Analysis of the clinical impact of NPM1 mutant allele burden in a large cohort of younger adult patients with acute myeloid leukaemia

Although an NPM1 mutation is generally considered to be a good prognostic marker in acute myeloid leukaemia, it has recently been suggested that a higher level of NPM1 mutant (NPM1MUT) alleles relative to wild‐type alleles is associated with poor clinical outcome. We therefore sought to confirm this finding in a larger study of 876 NPM1MUT cases entered into UK national trials. In univariate analysis, the higher NPM1MUT allele burden was associated with a lower complete remission (CR) rate, higher relapse rate and reduced overall survival, but this was largely attributable to the association of the higher NPM1MUT allele burden with other known poor risk factors, particularly the presence of a concomitant FLT3 internal tandem duplication. In multivariate analysis, there was no significant impact of the NPM1MUT allele burden on CR rates, and the impact on relapse and overall survival, whilst still significant, was greatly reduced. This impact was similar in patients who did or did not receive an allogeneic transplant in first CR. We conclude that the binary presence or absence of an NPM1 mutation, combined with minimal residual disease levels following induction therapy, should continue to be used in therapeutic management rather than stratification according to the NPM1MUT level

Vertical structure of near-bed cross-shore flow velocities in the swash zone of a dissipative beach

Cross-shore velocity profiles are measured at 0.001m vertical resolution and at 100Hz over the lower 0.02-0.07m of the water column in the mid swash zone on a dissipative, macrotidal beach. Swash motion is predominantly at infragravity frequencies and forced by significant wave heights exceeding 1.5m and peak wave periods over 15s. Observations of long duration (> 14s) swashes during two rising tides are used to quantify the vertical structure of cross-shore flow velocities and estimate corresponding bed shear stress and friction coefficients. Analysis is performed on an individual swash event to an elevation of 0.07 m and an ensemble event made up of 24 individual swash events to an elevation of 0.02m. Cross-shore velocities exceed 2 m s-1 and are of a similar magnitude during both the uprush and the backwash. Changes in velocity with elevation indicate that the swash zone boundary layer extends to 0.07m during the strongest flows and is well-represented by the logarithmic model applied to this elevation, except near flow reversal. Maximum bed shear stresses estimated using the logarithmic model are 22 N m-2 and 10 N m-2 for the individual event and ensemble event respectively and mean values are larger during the backwash than the uprush. Mean friction coefficients estimated from equating the logarithmic model and the quadratic drag law are 0.018 and 0.019 for the individual event and ensemble event respectively. Bed shear stress may be underestimated if the logarithmic model is fit to a velocity profile that is only part boundary layer, emphasising the need for high resolution velocity profiles close to the bed for accurate bed shear stress predictions in the swash zone

Therapy for isocitrate dehydrogenase 2 (IDH2)(R172)-mutant acute myeloid leukaemia

Although we earlier reported a very poor outcome for younger adult patients with isocitrate dehydrogenase 2 (IDH2)R172-mutated acute myeloid leukaemia (AML) entered into UK trials compared to IDH2WT and IDH2R140-mutated patients, this was not corroborated by a study from the German-Austrian AML Study Group. We have therefore investigated a later cohort of IDH2-mutated patients to identify any changes in outcome and whether this could inform the optimal treatment for IDH2R172 AML. We found an improved outcome for IDH2R172-mutated AML in the later trials and the data suggests that this may be due to the increased use of allogeneic transplantation to consolidate first remission

Background segmentation to enhance remote field eddy current signals

Pipe condition assessment is critical to avoid breakages. Remote Field Eddy Current (RFEC) is a commonly used technology to assess the condition of pipes. The nature of this technology induces some particular noise into its measurements. In this paper, we develop a 3D simulation based on the Finite Element Analysis to study the properties of this noise. Moreover, we propose a filtering process based on a modified version of graph-cuts segmentation method to remove the influence of this noise. Simulated data together with an experimental data-set obtained from a real RFEC inspection show the validity of the proposed approach

Additional impact of mutational genotype on prognostic determination in resistant and relapsed acute myeloid leukaemia

