Out-of-field cell survival following exposure to intensity-modulated radiation fields

PURPOSE:
To determine the in-field and out-of-field cell survival of cells irradiated with either primary field or scattered radiation in the presence and absence of intercellular communication.
METHODS AND MATERIALS:
Cell survival was determined by clonogenic assay in human prostate cancer (DU145) and primary fibroblast (AGO1552) cells following exposure to different field configurations delivered using a 6-MV photon beam produced with a Varian linear accelerator.
RESULTS:
Nonuniform dose distributions were delivered using a multileaf collimator (MLC) in which half of the cell population was shielded. Clonogenic survival in the shielded region was significantly lower than that predicted from the linear quadratic model. In both cell lines, the out-of-field responses appeared to saturate at 40%-50% survival at a scattered dose of 0.70 Gy in DU-145 cells and 0.24 Gy in AGO1522 cells. There was an approximately eightfold difference in the initial slopes of the out-of-field response compared with the a-component of the uniform field response. In contrast, cells in the exposed part of the field showed increased survival. These observations were abrogated by direct physical inhibition of cellular communication and by the addition of the inducible nitric oxide synthase inhibitor aminoguanidine known to inhibit intercellular bystander effects. Additional studies showed the proportion of cells irradiated and dose delivered to the shielded and exposed regions of the field to impact on response.
CONCLUSIONS:
These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields with cellular communication between differentially irradiated cell populations playing an important role. Validation of these observations in additional cell models may facilitate the refinement of existing radiobiological models and the observations considered important determinants of cell survival.

New ruthenium(II) complexes of functionalized monoanionic aryldiamine N,C,N'-terdentate ligands: Syntheses of [Ru-II{2,6-(Me(2)NCH(2))(2)-4-R-C6H2}(terpy)]Cl+(-); X-ray structure of a dimeric organolithium compound,[Li{2,6-(Me(2)NCH(2))(2)-4-Ph-C6H2}](2)

The new anionic functionalized aryldiamine ligands [2,6-(Me(2)NCH(2))(2)-4-R-C6H2](-) (R = Me(3)SiC=C, C6H5, Me(3)Si), formally derived from [2,6-(Me(2)NCH(2))(2)C6H3](-), have been prepared as their lithium compounds. The compound [Li{2,6-(Me(2)NCH(2))(2)-4-Ph-C6H2}](2) crystallizes in the monoclinic space group C2/c (no. 15) with a = 13.1225(5), b = 13.5844(7), c = 15.9859(12) Angstrom, beta = 105.329(5)degrees, V = 3264.0(3)Angstrom(3), Z = 4. The structure refinement converged to R(1) = 0.0374 for 2037 observed reflections [F-o>4 sigma(F-o)] and wR(2) = 0.0922 for 2560 unique data. The organolithium compounds have been used in transmetalation reactions to give the corresponding functionalized organoruthenium(II) complexes [Ru-II{2,6-(Me(2)NCH(2))(2)-4-R-C6H2}(terpy)]Cl-+(-) (terpy = 2,2';6',2 ''-terpyridine). The Ru-II species with R = HC = C has also been synthesized.

Cell survival responses after exposure to modulated radiation fields.

In the present study survival responses were determined in cells with differing radiosensitivity, specifically primary fibroblast (AG0-1522B), human breast cancer (MDA-MB-231), human prostate cancer (DU-145) and human glioma (T98G) cells, after exposure to modulated radiation fields delivered by shielding 50% of the tissue culture flask. A significant decrease (P < 0.05) in cell survival was observed in the shielded area, outside the primary treatment field (out-of-field), that was lower than predicted when compared to uniform exposures fitted to the linear-quadratic model. Cellular radiosensitivity was demonstrated to be an important factor in the level of response for both the in- and out-of-field regions. These responses were shown to be dependent on secretion-mediated intercellular communication, because inhibition of cellular secreted factors between the in- and out-of-field regions abrogated the response. Out-of-field cell survival was shown to increase after pretreatment of cells with agents known to inhibit factors involved in mediating radiation-induced bystander signaling (aminoguanidine, DMSO or cPTIO). These data illustrate a significant decrease in survival out-of-field, dependent upon intercellular communication, in several cell lines with varying radiosensitivity after exposure to a modulated radiation field. This study provides further evidence for the importance of intercellular signaling in modulated exposures, where dose gradients are present, and may inform the refinement of established radiobiological models to facilitate the optimization of advanced radiotherapy treatment plans.

