Because of its antitumor effect, the immunosuppressant rapamycin holds great promise for organ transplant recipients in that it may lower their cancer risk. In a mouse model, we showed previously ...that rapamycin inhibits the outgrowth of primary skin carcinomas induced by UV radiation. However, the tumors that did grow out showed an altered p53 mutation spectrum. Here, we investigated whether this shift in p53 mutations already occurred in the smallest tumors, which were not affected in onset. We found that rapamycin did not alter the mutational spectrum in small tumors and in preceding microscopic clusters of cells expressing mutant‐p53. However, rapamycin did reduce the number of these cell clusters. As this reduction did not affect tumor onset, we subsequently investigated whether rapamycin merely suppressed expression of mutated p53. This was not the case, as we could demonstrate that switching from a diet with rapamycin to one without, or vice versa, did not affect the number of existing mutant‐p53 expressing cell clusters. Hence, rapamycin actually reduced the formation of mutant‐p53 cell clusters. In wild‐type and p53‐mutant mice, we could not measure a significant enhancement of UV‐induced apoptosis, but we did observe clear enhancement in human skin equivalents. This was associated with a clear suppression of HIF1α accumulation. Thus, we conclude that rapamycin reduces the formation of mutant‐p53‐expressing cell clusters without affecting tumor onset, suggesting that tumors grow out of a minor subset of cell clusters, the formation of which is not affected by rapamycin.
Increased skin cancer risk in organ transplant recipients has been experimentally emulated with enhanced UV carcinogenesis from administering conventional immunosuppressants. However, newer ...generation immunosuppressive drugs, rapamycin (Rapa) and mycophenolate mofetil (MMF), have been shown to impair angiogenesis and outgrowth of tumor implants. To ascertain the overall effect on UV carcinogenesis, Rapa and MMF were admixed into the food pellets of hairless SKH1 mice receiving daily sub‐sunburn UV dosages. With immunosuppressive blood levels neither of the drugs affected onset of tumors (<2 mm), but in contrast to MMF, Rapa significantly increased latency of large tumors (≥4 mm, medians of 190 vs 125 days) and reduced their multiplicity (1.6 vs 4.5 tumors per mouse at 200 days). Interestingly, tumors (>2 mm) from the Rapa‐fed group showed a reduction in UV‐signature p53 mutations (39% vs 90%) in favor of mutations from putative base oxidation. This shift in mutation spectrum was not essentially linked to the reduction in large tumors because it was absent in large tumors similarly reduced in number when feeding Rapa in combination with MMF, possibly owing to an antioxidant effect of MMF. Significantly fewer tumor cells were Vegf‐positive in the Rapa‐fed groups, but a correspondingly reduced expression of Hif1α target genes (Vegf, Ldha, Glut1, Pdk1) that would indicate altered glucose metabolism with increased oxidative stress was not found. Remarkably, we observed no effect of the immunosuppressants on UV‐induced tumor onset, and with impaired tumor outgrowth Rapa could therefore strongly reduce skin carcinoma morbidity and mortality rates in organ transplant recipients.
We present nuclear reaction network calculations to investigate the influence of nuclear structure on the rp-process between Ge and Sn in various scenarios. Due to the lack of experimental data for ...neutron-deficient nuclei in this region, we discuss currently available model predictions for nuclear masses and deformations as well as methods of calculating reaction rates (Hauser-Feshbach) and β-decay rates (QRPA and shell model). In addition, we apply a valence nucleon (
N
p
N
n) correlation scheme for the prediction of masses and deformations. We also describe the calculations of 2p-capture reactions, which had not been considered before in this mass region. We find that in X-ray bursts 2p-capture reactions accelerate the reaction flow into the
Z ≥ 36 region considerably. Therefore, the rp-process in most X-ray bursts does not end in the
Z = 32–36 region as previously assumed and overproduction factors of 10
7–10
8 are reached for some light p-nuclei in the
A = 80–100 region. This might be of interest in respect of the yet unexplained large observed solar system abundances of these nuclei. Nuclei in this region can also be produced via the rp-proces in accretion disks around low mass black holes. Our results indicate that the rp-process energy production in the
Z > 32 region cannot be neglected in these scenarios. We discuss in detail the influence of the various nuclear structure input parameters and their current uncertainties on these results. It turns out that rp-process nucleosynthesis is mainly determined by nuclear masses and β-decay rates of nuclei along the proton drip line. We present a detailed list of nuclei for which mass or β-decay rate measurements would be crucial to further constrain the models.
