Radiation therapy and concurrent plus adjuvant temsirolimus (CCI-779) versus chemoirradiation with temozolomide in newly diagnosed glioblastoma without methylation of the MGMT gene promoter.

Background: Preclinical data indicate activity of mammalian target of rapamycin inhibitors and synergistic activity together with radiotherapy in glioblastoma. The aim of this trial is to assess the therapeutic activity of temsirolimus (CCI-779), an intravenous mTOR inhibitor, in patients with newly diagnosed glioblastoma with unmethylated O6 methlyguanine-DNA-methlytransferase (MGMT)promoter. Methods: Patients (n=257) with newly diagnosed glioblastoma after open surgical biopsy or resection fulfilling basic eligibility criteria underwent a central MGMT promoter analysis using quantitative methylation specific PCR. Patients with glioblastoma harboring an unmethylated MGMT promoter (n=111) were randomized 1:1 between radiotherapy (60 Gy; 5 times 2 Gy per week) plus concomitant and six cycles of maintenance temozolomide or radiotherapy plus weekly temsirolimus at 25 mg flat dose to be continued until progression or undue toxicity. Primary endpoint was overall survival at 12 months (OS12). Sample size of the investigational treatment arm required 54 patients to assess adequacy of temsirolimus activity set at 80%. More than 38 patients alive at 12 months in the per protocol population was considered a positive signal. A control arm of 54 patients treated with the standard of care was implemented to evaluate the assumptions on OS12. Results: Between December 2009 and October 2012, 111 pts in 14 centers were randomized and treated. Median age was 55 and 58 years in the temsirolimus and standard arm, respectively. Most patients (95.5%) had a WHO performance status of 0 or 1. Both therapies were properly administered with a median of 13 cycles of maintenance temsirolimus. In the per protocolpopulation, exactly 38 patients treated with temsirolimus (out of 54 eligible) reached OS12. In the intention to treat population OS12 was 72.2% [95% CI (58.2, 82.2)] in the temozolomide arm and 69.6% [95% CI (55.8, 79.9) in the temsirolimus arm [HR=1.16 95% CI (0.77, 1.76), p=0.47]. Conclusions: The therapeutic activity of temsirolimus in patients with newly diagnosed glioblastoma with an unmethylated MGMT promoter is too low.

Ionizing radiation enhances immunogenicity of cells expressing a tumor-specific T-cell epitope.

BACKGROUND: p53 point mutations represent potential tumor-specific cytolytic T lymphocyte (CTL) epitopes. Whether ionizing radiation (IR) alters the immunological properties of cells expressing mutant p53 in respect of the CTL epitope generated by a defined point mutation has not been evaluated. METHODS: Mutant p53-expressing syngeneic, nontumor forming BALB/c 3T3 fibroblasts, tumor forming ras-transfected BALB/c 3T3 sarcomas, and DBA/2-derived P815 mastocytoma cells, which differ at the level of minor histocompatibility antigens, were used as cellular vaccines. Cells were either injected with or without prior IR into naive BALB/c mice. Cellular cytotoxicity was assessed after secondary restimulation of effector spleen cells in vitro. RESULTS: Injection of P815 mastocytoma cells expressing the mutant p53 induced mutation-specific CTL in BALB/c mice irrespective of prior irradiation. However, syngeneic fibroblasts or fibrosarcomas endogenously expressing mutant p53 were able to induce significant mutation-specific CTL only when irradiated prior to injection into BALB/c mice. IR of fibroblasts did not detectably alter the expression of cell surface molecules involved in immune response induction, nor did it alter the short-term in vitro viability of the fibroblasts. Interestingly, radioactively-labeled fibroblasts injected into mice after irradiation showed altered organ distribution, suggesting that the in vivo fate of these cells may play a crucial role in their immunogenicity. CONCLUSIONS: These findings indicate that IR can alter the immunogenicity of syngeneic normal as well as tumor forming fibroblasts in vivo, and support the view that ionizing radiation enhances immunogenicity of cellular tumor vaccines.

Feasibility and efficacy of accelerated weekly concomitant boost postoperative radiation therapy combined with concomitant chemotherapy in patients with locally advanced head and neck cancer.

