Acute myeloid leukaemia in the elderly: Clinical management and the application of molecular cytogenetic techniques

PhDIn Western Europe and North America, acute myeloid leukaemia (AML) is predominantly a disease of the elderly, with a median age at the time of presentation in excess of 60 years. However, many clinical trials in AML fail to recruit elderly adults due to a combination of strict entry criteria, or physician or patient bias. Thus, clinical outcome data from many trials may not be readily applicable to older patients with the disease. Furthermore, because the clinical outcome for many older patients with AML is frequently poor, elderly patients who receive intensive chemotherapy with curative intent are frequently selected for treatment on clinical criteria rather than on objective prognostic criteria that may define clinical outcome. The karyotype at the time of presentation may be considered one of the most important prognostic factors in adult AML. Therefore, the aim of this thesis were firstly to analyse the clinical outcome data from a cohort of elderly patients managed at a single centre in order to document the cytogenetic features of AML in an elderly population, to define the prognostic importance of presentation karyotype in the elderly, and to identify other prognostic factors. Retrospective analysis clearly demonstrated improved clinical outcome for older patients with AML over time, primarily as a consequence of improved supportive care and the delivery of more intensive chemotherapy. In addition, 'unfavourable' presentation karyotype, increasing age and raised serum LDH were found to correlate with poor clinical outcome Molecular cytogenetic techniques based upon fluorescence in-situ hybridisation technology offer the chance to detect and analyse cytogenetic aberrations at a higher resolution than can be achieved with conventional techniques. The cytogenetic data provided by comparative genomic hybridisation and mulitplex fluorescence in-situ hybridisation when used in the analysis of elderly patients with AML were found to correlate well with results obtained by conventional methods. Importantly, additive cytogenetic data were more likely to be provided if multiplex-fluorescence in-situ hybridisation was used in the analysis of cases with marker chromosomes or in cases with complex karyotype, although the technique was limited by an inability to reliably detect telomeric translocations. In addition, although both techniques can be used to complement conventional G-banding analysis, conventional FISH methods are often required to confirm the results.Joint Research Board of St Bartholomew's Hospital Imperial Cancer Research Fund

Reward-Related Dorsal Striatal Activity Differences between Former and Current Cocaine Dependent Individuals during an Interactive Competitive Game

Cocaine addiction is characterized by impulsivity, impaired social relationships, and abnormal mesocorticolimbic reward processing, but their interrelationships relative to stages of cocaine addiction are unclear. We assessed blood-oxygenation-level dependent (BOLD) signal in ventral and dorsal striatum during functional magnetic resonance imaging (fMRI) in current (CCD; n = 30) and former (FCD; n = 28) cocaine dependent subjects as well as healthy control (HC; n = 31) subjects while playing an interactive competitive Domino game involving risk-taking and reward/punishment processing. Out-of-scanner impulsivity-related measures were also collected. Although both FCD and CCD subjects scored significantly higher on impulsivity-related measures than did HC subjects, only FCD subjects had differences in striatal activation, specifically showing hypoactivation during their response to gains versus losses in right dorsal caudate, a brain region linked to habituation, cocaine craving and addiction maintenance. Right caudate activity in FCD subjects also correlated negatively with impulsivity-related measures of self-reported compulsivity and sensitivity to reward. These findings suggest that remitted cocaine dependence is associated with striatal dysfunction during social reward processing in a manner linked to compulsivity and reward sensitivity measures. Future research should investigate the extent to which such differences might reflect underlying vulnerabilities linked to cocaine-using propensities (e.g., relapses)

Transcriptional Landscape of the Prenatal Human Brain

Summary The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

The slipstream and wake of a high speed train

Abstract: This paper describes the results of experimentalwork to determine the structure of the slipstream and wake of a high speed train. The experiments were carried out using a 1/25th scale model of a four-coach train on a moving model rig (MMR). Flow velocities were measured using a rake of single hot films positioned close to the model side or roof. Tests were carried out at different model speeds, with and without the simulation of a crosswind. Velocity time histories for each configuration were obtained from ensemble averages of the results of a number of runs. A small number of particle imaging velocimetry (PIV) experiments were also carried out, and a wavelet analysis revealed details of the unsteady flow structure around the vehicle. It was shown that the flowfield around the vehicle could be divided into a number of different regions of distinct flow characteristics: an upstream region, a nose region, a boundary layer region, a near wake region and a far wake region. If the results were suitably normalized, the effect of model speed was small. The effect of crosswinds was to add an increment to the slipstream and wake velocities, and this resulted in very high slipstream velocities in the nose region