Employing Laser-Accelerated Proton Beams to Diagnose High Intensity Laser-Plasma Interactions

A review of the proton radiography technique will be presented. This technique employs laser-accelerated laminar bunches of protons to diagnose the temporal and spatial characteristic of the electric and magnetic fields generated during high-intensity laser-plasma interactions. The remarkable temporal and spatial resolution that this technique can achieve (of the order of a picosecond and a few microns respectively) candidates this technique as the preferrable one, if compared to other techniques, to probe high intensity laser-matterinteractions.

Radiochromic film imaging spectroscopy of laser-accelerated proton beams

This article reports on an experimental method to fully reconstruct laser-accelerated proton beam parameters called radiochromic film imaging spectroscopy (RIS). RIS allows for the characterization of proton beams concerning real and virtual source size, envelope- and microdivergence, normalized transverse emittance, phase space, and proton spectrum. This technique requires particular targets and a high resolution proton detector. Therefore thin gold foils with a microgrooved rear side were manufactured and characterized. Calibrated GafChromic radiochromic film (RCF) types MD-55, HS, and HD-810 in stack configuration were used as spatial and energy resolved film detectors. The principle of the RCF imaging spectroscopy was demonstrated at four different laser systems. This can be a method to characterize a laser system with respect to its proton-acceleration capability. In addition, an algorithm to calculate the spatial and energy resolved proton distribution has been developed and tested to get a better idea of laser-accelerated proton beams and their energy deposition with respect to further applications.

Expression of the NF-κB inhibitor A20 is altered in the Cystic Fibrosis epithelium

Research Question: A20 is an LPS-inducible, cytoplasmic zinc finger protein, that inhibits TLR-activated NF-?B signalling by deubiquitinating TRAF6. A20 action is facilitated by complex formation with RNF11, Itch and TAX1BP1. This study investigates if the expression of A20 is altered in the chronically inflamed Cystic Fibrosis (CF) airway epithelium.

Methods: Nasal epithelial cells from CF patients (F508del homozygous), non-CF controls and immortalised epithelial cells (16HBE14o- and CFBE41o-) were stimulated with LPS. Cytoplasmic expression of A20 and expression of NF-?B subunits was analysed. Formation of the A20 ubiquitin editing complex was also investigated.

Results: In CFBE41o-, peak LPS-induced A20 expression was delayed compared with 16HBE14o- and fell significantly below basal levels 12-24 h after LPS stimulation. This was confirmed in primary CF airway cells. Additionally, a significant inverse relationship between A20 and p65 expression was observed. Inhibitor studies showed that A20 does not undergo proteasomal degradation in CFBE41o-. A20 interacted with TAX1BP1, RNF11 and TRAF6 in 16HBE14o- cells, but these interactions were not observed in CFBE41o-.

Conclusion: he expression of A20 is significantly altered in CF and important interactions with complex members and target proteins are lost, which may contribute to the state of chronic NF-?B-driven inflammation.

Generation of a quasi-monoergetic proton beam from laser-irradiated sub-micron droplets

Proton bursts with a narrow spectrum at an energy of (2.8 +/- 0.3 MeV) are accelerated from sub-micron water spray droplets irradiated by high-intensity (similar to 5 x 10(19)W/cm(2)), high-contrast (similar to 10(10)), ultra-short (40 fs) laser pulses. The acceleration is preferentially in the laser propagation direction. The explosion dynamics is governed by a residual ps-scale laser pulse pedestal which "mildly" preheats the droplet and changes its density profile before the arrival of the high intensity laser pulse peak. As a result, the energetic electrons extracted from the modified target by the high-intensity part of the laser pulse establish an anisotropic electrostatic field which results in anisotropic Coulomb explosion and proton acceleration predominantly in the forward direction. Hydrodynamic simulations of the target pre-expansion and 3D particle-in-cell simulations of the measured energy and anisotropy of the proton emission have confirmed the proposed acceleration scenario. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4731712]

Radiochromic film spectroscopy of laser-accelerated proton beams using the FLUKA code and dosimetry traceable to primary standards

A new approach to spectroscopy of laser induced proton beams using radiochromic film (RCF) is presented. This approach allows primary standards of absorbed dose-to-water as used in radiotherapy to be transferred to the calibration of GafChromic HD-810 and EBT in a 29 MeV proton beam from the Birmingham cyclotron. These films were then irradiated in a common stack configuration using the TARANIS Nd:Glass multi-terawatt laser at Queens University Belfast, which can accelerate protons to 10-12 MeV, and a depth-dose curve was measured from a collimated beam. Previous work characterizing the relative effectiveness (RE) of GafChromic film as a function of energy was implemented into Monte Carlo depth-dose curves using FLUKA. A Bragg peak (BP) "library" for proton energies 0-15 MeV was generated, both with and without the RE function. These depth-response curves were iteratively summed in a FORTRAN routine to solve for the measured RCF depth-dose using a simple direct search algorithm. By comparing resultant spectra with both BP libraries, it was found that the effect of including the RE function accounted for an increase in the total number of protons by about 50%. To account for the energy loss due to a 20 mu m aluminum filter in front of the film stack, FLUKA was used to create a matrix containing the energy loss transformations for each individual energy bin. Multiplication by the pseudo-inverse of this matrix resulted in "up-shifting" protons to higher energies. Applying this correction to two laser shots gave further increases in the total number of protons, N of 31% and 56%. Failure to consider the relative response of RCF to lower proton energies and neglecting energy losses in a stack filter foil can potentially lead to significant underestimates of the total number of protons in RCF spectroscopy of the low energy protons produced by laser ablation of thin targets.

