Dasatinib, nilotinib and standard-dose imatinib for the first line treatment of chronic myeloid leukaemia: Systematic reviews and economic analyses

- Background Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). - Objective This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. - Data sources Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. - Review methods A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. - Results Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. - Limitations Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. - Conclusions From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. - Funding The Health Technology Assessment Programme of the National Institute for Health Research.

Targeting resource investments to achieve sediment reduction and improved Great Barrier Reef health

Concerns about excessive sediment loads entering the Great Barrier Reef (GBR) lagoon in Australia have led to a focus on improving ground cover in grazing lands. Ground cover has been identified as an important factor in reducing sediment loads, but improving ground cover has been difficult for reef stakeholders in major catchments of the GBR. To provide better information an optimising linear programming model based on paddock scale information in conjunction with land type mapping was developed for the Fitzroy, the largest of the GBR catchments. This identifies at a catchment scale which land types allow the most sediment reduction to be achieved at least cost. The results suggest that from the five land types modelled, the lower productivity land types present the cheapest option for sediment reductions. The study allows more informed decision making for natural resource management organisations to target investments. The analysis highlights the importance of efficient allocation of natural resource management funds in achieving sediment reductions through targeted land type investments. © 2012.

Molecular Modelling of Estrogen-Producing Enzymes CYP450 Aromatase and 17beta-Hydroxysteroid Dehydrogenase Type 1

Breast cancer is the most common cancer in women in the western countries. Approximately two-thirds of breast cancer tumours are hormone dependent, requiring estrogens to grow. Estrogens are formed in the human body via a multistep route starting from cholesterol. The final steps in the biosynthesis include the CYP450 aromatase enzyme, converting the male hormones androgens (preferred substrate androstenedione ASD) into estrogens(estrone E1), and the 17beta-HSD1 enzyme, converting the biologically less active E1 into the active hormone 17beta-hydroxyestradiol E2. E2 is bound to the nuclear estrogen receptors causing a cascade of biochemical reactions leading to cell proliferation in normal tissue, and to tumour growth in cancer tissue. Aromatase and 17beta-HSD1 are expressed in or near the breast tumour, locally providing the tissue with estrogens. One approach in treating hormone dependent breast tumours is to block the local estrogen production by inhibiting these two enzymes. Aromatase inhibitors are already on the market in treating breast cancer, despite the lack of an experimentally solved structure. The structure of 17beta-HSD1, on the other hand, has been solved, but no commercial drugs have emerged from the drug discovery projects reported in the literature. Computer-assisted molecular modelling is an invaluable tool in modern drug design projects. Modelling techniques can be used to generate a model of the target protein and to design novel inhibitors for them even if the target protein structure is unknown. Molecular modelling has applications in predicting the activities of theoretical inhibitors and in finding possible active inhibitors from a compound database. Inhibitor binding at atomic level can also be studied with molecular modelling. To clarify the interactions between the aromatase enzyme and its substrate and inhibitors, we generated a homology model based on a mammalian CYP450 enzyme, rabbit progesterone 21-hydroxylase CYP2C5. The model was carefully validated using molecular dynamics simulations (MDS) with and without the natural substrate ASD. Binding orientation of the inhibitors was based on the hypothesis that the inhibitors coordinate to the heme iron, and were studied using MDS. The inhibitors were dietary phytoestrogens, which have been shown to reduce the risk for breast cancer. To further validate the model, the interactions of a commercial breast cancer drug were studied with MDS and ligand–protein docking. In the case of 17beta-HSD1, a 3D QSAR model was generated on the basis of MDS of an enzyme complex with active inhibitor and ligand–protein docking, employing a compound library synthesised in our laboratory. Furthermore, four pharmacophore hypotheses with and without a bound substrate or an inhibitor were developed and used in screening a commercial database of drug-like compounds. The homology model of aromatase showed stable behaviour in MDS and was capable of explaining most of the results from mutagenesis studies. We were able to identify the active site residues contributing to the inhibitor binding, and explain differences in coordination geometry corresponding to the inhibitory activity. Interactions between the inhibitors and aromatase were in agreement with the mutagenesis studies reported for aromatase. Simulations of 17beta-HSD1 with inhibitors revealed an inhibitor binding mode with hydrogen bond interactions previously not reported, and a hydrophobic pocket capable of accommodating a bulky side chain. Pharmacophore hypothesis generation, followed by virtual screening, was able to identify several compounds that can be used in lead compound generation. The visualisation of the interaction fields from the QSAR model and the pharmacophores provided us with novel ideas for inhibitor development in our drug discovery project.