Improved structure optimization for fuzzy-neural networks

Fuzzy-neural-network-based inference systems are well-known universal approximators which can produce linguistically interpretable results. Unfortunately, their dimensionality can be extremely high due to an excessive number of inputs and rules, which raises the need for overall structure optimization. In the literature, various input selection methods are available, but they are applied separately from rule selection, often without considering the fuzzy structure. This paper proposes an integrated framework to optimize the number of inputs and the number of rules simultaneously. First, a method is developed to select the most significant rules, along with a refinement stage to remove unnecessary correlations. An improved information criterion is then proposed to find an appropriate number of inputs and rules to include in the model, leading to a balanced tradeoff between interpretability and accuracy. Simulation results confirm the efficacy of the proposed method.

Technology Assessment for a Complex Aircraft System using Technology Scenarios

Military decision makers need to understand and assess the benefits and consequences of their decisions in order to make cost efficient, timely, and successful choices. Technology selection is one such critical decision, especially when considering the design or retrofit of a complex system, such as an aircraft. An integrated and systematic methodology that will support decision-making between technology alternatives and options while assessing the consequences of such decisions is a key enabler. This paper presents and demonstrates, through application to a notional medium range short takeoff and landing (STOL) aircraft, one such enabler: the Technology Impact Forecasting (TIF) method. The goal of the TIF process is to explore both generic, undefined areas of technology, as well as specific technologies, and assess their potential impacts. This is actualized through the development and use of technology scenarios, and allows the designer to determine where to allocate resources for further technology definition and refinement, as well as provide useful design information. The paper particularly discusses the use of technology scenarios and demonstrates their use in the exploration of seven technologies of varying technology readiness levels.

Core-based Methodology: An Automated Approach for Implementing a Complete System From Algorithms to a Heterogeneous Network Including FPGAs

In this paper, we present a methodology for implementing a complete Digital Signal Processing (DSP) system onto a heterogeneous network including Field Programmable Gate Arrays (FPGAs) automatically. The methodology aims to allow design refinement and real time verification at the system level. The DSP application is constructed in the form of a Data Flow Graph (DFG) which provides an entry point to the methodology. The netlist for parts that are mapped onto the FPGA(s) together with the corresponding software and hardware Application Protocol Interface (API) are also generated. Using a set of case studies, we demonstrate that the design and development time can be significantly reduced using the methodology developed.

Influence of Different European Cements (CEM) on the Hydration of Cover-Zone Concrete during the Curing and Post Curing Periods

The durability of reinforced concrete structures depends, in the main, on the performance of the cover-zone concrete as it is this which protects the steel from the external environment. This paper focusses on the use of discretised electrical property measurements to study depth-related features during both the curing and post-curing period thereby allowing an integrated assessment of the protective properties of the cover region. In the current work, use is made of a small, multi-electrode array embedded within the surface 75mm of concrete specimens. Concretes were manufactured with different European cements (CEM) and water/binder ratios representing mixes which satisfied the minimum requirements for a range of environmental exposure classes including exposure to chlorides. Electrical resistance measurements were taken over a period in excess of 300 days which showed on-going hydration, pozzolanic reaction and pore-structure refinement; in addition, in the post-curing period, when exposed to a cyclic chloride ponding regime, measurements could be used to study the convective zone and ionic enrichment of the surface layer.

In-vitro investigation of out-of-field cell survival following the delivery of conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans

The aim of this work is to determine the out-of-field survival of cells irradiated with either the primary field or scattered radiation in the presence and absence of intercellular communication following delivery of conformal, IMRT and VMAT treatment plans. Single beam, conformal, IMRT and VMAT plans were created to deliver 3 Gy to half the area of a T80 flask containing either DU-145 or AGO-1522 cells allowing intercellular communication between the in-and out-of-field cell populations. The same plans were delivered to a similar custom made phantom used to hold two T25 culture flasks, one flask in-field and one out-of-field to allow comparison of cell survival responses when intercellular communication is physically inhibited. Plans were created for the delivery of 8 Gy to the more radio-resistant DU-145 cells only in the presence and absence of intercellular communication. Cell survival was determined by clonogenic assay. In both cell lines, the out-of-field survival was not statistically different between delivery techniques for either cell line or dose. There was however, a statistically significant difference between survival out-of-field when intercellular communication was intact (single T80 culture flask) or inhibited (multiple T25 culture flasks) to in-field for all plans. No statistically significant difference was observed in-field with or without cellular communication to out-of-field for all plans. These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields when cellular communication between differentially irradiated cell populations is present. This data is further evidence that refinement of existing radiobiological models to include indirect cell killing effects is required.

