Improving on whole-brain radiotherapy in patients with large brain metastases: a planning study to support the AROMA clinical trial

PURPOSE: To develop a novel dose-escalated volumetric modulated arc therapy (VMAT) strategy for patients with single or multiple large brain metastases which can deliver a higher dose to individual lesions for better local control (LC), and to compare dosimetry between whole brain radiotherapy (WBRT), hippocampal-sparing whole brain radiotherapy (HS-WBRT) and different VMAT-based focal radiotherapy approaches. METHODS AND MATERIALS: We identified 20 patients with one to ten brain metastases and at least one lesion larger than 15 cm3 who had received WBRT as part of routine care. For each patient, we designed and evaluated five radiotherapy treatment plans, including WBRT, HS-WBRT and three VMAT dosing models. A dose of 20 Gy in 5 fractions was prescribed to the whole brain or target volumes depending on the plan, with higher doses to smaller lesions and dose-escalated inner planning target volumes (DE-iPTV) in VMAT plans, respectively. Treatment plans were evaluated using the efficiency index, mean dose and D0.1cc to the target volumes and organs at risk. RESULTS: Compared with WBRT, VMAT plans achieved a significantly more efficient dose distribution in brain lesions, especially with our DE-iPTV model, while minimising the dose to the normal brain and other organs at risks (OARs) (p < 0.05). CONCLUSIONS: VMAT plans obtained higher doses to brain metastases and minimised doses to OARs. Dose-escalated VMAT for larger lesions allows higher radiotherapy doses to be delivered to larger lesions while maintaining safe doses to OARs

Promoting Physical Activity with Hard-to-Reach Women: An Iterative and Participatory Research Study

Approximately half of all UK women are insufficiently physically active, with the lowest activity rates among ‘Hard-to-Reach’ or unreached women. In this article, Kathryn Brook, Dr Andy Pringle FRSPH, Dr Jackie Hargreaves and Dr Nicky Kime of Leeds Beckett University outline their research into developing methods to assess and meet the needs of ‘Hard-to-Reach’ women in needs-led and person-centred interventions

Human Cytomegalovirus Impairs the Function of Plasmacytoid Dendritic Cells in Lymphoid Organs

Human dendritic cells (DCs) are the main antigen presenting cells (APC) and can be divided into two main populations, myeloid and plasmacytoid DCs (pDCs), the latter being the main producers of Type I Interferon. The vast majority of pDCs can be found in lymphoid organs, where the main pool of all immune cells is located, but a minority of pDCs also circulate in peripheral blood. Human cytomegalovirus (HCMV) employs multiple mechanisms to evade the immune system. In this study, we could show that pDCs obtained from lymphoid organs (tonsils) (tpDCs) and from blood (bpDCs) are different subpopulations in humans. Interestingly, these populations react in opposite manner to HCMV-infection. TpDCs were fully permissive for HCMV. Their IFN-α production and the expression of costimulatory and adhesion molecules were altered after infection. In contrast, in bpDCs HCMV replication was abrogated and the cells were activated with increased IFN-α production and upregulation of MHC class I, costimulatory, and adhesion molecules. HCMV-infection of both, tpDCs and bpDCs, led to a decreased T cell stimulation, probably mediated through a soluble factor produced by HCMV-infected pDCs. We propose that the HCMV-mediated impairment of tpDCs is a newly discovered mechanism selectively targeting the host's major population of pDCs residing in lymphoid organs

The Chromatin Remodeling Factor SMARCB1 Forms a Complex with Human Cytomegalovirus Proteins UL114 and UL44

Background: Human cytomegalovirus (HCMV) uracil DNA glycosylase, UL114, is required for efficient viral DNA replication. Presumably, UL114 functions as a structural partner to other factors of the DNA-replication machinery and not as a DNA repair protein. UL114 binds UL44 (HCMV processivity factor) and UL54 (HCMV-DNA-polymerase). In the present study we have searched for cellular partners of UL114. Methodology/Principal Findings: In a yeast two-hybrid screen SMARCB1, a factor of the SWI/SNF chromatin remodeling complex, was found to be an interacting partner of UL114. This interaction was confirmed in vitro by coimmunoprecipitation and pull-down. Immunofluorescence microscopy revealed that SMARCB1 along with BRG-1, BAF170 and BAF155, which are the core SWI/SNF components required for efficient chromatin remodeling, were present in virus replication foci 24–48 hours post infection (hpi). Furthermore a direct interaction was also demonstrated for SMARCB1 and UL44. Conclusions/Significance: The core SWI/SNF factors required for efficient chromatin remodeling are present in the HCMV replication foci throughout infection. The proteins UL44 and UL114 interact with SMARCB1 and may participate in the recruitment of the SWI/SNF complex to the chromatinized virus DNA. Thus, the presence of the SWI/SNF chromatin remodeling complex in replication foci and its association with UL114 and with UL44 might imply its involvement i