Age, Occupational Strain, and Well-Being: A Person-Environment Fit Perspective

We develop a conceptual model, based on person-environment fit theory, which explains how employee age affects occupational strain and well-being. We begin by explaining how age directly affects different dimensions of objective and subjective P-E fit. Next, we illustrate how age can moderate the relationship between objective P-E fit and subjective P-E fit. Third, we discuss how age can moderate the relationships between P-E fit, on one hand, and occupational strain and well-being on the other. Fourth, we explain how age can impact occupational strain and well-being directly independent of P-E fit. The chapter concludes with implications for future research and practice.

Genetic differentiation analysis for the identification of complementary parental pools for sorghum hybrid breeding in Ethiopia

Key message The potential for exploiting heterosis for sorghum hybrid production in Ethiopia with improved local adaptation and farmers preferences has been investigated and populations suitable for initial hybrid development have been identified. Abstract Hybrids in sorghum have demonstrated increased productivity and stability of performance in the developed world. In Ethiopia, the uptake of hybrid sorghum has been limited to date, primarily due to poor adaptation and absence of farmer’s preferred traits in existing hybrids. This study aimed to identify complementary parental pools to develop locally adapted hybrids, through an analysis of whole genome variability of 184 locally adapted genotypes and introduced hybrid parents (R and B). Genetic variability was assessed using genetic distance, model-based STRUCTURE analysis and pair-wise comparison of groups. We observed a high degree of genetic similarity between the Ethiopian improved inbred genotypes and a subset of landraces adapted to lowland agro-ecology with the introduced R lines. This coupled with the genetic differentiation from existing B lines, indicated that these locally adapted genotype groups are expected to have similar patterns of heterotic expression as observed between introduced R and B line pools. Additionally, the hybrids derived from these locally adapted genotypes will have the benefit of containing farmers preferred traits. The groups most divergent from introduced B lines were the Ethiopian landraces adapted to highland and intermediate agro-ecologies and a subset of lowland-adapted genotypes, indicating the potential for increased heterotic response of their hybrids. However, these groups were also differentiated from the R lines, and hence are different from the existing complementary heterotic pools. This suggests that although these groups could provide highly divergent parental pools, further research is required to investigate the extent of heterosis and their hybrid performance.

Bayesian analysis of community dynamics

Elucidating the mechanisms responsible for the patterns of species abundance, diversity, and distribution within and across ecological systems is a fundamental research focus in ecology. Species abundance patterns are shaped in a convoluted way by interplays between inter-/intra-specific interactions, environmental forcing, demographic stochasticity, and dispersal. Comprehensive models and suitable inferential and computational tools for teasing out these different factors are quite limited, even though such tools are critically needed to guide the implementation of management and conservation strategies, the efficacy of which rests on a realistic evaluation of the underlying mechanisms. This is even more so in the prevailing context of concerns over climate change progress and its potential impacts on ecosystems. This thesis utilized the flexible hierarchical Bayesian modelling framework in combination with the computer intensive methods known as Markov chain Monte Carlo, to develop methodologies for identifying and evaluating the factors that control the structure and dynamics of ecological communities. These methodologies were used to analyze data from a range of taxa: macro-moths (Lepidoptera), fish, crustaceans, birds, and rodents. Environmental stochasticity emerged as the most important driver of community dynamics, followed by density dependent regulation; the influence of inter-specific interactions on community-level variances was broadly minor. This thesis contributes to the understanding of the mechanisms underlying the structure and dynamics of ecological communities, by showing directly that environmental fluctuations rather than inter-specific competition dominate the dynamics of several systems. This finding emphasizes the need to better understand how species are affected by the environment and acknowledge species differences in their responses to environmental heterogeneity, if we are to effectively model and predict their dynamics (e.g. for management and conservation purposes). The thesis also proposes a model-based approach to integrating the niche and neutral perspectives on community structure and dynamics, making it possible for the relative importance of each category of factors to be evaluated in light of field data.