BACKGROUND: The aim of this study was to assess feasibility and efficacy of weekly concomitant boost accelerated postoperative radiation therapy (PORT) with concomitant chemotherapy (CT) in patients with locally advanced head and neck cancer (LAHNC). METHODS AND MATERIALS: Conformal or intensity-modulated 66-Gy RT was performed in 5.5 weeks in 40 patients. Cisplatin was given at days 1, 22, and 43. Median follow-up was 36 months. RESULTS AND DISCUSSION: Grade 3 mucositis, dysphagia, and erythema was observed in ten (25%), nine (23%), and six (13%) patients, respectively. Grade 3 or more anemia was observed in two (6%) patients, and leukopenia in five (13%) patients. No grade 3 or 4 thrombocytopenia was observed. Grade 3 nephrotoxicity was observed in one patient (3%). No treatment-related mortality was observed. Grade 2 or more xerostomia and edema were observed in ten (25%) and one (3%) patient, respectively. Locoregional relapse occurred in eight patients, and seven patients developed distant metastases. Median time to locoregional relapse was 6 months. Three-year overall, disease-free survival, and locoregional control rates were 63%, 62%, and 81%, respectively. Multivariate analysis revealed that the only prognostic factor was nodal status. CONCLUSION: Reducing overall treatment time using accelerated PORT/CT by weekly concomitant boost (six fractions per week) combined with concomitant cisplatin CT is easily feasible with acceptable morbidity.

Water-filtered infrared-A radiation (wIRA) is not implicated in cellular degeneration of human skin.

BACKGROUND: Excessive exposure to solar ultraviolet radiation is involved in the complex biologic process of cutaneous aging. Wavelengths in the ultraviolet-A and -B range (UV-A and UV-B) have been shown to be responsible for the induction of proteases, e. g. the collagenase matrix metalloproteinase 1 (MMP-1), which are related to cell aging. As devices emitting longer wavelengths are widely used in therapeutic and cosmetic interventions and as the induction of MMP-1 by water-filtered infrared-A (wIRA) had been discussed, it was of interest to assess effects of wIRA on the cellular and molecular level known to be possibly involved in cutaneous degeneration. OBJECTIVES: Investigation of the biological implications of widely used water-filtered infrared-A (wIRA) radiators for clinical use on human skin fibroblasts assessed by MMP-1 gene expression (MMP-1 messenger ribonucleic acid (mRNA) expression).Methods: Human skin fibroblasts were irradiated with approximately 88% wIRA (780-1400 nm) and 12% red light (RL, 665-780 nm) with 380 mW/cm(2) wIRA(+RL) (333 mW/cm(2) wIRA) on the one hand and for comparison with UV-A (330-400 nm, mainly UV-A1) and a small amount of blue light (BL, 400-450 nm) with 28 mW/cm(2) UV-A(+BL) on the other hand. Survival curves were established by colony forming ability after single exposures between 15 minutes and 8 hours to wIRA(+RL) (340-10880 J/cm(2) wIRA(+RL), 300-9600 J/cm(2) wIRA) or 15-45 minutes to UV-A(+BL) (25-75 J/cm(2) UV-A(+BL)). Both conventional Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and quantitative real-time RT-PCR techniques were used to determine the induction of MMP-1 mRNA at two physiologic temperatures for skin fibroblasts (30 degrees C and 37 degrees C) in single exposure regimens (15-60 minutes wIRA(+RL), 340-1360 J/cm(2) wIRA(+RL), 300-1200 J/cm(2) wIRA; 30 minutes UV-A(+BL), 50 J/cm(2) UV-A(+BL)) and in addition at 30 degrees C in a repeated exposure protocol (up to 10 times 15 minutes wIRA(+RL) with 340 J/cm(2) wIRA(+RL), 300 J/cm(2) wIRA at each time). RESULTS: Single exposure of cultured human dermal fibroblasts to UV-A(+BL) radiation yielded a very high increase in MMP-1 mRNA expression (11 +/-1 fold expression for RT-PCR and 76 +/-2 fold expression for real-time RT-PCR both at 30 degrees C, 75 +/-1 fold expression for real-time RT-PCR at 37 degrees C) and a dose-dependent decrease in cell survival. In contrast, wIRA(+RL) did not produce cell death and did not induce a systematic increase in MMP-1 mRNA expression (less than twofold expression, within the laboratory range of fluctuation) detectable with the sensitive methods applied. Additionally, repeated exposure of human skin fibroblasts to wIRA(+RL) did not induce MMP-1 mRNA expression systematically (less than twofold expression by up to 10 consecutive wIRA(+RL) exposures and analysis with real-time RT-PCR). CONCLUSIONS: wIRA(+RL) even at the investigated disproportionally high irradiances does not induce cell death or a systematic increase of MMP-1 mRNA expression, both of which can be easily induced by UV-A radiation. Furthermore, these results support previous findings of in vivo investigations on collagenase induction by UV-A but not wIRA and show that infrared-A with appropriate irradiances does not seem to be involved in MMP-1 mediated photoaging of the skin. As suggested by previously published studies wIRA could even be implicated in a protective manner.

