed with diverse biological capabilities driven by myriad inherited and somatic genetic and epigenetic aberrations that commandeer key cancer-relevant pathways. Efforts to elucidate these aberrations began with Boveri's hypothesis of aberrant mitoses causing cancer and continue today with a suite of powerful high-resolution technologies that enable detailed catalogues of genomic aberrations and epigenomic modifications. Tomorrow will likely bring the complete atlas of reversible and irreversible alteration in individual cancers. The challenge now is to discern causal molecular abnormalities from genomic and epigenomic 'noise', to understand how the ensemble of these aberrations collaborate to drive cancer pathophysiology. Here, we highlight lessons learned from now classical examples of successful translation of genomic discoveries into clinical practice, lessons that may be used to guide and accelerate translation of emerging genomic insights into practical clinical endpoints that can impact on practice of cancer medicine.

This Geotechnical Analysis Report (GAR) presents and interprets the geotechnical data from the underground excavations at the Waste Isolation Pilot Plant (WIPP). The data, which are obtained as part of a regular monitoring program, are used to characterize conditions, to compare actual performance to the design assumptions, and to evaluate and forecast the performance of the underground excavations. GARs have been available to the public since 1983. During the Site and Preliminary Design Validation (SPDV) Program, the architect/engineer for the project produced these reports quarterly to document the geomechanical performance during and immediately after early excavations of the underground facility. Since the completion of the construction phase of the project in 1987, the management and operating contractor for the facility has prepared these reports annually. This report describes the performance and condition of selected areas from July 1, 2004, to June 30, 2005. It is divided into nine chapters. Chapter 1 provides background information on WIPP, its mission, and the purpose and scope of the Geomechanical Monitoring Program. Chapter 2 describes the local and regional geology of the WIPP site. Chapters 3 and 4 describe the geomechanical instrumentation in the shafts and shaft stations, present the data collected by that …

The genomes of many epithelial tumors exhibit extensive chromosomal rearrangements. All classes of genome rearrangements can be identified using End Sequencing Profiling (ESP), which relies on paired-end sequencing of cloned tumor genomes. In this study, brain, breast, ovary and prostate tumors along with three breast cancer cell lines were surveyed with ESP yielding the largest available collection of sequence-ready tumor genome breakpoints and providing evidence that some rearrangements may be recurrent. Sequencing and fluorescence in situ hybridization (FISH) confirmed translocations and complex tumor genome structures that include coamplification and packaging of disparate genomic loci with associated molecular heterogeneity. Comparison of the tumor genomes suggests recurrent rearrangements. Some are likely to be novel structural polymorphisms, whereas others may be bona fide somatic rearrangements. A recurrent fusion transcript in breast tumors and a constitutional fusion transcript resulting from a segmental duplication were identified. Analysis of end sequences for single nucleotide polymorphisms (SNPs) revealed candidate somatic mutations and an elevated rate of novel SNPs in an ovarian tumor. These results suggest that the genomes of many epithelial tumors may be far more dynamic and complex than previously appreciated and that genomic fusions including fusion transcripts and proteins may be common, possibly yielding tumor-specific …

Eight different polymer binders were formulated with bimodal distributions of 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105) in 5/95 weight ratio of polymer to explosive at the 25 gram level. The polymers evaluated included: Kel-F 800, Viton A, Oxy 461, Cytop A, Hyflon AD 60, Hytemp 5545, Technoflon PFR 91 and Technoflon P 459. LLM-105 had an average particle size of 35.6 {+-} 0.6 {micro}m. This material was ground in a ball mill for 24 h to achieve a particle size of 0.72 {+-} 0.02 {micro}m. Small angle light scattering measurements were used to obtain particle size distributions on both ground and unground LLM-105. Optical microscopy was used to characterize the morphology of the crystals. Bimodal mixes of approximately 75/25% coarse to fine LLM-105 were used in all formulations. Cylinders 1.27 cm diameter by 2.54 cm long were compression molded using 3 three-minute cycles at 105 C, except in the case of Cytop and Hyflon formulations which were molded at {approx}130 C. Densities varied between 94-98% of theoretical maximum. Stress strain measurements were made in compression at -30, ambient and 74 C at a strain rate of 0.0001 sec{sup -1}. As expected, the mechanical strength scaled with temperature depending on the glass transition temperature of …