A Modified Dubins Method for Optimal Path Planning of a Miniature Air Vehicle Converging to a Straight Line Path

This paper presents a Dubins model based strategy to determine the optimal path of a Miniature Air Vehicle (MAV), constrained by a bounded turning rate, that would enable it to fly along a given straight line, starting from an arbitrary initial position and orientation. The method is then extended to meet the same objective in the presence of wind which has a magnitude comparable to the speed of the MAV. We use a modification of the Dubins' path method to obtain the complete optimal solution to this problem in all its generality.

Where and how to conserve: Extending the scope of spatial reserve network design

Ongoing habitat loss and fragmentation threaten much of the biodiversity that we know today. As such, conservation efforts are required if we want to protect biodiversity. Conservation budgets are typically tight, making the cost-effective selection of protected areas difficult. Therefore, reserve design methods have been developed to identify sets of sites, that together represent the species of conservation interest in a cost-effective manner. To be able to select reserve networks, data on species distributions is needed. Such data is often incomplete, but species habitat distribution models (SHDMs) can be used to link the occurrence of the species at the surveyed sites to the environmental conditions at these locations (e.g. climatic, vegetation and soil conditions). The probability of the species occurring at unvisited location is next predicted by the model, based on the environmental conditions of those sites. The spatial configuration of reserve networks is important, because habitat loss around reserves can influence the persistence of species inside the network. Since species differ in their requirements for network configuration, the spatial cohesion of networks needs to be species-specific. A way to account for species-specific requirements is to use spatial variables in SHDMs. Spatial SHDMs allow the evaluation of the effect of reserve network configuration on the probability of occurrence of the species inside the network. Even though reserves are important for conservation, they are not the only option available to conservation planners. To enhance or maintain habitat quality, restoration or maintenance measures are sometimes required. As a result, the number of conservation options per site increases. Currently available reserve selection tools do however not offer the ability to handle multiple, alternative options per site. This thesis extends the existing methodology for reserve design, by offering methods to identify cost-effective conservation planning solutions when multiple, alternative conservation options are available per site. Although restoration and maintenance measures are beneficial to certain species, they can be harmful to other species with different requirements. This introduces trade-offs between species when identifying which conservation action is best applied to which site. The thesis describes how the strength of such trade-offs can be identified, which is useful for assessing consequences of conservation decisions regarding species priorities and budget. Furthermore, the results of the thesis indicate that spatial SHDMs can be successfully used to account for species-specific requirements for spatial cohesion - in the reserve selection (single-option) context as well as in the multi-option context. Accounting for the spatial requirements of multiple species and allowing for several conservation options is however complicated, due to trade-offs in species requirements. It is also shown that spatial SHDMs can be successfully used for gaining information on factors that drive a species spatial distribution. Such information is valuable to conservation planning, as better knowledge on species requirements facilitates the design of networks for species persistence. This methods and results described in this thesis aim to improve species probabilities of persistence, by taking better account of species habitat and spatial requirements. Many real-world conservation planning problems are characterised by a variety of conservation options related to protection, restoration and maintenance of habitat. Planning tools therefore need to be able to incorporate multiple conservation options per site, in order to continue the search for cost-effective conservation planning solutions. Simultaneously, the spatial requirements of species need to be considered. The methods described in this thesis offer a starting point for combining these two relevant aspects of conservation planning.

