Linear Breit-Wheeler process driven by compact lasers.

We report a proposal to observe the two-photon Breit-Wheeler process in plasma driven by compact lasers. A high-charge electron bunch can be generated from laser plasma wakefield acceleration when a tightly focused laser pulse propagates in a subcritical density plasma. The electron bunch scatters with the laser pulse coming from the opposite direction and resulting in the emission of high brilliance x-ray pulses. In a three-dimensional particle-in-cell simulation with a laser pulse of ∼10 J, one could produce an x-ray pulse with a photon number higher than 3×10^{11} and brilliance above 1.6×10^{23} photons/s/mm^{2}/mrad^{2}/0.1%BW at 1 MeV. The x-ray pulses collide in the plasma and create more than 1.1×10^{5} electron-positron pairs per shot. It is also found that the positrons can be accelerated transversely by a transverse electric field generated in the plasma, which enables the safe detection in the direction away from the laser pulses. This proposal enables the observation of the linear Breit-Wheeler process in a compact device with a single shot.

A versatile control program for positioning and shooting targets in laser-plasma experiments.

We introduce a LabVIEW-based control program that significantly improves the efficiency and flexibility in positioning and shooting solid targets in laser-plasma experiments. The hardware driven by this program incorporates a target positioning subsystem and an imaging subsystem, which enables us to install up to 400 targets for one experimental campaign and precisely adjust them in six freedom degrees. The overall architecture and the working modes of the control program are demonstrated in detail. In addition, we characterized the distributions of target positions of every target holder and simultaneously saved the target images, resulting in a large dataset that can be used to train machine learning models and develop image recognition algorithms. This versatile control system has become an indispensable platform when preparing and conducting laser-plasma experiments.

High efficiency and collimated terahertz pulse from ultra-short intense laser and cone target.

We propose a new, to the best of our knowledge, method to radiate a high-efficiency and collimated terahertz (THz) pulse from a relativistic femtosecond laser and cone target. Particle-in-cell simulations demonstrate that a THz source of 40 mJ, pointing at an angle of ∼20 ∘, can be generated from a laser pulse of 1.9 J by using a cone target whose open angle is 10 ∘. The peak power of the THz pulse is 1011 W. This method, which manipulates the divergence angle and the energy conversion efficiency of the THz source, should promote THz science into the extra strong region with a compact laser system.

Detection and analysis of laser driven proton beams by calibrated Gafchromic HD-V2 and MD-V3 radiochromic films.

The radiochromic film (RCF) is a high-dose, high-dynamic range dosimetry detection medium. A stack of RCFs can be used to detect both spatial and energetic distribution of laser driven ion beams with a large divergence angle and continuous energy spectrum. Two types of RCFs (HD-V2 and MD-V3, from Radiation Products Design, Inc.) have been calibrated using MeV energy protons and carbon ions produced by using a 2 × 6 MV tandem electrostatic accelerator. The proportional relationship is obtained between the optical density and the irradiation dose. For protons, the responses are consistent at all energies with a variation of about 15%. For carbon ions, the responses are energy related, which should be noted for heavy ion detection. Based on the calibration, the broad energy spectrum and charge distribution of laser accelerated proton beam with energy from 3 to 8 MeV and pC charge were detected and reconstructed at the Compact LAser Plasma Accelerator at Peking University.

Deflection of a reflected intense circularly polarized light beam induced by asymmetric radiation pressure.

A deflection effect of an intense laser beam with spin angular momentum is revealed theoretically by an analytical modeling using radiation pressure and momentum balance of laser plasma interaction in the relativistic regime as a deviation from the law of reflection. The reflected beam deflects out of the plane of incidence with a deflection angle up to several milliradians, when a nonlinear polarized laser, with the intensity I_{0}∼10^{19}W/cm^{2} and duration around tens of femtoseconds, is obliquely incident and reflected by an overdense plasma target. This effect originates from the asymmetric radiation pressure caused by spin angular momentum of the laser photons. The dependence of the deflection angle of a Gaussian-type laser on the parameters of laser pulse and plasma foil is theoretically derived, which is also confirmed by three-dimensional particle-in-cell simulations of circularly polarized laser beams with the different intensity and pulse duration.