Forecasting the Earth"s radiation belts and modeling solar energetic particle events: Recent results from SPACECAST

High-energy charged particles in the van Allen radiation belts and in solar energetic particle events can damage satellites on orbit leading to malfunctions and loss of satellite service. Here we describe some recent results from the SPACECAST project on modelling and forecasting the radiation belts, and modelling solar energetic particle events. We describe the SPACECAST forecasting system that uses physical models that include wave-particle interactions to forecast the electron radiation belts up to 3 h ahead. We show that the forecasts were able to reproduce the >2 MeV electron flux at GOES 13 during the moderate storm of 7-8 October 2012, and the period following a fast solar wind stream on 25-26 October 2012 to within a factor of 5 or so. At lower energies of 10- a few 100 keV we show that the electron flux at geostationary orbit depends sensitively on the high-energy tail of the source distribution near 10 RE on the nightside of the Earth, and that the source is best represented by a kappa distribution. We present a new model of whistler mode chorus determined from multiple satellite measurements which shows that the effects of wave-particle interactions beyond geostationary orbit are likely to be very significant. We also present radial diffusion coefficients calculated from satellite data at geostationary orbit which vary with Kp by over four orders of magnitude. We describe a new automated method to determine the position at the shock that is magnetically connected to the Earth for modelling solar energetic particle events and which takes into account entropy, and predict the form of the mean free path in the foreshock, and particle injection efficiency at the shock from analytical theory which can be tested in simulations.

Forecasting the Earth"s radiation belts and modeling solar energetic particle events: Recent results from SPACECAST

High-energy charged particles in the van Allen radiation belts and in solar energetic particle events can damage satellites on orbit leading to malfunctions and loss of satellite service. Here we describe some recent results from the SPACECAST project on modelling and forecasting the radiation belts, and modelling solar energetic particle events. We describe the SPACECAST forecasting system that uses physical models that include wave-particle interactions to forecast the electron radiation belts up to 3 h ahead. We show that the forecasts were able to reproduce the >2 MeV electron flux at GOES 13 during the moderate storm of 7-8 October 2012, and the period following a fast solar wind stream on 25-26 October 2012 to within a factor of 5 or so. At lower energies of 10- a few 100 keV we show that the electron flux at geostationary orbit depends sensitively on the high-energy tail of the source distribution near 10 RE on the nightside of the Earth, and that the source is best represented by a kappa distribution. We present a new model of whistler mode chorus determined from multiple satellite measurements which shows that the effects of wave-particle interactions beyond geostationary orbit are likely to be very significant. We also present radial diffusion coefficients calculated from satellite data at geostationary orbit which vary with Kp by over four orders of magnitude. We describe a new automated method to determine the position at the shock that is magnetically connected to the Earth for modelling solar energetic particle events and which takes into account entropy, and predict the form of the mean free path in the foreshock, and particle injection efficiency at the shock from analytical theory which can be tested in simulations.