The U.S. fusion energy program is focused on research with the potential for studying plasmas at thermonuclear temperatures, currently epitomized by the tokamak-based International Thermonuclear Experimental Reactor (ITER) but also continuing exploratory work on other plasma confinement concepts. Among the latter is the spheromak pursued on the SSPX facility at LLNL. Experiments in SSPX using electrostatic current drive by coaxial guns have now demonstrated stable spheromaks with good heat confinement, if the plasma is maintained near a Taylor state, but the anticipated high current amplification by gun injection has not yet been achieved. In future experiments and reactors, creating and maintaining a stable spheromak configuration at high magnetic field strength may require auxiliary current drive using neutral beams or RF power. Here we show that neutral beam current drive soon to be explored on SSPX could yield a compact spheromak reactor with current drive efficiency comparable to that of steady state tokamaks. Thus, while more will be learned about electrostatic current drive in coming months, results already achieved in SSPX could point to a productive parallel development path pursuing auxiliary current drive, consistent with plans to install neutral beams on SSPX in the near future. Among possible outcomes, spheromak research …

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The Clostridial neurotoxins, botulinum and tetanus, gain entry into neuronal cells by protein recognition involving cell specific binding sites. The sialic or N-acetylneuraminic acid (NeuAc) residues of gangliosides attached to the surface of motor neurons are the suspected recognition and interaction points with Clostridial neurotoxins, although not necessarily the only ones. We have used electrospray ionization mass spectrometry (ESIMS) to examine formation of complexes between the tetanus toxin C fragment, or targeting domain, and carbohydrates containing NeuAc groups to determine how NeuAc residues contribute to ganglioside binding. ESI-MS was used to rapidly and efficiently measure dissociation constants for a number of related NeuAc-containing carbohydrates and NeuAc oligomers, information that has helped identify the structural features of gangliosides that determine their binding to tetanus toxin. The strength of the interactions between the C fragment and (NeuAc){sub n}, are consistent with the topography of the targeting domain of tetanus toxin and the nature of its carbohydrate binding sites. The results suggest that the targeting domain of tetanus toxin contains two binding sites that can accommodate NeuAc (or a dimer). This study also shows that NeuAc must play an important role in ganglioside binding and molecular recognition, a process critical for normal cell …

This 7th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from January 1st through March 31st of 2006. It also summarizes the subsequent purchasing activity, dryer/process construction, and testing. The Design Team began conferencing again as construction completed and the testing program began. Primary focus this quarter was construction/installation completion. Phase 1 extension recommendation, and subsequent new project estimate, Forms 424 and 4600 were accepted by DOE headquarters. DOE will complete the application and amended contract. All major mechanical equipment was run, checked out, and tested this quarter. All water, air, and coal flow loops were run and tested. The system was run on January 30th, shut down to adjust equipment timing in the control system on the 31st, and run to 75 ton//hour on February 1st. It ran for seven to eight hours per day until March 20th when ''pairs'' testing ( 24 hour running) began. ''Pairs'' involves comparative testing of unit performance with seven ''wet'' pulverizers versus six ''wet'' and one ''dry''. During the interim, more operators were brought up to speed on system operation and control was shifted to the main Unit No.2 Control Room. The system is run now from the Unit …