Monitoring HSVtk suicide gene therapy: the role of [18F]FHPG membrane transport

Favourable pharmacokinetics of the prodrug are essential for successful HSVtk/ganciclovir (GCV) suicide gene therapy. [F-18] FHPG PET might be a suitable technique to assess the pharmacokinetics of the prodrug GCV noninvasively, provided that [F-18] FHPG mimics the behaviour of GCV. Since membrane transport is an important aspect of the pharmacokinetics of the prodrug, we investigated the cellular uptake mechanism of [F-18] FHPG in an HSVtk expressing C6 rat glioma cell line and in tumour- bearing rats. The nucleoside transport inhibitors dipyridamol, NBMPR and 2- chloroadenosine did not significantly affect the [F-18] FHPG uptake in vitro. Thymidine and uridine significantly decreased [F-18] FHPG uptake by 84 and 58%, respectively, but an enzyme assay revealed that this decline was due to inhibition of the HSVtk enzyme rather than membrane transport. Nucleobase transport inhibitors, thymine and adenine, caused a 58 and 55% decline in tracer uptake, respectively. In vivo, the ratio of [F-18] FHPG uptake in C6tk and C6 tumours decreased from 3.070.5 to 1.070.2 after infusion of adenine. Thus, in our tumour model, [F-18] FHPG transport exclusively occurred via purine nucleobase transport. In this respect, FHPG does not resemble GCV, which is predominantly taken up via the nucleoside transporter, but rather acyclovir, which is also taken up via the purine nucleobase carrier

Relationship between nano-architectured Ti1−xCux thin film and electrical resistivity for resistance temperature detectors

Ti1−xCux thin films were produced by the glancing angle deposition technique (GLAD) for resistance temperature measurements. The deposition angle was fixed at α = 0° to growth columnar structures and α = 45° to growth zigzag structures. The Ti-to-Cu atomic concentration was tuned from 0 to 100 at.% of Cu in order to optimize the temperature coefficient of resistance (TCR) value. Increasing the amount of Cu in the Ti1−xCux thin films, the electrical conductivity was gradually changed from 4.35 to 7.87 × 105 Ω−1 m−1. After thermal “stabilization,” the zigzag structures of Ti1−xCux films induce strong variation of the thermosensitive response of the materials and exhibited a reversible resistivity versus temperature between 35 and 200 °C. The results reveal that the microstructure has an evident influence on the overall response of the films, leading to values of TCR of 8.73 × 10−3 °C−1 for pure copper films and of 4.38 × 10−3 °C−1 for a films of composition Ti0.49Cu0.51. These values are very close to the ones reported for the bulk platinum (3.93 × 10−3 °C−1), which is known to be one of the best material available for these kind of temperature-related applications. The non-existence of hysteresis in the electrical response of consecutive heating and cooling steps indicates the viability of these nanostructured zigzag materials to be used as thermosensitive sensors.Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2013 and Project PTDC/EEI-SII/5582/2014. A. Ferreira and C. Lopes thanks the FCT for Grant SFRH/BPD/102402/2014 and SFRH/BD/103373/2014. The authors thank financial support from the Basque Government Industry Department under the ELKARTEK Programinfo:eu-repo/semantics/publishedVersio

Home on the Range: Factors Explaining Partial Migration of African Buffalo in a Tropical Environment

Partial migration (when only some individuals in a population undertake seasonal migrations) is common in many species and geographical contexts. Despite the development of modern statistical methods for analyzing partial migration, there have been no studies on what influences partial migration in tropical environments. We present research on factors affecting partial migration in African buffalo (Syncerus caffer) in northeastern Namibia. Our dataset is derived from 32 satellite tracking collars, spans 4 years and contains over 35,000 locations. We used remotely sensed data to quantify various factors that buffalo experience in the dry season when making decisions on whether and how far to migrate, including potential man-made and natural barriers, as well as spatial and temporal heterogeneity in environmental conditions. Using an information-theoretic, non-linear regression approach, our analyses showed that buffalo in this area can be divided into 4 migratory classes: migrants, non-migrants, dispersers, and a new class that we call “expanders”. Multimodel inference from least-squares regressions of wet season movements showed that environmental conditions (rainfall, fires, woodland cover, vegetation biomass), distance to the nearest barrier (river, fence, cultivated area) and social factors (age, size of herd at capture) were all important in explaining variation in migratory behaviour. The relative contributions of these variables to partial migration have not previously been assessed for ungulates in the tropics. Understanding the factors driving migratory decisions of wildlife will lead to better-informed conservation and land-use decisions in this area

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Tuning fresh: radiation through rewiring of central metabolism in streamlined bacteria

Most free-living planktonic cells are streamlined and in spite of their limitations in functional flexibility, their vast populations have radiated into a wide range of aquatic habitats. Here we compared the metabolic potential of subgroups in the Alphaproteobacteria lineage SAR11 adapted to marine and freshwater habitats. Our results suggest that the successful leap from marine to freshwaters in SAR11 was accompanied by a loss of several carbon degradation pathways and a rewiring of the central metabolism. Examples for these are C1 and methylated compounds degradation pathways, the Entner–Doudouroff pathway, the glyoxylate shunt and anapleuretic carbon fixation being absent from the freshwater genomes. Evolutionary reconstructions further suggest that the metabolic modules making up these important freshwater metabolic traits were already present in the gene pool of ancestral marine SAR11 populations. The loss of the glyoxylate shunt had already occurred in the common ancestor of the freshwater subgroup and its closest marine relatives, suggesting that the adaptation to freshwater was a gradual process. Furthermore, our results indicate rapid evolution of TRAP transporters in the freshwater clade involved in the uptake of low molecular weight carboxylic acids. We propose that such gradual tuning of metabolic pathways and transporters toward locally available organic substrates is linked to the formation of subgroups within the SAR11 clade and that this process was critical for the freshwater clade to find and fix an adaptive phenotype.This work was supported by the Swedish Research Council (Grant Numbers 2012-4592 to AE and 2012-3892 to SB) and the Communiy Sequencing Programme of the US Department of Energy Joint Genome Institute. The work conducted by the US Department of Energy Joint Genome Institute, a DOE Office of Science User Facility, is supported under Contract No. DE-AC02-05CH11231