CO2-response function of radiation use efficiency in rice for climate change scenarios

The objective of this work was to evaluate a generalized response function to the atmospheric CO2 concentration [f(CO2)] by the radiation use efficiency (RUE) in rice. Experimental data on RUE at different CO2 concentrations were collected from rice trials performed in several locations around the world. RUE data were then normalized, so that all RUE at current CO2 concentration were equal to 1. The response function was obtained by fitting normalized RUE versus CO2 concentration to a Morgan-Mercer-Flodin (MMF) function, and by using Marquardt's method to estimate the model coefficients. Goodness of fit was measured by the standard deviation of the estimated coefficients, the coefficient of determination (R²), and the root mean square error (RMSE). The f(CO2) describes a nonlinear sigmoidal response of RUE in rice, in function of the atmospheric CO2 concentration, which has an ecophysiological background, and, therefore, renders a robust function that can be easily coupled to rice simulation models, besides covering the range of CO2 emissions for the next generation of climate scenarios for the 21st century.

Anatomical exposure patterns of skin to sunlight: relative contributions of direct, diffuse and reflected ultraviolet radiation

Summary Background  The dose-response between ultraviolet (UV) exposure patterns and skin cancer occurrence is not fully understood. Sun-protection messages often focus on acute exposure, implicitly assuming that direct UV radiation is the key contributor to the overall UV exposure. However, little is known about the relative contribution of the direct, diffuse and reflected radiation components. Objective  To investigate solar UV exposure patterns at different body sites with respect to the relative contribution of the direct, diffuse and reflected radiation. Methods  A three-dimensional numerical model was used to assess exposure doses for various body parts and exposure scenarios of a standing individual (static and dynamic postures). The model was fed with erythemally weighted ground irradiance data for the year 2009 in Payerne, Switzerland. A year-round daily exposure (08:00-17:00 h) without protection was assumed. Results  For most anatomical sites, mean daily doses were high (typically 6·2-14·6 standard erythemal doses) and exceeded the recommended exposure values. Direct exposure was important during specific periods (e.g. midday during summer), but contributed moderately to the annual dose, ranging from 15% to 24% for vertical and horizontal body parts, respectively. Diffuse irradiation explained about 80% of the cumulative annual exposure dose. Acute diffuse exposures were also observed during cloudy summer days. Conclusions  The importance of diffuse UV radiation should not be underestimated when advocating preventive measures. Messages focused on avoiding acute direct exposures may be of limited efficiency to prevent skin cancers associated with chronic exposure.

Phylogenetic analysis of plastid and nuclear DNA sequences reveals a rapid late Miocene radiation of the temperate bamboo tribe Arundinarieae (Poaceae, Bambusoideae)

Background: Arundinarieae are a large tribe of temperate woody bamboos for which phylogenetics are poorly understood because of limited taxon sampling and lack of informative characters. Aims: This study assessed phylogenetic relationships, origins and classification of Arundinarieae. Methods: DNA sequences (plastid trnL-F; nuclear ITS) were used for parsimony and Bayesian inference including 41 woody bamboo taxa. Divergence dates were estimated using a relaxed Bayesian clock. Results: Arundinarieae were monophyletic but their molecular divergence was low compared to the tropical Bambuseae. Ancestors of the Arundinarieae lineage were estimated to have diverged from the other bamboos 23 (15-30) million years ago (Mya). However, the Arundinarieae radiation occurred 10 (6-16) Mya compared to 18 (11-25) Mya for the tropical Bambuseae. Some groups could be defined within Arundinarieae, but they do not correspond to recognised subtribes such as Arundinariinae or Shibataeinae. Conclusions: Arundinarieae are a relatively ancient bambusoid lineage that underwent a rapid radiation in the late Miocene. The radiation coincides with the continental collision of the Indo-Australian and Eurasian Plates. Arundinarieae are distributed primarily in East Asia and the Himalayas to northern Southeast Asia. It is unknown whether they were present in Asia long before their radiation, but we believe recent dispersal is a more likely scenario. Keywords: Arundinarieae; Bambuseae; internal transcribed spacer (ITS); molecular clock; phylogenetics; radiation; temperate bamboos; Thamnocalaminae; trnL-F

Timeframe of speciation inferred from secondary contact zones in the European tree frog radiation (Hyla arborea group).

