Specific inhibitors of MEK have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway. We employed a systems-based approach to identify breast cancer subtypes particularly susceptible to MEK inhibitors and to understand molecular mechanisms conferring resistance to such compounds. Basal-type breast cancer cells were found to be particularly susceptible to growth-inhibition by small-molecule MEK inhibitors. Activation of the PI3 kinase pathway in response to MEK inhibition through a negative MEK-EGFR-PI3 kinase feedback loop was found to limit efficacy. Interruption of this feedback mechanism by targeting MEK and PI3 kinase produced synergistic effects, including induction of apoptosis and, in some cell lines, cell cycle arrest and protection from apoptosis induced by proapoptotic agents. These findings enhance our understanding of the interconnectivity of oncogenic signal transduction circuits and have implications for the design of future clinical trials of MEK inhibitors in breast cancer by guiding patient selection and suggesting rational combination therapies.

This annual report provides details on the research conducted at EMSL--the Environmental Molecular Sciences Laboratory in Fiscal Year 2008.

Failure occurs when one or more of the intended functions of a product are no longer fulfilled to the customer's satisfaction. The most critical product failures are those that escape design reviews and in-house quality inspection and are found by the customer. The product may work for a while until its performance degrades to an unacceptable level or it may have not worked even before customer took possession of the product. The end results of failures which may lead to unsafe conditions or major losses of the main function are rated high in severity. Failure Modes and Effects Analysis (FMEA) is a tool widely used in the automotive, aerospace, and electronics industries to identify, prioritize, and eliminate known potential failures, problems, and errors from systems under design, before the product is released (Stamatis, 1997). Several industrial FMEA standards such as those published by the Society of Automotive Engineers, US Department of Defense, and the Automotive Industry Action Group employ the Risk Priority Number (RPN) to measure risk and severity of failures. The Risk Priority Number (RPN) is a product of 3 indices: Occurrence (O), Severity (S), and Detection (D). In a traditional FMEA process design engineers typically analyze the 'root …

The resummation of soft gluon exchange for QCD hard scattering requires a matrix of anomalous dimensions, which has been computed through two loops. The two-loop matrix is proportional to the one-loop matrix. Recently there have been proposals that this proportionality extends to higher loops. One can test such proposals by computing the dependence of this matrix on the matter content in a generic gauge theory. It is shown that for the matter-dependent part the proportionality extends to three loops for arbitrary massless processes.

During the summers of 2004 and 2006, extinction and scattering coefficients of particle emissions inside a San Francisco Bay Area roadway tunnel were measured using a combined cavity ring-down and nephelometer instrument. Particle size distributions and humidification were also measured, as well as several gas phase species. Vehicles in the tunnel traveled up a 4% grade at a speed of approximately 60 km h{sup -1}. The traffic situation in the tunnel allows the apportionment of emission factors between light duty gasoline vehicles and diesel trucks. Cross-section emission factors for optical properties were determined for the apportioned vehicles to be consistent with gas phase and particulate matter emission factors. The absorption emission factor (the absorption cross-section per mass of fuel burned) for diesel trucks (4.4 {+-} 0.79 m{sup 2} kg{sup -1}) was 22 times larger than for light-duty gasoline vehicles (0.20 {+-} 0.05 m{sup 2} kg{sup -1}). The single scattering albedo of particles - which represents the fraction of incident light that is scattered as opposed to absorbed - was 0.2 for diesel trucks and 0.3 for light duty gasoline vehicles. These facts indicate that particulate matter from motor vehicles exerts a positive (i.e., warming) radiative climate forcing. Average particulate mass …

It is a challenge to generate full charge electrons from the electron sources without compromising polarization for the proposed ILC and CLIC. It is essential to advance polarized photocathodes to meet the requirements. SLAC has worldwide unique dedicated test facilities, Cathode Test System and dc-Gun Test Laboratory, to fully characterize polarized photocathodes. Recent systematic measurements on a strained-well InAlGaAs/AlGaAs cathode at the facilities show that 87% polarization and 0.3% QE are achieved. The QE can be increased to {approx}1.0% with atomic hydrogen cleaning. The surface charge limit at a very low current intensity and the clear dependence of the polarization on the surface charge limit are observed for the first time. On-going programs to develop photocathodes for the ILC and CLIC are briefly introduced.

The XRD-31 is a fast, windowless X-ray vacuum photodiode developed by EG&G. It is currently the primary fast X-ray detector used to diagnose the X-rays on NIF and OMEGA on the multichannel DANTE spectrometer. The XRD-31 has a dynamic range of less than 1e-12 amps to more than 10 amps. A technique is described to measure the impulse response of the diodes to a 150 fs pulse of 200 nm laser light and a method to calculate the “risetime” for a square pulse and compare it with the computed electron transit time from the photocathode to the anode. Measured response time for 5 XRD-31s assembled in early 2004 was 149.7 ps +-2.75 ps.