Gene Expression : From Microarrays to Functional Genomics

The time of the large sequencing projects has enabled unprecedented possibilities of investigating more complex aspects of living organisms. Among the high-throughput technologies based on the genomic sequences, the DNA microarrays are widely used for many purposes, including the measurement of the relative quantity of the messenger RNAs. However, the reliability of microarrays has been strongly doubted as robust analysis of the complex microarray output data has been developed only after the technology had already been spread in the community. An objective of this study consisted of increasing the performance of microarrays, and was measured by the successful validation of the results by independent techniques. To this end, emphasis has been given to the possibility of selecting candidate genes with remarkable biological significance within specific experimental design. Along with literature evidence, the re-annotation of the probes and model-based normalization algorithms were found to be beneficial when analyzing Affymetrix GeneChip data. Typically, the analysis of microarrays aims at selecting genes whose expression is significantly different in different conditions followed by grouping them in functional categories, enabling a biological interpretation of the results. Another approach investigates the global differences in the expression of functionally related groups of genes. Here, this technique has been effective in discovering patterns related to temporal changes during infection of human cells. Another aspect explored in this thesis is related to the possibility of combining independent gene expression data for creating a catalog of genes that are selectively expressed in healthy human tissues. Not all the genes present in human cells are active; some involved in basic activities (named housekeeping genes) are expressed ubiquitously. Other genes (named tissue-selective genes) provide more specific functions and they are expressed preferably in certain cell types or tissues. Defining the tissue-selective genes is also important as these genes can cause disease with phenotype in the tissues where they are expressed. The hypothesis that gene expression could be used as a measure of the relatedness of the tissues has been also proved. Microarray experiments provide long lists of candidate genes that are often difficult to interpret and prioritize. Extending the power of microarray results is possible by inferring the relationships of genes under certain conditions. Gene transcription is constantly regulated by the coordinated binding of proteins, named transcription factors, to specific portions of the its promoter sequence. In this study, the analysis of promoters from groups of candidate genes has been utilized for predicting gene networks and highlighting modules of transcription factors playing a central role in the regulation of their transcription. Specific modules have been found regulating the expression of genes selectively expressed in the hippocampus, an area of the brain having a central role in the Major Depression Disorder. Similarly, gene networks derived from microarray results have elucidated aspects of the development of the mesencephalon, another region of the brain involved in Parkinson Disease.

Country-scale carbon accounting of the vegetation and mineral soils of Finland

The increase in global temperature has been attributed to increased atmospheric concentrations of greenhouse gases (GHG), mainly that of CO2. The threat of severe and complex socio-economic and ecological implications of climate change have initiated an international process that aims to reduce emissions, to increase C sinks, and to protect existing C reservoirs. The famous Kyoto protocol is an offspring of this process. The Kyoto protocol and its accords state that signatory countries need to monitor their forest C pools, and to follow the guidelines set by the IPCC in the preparation, reporting and quality assessment of the C pool change estimates. The aims of this thesis were i) to estimate the changes in carbon stocks vegetation and soil in the forests in Finnish forests from 1922 to 2004, ii) to evaluate the applied methodology by using empirical data, iii) to assess the reliability of the estimates by means of uncertainty analysis, iv) to assess the effect of forest C sinks on the reliability of the entire national GHG inventory, and finally, v) to present an application of model-based stratification to a large-scale sampling design of soil C stock changes. The applied methodology builds on the forest inventory measured data (or modelled stand data), and uses statistical modelling to predict biomasses and litter productions, as well as a dynamic soil C model to predict the decomposition of litter. The mean vegetation C sink of Finnish forests from 1922 to 2004 was 3.3 Tg C a-1, and in soil was 0.7 Tg C a-1. Soil is slowly accumulating C as a consequence of increased growing stock and unsaturated soil C stocks in relation to current detritus input to soil that is higher than in the beginning of the period. Annual estimates of vegetation and soil C stock changes fluctuated considerably during the period, were frequently opposite (e.g. vegetation was a sink but soil was a source). The inclusion of vegetation sinks into the national GHG inventory of 2003 increased its uncertainty from between -4% and 9% to ± 19% (95% CI), and further inclusion of upland mineral soils increased it to ± 24%. The uncertainties of annual sinks can be reduced most efficiently by concentrating on the quality of the model input data. Despite the decreased precision of the national GHG inventory, the inclusion of uncertain sinks improves its accuracy due to the larger sectoral coverage of the inventory. If the national soil sink estimates were prepared by repeated soil sampling of model-stratified sample plots, the uncertainties would be accounted for in the stratum formation and sample allocation. Otherwise, the increases of sampling efficiency by stratification remain smaller. The highly variable and frequently opposite annual changes in ecosystem C pools imply the importance of full ecosystem C accounting. If forest C sink estimates will be used in practice average sink estimates seem a more reasonable basis than the annual estimates. This is due to the fact that annual forest sinks vary considerably and annual estimates are uncertain, and they have severe consequences for the reliability of the total national GHG balance. The estimation of average sinks should still be based on annual or even more frequent data due to the non-linear decomposition process that is influenced by the annual climate. The methodology used in this study to predict forest C sinks can be transferred to other countries with some modifications. The ultimate verification of sink estimates should be based on comparison to empirical data, in which case the model-based stratification presented in this study can serve to improve the efficiency of the sampling design.

