Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis

Myeloid leukaemias share the common characteristics of being stem cell-derived clonal diseases, characterised by excessive proliferation of one or more myeloid lineage. Chronic myeloid leukaemia (CML) arises from a genetic alteration in a normal haemopoietic stem cell (HSC) giving rise to a leukaemic stem cell (LSC) within the bone marrow (BM) ‘niche’. CML is characterised by the presence of the oncogenic tyrosine kinase fusion protein breakpoint cluster region-abelson murine leukaemia viral oncogene homolog 1 (BCR-ABL), which is responsible for driving the disease through activation of downstream signal transduction pathways. Recent evidence from our group and others indicates that important regulatory networks involved in establishing primitive and definitive haemopoiesis during development are reactivated in myeloid leukaemia, giving rise to an LSC population with altered self-renewal and differentiation properties. In this review, we explore the role the bone morphogenic protein (BMP) signalling plays in stem cell pluripotency, developmental haemopoiesis, HSC maintenance and the implication of altered BMP signalling on LSC persistence in the BM niche. Overall, we emphasise how the BMP and Wnt pathways converge to alter the Cdx–Hox axis and the implications of this in the pathogenesis of myeloid malignancies

Targeting self-renewal pathways in myeloid malignancies

A fundamental property of hematopoietic stem cells (HSCs) is the ability to self-renew. This is a complex process involving multiple signal transduction cascades which control the fine balance between self-renewal and differentiation through transcriptional networks. Key activators/regulators of self-renewal include chemokines, cytokines and morphogens which are expressed in the bone marrow niche, either in a paracrine or autocrine fashion, and modulate stem cell behaviour. Increasing evidence suggests that the downstream signaling pathways induced by these ligands converge at multiple levels providing a degree of redundancy in steady state hematopoiesis. Here we will focus on how these pathways cross-talk to regulate HSC self-renewal highlighting potential therapeutic windows which could be targeted to prevent leukemic stem cell self-renewal in myeloid malignancies

Classification Accuracy and Consistency under Item Response Theory Models Using the Package classify

The R package classify presents a number of useful functions which can be used to estimate the classification accuracy and consistency of assessments. Classification accuracy refers to the probability that an examinee’s achieved grade classification on an assessment reflects their true grade. Classification consistency refers to the probability that an examinee will be classified into the same grade classification under repeated administrations of an assessment. Understanding the classification accuracy and consistency of assessments is important where key decisions are being taken on the basis of grades or classifications. The study of classification accuracy can help to improve the design of assessments and aid public understanding and confidence in those assessments

An Analysis of the Programs of Fourteen FSA Farms at Prairie View, Texas

This study is an analysis of the programs of the fourteen farms under the Federal Security Administration which are located at Prairie View, Texas. Its purpose is to determine through such analysis if the programs of these farmers from the time they were begun to the present have proved successful, thereby determining if the farmers to whom the farm ownership loans have been made are good risks. A history of the Federal Security Administration is first given in the introduction; then follow case studies of the fourteen farms based upon information obtained from the inquiry forms that the writer took to each farm and filled out and from interviews with the Senior Administrative Assistant of the Farm Home Administration, the present agency having control of these farms, and upon the observations of the writer upon visiting each of the farms. Each of the case studies gives personal data on the farmer, a description of the farm lay-out, a detailed analysis of each enterprise Included in the farm program, with the income from each enterprise being given, and a summary of the condition of the farm as observed by the writer. The summary gives a statement of the trends of the fourteen farms

AMFESYS: Modelling and diagnosis functions for operations support

Packetized telemetry, combined with low station coverage for close-earth satellites, may introduce new problems in presenting to the operator a clear picture of what the spacecraft is doing. A recent ESOC study has gone some way to show, by means of a practical demonstration, how the use of subsystem models combined with artificial intelligence techniques, within a real-time spacecraft control system (SCS), can help to overcome these problems. A spin-off from using these techniques can be an improvement in the reliability of the telemetry (TM) limit-checking function, as well as the telecommand verification function, of the Spacecraft Control systems (SCS). The problem and how it was addressed, including an overview of the 'AMF Expert System' prototype are described, and proposes further work which needs to be done to prove the concept. The Automatic Mirror Furnace is part of the payload of the European Retrievable Carrier (EURECA) spacecraft, which was launched in July 1992

