PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors.

Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway have a key role in the pathogenesis of numerous cancers by altering cell growth, metabolism, proliferation and apoptosis. Interest in targeting the PI3K signaling cascade continues, as new agents are being clinically evaluated. PIK3CA mutations result in a constitutively active PI3K and are present in a subset of pancreatic cancers. Here we examine mutant PIK3CA-mediated pancreatic tumorigenesis and the response of PIK3CA mutant pancreatic cancers to dual PI3K/mammalian target of rapamycin (mTOR) inhibition. Two murine models were generated expressing a constitutively active PI3K within the pancreas. An increase in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasms (PanINs) was identified. In one model these lesions were detected as early as 10 days of age. Invasive pancreatic ductal adenocarcinoma developed in these mice as early as 20 days of age. These cancers were highly sensitive to treatment with dual PI3K/mTOR inhibition. In the second model, PanINs and invasive cancer develop with a greater latency owing to a lesser degree of PI3K pathway activation in this murine model. In addition to PI3K pathway activation, increased ERK1/2 signaling is common in human pancreatic cancers. Phosphorylation of ERK1/2 was also investigated in these models. Phosphorylation of ERK1/2 is demonstrated in the pre-neoplastic lesions and invasive cancers. This activation of ERK1/2 is diminished with dual PI3K/mTOR inhibition. In summary, PIK3CA mutations can initiate pancreatic tumorigenesis and these cancers are particularly sensitive to dual PI3K/mTOR inhibition. Future studies of PI3K pathway inhibitors for patients with PIK3CA mutant pancreatic cancers are warranted.

Kirkpatrick-Baez microscope for hard X-ray imaging of fast ignition experiments.

A Kirkpatrick-Baez X-ray microscope has been developed for use on the Titan laser facility at the Lawrence Livermore National Laboratory in Fast Ignition experiments. It was developed as a broadband alternative to narrow band Bragg crystal imagers for imaging Kα emission from tracer layers. A re-entrant design is employed which allows for alignment from outside the chamber. The mirrors are coated with Pt and operate at a grazing incident angle of 0.5° providing higher resolution than an equal brightness pinhole and sufficient bandwidth to image thermally shifted characteristic Kα emission from heated Cu tracer layers in Fast Ignition experiments. The superpolished substrates (<1 Å rms roughness) had a final visible wavelength roughness of 1.7 Å after coating, and exhibited a reflectivity corresponding to an X-ray wavelength roughness of 7 ± 1 Å. A unique feature of this design is that during experiments, the unfiltered direct signal along with the one-dimensional reflections are retained on the detector in order to enable a live indication of alignment and incident angle. The broad spectral window from 4 to 9 keV enables simultaneous observation of emission from several spectral regions of interest, which has been demonstrated to be particularly useful for cone-wire targets. An experimentally measured resolution of 15 µm has been obtained at the center of the field of view.

South pole bang-time diagnostic on the National Ignition Facility (invited).

The south pole bang-time diagnostic views National Ignition Facility (NIF) implosions through the lower Hohlraum laser entrance hole to measure the time of peak x-ray emission (peak compression) in indirect-drive implosions. Five chemical-vapor-deposition diamond photoconductive detectors with different filtrations and sensitivities record the time-varying x rays emitted by the target. Wavelength selecting highly oriented pyrolytic graphite crystal mirror monochromators increase the x-ray signal-to-background ratio by filtering for 11-keV emission. Diagnostic timing and the in situ temporal instrument response function are determined from laser impulse shots on the NIF. After signal deconvolution and background removal, the bang time is determined to 45-ps accuracy. The x-ray "yield" (mJ∕sr∕keV at 11 keV) is determined from the time integral of the corrected peak signal.

Dynamics of relativistic laser-plasma interaction on solid targets.

A novel time-resolved diagnostic is used to record the critical surface motion during picosecond-scale relativistic laser interaction with a solid target. Single-shot measurements of the specular light show a redshift decreasing with time during the interaction, corresponding to a slowing-down of the hole boring process into overdense plasma. On-shot full characterization of the laser pulse enables simulations of the experiment without any free parameters. Two-dimensional particle-in-cell simulations yield redshifts that agree with the data, and support a simple explanation of the slowing-down of the critical surface based on momentum conservation between ions and reflected laser light.

Experimental study of neutron induced background noise on gated x-ray framing cameras.

A temporally gated x-ray framing camera based on a proximity focus microchannel plate is one of the most important diagnostic tools of inertial confinement fusion experiments. However, fusion neutrons produced in imploded capsules interact with structures surrounding the camera and produce background to x-ray signals. To understand the mechanisms of this neutron induced background, we tested several gated x-ray cameras in the presence of 14 MeV neutrons produced at the Omega laser facility. Differences between background levels observed with photographic film readout and charge-coupled-device readout have been studied.