Outcome after failure of initial therapy in younger adult patients with acute myeloid leukaemia (AML) is highly variable. Cytogenetics, length of first remission (CR1) before relapse, and allogeneic transplantation are known prognostic factors, but the contribution of leukaemic genotype is less clear, particularly in resistant disease. Of 5,651 younger adult patients entered into UK MRC/NCRI AML trials between 1988 and 2014 with available FLT3ITD and NPM1 genotype, 326 (6%) had resistant disease and 2338 (41 %) relapsed after achieving CR1. Overall survival (OS) was significantly higher in relapsed compared to resistant disease (p = 0·03). Independent favourable prognostic factors for OS in resistant disease included lower blast cell percentage after two courses of induction therapy (p = 0.0006) and NPM1 mutant (NPM1MUT) (p = 0.04). In relapsed disease, longer CR1 was a favourable independent factor for attainment of CR2 (p < 0.0001) and OS from time of relapse (p < 0.0001), but CR2 rate and OS from relapse were significantly worse in those who had received an allograft in CR1 (respectively p < 0.05, p < 0·002). NPM1MUT was marginally beneficial for OS (p = 0.04). FLT3ITD and DNMT3AMUT were adverse factors for OS (respectively p < 0.0001, p = 0.02). Mutational analysis adds additional independent prognostic information to demographic features and previous therapy in patients with resistant and relapsed disease

Unrelated Helpers in a Primitively Eusocial Wasp: Is Helping Tailored Towards Direct Fitness?

The paper wasp Polistes dominulus is unique among the social insects in that nearly one-third of co-foundresses are completely unrelated to the dominant individual whose offspring they help to rear and yet reproductive skew is high. These unrelated subordinates stand to gain direct fitness through nest inheritance, raising the question of whether their behaviour is adaptively tailored towards maximizing inheritance prospects. Unusually, in this species, a wealth of theory and empirical data allows us to predict how unrelated subordinates should behave. Based on these predictions, here we compare helping in subordinates that are unrelated or related to the dominant wasp across an extensive range of field-based behavioural contexts. We find no differences in foraging effort, defense behaviour, aggression or inheritance rank between unrelated helpers and their related counterparts. Our study provides no evidence, across a number of behavioural scenarios, that the behaviour of unrelated subordinates is adaptively modified to promote direct fitness interests

Identification of novel modifiers of Aβ toxicity by transcriptomic analysis in the fruitfly.

The strongest risk factor for developing Alzheimer's Disease (AD) is age. Here, we study the relationship between ageing and AD using a systems biology approach that employs a Drosophila (fruitfly) model of AD in which the flies overexpress the human Aβ42 peptide. We identified 712 genes that are differentially expressed between control and Aβ-expressing flies. We further divided these genes according to how they change over the animal's lifetime and discovered that the AD-related gene expression signature is age-independent. We have identified a number of differentially expressed pathways that are likely to play an important role in the disease, including oxidative stress and innate immunity. In particular, we uncovered two new modifiers of the Aβ phenotype, namely Sod3 and PGRP-SC1b

The role of usability engineering in the development of an intelligent decision support system

This paper presents an overview of the usability engineering process for the development of a personalised clinical decision support system for the management of type 1 diabetes. The tool uses artificial intelligence (AI) techniques to provide insulin bolus dose advice and carbohydrate recommendations that adapt to the individual. We describe the role of human factors and user-centred design in the creation of medical systems that must adhere to international standards. We focus specifically on the formative evaluation stage of this process. The preliminary analysis of data shows promising results

Does BCR/ABL1 positive Acute Myeloid Leukaemia Exist?

The BCR/ABL1 fusion gene, usually carried by the Philadelphia chromosome (Ph) resulting from t(9;22)(q34;q11) or variants, is pathognomonic for chronic myeloid leukaemia (CML). It is also occasionally found in acute lymphoblastic leukaemia (ALL) mostly in adults and rarely in de novo acute myeloid leukaemia (AML). Array Comparative Genomic Hybridization (aCGH) was used to study six Ph(+)AML, three bi-lineage and four Ph(+)ALL searching for specific genomic profiles. Surprisingly, loss of the IKZF1 and/or CDKN2A genes, the hallmark of Ph(+)ALL, were recurrent findings in Ph(+)AML and accompanied cryptic deletions within the immunoglobulin and T cell receptor genes. The latter two losses have been shown to be part of 'hot spot' genome imbalances associated with BCR/ABL1 positive pre-B lymphoid phenotype in CML and Ph(+)ALL. We applied Significance Analysis of Microarrays (SAM) to data from the 'hot spot' regions to the Ph(+)AML and a further 40 BCR/ABL1(+) samples looking for differentiating features. After exclusion of the most dominant markers, SAM identified aberrations unique to de novo Ph(+)AML that involved relevant genes. While the biological and clinical significance of this specific genome signature remains to be uncovered, the unique loss within the immunoglobulin genes provides a simple test to enable the differentiation of clinically similar de novo Ph(+) AML and myeloid blast crisis of CML. © 2013 John Wiley & Sons Ltd and Crown