4HPR-X radiation mechanisms of interactions in non-small cell lung cancer (NSCLC) cells in vitro

Lung cancer is the leading cause of cancer death. However, poor survival using conventional therapies fuel the search for more rational interventions. The objective of this study was to design and implement a 4HPR-radiation interaction model in NSCLC, employing a traditional clinical modality (radiation), a relatively new, therapeutically unexplored agent (4HPR) and rationally combining them based on molecular mechanistic findings pertaining to their interactions. To test the hypothesis that 4HPR sensitizes cells to radiation-induced cell death via G2+M accumulation, we designed a working model consisting of H522 adenocarcinoma cells (p53, K-ras mutated) derived from an NSCLC patient; 4HPR at concentrations up to 10 μM; and X radiation up to 6 Gy generated by a patient-dedicated Phillips RT-250 X ray unit at 250 KV, 15 mA, 1.85 Gy/min. We found that 4HPR produced time- and dose-dependent morphological changes, growth inhibition, and DNA damage-inducing enhancement of reactive oxygen species. A transient G2+M accumulation of cells maximal at 24 h of continuous 4HPR exposure was used for irradiation time scheduling. Our data demonstrated enhanced cell death (both apoptotic and necrotic) in irradiated cells pre-treated with 4HPR versus those with either stressor alone. 4HPR's effect of increased NSCLC cells' radioresponse was confirmed by clonogenic assay. To explore these practical findings from a molecular mechanistic perspective, we further investigated and showed that levels of cyclin B1 and p34cdc2 kinase—both components of the mitosis promoting factor (MPF) regulating the G2/M transition—did not change following 4HPR treatment. Likewise, cdc25C phosphatase was not altered. However, enhanced p34cdc2 phosphorylation on its Thr14Tyr15 residues—indicative of its inactivation and increased expression of MPF negative regulators chk1 and wee1 kinases—were supportive of explaining 4HPR-treated cells' accumulation. Hence, p34cdc2 phosphorylation, chk1, and wee1 warrant further evaluation as potential molecular targets for 4HPR-X radiation combination. In summary, we (1) demonstrated that 4HPR not only induces cell death by itself, but also increases NSCLC cells' subsequent radioresponse, indicative of potential clinical applicability, and (2) for the first time, shed light on deciphering 4HPR-X radiation molecular mechanisms of interaction, including the finding of 4HPR's role as a p34cdc2 inactivator via Thr14Tyr15 phosphorylation. ^

A three-dimensional analytical solution of the microheater temperature before bubble nucleation

A three-dimensional analytical solution of the microheater temperature based on heat diffusion equation is developed and compared with experimental results. Dimensionless parameters are introduced to analyze the temperature rise time and the distribution under steady state. To study the microheater temperatures before bubble nucleation, a set of working fluids and microheaters are considered. It is shown that the dimensionless time xi(-)(0) required for the temperature rise from room to 95% of the steady state temperature is about 75, not dependent on working fluids and microheaters. Heat transfer to the surrounding liquid is mainly caused by conduction, not by convection and radiation mechanisms. The microheater length affects the surface temperature uniformity, while its width influences the steady temperatures significantly, yielding the transition from heterogeneous to homogeneous nucleation mechanism from square microheaters to narrow line microheaters. 

COMPUTATION OF SYNTHETIC SPECTRA FROM SIMULATIONS OF RELATIVISTIC SHOCKS

Particle-in-cell (PIC) simulations of relativistic shocks are in principle capable of predicting the spectra of photons that are radiated incoherently by the accelerated particles. The most direct method evaluates the spectrum using the fields given by the Lienard-Wiechart potentials. However, for relativistic particles this procedure is computationally expensive. Here we present an alternative method that uses the concept of the photon formation length. The algorithm is suitable for evaluating spectra both from particles moving in a specific realization of a turbulent electromagnetic field or from trajectories given as a finite, discrete time series by a PIC simulation. The main advantage of the method is that it identifies the intrinsic spectral features and filters out those that are artifacts of the limited time resolution and finite duration of input trajectories.