This multi-investigator project was concerned with the development and application of new methods and computer codes that would allow realistic modeling of nanosystems. Carter's part in this team effort involved two method/algorithm/code development projects during the first 14 months of this grant. Carter's group has been advancing theory and applications of the orbital-free density functional theory (OF-DFT), the only DFT method that exhibits linear scaling for metals. Such a method offers the possibility of simulating large numbers of atoms with quantum mechanics, such that properties of metallic nanostructures (e.g. nanowires of realistic dimensions) could be investigated. In addition, her group has been developing and applying an embedded correlated wavefunction theory for treating localized excited states in condensed matter (including metals). The application of interest here is spin manipulation at the nanoscale, i.e., spintronics, in which local electron excitations interact with the surrounding material. Her embedded correlation method is ideal for studying such problems.

This document summarizes the performance of the groundwater restoration systems installed by the Commodity Credit Corporation of the U.S. Department of Agriculture (CCC/USDA) at the former CCC/USDA grain storage facility in Utica, Nebraska, during the fourth year of system operation, from December 1, 2007, until November 30, 2008. Performance in earlier years was reported previously (Argonne 2005, 2006, 2008). In the project at Utica, the CCC/USDA is cooperating with multiple state and federal agencies to remove carbon tetrachloride contamination from a shallow aquifer underlying the town and to provide supplemental treated groundwater for use in the restoration of a nearby wetlands area. Argonne National Laboratory assisted the CCC/USDA by providing technical oversight for the aquifer restoration effort and facilities during this review period. This document presents overviews of the aquifer restoration facilities (Section 2) and system operations (Section 3). The report then describes groundwater production results (Section 4); groundwater treatment results (Section 5); and associated maintenance, system modifications, and costs during the review period (Section 6). Section 7 summarizes the present year of operation.

An evaluation of a large number of air sample filters was undertaken using a commercial alpha and beta spectroscopy system employing a passive implanted planar silicon (PIPS) detector. Samples were only measured after air flow through the filters had ceased. Use of a commercial radon stripping algorithm was implemented to discriminate anthropogenic alpha and beta activity on the filters from the radon progeny. When uncontaminated air filters were evaluated, the results showed that there was a time-dependent bias in both average estimates and measurement dispersion with the relative bias being small compared to the dispersion. By also measuring environmental air sample filters simultaneously with electroplated alpha and beta sources, use of the radon stripping algorithm demonstrated a number of substantial unexpected deviations. Use of the current algorithm is therefore not recommended for assay applications and so use of the PIPS detector should only be utilized for gross counting without appropriate modifications to the curve fitting algorithm. As a screening method, the radon stripping algorithm might be expected to see elevated alpha and beta activities on air sample filters (not due to radon progeny) around the 200 dpm level.

Recent developments in the theory of strong interactions are discussed in the framework of the AdS/CFT duality between string theories of gravity in a higher dimension Anti-de Sitter space and conformal quantum field theories in physical space-time. This novel theoretical approach, combined with 'light-front holography', leads to new insights into the quark and gluon structure of hadrons and a viable first approximation to quantum chromodynamics, the fundamental theory of the strong and nuclear interactions.

Using an extreme-ultraviolet (EUV) microscope to produce high-quality images of EUV reticles, we have developed a new wavelength tuning method to acquire through-focus data series with a higher level of stability and repeatability than was previously possible. We utilize the chromatic focal-length dependence of a diffractive Fresnel zoneplate objective lens, and while holding the mask sample mechanically still, we tune the wavelength through a narrow range, in small steps. In this paper, we demonstrate the method and discuss the relative advantages that this data collection technique affords.

A system for collecting solid, post-explosion debris samples from the NIF chamber and their subsequent radiochemical analysis is currently under development. If the debris that condenses out of the plasma can be collected and analyzed, the number and type of nuclear reactions that occurred in the capsule material can be determined. this has applications both for radiochemical diagnostics of NIF capsule performance as well as radiochemical measurements relevant to basic science and stockpile stewardship. Several design prototypes have been studied and a prioritized list of radiochemical measurements that could be performed on NIF is under development based on interactions with capsule design, fabrication, and WCI design divisions.