Wave-turbulence interaction in shallow water numerical models: asymptotic limits, and subgrid interactions

The ability to directly simulate all atmospheric motion is currently well beyond the limits of the computers available to us. As such techniques must be developed that accurately model important processes in an affordable manner. Large-scale balanced motion is well understood, but as affordable resolution increases, models are able to resolve scales where large-scale turbulence and small-scale waves are important. This requires a new set of techniques that respect the interactions between these different kinds of motion. In this thesis we look at two ways of assessing the accuracy of models capable of representing the scales at which these interactions occur. The first approach uses asymptotic limit solutions to derive a set of terms whose scale is known. These terms can then be evaluated as the model approaches a relevant asymptotic regime, and a `good' model should reproduce the expected rate of scaling. We apply this method of asymptotic limit solutions to an Eulerian and a Lagrangian shallow water model. The former is based upon ENDGame, the model currently in use at the Met Office, and the latter is based upon a candidate model from GungHo which is seeking a replacement for ENDGame. In addition, the Eulerian model is evaluated with both small and large timesteps and the results confirm the ability of the semi-implicit scheme to retain accuracy at large timesteps. Errors in the higher-order diagnostics used in this section highlight the need to make these analytic diagnostics consistent with the discretisations of the model in question. The second method involves looking at the exchanges of energy in a spectral shallow water model in order to inform the design of subgrid models. By running a high-resolution simulation and truncating the energy at a certain wavenumber, comparing the result to a run without truncation shows the contribution of the scales below the truncation limit. We extend this by separating the total energy into separate components that may be truncated and evaluated individually in order to give a more complete picture of energy exchanges at the subgrid scale

An Item Response Theory Approach to the Maintenance of Standards in Public Examinations in England

Abstract Every year outcomes from public examinations in the UK rise: politicians congratulate pupils on their hard earned achievement; the media questions whether this achievement is real; those responsible for administrating the examinations defend their standards; various subject councils and employers decry the failings of candidates with high grades; admissions officers from the elite universities report their struggle with the decrease in discrimination in grades achieved; and academics debate what it means to compare standards from one year to the next. The debate cannot be easily resolved because examination results are put to many purposes some of which are more suited to certain definitions of comparability than others. In procedural terms, however, it should be relatively straightforward to evaluate the strength of the evidence that is put forward on the comparability of standards against various definitions. Broadly, solely in terms of discrimination, the statistical evidence in the maintenance of standards over time and between qualifications can be evaluated by reference to measures such as model fit, significance and effect size. An evaluation of the literature suggests that predictive statistical models, where employed in the maintenance of standards to meet definitions of cohort referencing, tend to be robust. Beyond discrimination, measures of performance standards are required to support inferences drawn from grades on what candidates can actually do. These are, and have been for many years, underpinned by processes reliant on human judgement. An evaluation of the literature suggests that judgement provides very weak evidence and is subject to unknown bias. The combination of statistical and judgemental evidence is poorly specified, has no theoretical basis and is therefore impossible to evaluate. If anything more than pure cohort referencing is required from public examinations in the UK there is clearly a need to explore models with a sound theoretical basis whose evidence can be evaluated in terms of model fit, significance and effect size. The task of maintaining a performance standard can essentially be reduced under test theory to making comparisons between persons that are independent of the items on the basis of which these comparisons are made. Test theory however has been sparingly applied to comparability issues in UK public examinations. This study considers which test theory model would be most suited to the examinations in use in the UK, examines issues of model fit under frequentist and Bayesian frameworks, compares the results from different test equating methods and the practical issues of implementing a test equating design under the given constraints of the UK examination system. To begin with the Rasch model and the One Parameter Logistic Model were fitted to operational data gathered from examinations in a range of subject domains where marking reliability would not be considered as a potential confound. In this framework the Rasch model requirement of a single discrimination parameter across items appeared overly restrictive. Further, potential issues with model fit were highlighted related to dimensionality, guessing and weak local independence. More complex models were therefore pursued under a Bayesian framework. The Posterior Predictive Model Checking Procedures and Deviance Information Criterion confirmed that a model which allowed discrimination to vary across items, such as the two-parameter Item Response Theory model, would produce better model predictions. Use of the Multi-Class Mixture Rasch Model suggested that multidimensionality due to a confounding speededness factor could result in misleading inferences being drawn from unidimensional models. The Testlet Response Theory model showed enhanced predictions where weak local independence was correctly specified; however it proved difficult to specify where this weak local independence was expected. When tests from one of the examinations particularly affected by speededness were equated OPLM proved more robust to the confounding speededness factor than the Rasch model. A Post-equating Non-Equivalent Groups Design was then set up as an experiment using a set of relatively simple Science examinations and candidates at a later stage in their programme of study than those who would take the live examinations in order to understand some of the practical issues involved in equating designs. The study found that item parameters were not stable across samples due to context effects, school effects and maturity effects. These results were partly due to the scale of study, which, though small, still produced reasonably sensible outcomes. It is suggested that more care paid to the context of linking items, their underlying construct, and the sampling of schools would yield more robust results. Finally, a qualitative exploration of views related to test equating designs suggested that teachers, pupils and examiners would not reject the possibility of embedding equating items into live tests. For examinations where marking reliability is not considered an issue the results reported here suggest that the use of test theory could provide a unified theoretical framework for the maintenance of standards in UK public examinations which would allow the strength of the evidence presented to be evaluated. This would represent a substantial improvement over the current situation in which no comprehensive or coherent evaluation can be made. The time and investment required, however, to introduce such a framework is also substantial. A suitable technical infrastructure is required as well as psychometric expertise. The alternative is to revert to an examinations system that is essentially cohort referenced and focuses on discrimination between candidates in any one year rather than attempting to quality assure, as it cannot do, performance standards from one year to the next