RADIATIVE SIGNATURES OF RELATIVISTIC SHOCKS

Particle-in-cell simulations of relativistic, weakly magnetized collisionless shocks show that particles can gain energy by repeatedly crossing the shock front. This requires scattering off self-generated small length-scale magnetic fluctuations. The radiative signature of this first-order Fermi acceleration mechanism is important for models of both the prompt and afterglow emission in gamma-ray bursts and depends on the strength parameter a = lambda e/delta B/mc(2) of the fluctuations (lambda is the length scale and vertical bar delta B vertical bar is the magnitude of the fluctuations). For electrons (and positrons), acceleration saturates when the radiative losses produced by the scattering cannot be compensated by the energy gained on crossing the shock. We show that this sets an upper limit on both the electron Lorentz factor gamma <10(6) (n/1 cm(-3))(-1/6)(-1/6) and on the energy of the photons radiated during the scattering process h omega(max) <40Max(a, 1)(n/1 cm(-3))(1/6)(-1/6) eV, where n is the number density of the plasma and (gamma) over bar is the thermal Lorentz factor of the downstream plasma, provided a <a(crit) similar to 10(6). This rules out "jitter" radiation on self-excited fluctuations with a <I as a source of gamma rays, although high-energy photons might still be produced when the jitter photons are upscattered in an analog of the synchrotron self-Compton process. In fluctuations with a > 1, radiation is generated by the standard synchrotron mechanism, and the maximum photon energy rises linearly with a, until saturating at 70 MeV, when a = a(crit).

LINEAR ACCELERATION EMISSION IN PULSAR MAGNETOSPHERES

Linear acceleration emission occurs when a charged particle is accelerated parallel to its velocity. We evaluate the spectral and angular distribution of this radiation for several special cases, including constant acceleration (hyperbolic motion) of finite duration. Based on these results, we find the following general properties of the emission from an electron in a linear accelerator that can be characterized by an electric field E acting over a distance L: (1) the spectrum extends to a cutoff frequency (h) over bar omega(c)/mc(2) approximate to L(E/E(Schw))(2)/(lambda) over bar (C), where E(Schw) = 1.3 x 10(18) V m(-1) is the Schwinger critical field and (lambda) over bar (C) = (h) over bar /mc = 3.86 x 10(-13) m is the Compton wavelength of the electron, (2) the total energy emitted by a particle traversing the accelerator is 4/3 alpha(f)(h) over bar omega(c) in accordance with the standard Larmor formula where alpha(f) is the fine-structure constant, and (3) the low frequency spectrum is flat for hyperbolic trajectories, but in general depends on the details of the accelerator. We also show that linear acceleration emission complements curvature radiation in the strongly magnetized pair formation regions in pulsar magnetospheres. It dominates when the length L of the accelerator is less than the formation length rho/gamma of curvature photons, where rho is the radius of curvature of the magnetic field lines and gamma the Lorentz factor of the emitting particle. In standard static models of pair creating regions linear acceleration emission is negligible, but it is important in more realistic dynamical models in which the accelerating field fluctuates on a short length scale.

ON THE DOUBLE NATURED SOLUTIONS OF THE TWO-TEMPERATURE EXTERNAL SOFT PHOTON COMPTONIZED ACCRETION DISKS

We have analyzed pair production in the innermost region of a two-temperature external soft photon Comptonized accretion disk. We have shown that, if the viscosity parameter is greater than a critical value alpha(c), the solution to the disk equation is double valued: one, advection dominated, and the other, radiation dominated. When alpha <= alpha(c), the accretion rate has to satisfy (m) over dot(1) <= (m) over dot <= (m) over dot(c) in order to have two steady-state solutions. It is shown that these critical parameters (m) over dot(1), (m) over dot(c) are functions of r, alpha, and theta(e), and alpha(c) is a function of r and theta(e). Depending on the combination of the parameters, the advection-dominated solution may not be physically consistent. It is also shown that the electronic temperature is maximum at the onset of the thermal instability, from which results this inner region. These solutions are stable against perturbations in the electron temperature and in the density of pairs.

Bayesian analysis of weak gravitational lensing and Sunyaev-Zel'dovich data for six galaxy clusters

We present an analysis of observations made with the Arcminute Microkelvin Imager (AMI) and the CanadaFranceHawaii Telescope (CFHT) of six galaxy clusters in a redshift range of 0.160.41. The cluster gas is modelled using the SunyaevZeldovich (SZ) data provided by AMI, while the total mass is modelled using the lensing data from the CFHT. In this paper, we (i) find very good agreement between SZ measurements (assuming large-scale virialization and a gas-fraction prior) and lensing measurements of the total cluster masses out to r200; (ii) perform the first multiple-component weak-lensing analysis of A115; (iii) confirm the unusual separation between the gas and mass components in A1914 and (iv) jointly analyse the SZ and lensing data for the relaxed cluster A611, confirming our use of a simulation-derived masstemperature relation for parametrizing measurements of the SZ effect.