Chronic ultraviolet (UV) exposure induces clones of cells overexpressing mutant p53 in the interfollicular (IF) epidermis and subsequently squamous cell carcinomas (SCCs) with similar p53 mutations. ...Mutated p53 may give cells growth advantage over neighbouring cells by impaired apoptosis. We tested this by UV overexposure of skin laden with p53-mutant clones and assessed the impact on subsequent tumour development. P53-mutant clones were induced in two groups of hairless SKH1 mice by daily exposures (500 J/m(2) UV from TL12 lamps) for 28 days. On day 29, one group was overexposed (to 10 kJ/m(2) UV), whereas the control group received the regular daily dose. After 1 week of recovery, the daily exposures were resumed in both groups to induce SCCs. UV overexposure forced the entire IF basal layer into caspase-3-driven apoptosis while leaving overlying layers with sunburn cells intact. No apparent regions were spared from apoptosis. Pulse-chase BrdU labelling showed the IF epidermis to be repopulated from the hair follicles (remaining p63 positive). One week after overexposure, the p53-mutant clones had virtually disappeared (0.6, 95% confidence interval 0.5-0.8 per mouse versus 102, 59-179, without overexposure). Tumour development was significantly delayed after UV overexposure (P < 0.0001) by an average of 27 days (standard error of the mean 3); a period matching that of daily exposures preceding the overexposure. Thus, we found that UV-induced ablation of the IF epidermal basal layer eliminates p53-mutant clones and resets UV carcinogenesis. Furthermore, and in contrast with earlier reports, our data show that UV-induced p53-mutant clones and SCCs originate from the IF epidermis.
The reconstruction of Extensive Air Showers (EAS) observed by particle detectors at the ground is based on the characteristics of observables like the lateral particle density and the arrival times. ...The lateral densities, inferred for different EAS components from detector data, are usually parameterised by applying various lateral distribution functions (LDFs). The LDFs are used in turn for evaluating quantities like the total number of particles or the density at particular radial distances. Typical expressions for LDFs anticipate azimuthal symmetry of the density around the shower axis. The deviations of the lateral particle density from this assumption arising from various reasons are smoothed out in the case of compact arrays like KASCADE, but not in the case of arrays like Grande, which only sample a smaller part of the azimuthal variation.
KASCADE-Grande, an extension of the former KASCADE experiment, is a multi-component Extensive Air Shower (EAS) experiment located at the Karlsruhe Institute of Technology (Campus North), Germany. The lateral distributions of charged particles are deduced from the basic information provided by the Grande scintillators – the energy deposits – first in the observation plane, then in the intrinsic shower plane. In all steps azimuthal dependences should be taken into account. As the energy deposit in the scintillators is dependent on the angles of incidence of the particles, azimuthal dependences are already involved in the first step: the conversion from the energy deposits to the charged particle density. This is done by using the Lateral Energy Correction Function (LECF) that evaluates the mean energy deposited by a charged particle taking into account the contribution of other particles (e.g. photons) to the energy deposit. By using a very fast procedure for the evaluation of the energy deposited by various particles we prepared realistic LECFs depending on the angle of incidence of the shower and on the radial and azimuthal coordinates of the location of the detector. Mapping the lateral density from the observation plane onto the intrinsic shower plane does not remove the azimuthal dependences arising from geometric and attenuation effects, in particular for inclined showers. Realistic procedures for applying correction factors are developed. Specific examples of the bias due to neglecting the azimuthal asymmetries in the conversion from the energy deposit in the Grande detectors to the lateral density of charged particles in the intrinsic shower plane are given.