ESSOPE: Towards S/C operations with reactive schedule planning

The ESSOPE is a prototype front-end tool running on a Sun workstation and interfacing to ESOC's MSSS spacecraft control system for the exchange of telecommand requests (to MSSS) and telemetry reports (from MSSS). ESSOPE combines an operations Planner-Scheduler, with a Schedule Execution Control function. Using an internal 'model' of the spacecraft, the Planner generates a schedule based on utilization requests for a variety of payload services by a community of Olympus users, and incorporating certain housekeeping operations. Conflicts based on operational constraints are automatically resolved, by employing one of several available strategies. The schedule is passed to the execution function which drives MSSS to perform it. When the schedule can no longer be met, either because the operator interferes (by delays or changes of requirements), or because ESSOPE has recognized some spacecraft anomalies, the Planner produces a modified schedule maintaining the on-going procedures as far as consistent with the new constraints or requirements

Chronic myeloid leukemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal

Leukaemic stem cell (LSC) persistence remains a major obstacle to curing chronic myeloid leukaemia (CML). The bone morphogenic protein (BMP) pathway is deregulated in CML, with altered expression and response to the BMP ligands shown to impact on LSC expansion and behaviour. In this study, we determined whether alterations in the BMP pathway gene signature had any predictive value for therapeutic response by profiling 60 CML samples at diagnosis from the UK SPIRIT2 trial and correlating the data to treatment response using the 18-month follow-up data. There was significant deregulation of several genes involved in the BMP pathway with ACV1C, INHBA, SMAD7, SNAIL1 and SMURF2 showing differential expression in relation to response. Therapeutic targeting of CML cells using BMP receptor inhibitors, in combination with tyrosine kinase inhibitor (TKI), indicate a synergistic mode of action. Furthermore, dual treatment resulted in altered cell cycle gene transcription and irreversible cell cycle arrest, along with increased apoptosis compared to single agents. Targeting CML CD34+ cells with BMP receptor inhibitors resulted in fewer cell divisions, reduced numbers of CD34+ cells and colony formation when compared to normal donor CD34+ cells, both in the presence and absence of BMP4. In an induced pluripotent stem cell (iPSC) model generated from CD34+ hematopoietic cells, we demonstrate altered cell cycle profiles and dynamics of ALK expression in CML-iPSCs in the presence and absence of BMP4 stimulation, when compared to normal iPSC. Moreover, dual targeting with TKI and BMP inhibitor prevented the self-renewal of CML-iPSC and increased meso-endodermal differentiation. These findings indicate that transformed stem cells may be more reliant on BMP signalling than normal stem cells. These changes offer a therapeutic window in CML, with intervention using BMP inhibitors in combination with TKI having the potential to target LSC self-renewal and improve long-term outcome for patients