Aerial images for isolated defects and the interactions of defects with features are compared between the Actinic Inspection Tool (AIT) at Lawrence Berkeley National Laboratory (LBNL) and the fast EUV simulation program RADICAL. Comparisons between AIT images from August 2007 and RADICAL simulations are used to extract aberrations. At this time astigmatism was the dominant aberration with a value of 0.55 waves RMS. Significant improvements in the imaging performance of the AIT were made between August 2007 and December 2008. A good match will be shown between the most recent AIT images and RADICAL simulations without aberrations. These comparisons will demonstrate that a large defect, in this case 7nm tall on the surface, is still printable even if it is centered under the absorber line. These comparisons also suggest that the minimum defect size is between 1.5nm and 0.8nm surface height because a 1.5nm defect was printable but a 0.8nm was not. Finally, the image of a buried defect near an absorber line through focus will demonstrate an inversion in the effect of the defect from a protrusion of the dark line into the space to a protrusion of the space into the line.

Geologic carbon sequestration is the injection of anthropogenic CO{sub 2} into deep geologic formations where the CO{sub 2} is intended to remain indefinitely. If successfully implemented, geologic carbon sequestration will have little or no impact on terrestrial ecosystems aside from the mitigation of climate change. However, failure of a geologic carbon sequestration site, such as large-scale leakage of CO{sub 2} into a potable groundwater aquifer, could cause impacts that would require costly remediation measures. Governments are attempting to develop regulations for permitting geologic carbon sequestration sites to ensure their safety and effectiveness. At present, these regulations focus largely on decreasing the probability of failure. In this paper we propose that regulations for the siting of early geologic carbon sequestration projects should emphasize limiting the consequences of failure because consequences are easier to quantify than failure probability.

The authors present a Dalitz-plot analysis of charmless B{sup {+-}} decays to the final state {pi}{sup {+-}}{pi}{sup {+-}}{pi}{sup {-+}} using a sample of (465 {+-} 5) x 10{sup 6} B{bar B} pairs collected by the BABAR experiment at {radical}s = 10.58 GeV. They measure the branching fractions {Beta}(B{sup {+-}} {yields} {pi}{sup {+-}}{pi}{sup {+-}}{pi}{sup {-+}}) = (15.2 {+-} 0.6 {+-} 1.2 {+-} 0.4) x 10{sup -6}, {Beta}(B{sup {+-}} {yields} {rho}{sup 0}(770){pi}{sup {+-}}) = (8.1 {+-} 0.7 {+-} 1.2{sub -1.1}{sup +0.4}) x 10{sup -6}, {Beta}(B{sup {+-}} {yields} f{sub 2}(1270){pi}{sup {+-}}) = (1.57 {+-} 0.42 {+-} 0.16{sub -0.19}{sup +0.53}) x 10{sup -6}, and {Beta}(B{sup {+-}} {yields} {pi}{sup {+-}}{pi}{sup {+-}}{pi}{sup {-+}} nonresonant) = (5.3 {+-} 0.7 {+-} 0.6{sub -0.5}{sup +1.1}) x 10{sup -6}, where the uncertainties are statistical, systematic, and model-dependent, respectively. Measurements of branching fractions for the modes B{sup {+-}} {yields} {rho}{sup 0}(1450){pi}{sup {+-}} and B{sup {+-}} {yields} f{sub 0}(1370){pi}{sup {+-}} are also presented. They observe no significant direct CP asymmetries for the above modes, and there is no evidence for the decays B{sup {+-}} {yields} f{sub 0}(980){pi}{sup {+-}}, B{sup {+-}} {yields} {chi}{sub c0}{pi}{sup {+-}}, or B{sup {+-}} {yields} {chi}{sub c2}{pi}{sup {+-}}.

We examine size dependent deliquescence/efflorescence phase transformation for particles down to several nanometers in size. A thin layer criterion (TLC) is introduced to define a deliquescence relative humidity (DRH) for small particles. The usual bulk deliquescence conditions are recovered in the limit of large dry particle size. Nano-size particles are shown to deliquesce to metastable states via a nucleation process at relative humidity just below the DRH. The nucleation barrier is located at a critical solution layer thickness and vanishes at the DRH defined by the TLC. Methods from nucleation theory form the basis for the analysis and yield new insights into the theory, facilitate the interpretation of measurements, and point to unification of deliquescence and efflorescence processes for particles in the nano regime. Methods include thermodynamic area constructions, Legendre transforms relating the binary free-energy surfaces for deliquescence and efflorescence processes, and application of nucleation theorems.

We consider the Bekenstein-Hawking entropy-area formula in four dimensional extended ungauged supergravity and its electric-magnetic duality property. Symmetries of both"large" and"small" extremal black holes are considered, as well as the ADM mass formula for N=4 and N=8 supergravity, preserving different fraction of supersymmetry. The interplay between BPS conditions and duality properties is an important aspect of this investigation.