Ionization in atmospheres of brown dwarfs and extrasolar planets. V. Alfvén Ionization

Observations of continuous radio and sporadic X-ray emission from low-mass objects suggest they harbor localized plasmas in their atmospheric environments. For low-mass objects, the degree of thermal ionization is insufficient to qualify the ionized component as a plasma, posing the question: what ionization processes can efficiently produce the required plasma that is the source of the radiation? We propose Alfv´en ionization as a mechanism for producing localized pockets of ionized gas in the atmosphere, having sufficient degrees of ionization ( 10−7) that they constitute plasmas. We outline the criteria required for Alfv´en ionization and demonstrate its applicability in the atmospheres of low-mass objects such as giant gas planets, brown dwarfs, and M dwarfs with both solar and sub-solar metallicities. We find that Alfv´en ionization is most efficient at mid to low atmospheric pressures where a seed plasma is easier to magnetize and the pressure gradients needed to drive the required neutral flows are the smallest. For the model atmospheres considered, our results show that degrees of ionization of 10−6–1 can be obtained as a result of Alfv´en ionization. Observable consequences include continuum bremsstrahlung emission, superimposed with spectral lines from the plasma ion species (e.g., He, Mg, H2, or CO lines). Forbidden lines are also expected from the metastable population. The presence of an atmospheric plasma opens the door to a multitude of plasma and chemical processes not yet considered in current atmospheric models. The occurrence of Alfv´en ionization may also be applicable to other astrophysical environments such as protoplanetary disks.

Temperature-averaged and total free-free Gaunt factors for κ and Maxwellian distributions of electrons

Aims. Optically thin plasmas may deviate from thermal equilibrium and thus, electrons (and ions) are no longer described by the Maxwellian distribution. Instead they can be described by κ-distributions. The free-free spectrum and radiative losses depend on the temperature-averaged (over the electrons distribution) and total Gaunt factors, respectively. Thus, there is a need to calculate and make available these factors to be used by any software that deals with plasma emission. Methods. We recalculated the free-free Gaunt factor for a wide range of energies and frequencies using hypergeometric functions of complex arguments and the Clenshaw recurrence formula technique combined with approximations whenever the difference between the initial and final electron energies is smaller than 10−10 in units of z2Ry. We used double and quadruple precisions. The temperature- averaged and total Gaunt factors calculations make use of the Gauss-Laguerre integration with 128 nodes. Results. The temperature-averaged and total Gaunt factors depend on the κ parameter, which shows increasing deviations (with respect to the results obtained with the use of the Maxwellian distribution) with decreasing κ. Tables of these Gaunt factors are provided.

potential mechanisms involved in resistant phenotype of MCF-7breast carcinoma cells to ionizing radiation induced apoptosis

In the present study, we investigated the mechanisms of apoptosis resistance and the roles of the phosphorylation of BRCA1, p21, the Bax/Bcl-2 protein ratio and cell cycle arrest in IR-induced apoptosis in MCF-7 cells. X-irradiation, in particular at low dose (1 Gy), but not carbon ion irradiation, had a significant antiproliferative effect on the growth of MCF-7 cells. 1 Gy X-irradiation resulted in G1 and G2 phase arrest, but 4 Gy induced a significant G1 block. In contrast, carbon ion irradiation resulted in a significant accumulation in the G2 phase. Concomitant with the phosphorylation of H2AX induced by DNA damage,carbon ion irradiation resulted in an approximately 1.9–2.8-fold increase in the phosphorylation of BRCA1 on serine residue 1524, significantly greater than that detected for X-irradiation. Carbon ion irradiation caused a dramatic increase in p21 expression and drastic decrease in Bax expression compared with X-irradiation. The data implicated that phosphorylation of BRCA1 on serine residue 1524 might,at least partially, induce p21 expression but repress Bax expression. Together, our results suggested that the phosphorylation of BRCA1 at Ser-1524 might contribute to the G2 phase arrest and might be an upstream signal involved in preventing apoptosis signal via upregulation of p21 and downregulation of the Bax/Bcl-2 ratio.

Survivin表达在高LET射线诱导细胞凋亡中作用机理的初步研究；A Preliminary Study on Action Mechanisms of Survivin Expression in Cell Apoptosis Induced by High-LET Radiation

先前的研究表明,肿瘤细胞中survivin的高表达与细胞对高传能线密度(LET)射线的辐射抗性相关。研究了survivin表达在高LET射线诱导的细胞凋亡中的作用,发现抑制survivin表达对高LETC离子辐射诱导的Bcl-2和Bax表达没有明显的影响。在高LET射线辐照中,survivin可能通过抑制caspase-3和-9活性的途径,抑制了细胞凋亡。