Lateral distributions for electrons and muons in extensive air showers measured with the array of the KASCADE experiment are compared to results of simulations based on the high-energy hadronic ...interaction models QGSJet and SIBYLL. It is shown, that the muon distributions are well described by both models. Deviations are found for the electromagnetic component, where both models predict a steeper lateral shape than observed in the data. For both models the observed lateral shapes of the electron component indicate a transition from a light to a more heavy composition of the cosmic ray spectrum above the knee.
Radio emission from particle showers can be used as a method of neutrino detection in the high and very high energy range as a Cherenkov pulse originates from the charge excess developing in the ...medium. Our study presents simulations of neutrino induced showers in rock salt and the radio emission that they generate, using the HERWIG, GEANT4 and AIRES codes. We have performed a complete study of all neutrino flavours interacting on nuclei, both for charged-current and neutral-current interactions, using the knowledge and codes available today. As primary neutrino energies we have chosen three values: 1012eV, 1015eV and 1017eV. We have injected all the particles resulting from the first interactions into shower simulation codes.
Salt is one of the dielectric media proposed for radio detection of neutrinos already in the sixties of last century, and can be found in large volumes throughout the world.
The calculation of the radio signal was performed considering the entire shower evolution, by approximating the shower with a current density. We have taken into account, in the equations, only the longitudinal profile. The aim of this study is to investigate whether different interactions can be discriminated in an experiment for detection of high energy particles based on the radio emission from the showers they initiate in a dense medium. For this we have performed and systematically analyzed simulations from several points of view.
▪ Abstract The Coulomb dissociation process, induced by the intense source of quasi-real photons acting as nuclear particles pass through the field of a heavy nucleus, has attracted a great deal of ...attention. As a specific application, and as a means of access to the time-reversed radiative-capture reactions, which are of astrophysical interest at stellar energies, this process provides several advantages, based on larger cross sections and on the flexibilities of the breakup kinematics. Difficulties in the analysis arise from possible interference by nuclear interactions and final-state effects through multiphoton exchange (postacceleration), which need careful consideration. A number of theoretical and experimental investigations that have been performed, since the introduction of this novel approach have provided interesting new information, resulting in an improved and detailed understanding of the experimental conditions, and of the theoretical basis of the method. The progress in experiment and theory is reviewed, and various cases of actual interest and current applications are discussed.
High levels of the p53 protein are immunohistochemically detectable in a majority of human nonmelanoma skin cancers and UVB-induced murine skin tumors. These increased protein levels are often ...associated with mutations in the conserved domains of the p53 gene. To investigate the timing of the p53 alterations in the process of UVB carcinogenesis, we used a well defined murine model (SKH:HR1 hairless mice) in which the time that tumors appear is predictable from the UVB exposures. The mice were subjected to a series of daily UVB exposures, either for 17 days or for 30 days, which would cause skin tumors to appear around 80 or 30 weeks, respectively. In the epidermis of these mice, we detected clusters of cells showing a strong immunostaining of the p53 protein, as measured with the CM-5 polyclonal antiserum. This cannot be explained by transient accumulation of the normal p53 protein as a physiological response to UVB-induced DNA damage. In single exposure experiments the observed transient CM-5 immunoreactivity lasted for only 3 days and was not clustered, whereas these clusters were still detectable as long as 56 days after 17 days of UVB exposure. In addition, ≈ 70% of these patches reacted with the mutant-specific monoclonal antibody PAb240, whereas transiently induced p53-positive cells did not. In line with indicative human data, these experimental results in the hairless mouse model unambiguously demonstrate that constitutive p53 alterations are causally related to chronic UVB exposure and that they are a very early event in the induction of skin cancer by UVB radiation.
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