We study effects of energy chirp on echo-enabled harmonic generation (EEHG). Analytical expressions are compared with numerical simulations for both harmonic and bunching factors. We also discuss the EEHG free-electron laser bandwidth increase due to an energy-modulated beam and its pulse length dependence on the electron energy chirp.

We present results on a table-top microscope that uses an EUV stepper geometry to capture full-field images with a halfpitch spatial resolution of 55 nm. This microscope uses a 13.2 nm wavelength table-top laser for illumination and acquires images of reflective masks with exposures of 20 seconds. These experiments open the path to the realization of high resolution table-top imaging systems for actinic defect characterization.

Sum frequency generation vibrational spectroscopy (SFG) and quartz crystal microbalance with dissipation monitoring (QCM-D) are employed to study the interfacial structure and adsorbed amount of the amino acids l-lysine and l-proline and their corresponding homopeptides, poly-l-lysine and poly-l-proline, at two liquid-solid interfaces. SFG and QCM-D experiments of these molecules are carried out at the interface between phosphate buffered saline at pH 7.4 (PBS) and the hydrophobic deuterated polystyrene (d{sub 8}-PS) surface as well as the interface between PBS and hydrophilic fused silica (SiO{sub 2}). The SFG spectra of the amino acids studied here are qualitatively similar to their corresponding homopeptides; however, the SFG signal from amino acids at the solid/PBS interface is smaller in magnitude relative to their more massive homopeptides at the concentrations studied here. Substantial differences are observed in SFG spectra for each species between the hydrophobic d{sub 8}-PS and the hydrophilic SiO{sub 2} liquid-solid interfaces, suggesting surface-dependent interfacial ordering of the biomolecules. Over the range of concentrations used in this study, QCM-D measurements also indicate that on both surfaces poly-l-lysine adsorbs to a greater extent than its constituent amino acid l-lysine. The opposite trend is demonstrated by poly-l-proline which sticks to both surfaces less extensively than its …

The Ernest Orlando Lawrence Berkeley National Laboratory (Berkeley Lab or LBNL) is a multi-program national research facility operated by the University of California for the Department of Energy (DOE). As an integral element of DOE's National Laboratory System, Berkeley Lab supports DOE's missions in fundamental science, energy resources, and environmental quality. Berkeley Lab programs advance four distinct goals for DOE and the nation: (1) To perform leading multidisciplinary research in the computing sciences, physical sciences, energy sciences, biosciences, and general sciences in a manner that ensures employee and public safety and protection of the environment. (2) To develop and operate unique national experimental facilities for qualified investigators. (3) To educate and train future generations of scientists and engineers to promote national science and education goals. (4) To transfer knowledge and technological innovations and to foster productive relationships among Berkeley Lab's research programs, universities, and industry in order to promote national economic competitiveness. Berkeley Lab's research and the Laboratory Directed Research and Development (LDRD) program support DOE's Strategic Themes that are codified in DOE's 2006 Strategic Plan (DOE/CF-0010), with a primary focus on Scientific Discovery and Innovation. For that strategic theme, the Fiscal Year (FY) 2008 LDRD projects support each one …

This report describes the installation, testing, and acceptance of the Waste Treatment and Immobilization Plant (WTP) procured laser ablation-inductively coupled plasma-atomic emission spectroscopy (LA-ICP-AES) system for remotely analyzing high-level waste (HLW) samples in a hot cell environment. The work was completed by the Analytical Process Development (APD) group in accordance with Task Order 2005-003; ATS MP 1027, Management Plan for Waste Treatment Plant Project Work Performed by Analytical Technical Services. The APD group at the 222-S Laboratory demonstrated acceptable turnaround time (TAT) and provide sufficient data to assess sensitivity, accuracy, and precision of the LA-ICP-AES method.

The results of a comparison of Multifaceted Asymmetric Radiation From the Edge (MARFE) theory with experiment in the National Spherical Torus Experiment (NSTX) are presented. A variety of MARFE behavior was observed using a fast-framing camera. A basic MARFE theory was applied to NSTX Multi-Pulse Thomson scattering (MPTS) and charge-exchange recombination spectroscopy (CHERS) data. MARFE theory showed some limited agreement with experiment, but uncertainty in the separatrix location constrained the analysis. A method based on shifting iso-Te flux surfaces was used to estimate the separatrix location. The movements of MARFEs in NSTX are interpreted to result from diamagnetic heat flux driven drifts relative to the background plasma velocity and imply slowing edge poloidal rotation and/or changing edge profiles before a large ELM.