Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors

FLT3 mutations, either internal tandem duplications (ITDs) or aspartate residue 835 (D835) point mutations, are present in approximately one third of patients with acute myeloid leukemia (AML) and have been associated with an increased relapse rate. We have studied FLT3 mutations in paired presentation and relapse samples to ascertain the biology of these mutations and to evaluate whether they can be used as markers of minimal residual disease. At diagnosis, 24 patients were wild-type FLT3, and 4 acquired a FLT3 mutation at relapse (2 D835+, 2 ITD+), with a further patient acquiring an ITD at second relapse. Of 20 patients positive at diagnosis (18 ITD+, 2 D835+), 5 who were all originally ITD+ had no detectable mutation at relapse, as determined by a sensitive radioactive polymerase chain reaction. One of these patients had acquired an N-Ras mutation not detectable at presentation. Furthermore, another patient had a completely different ITD at relapse, which could not be detected in the presentation sample. These results indicate that FLT3 mutations are secondary events in leukemogenesis, are unstable, and thus should be used cautiously for the detection of minimal residual disease

Determination of the absorption length of CO2, Nd:YAG and high power diode laser radiation for a selected grouting material

The laser beam absorption lengths of CO2, Nd:YAG and a high power diode laser (HPDL) radiation for a newly developed SiO2/Al2O3-based tile grout have been determined through the application of Beer-Lambert’s law. The findings revealed marked differences in the absorption lengths despite the material having similar beam absorption coefficients for the lasers. The absorption lengths for the SiO2/Al2O3-based tile grout for CO2, Nd:YAG and HPDL radiation were calculated as being 23211 m, 1934 m and 1838 m respectively. Moreover, this method of laser beam absorption length determination, which has hitherto been used predominantly with lasers operated in the pulsed mode, is shown to be valid for use with lasers operated in the continuous wave (CW) mode, depending upon the material being treated

A portable high power diode laser-based single-stage ceramic tile grout sealing system

By means of a 60 W high power diode laser (HPDL) and a specially developed grout material the void between adjoining ceramic tiles has been successfully sealed. A single-stage process has been developed which uses a crushed ceramic tile mix to act as a tough, inexpensive bulk substrate and a glazed enamel surface to provide an impervious surface glaze. The single-stage ceramic tile grout sealing process yielded seals produced in normal atmospheric conditions that displayed no discernible cracks and porosities. The single-stage grout is simple to formulate and easy to apply. Tiles were successfully sealed with power densities as low as 200 kW/mm2 and at rates of up to 600 mm/min. Bonding of the enamel to the crushed ceramic tile mix was identified as being primarily due to van der Waals forces and, on a very small scale, some of the crushed ceramic tile mix material dissolving into the glaze. In terms of mechanical, physical and chemical characteristics, the single-stage ceramic tile grout was found to be far superior to the conventional epoxy tile grout and, in many instances, matched and occasionally surpassed that of the ceramic tiles themselves. What is more, the development of a hand-held HPDL beam delivery unit and the related procedures necessary to lead to the commercialisation of the single-stage ceramic tile grout sealing process are presented. Further, an appraisal of the potential hazards associated with the use of the HPDL in an industrial environment and the solutions implemented to ensure that the system complies with the relevant safety standards are given

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype

Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia.

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112?151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.Molecular Psychiatry advance online publication, 26 January 2016; doi:10.1038/mp.2015.225

Benefits of maximum likelihood estimators for fracture attribute analysis: Implications for permeability and up-scaling

The authors thank Andrew Hurst for support during the field work, and also Antonio Grippa, Giuseppe Palladino and Gustavo Zvirtes for help and constructive discussions during the field work. We are particularly grateful to Tom Manzocchi for his important comments that greatly improved the first version of this paper. We acknowledge constructive reviews by Julia Gale and Ken McCaffrey, which have greatly improved our manuscript. This work forms part of a NERC New Investigator award for David Healy (NE/I001743/1), which is gratefully acknowledged. Finally, Roberto Emanuele Rizzo is very appreciative of AFES (Aberdeen Formation Evaluation Society) for funding support during his PhD.Peer reviewedPublisher PD

Directed flow in Au+Au, Xe+CsI and Ni+Ni collisions and the nuclear equation of state

We present new experimental data on directed flow in collisions of Au+Au, Xe+CsI and Ni+Ni at incident energies from 90 to 400A MeV. We study the centrality and system dependence of integral and differential directed flow for particles selected according to charge. All the features of the experimental data are compared with Isospin Quantum Molecular Dynamics (IQMD) model calculations in an attempt to extract information about the nuclear matter equation of state (EoS). We show that the combination of rapidity and transverse momentum analysis of directed flow allow to disentangle various parametrizations in the model. At 400A MeV, a soft EoS with momentum dependent interactions is best suited to explain the experimental data in Au+Au and Xe+CsI, but in case of Ni+Ni the model underpredicts flow for any EoS. At 90A MeV incident beam energy, none of the IQMD parametrizations studied here is able to consistently explain the experimental data.Comment: RevTeX, 20 pages, 30 eps figures, accepted for publication in Phys. Rev. C. Data files available at http://www.gsi.de/~fopiwww/pub

Acute biphenotypic leukaemia: immunophenotypic and cytogenetic analysis

The incidence of acute biphenotypic leukaemia has ranged from less than 1% to almost 50% in various reports in the literature. This wide variability may be attributed to a number of reasons including lack of consistent diagnostic criteria, use of various panels of antibodies, and the failure to recognize the lack of lineage specificity of some of the antibodies used. The morphology, cytochemistry, immunophenotype and cytogenetics of acute biphenotypic leukaemias from our institution were studied. The diagnostic criteria took into consideration the morphology of the analysed cells, light scatter characteristics, and evaluation of antibody fluorescence histograms in determining whether the aberrant marker expression was arising from leukaemic blasts or differentiated bone marrow elements. Fifty-two of 746 cases (7%) fulfilled our criteria for acute biphenotypic leukaemias. These included 30 cases of acute lymphoblastic leukaemia (ALL) expressing myeloid antigens, 21 cases of acute myelogenous leukaemia (AML) expressing lymphoid markers, and one case of ALL expressing both B- and T-cell associated antigens. The acute biphenotypic leukaemia cases consisted of four major immunophenotypic subgroups: CD2± AML (11), CD19± AML (8), CD13 and/or CD33± ALL (24), CD11b± ALL (5) and others (4). Chromosomal analysis was carried out in 42/52 of the acute biphenotypic leukaemia cases; a clonal abnormality was found in 31 of these 42 cases. This study highlights the problems encountered in the diagnosis of acute biphenotypic leukaemia, some of which may be reponsible for the wide variation in the reported incidence of this leukaemia. We suggest that the use of strict, uniform diagnostic criteria may help in establishing a more consistent approach towards diagnosis of this leukaemic entity. We also suggest that biphenotypic leukaemia is comprised of biologically different groups of leukaemia based on immunophenotypic and cytogenetic findings.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73301/1/j.1365-2141.1993.tb03024.x.pd

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer : long-term survival results from the STAMPEDE trial

Background STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. Methods We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. Results Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P  0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden