Enhancing Bremsstrahlung Production From Ultraintense Laser-Solid Interactions With Front Surface Structures

We report the results of a combined study of particle-in-cell and Monte Carlo modeling that investigates the production of Bremsstrahlung radiation produced when an ultraintense laser interacts with a tower-structured target. These targets are found to significantly narrow the electron angular distribution as well as produce significantly higher energies. These features combine to create a significant enhancement in directionality and energy of the Bremstrahlung radiation produced by a high-Z converter target. These studies employ short-pulse, high intensity laser pulses, and indicate that novel target design has potential to greatly enhance the yield and narrow the directionality of high energy electrons and $\gamma$-rays. We find that the peak $\gamma$-ray brightness for this source is 6.0$\times$10$^{19}$ ${\rm s^{-1}mm^{-2}mrad^{-2}}$ at 10MeV and 1.4$\times$10$^{19}$ ${\rm s^{-1}mm^{-2}mrad^{-2}}$ at 100MeV (0.1$\%$ bandwidth).Comment: arXiv admin note: text overlap with arXiv:1310.328

Fast Ignition Experimental and Theoretical Studies

We are becoming dependent on energy more today than we were a century ago, and with increasing world population and booming economies, sooner or later our energy sources will be exhausted. Moreover, our economy and welfare strongly depends on foreign oil and in the shadow of political uncertainties, there is an urgent need for a reliable, safe, and cheap energy source. Thermonuclear fusion, if achieved, is that source of energy which not only will satisfy our demand for today but also for centuries to come. Today, there are two major approaches to achieve fusion: magnetic confinement fusion (MFE) and inertial confinement fusion (ICF). This dissertation explores the inertial confinement fusion using the fast ignition concept. Unlike the conventional approach where the same laser is used for compression and ignition, in fast ignition separate laser beams are used. This dissertation addresses three very important topics to fast ignition inertial confinement fusion. These are laser-to-electron coupling efficiency, laser-generated electron beam transport, and the associated isochoric heating. First, an integrated fast ignition experiment is carried out with 0.9 kJ of energy in the compression beam and 70 J in the ignition beam. Measurements of absolute K{sub {alpha}} yield from the imploded core revealed that about 17% of the laser energy is coupled to the suprathermal electrons. Modeling of the transport of these electrons and the associated isochoric heating, with the previously determined laser-to-electron conversion efficiency, showed a maximum target temperature of 166 eV at the front where the electron flux is higher and the density is lower. The contribution of the potential, induced by charge separation, in opposing the motion of the electrons was moderate. Second, temperature sensitivity of Cu K{sub {alpha}} imaging efficiency using a spherical Bragg reflecting crystal is investigated. It was found that due to the shifting and broadening of the K{sub {alpha}} line, with increasing temperature, both the brightness and the pattern of K{sub {alpha}} intensity are affected. Finally, x-ray spectroscopy of a 500 J 0.7 ps laser-solid interactions showed the formation of a hot surface layer({approx} 1 {micro}m) at the front of the target. PIC simulations confirm surface heating

Low-molecular-weight cyclin E: the missing link between biology and clinical outcome

Cyclin E, a key mediator of transition during the G(1)/S cellular division phase, is deregulated in a wide variety of human cancers. Our group recently reported that overexpression and generation of low-molecular-weight (LMW) isoforms of cyclin E were associated with poor clinical outcome among breast cancer patients. However, the link between LMW cyclin E biology in mediating a tumorigenic phenotype and clinical outcome is unknown. To address this gap in knowledge, we assessed the role of LMW isoforms in breast cancer cells; we found that these forms of cyclin E induced genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. These findings suggest that high levels of LMW isoforms of cyclin E not only can predict failure to endocrine therapy but also are true prognostic indicators because of their influence on cell proliferation and genetic instability

LMW-E/CDK2 Deregulates Acinar Morphogenesis, Induces Tumorigenesis, and Associates with the Activated b-Raf-ERK1/2-mTOR Pathway in Breast Cancer Patients

Elastase-mediated cleavage of cyclin E generates low molecular weight cyclin E (LMW-E) isoforms exhibiting enhanced CDK2–associated kinase activity and resistance to inhibition by CDK inhibitors p21 and p27. Approximately 27% of breast cancers express high LMW-E protein levels, which significantly correlates with poor survival. The objective of this study was to identify the signaling pathway(s) deregulated by LMW-E expression in breast cancer patients and to identify pharmaceutical agents to effectively target this pathway. Ectopic LMW-E expression in nontumorigenic human mammary epithelial cells (hMECs) was sufficient to generate xenografts with greater tumorigenic potential than full-length cyclin E, and the tumorigenicity was augmented by in vivo passaging. However, cyclin E mutants unable to interact with CDK2 protected hMECs from tumor development. When hMECs were cultured on Matrigel, LMW-E mediated aberrant acinar morphogenesis, including enlargement of acinar structures and formation of multi-acinar complexes, as denoted by reduced BIM and elevated Ki67 expression. Similarly, inducible expression of LMW-E in transgenic mice generated hyper-proliferative terminal end buds resulting in enhanced mammary tumor development. Reverse-phase protein array assay of 276 breast tumor patient samples and cells cultured on monolayer and in three-dimensional Matrigel demonstrated that, in terms of protein expression profile, hMECs cultured in Matrigel more closely resembled patient tissues than did cells cultured on monolayer. Additionally, the b-Raf-ERK1/2-mTOR pathway was activated in LMW-E–expressing patient samples, and activation of this pathway was associated with poor disease-specific survival. Combination treatment using roscovitine (CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (a pan kinase inhibitor targeting b-Raf) effectively prevented aberrant acinar formation in LMW-E–expressing cells by inducing G1/S cell cycle arrest. LMW-E requires CDK2–associated kinase activity to induce mammary tumor formation by disrupting acinar development. The b-Raf-ERK1/2-mTOR signaling pathway is aberrantly activated in breast cancer and can be suppressed by combination treatment with roscovitine plus either rapamycin or sorafenib

Neutrophil Elastase Remodels Mammary Tumors to Facilitate Lung Metastasis

Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE-/-) of breast cancer to interrogate the tumor-intrinsic and -extrinsic mechanisms by which NE can promote metastasis. Our results showed that genetic ablation of NE significantly reduced lung metastasis and improved metastasis-free survival. RNA-sequencing analysis of primary tumors indicated differential regulation of tumor-intrinsic actin cytoskeleton signaling pathways by NE. These NE-regulated pathways are critical for cell-to-cell contact and motility and consistent with the delay in metastasis in NE-/- mice. To evaluate whether pharmacologic inhibition of NE inhibited pulmonary metastasis and phenotypically mimicked PyMT NE-/- mice, we utilized AZD9668, a clinically available and specific NE inhibitor. We found AZD9668 treated PyMT-NE+/+ mice showed significantly reduced lung metastases, improved recurrence-free, metastasis-free and overall survival, and their tumors showed similar molecular alterations as those observed in PyMT-NE-/- tumors. Finally, we identified a NE-specific signature that predicts recurrence and metastasis in patients with breast cancer. Collectively, our studies suggest that genetic ablation and pharmacologic inhibition of NE reduces metastasis and extends survival of mouse models of breast cancer, providing rationale to examine NE inhibitors as a treatment strategy for the clinical management of patients with metastatic breast cancer