BACKGROUND: Hybridization between incipient species is expected to become progressively limited as their genetic divergence increases and reproductive isolation proceeds. Amphibian radiations and their secondary contact zones are useful models to infer the timeframes of speciation, but empirical data from natural systems remains extremely scarce. Here we follow this approach in the European radiation of tree frogs (Hyla arborea group). We investigated a natural hybrid zone between two lineages (Hyla arborea and Hyla orientalis) of Mio-Pliocene divergence (~5 My) for comparison with other hybrid systems from this group. RESULTS: We found concordant geographic distributions of nuclear and mitochondrial gene pools, and replicated narrow transitions (~30 km) across two independent transects, indicating an advanced state of reproductive isolation and potential local barriers to dispersal. This result parallels the situation between H. arborea and H. intermedia, which share the same amount of divergence with H. orientalis. In contrast, younger lineages show much stronger admixture at secondary contacts. CONCLUSIONS: Our findings corroborate the negative relationship between hybridizability and divergence time in European tree frogs, where 5 My are necessary to achieve almost complete reproductive isolation. Speciation seems to progress homogeneously in this radiation, and might thus be driven by gradual genome-wide changes rather than single speciation genes. However, the timescale differs greatly from that of other well-studied amphibians. General assumptions on the time necessary for speciation based on evidence from unrelated taxa may thus be unreliable. In contrast, comparative hybrid zone analyses within single radiations such as our case study are useful to appreciate the advance of speciation in space and time.

Collagen arrangement in hepatic granuloma in mice infected with Schistosoma mansoni: dependence on fiber radiation centers

The collagen structure of isolated and in situ liver granuloma from Swiss Webster mice infected with Schistosoma mansoni was sequentially and three-dimensionally analyzed during different times of infection (early acute, acute, transitional acute-chronic, and chronic phases) by laser scanning confocal microscopy and electron scanning variable vacuum microscopy. The initial granuloma structure is characterized by vascular collagen residues and by anchorage points (or fiber radiation centers), from where collagenous fibers are angularly shed and self-assembled. During the exudative-productive stage, the self-assembly of these fibers minimizes energy and mass through continuous tension and focal compression. The curvature or angles between collagen fibers probably depends on the fibroblastic or myofibroblastic organization of stress fibers. Gradually, the loose unstable lattice of the exudative-productive stage transforms into a highly packed and stable architecture as a result of progressive compactness. The three-dimensional architecture of granulomas provides increased tissue integrity, efficient distribution of soluble compounds and a haptotactic background to the cells.

Empirical evidence for a nonlinear effect of galactic cosmic rays on clouds

Galactic cosmic ray (GCR) changes have been suggested to affect weather and climate, and new evidence is presented here directly linking GCRs with clouds. Clouds increase the diffuse solar radiation, measured continuously at UK surface meteorological sites since 1947. The ratio of diffuse to total solar radiation-the diffuse fraction, (DF)-is used to infer cloud, and is compared with the daily mean neutron count rate measured at Climax; Colorado from 1951-2000, which provides a globally representative indicator of cosmic rays. Across the UK, oil days of high cosmic ray flux (above 3600 X 10(2) neutron counts h(-1), which occur 87% of the time on average) compared with low cosmic ray flux, (i) the chance of an overcast day increases by (19 +/- 4)%; and (ii) the diffuse fraction increases by (2 +/- 0.3)%. During sudden transient reductions in cosmic rays (e.g. Forbush events), simultaneous decreases occur in the diffuse fraction. The diffuse radiation changes are; therefore; unambiguously due to cosmic rays. Although the statistically significant nonlinear cosmic ray effect is small, it will have a considerably larger aggregate effect on longer timescale (e.g. centennial) climate variations when day-to-day variability averages out.

Galactic cosmic ray hazard in the unusual extended solar minimum between solar cycle 23 and 24

Galactic cosmic rays (GCRs) are extremely difficult to shield against and pose one of the most severe long-term hazards for human exploration of space. The recent solar minimum between solar cycles 23 and 24 shows a prolonged period of reduced solar activity and low interplanetary magnetic field strengths. As a result, the modulation of GCRs is very weak, and the fluxes of GCRs are near their highest levels in the last 25 years in the fall of 2009. Here we explore the dose rates of GCRs in the current prolonged solar minimum and make predictions for the Lunar Reconnaissance Orbiter (LRO) Cosmic Ray Telescope for the Effects of Radiation (CRaTER), which is now measuring GCRs in the lunar environment. Our results confirm the weak modulation of GCRs leading to the largest dose rates seen in the last 25 years over a prolonged period of little solar activity.