Relative biological effectiveness (RBE) and out-of-field cell survival responses to passive scattering and pencil beam scanning proton beam deliveries

The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in-and out-of-field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields

Na+/H+ exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion

Administration of Na(+)/H(+) exchange isoform-1 (NHE-1) inhibitors before ischemia has been shown to attenuate myocardial infarction in several animal models of ischemia-reperfusion injury. However, controversy still exists as to the efficacy of NHE-1 inhibitors in protection of myocardial infarction when administered at the onset of reperfusion. Furthermore, the efficacy of NHE-1 inhibition in protection of skeletal muscle from infarction (necrosis) has not been studied. This information has potential clinical applications in prevention or salvage of skeletal muscle from ischemia-reperfusion injury in elective and trauma reconstructive surgery. The objective of this research project is to test our hypothesis that the NHE-1 inhibitor cariporide is effective in protection of skeletal muscle from infarction when administered at the onset of sustained ischemia or reperfusion and to study the mechanism of action of cariporide. In our studies, we observed that intravenous administration of cariporide 10 min before ischemia (1 or 3 mg/kg) or reperfusion (3 mg/kg) significantly reduced infarction in pig latissimus dorsi muscle flaps compared with the control, when these muscle flaps were subjected to 4 h of ischemia and 48 h of reperfusion (P <0.05; n = 5 pigs/group). Both preischemic and postischemic cariporide treatment (3 mg/kg) induced a significant decrease in muscle myeloperoxidase activity and mitochondrial-free Ca(2+) content and a significant increase in muscle ATP content within 2 h of reperfusion (P <0.05; n = 4 pigs/group). Preischemic and postischemic cariporide treatment (3 mg/kg) also significantly inhibited muscle NHE-1 protein expression within 2 h of reperfusion after 4 h of ischemia, compared with the control (P <0.05; n = 3 pigs/group). These observations support our hypothesis that cariporide attenuates skeletal muscle infarction when administered at the onset of ischemia or reperfusion, and the mechanism involves attenuation of neutrophil accumulation and mitochondrial-free Ca(2+) overload and preservation of ATP synthesis in the early stage of reperfusion.

Innate host defense functions of secretory leucoprotease inhibitor

Chronic lung diseases such as cystic fibrosis and emphysema are characterized by a protease burden, an infective process and a dominant proinflammatory profile. Secretory leucoprotease inhibitor (SLPI) is a prominent innate immune protein of the respiratory tract, possessing serine protease inhibitor activity, antibacterial activity, and anti-inflammatory/immunomodulatory activity. In the course of this review, the authors highlight the findings from a range of studies that illustrate the multiple functions of SLPI and its role in the resolution of the immune response.

The role of secretory leucoprotease inhibitor in the resolution of inflammatory responses

Chronic lung disease is one of the most common causes of death and disability worldwide. This group of diseases is characterized by a protease burden, an infective process and a dominant pro-inflammatory profile. While SLPI (secretory leucoprotease inhibitor) was initially identified as a serine protease inhibitor, it has since been shown that SLPI possesses other properties distinct from those associated with its antiprotease capabilities that play an important role in protecting the host from infection and injury. In the course of this review, we will highlight the findings from a range of studies that illustrate the multiple functions of SLPI and its role in the resolution of the immune response.

Secretory leucoprotease inhibitor binds to NF-kappaB binding sites in monocytes and inhibits p65 binding

Secretory leucoprotease inhibitor (SLPI) is a nonglycosylated protein produced by epithelial cells. In addition to its antiprotease activity, SLPI has been shown to exhibit antiinflammatory properties, including down-regulation of tumor necrosis factor alpha expression by lipopolysaccharide (LPS) in macrophages and inhibition of nuclear factor (NF)-kappaB activation in a rat model of acute lung injury. We have previously shown that SLPI can inhibit LPS-induced NF-kappaB activation in monocytic cells by inhibiting degradation of IkappaBalpha without affecting the LPS-induced phosphorylation and ubiquitination of IkappaBalpha. Here, we present evidence to show that upon incubation with peripheral blood monocytes (PBMs) and the U937 monocytic cell line, SLPI enters the cells, becoming rapidly localized to the cytoplasm and nucleus, and affects NF-kappaB activation by binding directly to NF-kappaB binding sites in a site-specific manner. SLPI can also prevent p65 interaction with the NF-kappaB consensus region at concentrations commensurate with the physiological nuclear levels of SLPI and p65. We also demonstrate the presence of SLPI in nuclear fractions of PBMs and alveolar macrophages from individuals with cystic fibrosis and community-acquired pneumonia. Therefore, SLPI inhibition of NF-kappaB activation is mediated, in part, by competitive binding to the NF-kappaB consensus-binding site.