Investigation into the radiobiological consequences of pre-treatment verification imaging with megavoltage X-rays in radiotherapy

Objective: The aim of this study was to investigate the effect of pre-treatment verification imaging with megavoltage (MV) X-rays on cancer and normal cell survival in vitro and to compare the findings with theoretically modelled data. Since the dose received from pre-treatment imaging can be significant, incorporation of this dose at the planning stage of treatment has been suggested.

Methods: The impact of imaging dose incorporation on cell survival was investigated by clonogenic assay, irradiating DU-145 prostate cancer, H460 non-small cell lung cancer and AGO-1522b normal tissue fibroblast cells. Clinically relevant imaging-to-treatment times of 7.5 minutes and 15 minutes were chosen for this study. The theoretical magnitude of the loss of radiobiological efficacy due to sublethal damage repair was investigated using the Lea-Catcheside dose protraction factor model.

Results: For the cell lines investigated, the experimental data showed that imaging dose incorporation had no significant impact upon cell survival. These findings were in close agreement with the theoretical results.

Conclusions: For the conditions investigated, the results suggest that allowance for the imaging dose at the planning stage of treatment should not adversely affect treatment efficacy.

Advances in Knowledge: There is a paucity of data in the literature on imaging effects in radiotherapy. This paper presents a systematic study of imaging dose effects on cancer and normal cell survival, providing both theoretical and experimental evidence for clinically relevant imaging doses and imaging-to-treatment times. The data provide a firm foundation for further study into this highly relevant area of research.

IL-33 attenuates the development of experimental autoimmune uveitis

Interleukin (IL)-33 is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ(+) and IL-17(+) CD4(+) T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5(+) and IL-4(+) CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization towards an alternatively-activated macrophage (M2) phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis.

Effect of Post-weld Heat-treatment on the Stress Corrosion Cracking Behaviour of Laser-welded Shape Memory NiTi Wires in Hanks’ Solution

In this study, the stress-corrosion cracking (SCC) behaviour of laser-welded NiTi wires before and after post-weld heat-treatment (PWHT) was investigated. The samples were subjected to slow strain rate testing (SSRT) under tensile loading in Hanks’ solution at 37.5 °C (or 310.5 K) at a constant anodic potential (200 mVSCE). The current density of the samples during the SSRT was captured by a potentiostat, and used as an indicator to determine the susceptibility to SCC. Fractography was analyzed using scanning-electron microscopy (SEM). The experimental results showed that the laser-welded sample after PWHT was immune to the SCC as evidenced by the stable current density throughout the SSRT. This is attributed to the precipitation of fine and coherent nano-sized Ni4Ti3 precipitates in the welded regions (weld zone, WZ and heat-affected zone, HAZ) after PWHT, resulting in (i) enrichment of TiO2 content in the passive film and (ii) higher resistance against the local plastic deformation in the welded regions.

Optimisation of Kinetic Parameters for an After-treatment Catalyst

Mathematical modelling has become an essential tool in the design of modern catalytic systems. Emissions legislation is becoming increasingly stringent, and so mathematical models of aftertreatment systems must become more accurate in order to provide confidence that a catalyst will convert pollutants over the required range of conditions. 
Automotive catalytic converter models contain several sub-models that represent processes such as mass and heat transfer, and the rates at which the reactions proceed on the surface of the precious metal. Of these sub-models, the prediction of the surface reaction rates is by far the most challenging due to the complexity of the reaction system and the large number of gas species involved. The reaction rate sub-model uses global reaction kinetics to describe the surface reaction rate of the gas species and is based on the Langmuir Hinshelwood equation further developed by Voltz et al. [1] The reactions can be modelled using the pre-exponential and activation energies of the Arrhenius equations and the inhibition terms. 
The reaction kinetic parameters of aftertreatment models are found from experimental data, where a measured light-off curve is compared against a predicted curve produced by a mathematical model. The kinetic parameters are usually manually tuned to minimize the error between the measured and predicted data. This process is most commonly long, laborious and prone to misinterpretation due to the large number of parameters and the risk of multiple sets of parameters giving acceptable fits. Moreover, the number of coefficients increases greatly with the number of reactions. Therefore, with the growing number of reactions, the task of manually tuning the coefficients is becoming increasingly challenging. 
In the presented work, the authors have developed and implemented a multi-objective genetic algorithm to automatically optimize reaction parameters in AxiSuite®, [2] a commercial aftertreatment model. The genetic algorithm was developed and expanded from the code presented by Michalewicz et al. [3] and was linked to AxiSuite using the Simulink add-on for Matlab. 
The default kinetic values stored within the AxiSuite model were used to generate a series of light-off curves under rich conditions for a number of gas species, including CO, NO, C_{3H8 and C3H6. These light-off curves were used to generate an objective function.} 
This objective function was used to generate a measure of fit for the kinetic parameters. The multi-objective genetic algorithm was subsequently used to search between specified limits to attempt to match the objective function. In total the pre-exponential factors and activation energies of ten reactions were simultaneously optimized. 
The results reported here demonstrate that, given accurate experimental data, the optimization algorithm is successful and robust in defining the correct kinetic parameters of a global kinetic model describing aftertreatment processes.

