The added value of IKZF1 gene deletion (IKZF1(del)) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of ...the impact of IKZF1(del) in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1(del) had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75-3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1(del) remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1(del) increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19-5.55; P=0.013) and in 'B-other' ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45-3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1(del)-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3-99.0 versus 42.1; 95% CI=20.4-62.5). Thus, IKZF1(del) retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in 'B-other' ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1(del) patients in preventing relapses.
Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple ...café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.
Numerous manmade chemicals released into the environment can interfere with normal, hormonally regulated biological processes to adversely affect the development and reproductive functions of living ...species. Various in vivo and in vitro tests have been designed for detecting endocrine disruptors, but the number of chemicals to test is so high that to save time and money, (quantitative) structure-activity relationship ((Q)SAR) models are increasingly used as a surrogate for these laboratory assays. However, most of them focus only on a specific target (e.g. estrogenic or androgenic receptor) while, to be more efficient, endocrine disruption modelling should preferentially consider profiles of activities to better gauge this complex phenomenon. In this context, an attempt was made to evaluate the endocrine disruption profile of 220 structurally diverse pesticides using the Endocrine Disruptome simulation (EDS) tool, which simultaneously predicts the probability of binding of chemicals on 12 nuclear receptors. In a first step, the EDS web-based system was successfully applied to 16 pharmaceutical compounds known to target at least one of the studied receptors. About 13% of the studied pesticides were estimated to be potential disruptors of the endocrine system due to their high predicted affinity for at least one receptor. In contrast, about 55% of them were unlikely to be endocrine disruptors. The simulation results are discussed and some comments on the use of the EDS tool are made.
A suite of models is proposed for estimating the risk of pesticides against the grey partridge (Perdix perdix) and their clutches. Radio-tracked data of females, description and location of the ...clutches, and data on the pesticide treatments during the laying periods of the partridges were used as basic information. Quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) modelling allowed us to characterize the pesticides by their 1-octanol/water partition coefficient (log P), vapour pressure, primary and ultimate biodegradation potential, acute toxicity (LD
50
) on P. perdix, and endocrine disruption potential. From these physicochemical and toxicological data, the system of integration of risk with interaction of scores (SIRIS) method was used to design scores of risk for pesticides, alone or in mixture. A program, written in R (version 3.1.1), called Simulation of Toxicity in Perdix perdix (SimToxPP), was designed for estimating the risk of substances, considered alone or in mixture, against the grey partridge during breeding. The software tool is flexible enough to simulate realistic in situ scenarios. Different examples of applications are shown. The advantages and limitations of the approach are briefly discussed.
The surface tension of liquid silicon at high temperature Millot, F.; Sarou-Kanian, V.; Rifflet, J.-C. ...
Materials science & engineering. A, Structural materials : properties, microstructure and processing,
11/2008, Letnik:
495, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
The measurement of the surface tension of liquid silicon has a long history with many results but no general agreement between them. Two values at the melting temperature are cited in reviews (749 ...and 827
mN/m N. Eustathopoulos, E. Ricci, B. Drevet, Note Technique DEM No. 97/58, CEA, 1997) but there are few arguments to determine the correct one. In the present study, new data for the surface tension obtained with the analysis of characteristic frequencies of a levitating drop are presented. The effect of oxygen and nitrogen are also considered. These data are compared with former data obtained with contactless techniques. The most recent surface tension values obtained with drop weights ranging on two orders of magnitude and environments of different natures (argon, hydrogen and vacuum) show excellent agreement (within a 1.5% margin) at temperatures between 1350
K and 2400
K. The comparison of these data to others obtained with different techniques, reveal a good agreement, except those obtained with the sessile drop technique on some supports like BN, SiO
2 and MgO. However, these special cases may be connected with the reactivity of silicon with these supports.
To evaluate the prognostic significance of initial central nervous system (CNS) involvement of children with acute lymphoblastic leukemia (ALL) enrolled in the EORTC 58951 trial.
From 1998 to 2008, ...1930 ALL patients were included in the randomized EORTC 58951 trial. Overall treatment intensity was adjusted according to known prognostic factors including the level of minimal residual disease after induction treatment. CNS-directed therapy comprised four to 11 courses of i.v. methotrexate (5g/m2), and 10 to 19 intrathecal chemotherapy injections, depending on risk group and CNS status. Cranial irradiation was omitted for all patients.
The overall 8-year event-free survival (EFS) and overall survival (OS) rates were 81.3% and 88.1%, respectively. In the CNS-1, TPL+, CNS-2, and CNS-3 groups, the 8-year EFS rates were 82.1%, 77.1%, 78.3%, and 57.4%, respectively. Multivariable analysis indicated that initial CNS-3 status, but not CNS-2 or TLP+, was an independent adverse predictor of outcome. The 8-year incidence of isolated CNS relapse was 1.7% and of isolated or combined CNS relapse it was 3.7%. NCI high-risk group, male sex, CNS-2 and CNS-3 status were independent predictors for a higher incidence of any CNS relapse.
CNS-3 status remains associated with poor prognosis and requires intensification of both systemic and CNS-directed therapy.
This trial was registered at https://clinicaltrials.gov/under/NCT00003728.
Infectious diseases are still an important cause of morbidity and mortality in high-income countries and may preferentially affect predisposed children, especially immunocompromised children. We ...aimed to evaluate the frequency of recommended immunological tests in children with community-onset severe bacterial infection (COSBI) admitted to a pediatric intensive care unit. We also assessed the frequency and described the typology of diagnosed primary immune deficiency (PID).
We conducted a retrospective observational epidemiological study in six university hospitals in western France. All children from 1 month to 16 years of age admitted to hospital for bacterial meningitis, purpura fulminans, or meningococcal disease between August 2009 and January 2014 were included. We analyzed the frequency, type, and results of the immunological tests performed on children with meningitis, purpura fulminans, or a meningococcemia episode.
Among the 143 children included (144 episodes), 84 (59%) and 60 (41%) had bacterial meningitis and purpura fulminans or meningococcemia, respectively: 72 (50%) had immunological tests and 8% had a complete immunological investigation as recommended. Among the 72 children examined for PID, 11 (15%) had at least one anomaly in the immunological test results. Two children had a diagnosis of PID (one with C2 deficit and the other with C8 deficit) and seven other children had possible PID. Thus, the prevalence of a definite or possible diagnosis of PID was 12% among the children examined.
PID is rarely investigated after COSBI. We raise awareness of the need for immunological investigations after a severe infection requiring PICU admission.
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