High-efficiency γ-ray flash generation via multiple-laser scattering in ponderomotive potential well.

γ-ray flash generation in near-critical-density target irradiated by four symmetrical colliding laser pulses is numerically investigated. With peak intensities about 10^{23} W/cm^{2}, the laser pulses boost electron energy through direct laser acceleration, while pushing them inward with the ponderomotive force. After backscattering with counterpropagating laser, the accelerated electron is trapped in the electromagnetic standing waves or the ponderomotive potential well created by the coherent overlapping of the laser pulses, and emits γ-ray photons in a multiple-laser-scattering regime, where electrons act as a medium transferring energy from the laser to γ rays in the ponderomotive potential valley.

Intratracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD) is an important complication of mechanical ventilation in preterm infants, and no definite therapy can eliminate this complication. Pulmonary inflammation plays a crucial role in its pathogenesis, and glucocorticoid is one potential therapy to prevent BPD. OBJECTIVES: To compare the effect of intratracheal administration of surfactant/budesonide with that of surfactant alone on the incidence of death or BPD. METHODS: A clinical trial was conducted in three tertiary neonatal centers in the United States and Taiwan, in which 265 very-low-birth-weight infants with severe respiratory distress syndrome who required mechanical ventilation and inspired oxygen (fraction of inspired oxygen, ≥50%) within 4 hours of birth were randomly assigned to one of two groups (131 intervention and 134 control). The intervention infants received surfactant (100 mg/kg) and budesonide (0.25 mg/kg), and the control infants received surfactant only (100 mg/kg), until each infant required inspired O2 at less than 30% or was extubated. MEASUREMENTS AND MAIN RESULTS: The intervention group had a significantly lower incidence of BPD or death (55 of 131 [42.0%] vs. 89 of 134 [66%]; risk ratio, 0.58; 95% confidence interval, 0.44-0.77; P < 0.001; number needed to treat, 4.1; 95% confidence interval, 2.8-7.8). The intervention group required significantly fewer doses of surfactant than did the control group. The intervention group had significantly lower interleukin levels (IL-1, IL-6, IL-8) in tracheal aspirates at 12 hours and lower IL-8 at 3-5 and 7-8 days. CONCLUSIONS: In very-low-birth-weight infants with severe respiratory distress syndrome, intratracheal administration of surfactant/budesonide compared with surfactant alone significantly decreased the incidence of BPD or death without immediate adverse effect. Clinical trial registered with www.clinicaltrials.gov (NCT-00883532).

Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma.

Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾ 2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125-3.11 mg/m(2) on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1-36). MTD was determined to be 2.34 mg/m(2). Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ⩾ 3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ⩾ 3 events were reported. Plasma exposure increased dose proportionally from 0.5-3.11 mg/m(2); terminal half-life was 4-12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ⩾ 32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.

Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results.

Nilotinib (Tasigna) is a potent and selective BCR-ABL inhibitor approved for use in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CML-CP) and in patients with CML-CP and accelerated phase (CML-AP) who are resistant to or intolerant of imatinib. Patients with CML-AP (N = 137) with at least 24 months of follow-up or who discontinued early were evaluated to determine the efficacy and tolerability of nilotinib. The majority (55%) of patients achieved a confirmed hematologic response, and 31% attained a confirmed complete hematologic response on nilotinib treatment. Overall, 32% of patients achieved major cytogenetic responses (MCyR), with most being complete cytogenetic responses. Responses were durable, with 66% of patients maintaining MCyR at 24 months. The estimated overall and progression-free survival rates at 24 months were 70% and 33%, respectively. Grade 3/4 neutropenia and thrombocytopenia were each observed in 42% of patients. Non-hematologic adverse events were mostly mild to moderate; the safety profile of nilotinib has not changed with longer follow-up. In all, 20 (15%) patients remained on study at data cutoff. In summary, nilotinib has a manageable safety profile, and can provide favorable long-term outcomes in the pretreated CML-AP patient population for whom treatment options are limited.