Radiation hardening of gated x-ray imagers for the National Ignition Facility (invited).

The National Ignition Facility will soon be producing x-ray flux and neutron yields higher than any produced in laser driven implosion experiments in the past. Even a non-igniting capsule will require x-ray imaging of near burning plasmas at 10(17) neutrons, requiring x-ray recording systems to work in more hostile conditions than we have encountered in past laser facilities. We will present modeling, experimental data and design concepts for x-ray imaging with electronic recording systems for this environment (ARIANE). A novel instrument, active readout in a nuclear environment, is described which uses the time-of-flight difference between the gated x-ray signal and the neutron which induces a background signal to increase the yield at which gated cameras can be used.

Limitation on prepulse level for cone-guided fast-ignition inertial confinement fusion.

The viability of fast-ignition (FI) inertial confinement fusion hinges on the efficient transfer of laser energy to the compressed fuel via multi-MeV electrons. Preformed plasma due to the laser prepulse strongly influences ultraintense laser plasma interactions and hot electron generation in the hollow cone of an FI target. We induced a prepulse and consequent preplasma in copper cone targets and measured the energy deposition zone of the main pulse by imaging the emitted K_{alpha} radiation. Simulation of the radiation hydrodynamics of the preplasma and particle in cell modeling of the main pulse interaction agree well with the measured deposition zones and provide an insight into the energy deposition mechanism and electron distribution. It was demonstrated that a under these conditions a 100 mJ prepulse eliminates the forward going component of approximately 2-4 MeV electrons.

Effect of reentrant cone geometry on energy transport in intense laser-plasma interactions.

The energy transport in cone-guided low- Z targets has been studied for laser intensities on target of 2.5x10(20) W cm(-2). Extreme ultraviolet (XUV) imaging and transverse optical shadowgraphy of the rear surfaces of slab and cone-slab targets show that the cone geometry strongly influences the observed transport patterns. The XUV intensity showed an average spot size of 65+/-10 microm for slab targets. The cone slabs showed a reduced spot size of 44+/-10 microm. The shadowgraphy for the aforementioned shots demonstrate the same behavior. The transverse size of the expansion pattern was 357+/-32 microm for the slabs and reduced to 210+/-30 microm. A transport model was constructed which showed that the change in transport pattern is due to suppression of refluxing electrons in the material surrounding the cone.

A dual-channel, curved-crystal spectrograph for petawatt laser, x-ray backlighter source studies.

A dual-channel, curved-crystal spectrograph was designed to measure time-integrated x-ray spectra in the approximately 1.5 to 2 keV range (6.2-8.2 A wavelength) from small-mass, thin-foil targets irradiated by the VULCAN petawatt laser focused up to 4x10(20) W/cm(2). The spectrograph consists of two cylindrically curved potassium-acid-phthalate crystals bent in the meridional plane to increase the spectral range by a factor of approximately 10 compared to a flat crystal. The device acquires single-shot x-ray spectra with good signal-to-background ratios in the hard x-ray background environment of petawatt laser-plasma interactions. The peak spectral energies of the aluminum He(alpha) and Ly(alpha) resonance lines were approximately 1.8 and approximately 1.0 mJ/eV sr (approximately 0.4 and 0.25 J/A sr), respectively, for 220 J, 10 ps laser irradiation.

Development of backlighting sources for a Compton radiography diagnostic of inertial confinement fusion targets (invited).

We present scaled demonstrations of backlighter sources, emitting bremsstrahlung x rays with photon energies above 75 keV, that we will use to record x-ray Compton radiographic snapshots of cold dense DT fuel in inertial confinement fusion implosions at the National Ignition Facility (NIF). In experiments performed at the Titan laser facility at Lawrence Livermore National Laboratory, we measured the source size and the bremsstrahlung spectrum as a function of laser intensity and pulse length from solid targets irradiated at 2x10(17)-5x10(18) W/cm(2) using 2-40 ps pulses. Using Au planar foils we achieved source sizes down to 5.5 microm and conversion efficiencies of about 1x10(-13) J/J into x-ray photons with energies in the 75-100 keV spectral range. We can now use these results to design NIF backlighter targets and shielding and to predict Compton radiography performance as a function of the NIF implosion yield and associated background.

Diagnostics for fast ignition science (invited).

The ignition concept for electron fast ignition inertial confinement fusion requires sufficient energy be transferred from an approximately 20 ps laser pulse to the compressed fuel via approximately MeV electrons. We have assembled a suite of diagnostics to characterize such transfer, simultaneously fielding absolutely calibrated extreme ultraviolet multilayer imagers at 68 and 256 eV; spherically bent crystal imagers at 4.5 and 8 keV; multi-keV crystal spectrometers; MeV x-ray bremmstrahlung, electron and proton spectrometers (along the same line of sight), and a picosecond optical probe interferometer. These diagnostics allow careful measurement of energy transport and deposition during and following the laser-plasma interactions at extremely high intensities in both planar and conical targets. Together with accurate on-shot laser focal spot and prepulse characterization, these measurements are yielding new insights into energy coupling and are providing critical data for validating numerical particle-in-cell (PIC) and hybrid PIC simulation codes in an area crucial for fast ignition and other applications. Novel aspects of these diagnostics and how they are combined to extract quantitative data on ultrahigh intensity laser-plasma interactions are discussed.