This report is a compilation of work done over the past ten years in support of phase stability studies of Alloy 22 for the Yucca Mountain Project and contains information previously published, reported, and referenced. Most sections are paraphrased here for the convenience of readers. Evaluation of the fabrication processes involved in the manufacture of waste containers is important as these processes can have an effect on the metallurgical structure of an alloy. Because material properties such as strength, toughness, aging kinetics and corrosion resistance are all dependent on the microstructure, it is important that prototypes be built and evaluated for processing effects on the performance of the material. Of particular importance are welds, which have an as-cast microstructure with chemical segregation and precipitation of complex phases resulting from the welding process. The work summarized in this report contains information on the effects of fabrication processes such as solution annealing, stress mitigation, heat-to-heat variability, and welding on the kinetics of precipitation, mechanical, and corrosion properties. For a waste package lifetime of thousands of years, it is impossible to test directly in the laboratory the behavior of Alloy 22 under expected repository conditions. The changes that may occur in these materials …

Groundwater beneath T-Area, a former laboratory and semiworks operation at the Department of Energy (DOE) Savannah River Site, is contaminated by chlorinated solvents (cVOCs). Since the contamination was detected in the 1980s, the cVOCs at T-Area have been treated by a combination of soil vapor extraction and groundwater pump and treat. The site has received approval to discontinue the active treatments and implement a full scale test of enhanced attenuation--an engineering and regulatory strategy that has recently been developed by DOE and the Interstate Technology and Regulatory Council. Enhanced attenuation uses active engineering solutions to alter the target site in such a way that the contaminant plume will passively stabilize and shrink and to document that the action will be effective, timely, and sustainable. The paradigm recognizes that attenuation remedies are fundamentally based on a mass balance. Thus, long-term plume dynamics can be altered either by reducing the contaminant loading from the source or by increasing the rate of natural attenuation processes within all, or part of, the plume volume. The combination of technologies that emerged for T-Area included: (1) neat (pure) vegetable oil deployment in the deep vadose zone in the former source area, (2) emulsified vegetable oil deployment …

The pressure dependence of the Raman shift of diamond for highly stressed anvils at the diamond-anvil sample interface has been measured for different culet shapes up to 180 GPa at ambient temperature. By using hydrogen samples, which constitute both a quasi-hydrostatic medium and a sensitive pressure sensor, some of the effects of culet and tip size have been determined. We propose that the divergent results in the literature can be partly ascribed to different anvil geometries. Experiments show increasing second order dependence of the diamond Raman shift with pressure for decreasing tip size. This is an important consideration when using the diamond anvils as a pressure sensor.

Using both the absolute and relative surrogate techniques, the {sup 236}U(n,f) cross section was deduced over an equivalent neutron energy range of 0 to 20 MeV. A 42 MeV {sup 3}He beam from the 88-Inch Cyclotron at Lawrence Berkeley National Laboratory was used to perform a ({sup 3}He,{alpha}) pickup reaction on targets of {sup 235}U (J{sup {pi}}=7/2{sup -}) and {sup 238}U (J{sup {pi}}=0{sup +}) and the fission decay probabilities were determined. The {sup 235}U({sup 3}He,{alpha}f) and {sup 238}U({sup 3}He,{alpha}f) were surrogates for {sup 233}U(n,f) and {sup 236}U(n,f), respectively. The cross sections extracted using the Surrogate Method were compared to directly measured cross sections. The sensitivity of these cross sections to the J{sup {pi}}-population distributions was explored.

This Geotechnical Analysis Report (GAR) presents and interprets geotechnical data from the underground excavations at the Waste Isolation Pilot Plant (WIPP). The data, which are obtained as part of a regular monitoring program, are used to characterize conditions, to compare actual performance to the design assumptions, and to evaluate and forecast the performance of the underground excavations. GARs have been available to the public since 1983. During the Site and Preliminary Design Validation (SPDV) Program, the architect/engineer for the project produced these reports quarterly to document the geomechanical performance during and immediately after early excavations of the underground facility. Since completion of the construction phase of the project in 1987, the management and operating contractor for the facility has prepared these reports annually. This report describes the performance and condition of selected areas from July 1, 2005, to June 30, 2006. It is divided into nine chapters. Chapter 1 provides background information on WIPP, its mission, and the purpose and scope of the geomechanical monitoring program. Chapter 2 describes the local and regional geology of the WIPP site. Chapters 3 and 4 describe the geomechanical instrumentation in the shafts and shaft stations, present the data collected by that instrumentation, and …