A function-based treatment package aiming at decreasing self-injurious behaviour and tantrums.

Self-injurious and aggressive behaviours have often been identified as the cause for students’ lack of academic progress, parental distress, health risks and teachers´ low satisfaction levels. Functional analysis has been identified in the research literature as the benchmark of effective treatments for disruptive and/or inappropriate behaviours. The present study was completed with a girl diagnosed with ASD. An experimental functional analysis was conducted identifying the function of self-injurious behaviours and tantrums to be escaping from tasks. A treatment package was consequently put in place integrating several components that aimed at reducing overall levels of inappropriate behaviours. Results showed a clear and meaningful improvement in the student´s overall health and academic progress, as well as in parental involvement, teachers’ satisfaction and school inclusion. These outcomes are discussed in the light of evidence-based experimental procedures based on applied behaviour analysis and more specifically on the functional-analytic literature, which, if put in place consistently, can bring valuable positive changes in the quality of life of individuals with ASD.

Development of a slurry continuous flow reactor for photocatalytic treatment of industrial waste water

The water treatment capability of a novel photocatalytic slurry reactor was investigated using methylene blue (MB) as a model pollutant in an aqueous suspension. A pellet TiO ₂ catalyst was employed and this freed the system from the need of filtration of catalyst following photocatalysis. This configuration combines the high surface area contact of catalyst with pollutant of the slurry reactor and also offers a high illumination of catalyst by its unique array of weir-like baffles. In this work, the batch adsorption of MB from aqueous solution (10μM) onto the TiO ₂ catalyst was studied, adsorption isotherms and kinetics were determined from the experimental data. Complete degradation of MB was achieved within 60 min illumination with various loadings of catalyst (30-200 g L ^-1). A modest catalyst loading (30 g L ^-1) achieved 98% degradation within 60 min of irradiation. Experimental results indicate that this novel reactor configuration has a high effective mass transfer rate and UV light penetration characteristics. 

Grazing under experimental hypercapnia and elevated temperature does not affect the radula of a chiton (Mollusca, Polyplacophora, Lepidopleurida)

Chitons (class Polyplacophora) are benthic grazing molluscs with an eight-part aragonitic shell armature. The radula, a serial tooth ribbon that extends internally more than half the length of the body, is mineralised on the active feeding teeth with iron magnetite apparently as an adaptation to constant grazing on rocky substrates. As the anterior feeding teeth are eroded they are shed and replaced with a new row. The efficient mineralisation and function of the radula could hypothetically be affected by changing oceans in two ways: changes in seawater chemistry (pH and pCO(2)) may impact the biomineralisation pathway, potentially leading to a weaker or altered density of the feeding teeth; rising temperatures could increase activity levels in these ectothermic animals, and higher feeding rates could increase wear on the feeding teeth beyond the animals' ability to synthesise, mineralise, and replace radular rows. We therefore examined the effects of pH and temperature on growth and integrity in the radula of the chiton Leptochiton asellus. Our experiment implemented three temperature (similar to 10, 15, 20 degrees C) and two pCO(2) treatments (similar to 400 mu atm, pH 8.0; similar to 2000 mu atm, pH 7.5) for six treatment groups. Animals (n = 50) were acclimated to the treatment conditions for a period of 4 weeks. This is sufficient time for growth of ca. 7-9 new tooth rows or 20% turnover of the mineralised portion. There was no significant difference in the number of new (non-mineralised) teeth or total tooth row count in any treatment. Examination of the radulae via SEM revealed no differences in microwear or breakage on the feeding cusps correlating to treatment groups. The shell valves also showed no signs of dissolution. As a lineage, chitons have survived repeated shifts in Earth's climate through geological time, and at least their radulae may be robust to future perturbations.

The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

Eliciting and estimating valid subjective probabilities: An experimental investigation of the Exchangeability Method.

Using a laboratory experiment, we investigate whether incentive compatibility affects subjective probabilities elicited via the exchangeability method (EM), an elicitation technique consisting of several chained questions. We hypothesize that subjects who are aware of the chaining strategically behave and provide invalid subjective probabilities, while subjects who are not aware of the chaining state their real beliefs and provide valid subjective probabilities. The validity of subjective probabilities is investigated using de Finetti's notion of coherence, under which probability estimates are valid if and only if they obey all axioms of probability theory.
Four experimental treatments are designed and implemented. Subjects are divided into two initial treatment groups: in the first, they are provided with real monetary incentives, and in the second, they are not. Each group is further sub-divided into two treatment groups, in the first, the chained structure of the experimental design is made clear to the subjects, while, in the second, the chained structure is hidden by randomizing the elicitation questions.
Our results suggest that subjects provided with monetary incentives and randomized questions provide valid subjective probabilities because they are not aware of the chaining which undermines the incentive compatibility of the exchangeability method.