Ultrasonic degradation of poly(methyl methacrylate-co-alkyl acrylate) copolymers

The copolymers, poly(methyl methacrylate-co-methyl acrylate) (PMMAMA), poly(methyl methacrylate-co-ethyl acrylate) (PMMAEA) and poly(methyl methacrylate-co-butyl acrylate) (PMMABA), of different compositions were synthesized and characterized. The effect of alkyl acrylate content, alkyl group substituents and solvents on the ultrasonic degradation of these copolymers was studied. A model based on continuous distribution kinetics was used to study the kinetics of degradation. The rate coefficients were obtained by fitting the experimental data with the model. The linear dependence of the rate coefficients on the logarithm of the vapor pressure of the solvent indicated that vapor pressure is the crucial parameter that controls the degradation process. The rate of degradation increases with an increase in the alkyl acrylate content. At any particular copolymer composition, the rate of degradation follows the order: PMMAMA > PMMAEA > PMMABA. It was observed that the degradation rate coefficient varies linearly with the mole percentage of the alkyl acrylate in the copolymer.

Solubilities of palmitic and stearic fatty acids in supercritical carbon dioxide

The solubilities of two fatty acids, namely hexadecanoic acid (palmitic acid) and octadecanoic acid (stearic acid) in supercritical carbon dioxide (SCCO2), were determined at T = (328 and 338) K from 12.8 MPa to 22.6 MPa. Three models, namely a thermodynamic model based on the Peng-Robinson equation of state with Kwak and Mansoori mixing rules, a model based on dilute solution theory proposed by Mendez-Santiago and Teja and a new reformulated Chrastil equation model, were used to correlate the solubilities. In all the models, the correlation constants are temperature independent. All the models successfully correlated the experimental results for the solubilities of hexadecanoic acid within 3%.

Accurate Parameter Estimation of Contaminant Transport Inverse Problem using Particle Swarm Optimization

Swarm Intelligence techniques such as particle swarm optimization (PSO) are shown to be incompetent for an accurate estimation of global solutions in several engineering applications. This problem is more severe in case of inverse optimization problems where fitness calculations are computationally expensive. In this work, a novel strategy is introduced to alleviate this problem. The proposed inverse model based on modified particle swarm optimization algorithm is applied for a contaminant transport inverse model. The inverse models based on standard-PSO and proposed-PSO are validated to estimate the accuracy of the models. The proposed model is shown to be out performing the standard one in terms of accuracy in parameter estimation. The preliminary results obtained using the proposed model is presented in this work.

Inverted slot-mode slow-wave structures for traveling-wave tubes

The dispersion and impedance characteristics of an inverted slot-mode (ISM) slow-wave structure computed by three different techniques, i.e., an analytical model based on a periodic quasi-TEM approach, an equivalent-circuit model, and 3-D electromagnetic simulation are obtained and compared. The comparison was carried out for three different slot-mode structures at S-, C-, and X-bands. The approach was also validated with experimental measurements on a practical X-band ISM traveling-wave tube. The design of ferruleless ISM slow-wave structures, both in circular and rectangular formats, has also been proposed and the predicted dispersion characteristics for these two geometries are compared with 3-D simulation and cold-test measurements. The impedance characteristics for all three designs are also compared.

Investigations on magnetron sputtered ZnO thin films and Au/ZnO Schottky diodes

Magnetron sputtering is a promising technique for the growth of oxide materials including ZnO, which allows deposition of films at low temperatures with good electrical properties. The current-voltage (I-P) characteristics of An Schottky contacts on magnetron sputtered ZnO, films have been measured over a temperature range of 278-358K. Both effective barrier height (phi(B,eff)) and ideality factor (n) are found to be a function of temperature, and this behavior has been interpreted on the basis of a Gaussian distribution of barrier heights due to barrier height inhomogeneities that prevail at the interface. Density of states (DOS) near the Fermi level is determined using a model based on the space charge limited current (SCLC). The dispersion in both real and imaginary parts of the dielectric constant at low frequencies, with increase in temperature is attributed to the space charge effect. Complex impedance plots exhibited two semicircles, which corresponds to bulk grains and the grain boundaries. (c) 2006 Elsevier B.V. All rights reserved.