Rapid radiation in spiny lobsters (Palinurus spp) as revealed by classic and ABC methods using mtDNA and microsatellite data

Background: Molecular tools may help to uncover closely related and still diverging species from a wide variety of taxa and provide insight into the mechanisms, pace and geography of marine speciation. There is a certain controversy on the phylogeography and speciation modes of species-groups with an Eastern Atlantic-Western Indian Ocean distribution, with previous studies suggesting that older events (Miocene) and/or more recent (Pleistocene) oceanographic processes could have influenced the phylogeny of marine taxa. The spiny lobster genus Palinurus allows for testing among speciation hypotheses, since it has a particular distribution with two groups of three species each in the Northeastern Atlantic (P. elephas, P. mauritanicus and P. charlestoni) and Southeastern Atlantic and Southwestern Indian Oceans (P. gilchristi, P. delagoae and P. barbarae). In the present study, we obtain a more complete understanding of the phylogenetic relationships among these species through a combined dataset with both nuclear and mitochondrial markers, by testing alternative hypotheses on both the mutation rate and tree topology under the recently developed approximate Bayesian computation (ABC) methods. Results: Our analyses support a North-to-South speciation pattern in Palinurus with all the South-African species forming a monophyletic clade nested within the Northern Hemisphere species. Coalescent-based ABC methods allowed us to reject the previously proposed hypothesis of a Middle Miocene speciation event related with the closure of the Tethyan Seaway. Instead, divergence times obtained for Palinurus species using the combined mtDNA-microsatellite dataset and standard mutation rates for mtDNA agree with known glaciation-related processes occurring during the last 2 my. Conclusion: The Palinurus speciation pattern is a typical example of a series of rapid speciation events occurring within a group, with very short branches separating different species. Our results support the hypothesis that recent climate change-related oceanographic processes have influenced the phylogeny of marine taxa, with most Palinurus species originating during the last two million years. The present study highlights the value of new coalescent-based statistical methods such as ABC for testing different speciation hypotheses using molecular data.

Solar ultraviolet-B radiation and vitamin D: a cross-sectional population-based study using data from the 2007 to 2009 Canadian Health Measures Survey

Background: Exposure to solar ultraviolet-B (UV-B) radiation is a major source of vitamin D3. Chemistry climate models project decreases in ground-level solar erythemal UV over the current century. It is unclear what impact this will have on vitamin D status at the population level. The purpose of this study was to measure the association between ground-level solar UV-B and serum concentrations of 25-hydroxyvitamin D (25(OH)D) using a secondary analysis of the 2007 to 2009 Canadian Health Measures Survey (CHMS). Methods: Blood samples collected from individuals aged 12 to 79 years sampled across Canada were analyzed for 25(OH)D (n=4,398). Solar UV-B irradiance was calculated for the 15 CHMS collection sites using the Tropospheric Ultraviolet and Visible Radiation Model. Multivariable linear regression was used to evaluate the association between 25(OH)D and solar UV-B adjusted for other predictors and to explore effect modification. Results: Cumulative solar UV-B irradiance averaged over 91 days (91-day UV-B) prior to blood draw correlated significantly with 25(OH)D. Independent of other predictors, a 1 kJ/m 2 increase in 91-day UV-B was associated with a significant 0.5 nmol/L (95% CI 0.3-0.8) increase in mean 25(OH)D (P =0.0001). The relationship was stronger among younger individuals and those spending more time outdoors. Based on current projections of decreases in ground-level solar UV-B, we predict less than a 1 nmol/L decrease in mean 25(OH)D for the population. Conclusions: In Canada, cumulative exposure to ambient solar UV-B has a small but significant association with 25(OH)D concentrations. Public health messages to improve vitamin D status should target safe sun exposure with sunscreen use, and also enhanced dietary and supplemental intake and maintenance of a healthy body weight.