Projection optical systems built for Extreme Ultraviolet Lithography (EUVL) demonstrated the ability to produce, support and position reflective optical surfaces for achieving transmitted wavefront errors of 1 nm or less. Principal challenges included optical interferometry, optical manufacturing processes, multi-layer coating technology and opto mechanics. Our group was responsible for designing, building and aligning two different projection optical systems: a full-field, 0.1 NA, four-mirror system for 70 nm features and a small-field, 0.3 NA, two-mirror system for 30 nm features. Other than physical size and configuration, the two systems were very similar in the way they were designed, built and aligned. A key difference exists in the optic mounts, driven primarily by constraints from the metrology equipment used by different optics manufacturers. As mechanical stability and deterministic position control of optics will continue to play an essential role in future systems, we focus our discussion on opto-mechanics and primarily the optic mounts.

We examine the branching ratio of the N{sub 4,5} (4d {yields} 5f ) spectra of Th, U, Np, Pu, Am, and Cm metal using electron energy-loss spectroscopy (EELS) in a transmission electron microscope (TEM), together with many-electron atomic spectral calculations and the spin-orbit sum rule. Our results show that: (1) The actinide metals Pu, Am, and Cm exhibit intermediate coupling. (2) The intermediate coupling values for the 5f states as calculated using a many-electron atomic model are correct for the actinides, this being proven by our new results for curium. (3) The EELS branching ratio is sensitive to the degree of 5f electron delocalization, which is illustrated by the transition from LS to intermediate coupling between U and Pu.

The United States Department of Energy (U.S. DOE) has recently implemented a series of strategic initiatives to address long-term radiological surveillance needs at former U.S. nuclear test sites in the Marshall Islands (https://eed.llnl.gov/mi/). Local atoll governments have been actively engaged in developing shared responsibilities for protecting the health and safety of resettled and resettling population at risk from exposure to elevated levels of residual fallout contamination in the environment. Under the program, whole body counting facilities have been established at three locations in the Marshall Islands. These facilities are operated and maintained by Marshallese technicians with scientists from the Lawrence Livermore National Laboratory (LLNL) providing technical support services including data quality assurance and performance testing. We have also established a mirror whole body counting facility at the Lawrence Livermore National Laboratory as a technician training center. The LLNL facility also allows program managers to develop quality assurance and operational procedures, and test equipment and corrective actions prior to deployment at remote stations in the Marshall Islands. This document summarizes the results of external performance evaluation exercises conducted at each of the facilities (2002-2005) under the umbrella of the Oak Ridge National Laboratory Intercomparison Studies Program (ISP). The ISP was specifically …

The goal of this demonstration was to show that it is possible to generate electronic signals that can accurately mimic the signals that are produced by a high-purity germanium (HPGe) gamma-ray detector. As an example of this fidelity, we decided to show that it was possible to perform a complex, multiplet-resolution analysis of a portion of the spectrum acquired from the gamma-ray spectrum synthesizer. We further showed that the results of this analysis were consistent with what would be obtained from a spectrum acquired from a real plutonium source and a real HPGe detector. The gamma-ray synthesizer used in the JRC Ispra demonstration was our first laboratory prototype. In this version of the synthesizer we produced signals that mimicked the output of an HPGe detector preamplifier. Although not shown at Ispra, we have also demonstrated that we can produce signals that mimic the signals produced in the detector itself.