Clinical and acquired immunologic responses to West Nile virus infection of domestic chickens (Gallus gallus domesticus).

Numerous bird species are highly susceptible to North American strains of West Nile virus (WNV), and although domestic chickens are relatively resistant to WNV-associated disease, this species currently represents the most practical avian model for immune responses to WNV infection. Knowledge of the immunomodulation of susceptibility to WNV in birds is important for understanding taxonomic differences in infection outcomes. While focusing on immunophenotyping of CD3(+), CD4(+), CD8(+), and CD45(+) lymphocyte subpopulations, we compared lymphocyte subpopulations, blood chemistries, cloacal temperatures, IgM and IgG antibody titers, and differential whole-blood cell counts of WNV-infected and uninfected hens. Total blood calcium and lymphocyte numbers were lower in WNV-infected chickens compared with uninfected chickens. The heterophil-to-lymphocyte ratio increased over time from 2 to 22 d postinoculation (DPI) in uninfected chickens and from 2 to 8 DPI in WNV-infected chickens, although levels declined from 8 to 22 DPI in the latter group. No significant differences were found in the remaining immunological and hematological variables of the WNV-infected and uninfected groups. Our results reaffirm that chickens are resistant to WNV infection, and demonstrated that the heterophil-to-lymphocyte ratio differed between groups, allowing for sorting of infection status. Similar patterns in immune responses over time in both infected and uninfected hens may be related to age (i.e., 10 wk) and associated immune development.

Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy.

Nilotinib is a highly selective Bcr-Abl inhibitor approved for imatinib-resistant chronic myeloid leukemia (CML). Nilotinib and dasatinib, a multi-targeted kinase inhibitor also approved for second-line therapy in CML, have different patterns of kinase selectivity, pharmacokinetics, and cell uptake and efflux properties, and thus patients may respond to one following failure of the other. An international phase II study of nilotinib was conducted in CML patients (39 chronic phase (CP), 21 accelerated phase (AP)) after failure of both imatinib and dasatinib. Median times from diagnosis of CP or AP to nilotinib therapy were 89 and 83 months, respectively. Complete hematological response and major cytogenetic response (MCyR) rates in CP were 79% and 43%, respectively. Of 17 evaluable patients with CML-AP, 5 (29%) had a confirmed hematological response and 2 (12%) a MCyR. The median time to progression has not yet been reached in CP patients. At 18 months 59% of patients were progression-free. Median overall survival for both populations has not been reached, and the estimated 18-month survival rate in CML-CP was 86% and that at 12 months for CML-AP was 80%. Nilotinib is an effective therapy in CML-CP and -AP following failure of both imatinib and dasatinib therapy.

Evaluation of Bacillus anthracis and Yersinia pestis sample collection from nonporous surfaces by quantitative real-time PCR.

AIM: We will validate sample collection methods for recovery of microbial evidence in the event of accidental or intentional release of biological agents into the environment. METHODS AND RESULTS: We evaluated the sample recovery efficiencies of two collection methods - swabs and wipes - for both nonvirulent and virulent strains of Bacillus anthracis and Yersinia pestis from four types of nonporous surfaces: two hydrophilic surfaces, stainless steel and glass, and two hydrophobic surfaces, vinyl and plastic. Sample recovery was quantified using real-time qPCR to assay for intact DNA signatures. We found no consistent difference in collection efficiency between swabs or wipes. Furthermore, collection efficiency was more surface-dependent for virulent strains than nonvirulent strains. For the two nonvirulent strains, collection efficiency was similar between all four surfaces, albeit B. anthracis Sterne exhibited higher levels of recovery compared to Y. pestis A1122. In contrast, recovery of B. anthracis Ames spores and Y. pestis CO92 from the hydrophilic glass or stainless steel surfaces was generally more efficient compared to collection from the hydrophobic vinyl and plastic surfaces. CONCLUSIONS: Our results suggest that surface hydrophobicity may play a role in the strength of pathogen adhesion. The surface-dependent collection efficiencies observed with the virulent strains may arise from strain-specific expression of capsular material or other cell surface receptors that alter cell adhesion to specific surfaces. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings contribute to the validation of standard bioforensics procedures and emphasize the importance of specific strain and surface interactions in pathogen detection.

UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia.

Nilotinib is a novel BCR-ABL inhibitor with significantly improved potency and selectivity over imatinib. In Phase I and Phase II clinical studies of nilotinib in patients with a variety of leukemias, infrequent instances of reversible, benign elevation of bilirubin were observed. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) glucuronidates bilirubin in humans, and a polymorphism in the promoter of the gene that encodes it has been associated with hyperbilirubinemia during treatment with a number of drugs. Pharmacogenetic analysis of that TA-repeat polymorphism found an association between the (TA)7/(TA)7 genotype and risk of hyperbilirubinemia in Phase I patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL); this result was replicated in two separate analyses of the chronic phase (CP) and accelerated phase (AP) CML arms of a Phase II study. As nilotinib is not known to be glucuronidated by UGT1A1, the combined impact of inhibition of UGT1A1 activity by nilotinib and genetic polymorphism is the most likely cause of the increased rate of hyperbilirubinemia.

Isolation, molecular cloning and in vitro expression of rhesus monkey (Macaca mulatta) prominin-1.s1 complementary DNA encoding a potential hematopoietic stem cell antigen.

Human prominin-1 (CD133 or AC133) is an important cell surface marker used to isolate primitive hematopoietic stem cells. The commercially available antibody to human prominin-1 does not recognize rhesus prominin-1. Therefore, we isolated, cloned and characterized the complementary DNA (cDNA) of rhesus prominin-1 gene and determined its coding potential. Following the nomenclature of prominin family of genes, we named this cDNA as rhesus prominin-1.s1. The amino acid sequence data of the putative rhesus prominin-1.s1 could be used in designing antigenic peptides to raise antibodies for use in isolation of pure populations of rhesus prominin-1(+) hematopoietic cells. To the best of our knowledge, there has been no previously published report about the isolation of a prominin-1 cDNA from rhesus monkey (Macaca mulatta).

Preliminary look at why some vessels get atherosclerosis and others don't.

Atherosclerosis is a disease mainly of large, high pressure arteries and of valves, typically sparing veins and small, low pressure arteries. We investigate the resistances of the vena cava and the pulmonary artery to the flow of water and the infiltration of solutes into the vessel walls and compare them with similar processes in the aorta. The goal is to see if differences in macromolecular transport from the blood into the vessel wall amongst vessels can explain their different susceptibilities to atherosclerosis.

p38 Mitogen-activated protein kinase regulates Bax translocation in cyanide-induced apoptosis.

Execution of cyanide-induced apoptosis is mediated by release of cytochrome c from mitochondria. To determine how cyanide initiates cytochrome c release, Bax translocation was investigated in primary cultures of cortical neurons. Under nonapoptotic (control) conditions, Bax resided predominantly in the cytoplasm. After 300-microM cyanide treatment for 1 h, Bax translocated to the mitochondria, as shown by immunocytochemical staining and subcellular fractionation; Western blot analysis confirmed "cytosol-to-mitochondria" translocation of Bax. Temporal analysis showed that Bax translocation preceded cytochrome c release from the mitochondria, which was initiated 3 h after cyanide treatment. In double-immunofluorescence labeling for both Bax and cytochrome c, it was observed that cytochrome c was released only in cells showing Bax in mitochondria. The role of p38 mitogen-activated protein (MAP) kinase in Bax translocation was studied. The p38 MAP kinase was activated 30 min after cyanide, and its phosphorylation level of activity began to decrease 3 h later. SB203580, a p38 MAP kinase inhibitor, blocked translocation of Bax to mitochondria, whereas SB202474, a control peptide, had no effect on translocation. Inhibition of p38 MAP kinase by SB203580 blocked all downstream effects of Bax translocation, including cytochrome c release, caspase activation, and internucleosomal DNA fragmentation. These results demonstrated that Bax translocation is critical for cyanide-induced cytochrome c release and that p38 MAP kinase regulates Bax translocation from cytosol to mitochondria.