DNA damage responses following exposure to modulated radiation fields

During the delivery of advanced radiotherapy treatment techniques modulated beams are utilised to increase dose conformity across the target volume. Recent investigations have highlighted differential cellular responses to modulated radiation fields particularly in areas outside the primary treatment field that cannot be accounted for by scattered dose alone. In the present study, we determined the DNA damage response within the normal human fibroblast AG0-1522B and the prostate cancer cell line DU-145 utilising the DNA damage assay. Cells plated in slide flasks were exposed to 1 Gy uniform or modulated radiation fields. Modulated fields were delivered by shielding 25%, 50% or 75% of the flask during irradiation. The average number of 53BP1 or ?H2AX foci was measured in 2 mm intervals across the slide area. Following 30 minutes after modulated radiation field exposure an increase in the average number of foci out-of-field was observed when compared to non-irradiated controls. In-field, a non-uniform response was observed with a significant decrease in the average number of foci compared to uniformly irradiated cells. Following 24 hrs after exposure there is evidence for two populations of responding cells to bystander signals in-and out-of-field. There was no significant difference in DNA damage response between 25%, 50% or 75% modulated fields. The response was dependent on cellular secreted intercellular signalling as physical inhibition of intercellular communication abrogated the observed response. Elevated residual DNA damage observed within out-of-field regions decreased following addition of an inducible nitric oxide synthase inhibitor (Aminoguanidine). These data show, for the first time, differential DNA damage responses in-and out-of-field following modulated radiation field delivery. This study provides further evidence for a role of intercellular communication in mediating cellular radiobiological response to modulated radiation fields and may inform the refinement of existing radiobiological models for the optimization of advanced radiotherapy treatment plans. © 2012 Trainor et al.

SLPI and elafin: multifunctional antiproteases of the WFDC family

SLPI (secretory leucoprotease inhibitor) and elafin represent the archetypal members of the WFDC [WAP (whey acidic protein) four disulfide core] family of proteins, and were originally characterized as protease inhibitors but have since been shown to possess a wider repertoire of activities. These functions include antimicrobial and immunomodulatory properties, suggesting that these proteins may play key roles in the innate immune response, and indicate the potential to develop some of these proteins as novel therapeutics. Susceptibility to host and bacterial protease cleavage may, however, limit the efficacy of recombinant protein therapies in diseases with a high protease burden such as CF (cystic fibrosis) lung disease. To overcome this problem, further refinement of the native proteins will be required to provide effective treatment strategies.

A progressive failure model for composite laminates subjected to low velocity impact damage

This paper presents a 3-D failure model for predicting the dynamic material response of composite laminates under impact loading. The formulation is based on the Continuum Damage Mechanics (CDM) approach and enables the control of the energy dissipation associated with each failure mode regardless of mesh refinement and fracture plane orientation. Internal thermodynamically irreversible damage variables were defined in order to quantify damage concentration associated with each possible failure mode and predict the gradual stiffness reduction during the impact damage process. The material model has been implemented into LS-DYNA explicit finite element code within solid elements and it has proven to be capable of reproducing experimental results with good accuracy in terms of static/dynamic responses, absorbed energy and extent of damage.

Responding to desire to die statements from patients with advanced disease:recommendations for health professionals

It is not uncommon for patients with advanced incurable disease to express a desire to hasten their death. Health professionals often have difficulty responding to such statements, and find it challenging to ascertain why these statements are made. Health professionals may struggle to determine whether a 'desire to die' statement (DTDS) is about a request for hastened death, a sign of psychosocial distress, or merely a passing comment that is not intended to be heard literally as a death wish. Given the lack of guidelines to assist health professionals with this issue, we have prepared multidisciplinary recommendations for responding to a DTDS, underpinned by key principles of therapeutic communication and a systematic review of empirical literature. Where the relevant literature was lacking, the recommendations were drafted by the authors (clinicians and/ or academics from the following disciplines: nursing, medicine, psychiatry, psychology, sociology, aged care and theology), based on their expert opinion. Multiple drafts of the recommendations were circulated to the authors for refinement until consensus was reached. Strategies for advancing the evidence base for the maturation of guidelines in this area are offered.