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Major scientific and technological breakthroughs played a pivotal role in our ability to win the Cold War. The possibility of a different type of war, in response to terrorism, has long been recognized. Indeed, countermeasures to address specific terrorist acts have been developed and are deployed, for example, at special sporting and political events. The current threat environment, however, has created an intense and compelling set of concerns; consequently, the challenge to the scientific Community to develop new concepts and products on an accelerated timeframe is clear. Also, the spectrum of terrorist threats is broad. It includes the use of conventional, chemical, biological, and nuclear and radiological weapons, not to mention cyber-based attacks. The imperatives for advances have been amplified now that attacks are clearly possible within the U.S. borders. For example, advanced sensors and detectors that are able to monitor the proliferation of all the above warfare agents and their movement at entry points into the U.S. are clearly needed. The investments over the last decades in research and development efforts at the U.S. Department of Energy (DOE) national laboratories in nonproliferation have led unique technologies and detection capabilities that have proved useful; yet, many challenges remain. In particular, …

Interest in the synthesis of semiconductor nanoparticles has been generated by their unusual optical and electronic properties arising from quantum confinement effects. We have synthesized silicon and germanium nanoclusters by reacting Zintl phase precursors with either silicon or germanium tetrachloride in various solvents. Strategies have been investigated to stabilize the surface, including reactions with RLi and MgBrR (R = alkyl). This synthetic method produces group IV nanocrystals with passivated surfaces. These nanoparticle emit over a very large range in the visible region. These particles have been characterized using HRTEM, FTIR, UV-Vis, solid state NMR, and fluorescence. The synthesis and characterization of these nanoclusters will be presented.

Overall objective of this project was to develop a technology platform for cleaning/conditioning the syngas from an integrated gasification combined cycle (IGCC) system at elevated temperatures (500-1,000 F) and gasifier pressures to meet the tolerance limits for contaminants, including H{sub 2}S, COS, NH{sub 3}, HCl, Hg, and As. This technology development effort involved progressive development and testing of sorbent/catalytic materials and associated processes through laboratory, bench, pilot, and demonstration testing phases, coupled with a comprehensive systems analysis at various stages of development. The development of the regenerable RTI-3 desulfurization sorbent - a highly attrition-resistant, supported ZnO-based material - was the key discovery in this project. RTI-3's high attrition resistance, coupled with its high reactivity, effectively allowed its application in a high-velocity transport reactor system. Production of the RTI-3 sorbent was successfully scaled up to an 8,000-lb batch by Sued-Chemie. In October 2005, RTI obtained U.S Patent 6,951,635 to protect the RTI-3 sorbent technology and won the 2004 R&D 100 Award for development of this material. The RTI-3 sorbent formed the basis for the development of the High-Temperature Desulfurization System (HTDS), a dual-loop transport reactor system for removing the reduced sulfur species from syngas. An 83-foot-tall, pilot HTDS unit was constructed …

A new project began in 2005 to monitor the biological and physical effects of improved operations of Hungry Horse and Libby Dams, Montana, called for by the Northwest Power and Conservation Council (NPCC) Mainstem Amendment. This operating strategy was designed to benefit resident fish impacted by hydropower and flood control operations. Under the new operating guidelines, July through September reservoir drafts will be limited to 10 feet from full pool during the highest 80% of water supply years and 20 feet from full pool during the lowest 20% of water supply (drought) years. Limits were also established on how rapidly discharge from the dams can be increased or decreased depending on the season. The NPCC also directed the federal agencies that operate Libby and Hungry Horse Dams to implement a new flood control strategy (VARQ) and directed Montana Fish, Wildlife & Parks to evaluate biological responses to this operating strategy. The Mainstem Amendment operating strategy has not been fully implemented at the Montana dams as of June 2008 but the strategy will be implemented in 2009. This report highlights the monitoring methods used to monitor the effects of the Mainstem Amendment operations on fishes, habitat, and aquatic invertebrates upstream and …

The Idaho Department of Fish and Game maintained a total of about 2,743 acres of wildlife mitigation habitat in 2007, and protected another 921 acres. The total wildlife habitat mitigation debt has been reduced by approximately two percent (598.22 HU) through the Department's mitigation activities in 2007. Implementation of the vegetative monitoring and evaluation program continued across protected lands. For the next funding cycle, the IDFG is considering a package of restoration projects and habitat improvements, conservation easements, and land acquisitions in the project area.