Oxidative stress and cyclooxygenase-2 induction mediate cyanide-induced apoptosis of cortical cells.

Cyanide (KCN)-induced generation of reactive oxygen species (ROS) involves cyclooxygenase-2 (COX-2)-mediated reactions in some neurons. The present study examines the extent to which COX isoforms are involved in KCN-induced apoptotic cell death processes of cultured cortical cells. After treatment with KCN (10-300 microM), COX-2 was expressed in a time- and concentration-dependent manner increasing markedly over a 4-h period. However, no significant changes were observed in COX-1 levels at any cyanide concentration. Correlated with COX-2 up-regulation, KCN induced a time-dependent apoptotic death. TUNEL staining showed that the COX-2 inhibitor NS-398 (30 microM) blocked KCN-induced apoptosis, whereas the selective COX-1 inhibitor valeryl salicylate did not affect the level of apoptotic cell death. Exposure of cells to KCN (300 microM) for 24 h resulted in DNA fragmentation, which was also reduced by NS-398. Prostaglandin E(2) (PGE(2)) accumulation in cell culture supernatants was increased by KCN and NS-398 blocked PGE(2) generation. PCR studies further confirmed that COX-2 expression was increased by KCN. Antioxidants phenyl-N-test-butylnitrone, superoxide dismutase, and catalase significantly inhibited KCN-induced COX-2 up-regulation and subsequent apoptosis. N(G)-nitro-L-arginine methylester an inhibitor of nitric oxide synthase, blocked KCN-induced PGE(2) production and apoptosis, but not COX-2 expression. Increased nitric oxide levels caused by cyanide may directly activate the COX-2 enzyme. These data show that cyanide treatment of cortical cells involves increased COX-2 expression, PGE(2) accumulation, and ROS generation, resulting in apoptotic cell death.

Phosphorylated tyrosine-containing proteins in primary lung cancer correlates with proliferation and prognosis.

To determine the usefulness of tyrosine phosphorylation in evaluating biological characteristics, we attempted to evaluate the relationship between the amount of phosphorylated tyrosine-containing proteins and clinicopathological factors, cell proliferation and outcome in non-small cell lung cancer. To evaluate phosphorylated tyrosine-containing proteins we used 96 surgically resected materials of non-small cell lung cancer and normal peripheral lung, while immunohistochemical evaluation was performed. Cell proliferating ability was evaluated using the labelling index of proliferating cell nuclear antigen-positive nuclear staining cells. There were statistically significant differences between the expression levels of phosphorylated tyrosine-containing proteins of normal and cancerous tissues (P<0.0001). Evaluations based on clinicopathological factors apart from histopathological differentiation, showed no statistically significant differences of phosphorylated tyrosine-containing proteins expression. However, phosphorylated tyrosine-containing proteins correlated with cell proliferation activity evaluated (P((Low, High))<0.0001; P((Low, Int)) <0.0001; P((Int, High))<0.0001). Furthermore, non-small cell lung cancer cases with high expression and intermediate expression of phosphorylated tyrosine-containing proteins had a significantly shorter disease-free postoperative survival than those with low expression of phosphorylated tyrosine-containing proteins using log-rank analysis (P((Low, Int)) <0.0028; P((Low, High))=0.0002). Furthermore, phosphorylated tyrosine-containing proteins expression level statistically contributed to disease-free survival in Cox's proportional hazard model. Therefore, phosphorylated tyrosine-containing proteins in non-small cell lung cancer tissues seem to reflect its biological malignancy, and this evaluation may be valuable for constructing the most appropriate therapeutic strategy.