Pre-validation methods for developing a patient reported outcome instrument

BACKGROUND: Measures that reflect patients' assessment of their health are of increasing importance as outcome measures in randomised controlled trials. The methodological approach used in the pre-validation development of new instruments (item generation, item reduction and question formatting) should be robust and transparent. The totality of the content of existing PRO instruments for a specific condition provides a valuable resource (pool of items) that can be utilised to develop new instruments. Such 'top down' approaches are common, but the explicit pre-validation methods are often poorly reported. This paper presents a systematic and generalisable 5-step pre-validation PRO instrument methodology.

METHODS: The method is illustrated using the example of the Aberdeen Glaucoma Questionnaire (AGQ). The five steps are: 1) Generation of a pool of items; 2) Item de-duplication (three phases); 3) Item reduction (two phases); 4) Assessment of the remaining items' content coverage against a pre-existing theoretical framework appropriate to the objectives of the instrument and the target population (e.g. ICF); and 5) qualitative exploration of the target populations' views of the new instrument and the items it contains.

RESULTS: The AGQ 'item pool' contained 725 items. Three de-duplication phases resulted in reduction of 91, 225 and 48 items respectively. The item reduction phases discarded 70 items and 208 items respectively. The draft AGQ contained 83 items with good content coverage. The qualitative exploration ('think aloud' study) resulted in removal of a further 15 items and refinement to the wording of others. The resultant draft AGQ contained 68 items.

CONCLUSIONS: This study presents a novel methodology for developing a PRO instrument, based on three sources: literature reporting what is important to patient; theoretically coherent framework; and patients' experience of completing the instrument. By systematically accounting for all items dropped after the item generation phase, our method ensures that the AGQ is developed in a transparent, replicable manner and is fit for validation. We recommend this method to enhance the likelihood that new PRO instruments will be appropriate to the research context in which they are used, acceptable to research participants and likely to generate valid data.

Cast Offs (Touchstones in Practice)

The working process of an architect is not often shown publicly, as the finished buildings, more particularly images and publications on them tend to dominate how architecture is communicated. In this there is something lost. The experience of the building, which is its most valuable aspect, is only possible by being there physically. Photography and other means of representation of architecture can tend to an overly perfected and artificial read of both the building and how the design was produced. In truth the design process for a building is a complex one, full of chance discoveries, multiple abandoned ideas, and refinement which is lateral as well as rational.

When we were asked to exhibit it struck us that we should address this deficit in some small way. These are models made as part of the design process for four projects (an arts centre, a womens refuge, a villa and four artists studios). An important part of our work method is to try to explore the material qualities of the buildings we are working on. To advance this we commonly make models to allow us to make discoveries and to advance the project so that the finished building is imbued with material and spatial character. These models are not made to show the final design of the building but to highlight an aspect that we are interested in exploring, in some cases this is about a space, in others about texture and its relationship to form. We chose these four models as all in some way allowed us to make discoveries about the project being explored. This discovery, once made, is what we value. The model itself serves only to produce this, and once made we can cast off the model and move on. We show them, not as architecture, but as touchstones for ideas out of which architecture may come.

A Neutron Diffraction and Molecular Dynamics Investigation of Acetate-based Ionic Liquids as Solvents for Glucose

The liquid state structure of the ionic liquid, 1-ethyl-3-methylimidazolium acetate, and the solute/solvent structure of glucose dissolved in the ionic liquid at a 1: 6 molar ratio have been investigated at 323 K by molecular dynamics simulations and neutron diffraction experiments using H/D isotopically substituted materials. Interactions between hydrogen-bond donating cation sites and polar, directional hydrogen-bond accepting acetate anions are examined. Ion-ion radial distribution functions for the neat ionic liquid, calculated from both MD and derived from the empirical potential structure refinement model to the experimental data, show the alternating shell-structure of anions around the cation, as anticipated. Spatial probability distributions reveal the main anion-to-cation features as in-plane interactions of anions with imidazolium ring hydrogens and cation-cation planar stacking. Interestingly, the presence of the polarised hydrogen-bond acceptor anion leads to increased anion-anion tail-tail structuring within each anion shell, indicating the onset of hydrophobic regions within the anion regions of the liquid.