Laser heating of solid matter by light-pressure-driven shocks at ultrarelativistic intensities.

The heating of solid targets irradiated by 5 x 10(20) W cm(-2), 0.8 ps, 1.05 microm wavelength laser light is studied by x-ray spectroscopy of the K-shell emission from thin layers of Ni, Mo, and V. A surface layer is heated to approximately 5 keV with an axial temperature gradient of 0.6 microm scale length. Images of Ni Ly(alpha) show the hot region has 100 G bar light pressure compresses the preformed plasma and drives a shock into the solid, heating a thin layer.

Use of GafChromic film to diagnose laser generated proton beams.

A calibration of three types of GafChromic radiochromic film (HS, MD-55, and HD-810) was carried out on the Crocker Nuclear Laboratory's 76 in. cyclotron at UC Davis over doses ranging from 0.001 to 15 kGy. The film was digitized with a scanning microdensitometer with which it was scanned twice with two different filters to increase the film's effective dynamic range. We demonstrate how this calibrated film can be used to measure the spectrum and total energy of a laser generated proton beam. This technique was applied to an experiment on the 10 J, 100 fs Callisto laser at Lawrence Livermore National Laboratory. The resulting proton spectrum was compared to that obtained by simultaneous measurement of Ti nuclear activation; the two methods give the same proton beam slope temperature and agree in number of protons to within 27%.

Measurements of energy transport patterns in solid density laser plasma interactions at intensities of 5x10(20) W cm-2.

Kalpha x-ray emission, extreme ultraviolet emission, and plasma imaging techniques have been used to diagnose energy transport patterns in copper foils ranging in thickness from 5 to 75 microm for intensities up to 5x10(20) W cm-2. The Kalpha emission and shadowgrams both indicate a larger divergence angle than that reported in the literature at lower intensities [R. Stephens, Phys. Rev. E 69, 066414 (2004)]. Foils 5 microm thick show triple-humped plasma expansion patterns at the back and front surfaces. Hybrid code modeling shows that this can be attributed to an increase in the mean energy of the fast electrons emitted at large radii, which only have sufficient energy to form a plasma in such thin targets.

Proton radiography of a laser-driven implosion.

Protons accelerated by a picosecond laser pulse have been used to radiograph a 500 microm diameter capsule, imploded with 300 J of laser light in 6 symmetrically incident beams of wavelength 1.054 microm and pulse length 1 ns. Point projection proton backlighting was used to characterize the density gradients at discrete times through the implosion. Asymmetries were diagnosed both during the early and stagnation stages of the implosion. Comparison with analytic scattering theory and simple Monte Carlo simulations were consistent with a 3+/-1 g/cm3 core with diameter 85+/-10 microm. Scaling simulations show that protons>50 MeV are required to diagnose asymmetry in ignition scale conditions.

Effect of increased bronchial venous pressure on lung lymph flow.

We postulated that if the bronchial circulation affects lung fluid balance, increases in bronchial venous pressures may influence lung lymph flow. This hypothesis was tested in eight anesthetized sheep prepared with acute lung lymph fistulas. After control data, we increased bronchial venous pressure by infusing saline directly into the bronchial vein at a controlled infusion pressure of 20-25 cmH2O. Evans blue dye (2.5 mg/ml) was added into the saline as a marker for assessing leakage that might occur from either the catheter or the ruptured bronchial veins. Lymph flow was measured every 15 min. Lymph as well as plasma samples were collected every 30 min for measurement of protein. In five sheep we also measured Evans blue dye content both in lymph and plasma to further characterize the role of bronchial circulation in lung fluid balance. The control lymph flow was 1.9 +/- 0.2 ml/15 min, and lymph-to-plasma protein ratio was 0.65 +/- 0.3 (mean +/- SE). With infusion of saline into the bronchial vein, the mean lung lymph flow and lymph-to-plasma protein ratio did not change significantly. There was a progressive increase in dye content both in lymph and plasma. The mean Evans blue dye content in lymph was 0.087, 0.16, and 0.26 microgram/ml, whereas in plasma it was 0.43, 1.15, and 1.45 microgram/ml in samples obtained at 30, 60, and 90 min, respectively. The dye content was significantly higher in the plasma compared with the lymph in all three samples (less than 0.05). Pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output did not change significantly throughout the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)