Differentiation of hematopoietic stem cells is regulated by a concert of different transcription factors. Disturbed transcription factor function can be the basis of (pre)malignancies such as ...myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth factor independence 1b (Gfi1b) is a repressing transcription factor regulating quiescence of hematopoietic stem cells and differentiation of erythrocytes and platelets. Here, we show that low expression of
in blast cells is associated with an inferior prognosis of MDS and AML patients. Using different models of human MDS or AML, we demonstrate that AML development was accelerated with heterozygous loss of
, and latency was further decreased when
was conditionally deleted. Loss of
significantly increased the number of leukemic stem cells with upregulation of genes involved in leukemia development. On a molecular level, we found that loss of
led to epigenetic changes, increased levels of reactive oxygen species, as well as alteration in the p38/Akt/FoXO pathways. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS and AML development.
Abstract Women and families benefit from access to the full spectrum of reproductive care, including family planning services. We commend our family planning colleagues on their tireless dedication ...to preserve the rights of women through advocacy. While several of our perinatology peers have also set an example by dedication to these issues, advocacy for patient access to reproductive care options has not been a focus of the larger perinatology community. The time has come for individual perinatologists, as well as the overall perinatology community, to join them and do the work needed to preserve access to safe care, including contraception and abortion services. In this call to action, we detail several ways that individuals and the community can become more involved in working for reproductive rights.
Short duration gamma-ray bursts (SGRBs) are thought to be related to the violent merger of compact objects, such as neutron stars or black holes, which makes them promising sources of gravitational ...waves. The detection of a "kilonova"- likesignature associated to the Swift-detected GRB 130603B has suggested that this event is the result of a compact object merger. Our knowledge on SGRB has been, until now, mostly based on the absence of supernova signatures and the analysis of the host galaxies to which they cannot always be securely associated. Further progress has been significantly hampered by the faintness and rapid fading of their optical counterparts (afterglows), which has so far precluded spectroscopy of such events. Afterglow spectroscopy is the key tool to firmly determine the distance at which the burst was produced, crucial to understand its physics, and study its local environment. The merger is not associated with the most star-forming region of the galaxy; however, it did occur in a dense region, implying a rapid merger or a low natal kick velocity for the compact object binary.
Microwave radiation simplifies synthesis methods by reducing reaction times, requiring fewer materials, and also controlling reaction processes. We have successfully synthesized nanoparticles of iron ...oxide and zinc oxide coated on zeolite A using microwaves. The radiation assisted in displacing either ferrous or zinc ions from the pre-loaded zeolite network and increasing reaction speed with solution at the interface. Products were characterized by TEM, XRD, VSM, ICP-AES, and fluorescence. We demonstrate the ability of using cation-exchanged zeolites as microreactors to bias reactions onto the zeolite surface. Efficient structure-directed surface reactions are a potential route to making unique supported nanomaterials for applications such as sensors, environmental remediation, and chemical catalysis.
Summary
On 26 November 2000, the first autochthonous case of bovine spongiform encephalopathy (BSE) was detected in Germany. Since then, a total of 413 BSE cases have been confirmed, resulting in the ...culling and destruction of 17 313 heads of cattle. In view of the possible risks for human and animal health, Germany has adopted EU regulations along with some additional requirements concerning active surveillance and response measures after detecting a BSE‐positive animal. In this study, we used a stochastic model to estimate the costs incurred by the ensuing legislative amendments responding to BSE between November 2000 and December 2010. The total costs were estimated to range between 1847 and 2094 million Euros. They peaked in 2001 (about 394 million Euros) and declined since. About 54% of the costs (approximately 1000 million Euros) were incurred by the extension of the feed ban for animal protein to all farmed livestock. Active surveillance accounted for 21% (405 million Euros), the incineration of animal protein for 13% (249 million Euros) and the removal of specified risk material for 11% (225 million Euros). Only 1% of the costs was related to response measures after detecting a BSE‐positive animal, including indemnity payments for culled cattle and confiscated carcasses at the slaughterhouse.
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Background
Somatic mutations identified in patients with myelodysplastic syndromes (MDS) are associated with disease features and carry prognostic information independent of the International ...Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R). Risk models that include mutation information have been proposed, but not widely adopted. In practice, there is no consensus on how to best combine clinical information with tumor sequencing data to predict prognosis. To accomplish this, we must define the relevant genes to consider and accurately measure their prognostic impact. Here we examine the relationship between mutations in MDS-associated genes and clinically relevant measures, including overall survival, in a large, multi-center analysis of MDS patient cohorts collected around the globe.
Methods
Data on 3392 MDS patients gathered by members of the International Working Group for Prognosis in MDS-Molecular Committee were combined under the aegis of the MDS Foundation. Patients gave informed consent for collection of their data and tumor samples at their respective institutions in accordance with the Declaration of Helsinki. Samples were examined for somatic mutations primarily by next generation sequencing. Categorical variables were compared using a chi-squared test, while continuous variables were compared using a Wilcoxon rank-sum test. Overall survival (OS) was calculated from the date of the sequenced sample to the date of death and was censored at transplant or the last known follow-up time. P-values are two-sided and considered significant at the <0.001 level to adjust for multiple comparisons.
Results
Survival data were available for 3200 patients with a median follow up of 3.7 years and included 1671 deaths. Median survival of the cohort was 2.88 years. The 27 genes sequenced in at least half of the cohort and mutated in > 1.5% of samples were included for analysis (Figure 1). Mutations in 12 genes were strongly associated with shorter OS in univariate analyses (p<0.001 for each gene): ASXL1, CBL, EZH2, IDH2, NF1, NRAS, PTPN11, RUNX1, SRSF2, STAG2, TP53, and U2AF1. Only mutations of SF3B1 were associated with a longer OS at this significance threshold. The large size of the cohort allowed for more precise estimates of survival in less frequently mutated genes. For example, mutations of IDH2 (present in 3.4% of cases, n=103) were associated with shorter OS (hazard ratio HR 1.61, 95% confidence interval CI 1.26-2.05; p=0.0001) whereas IDH1 mutations (present in 2.4% of cases, n=77) were only marginal (HR 1.29, CI: 0.97-1.72; p=0.082), demonstrating the distinct impact of mutations in these highly related genes.
IPSS-R risk groups could be determined for 2173 patients and were strongly associated with OS. Adjusting the hazard ratio of death for IPSS-R risk groups identified several mutated genes with independent prognostic significance: TP53 (HR 2.37, CI 1.94-2.90), CBL (HR 1.57, CI 1.22-2.03), EZH2 (HR 1.55, CI 1.22-2.03), and RUNX1 (HR 1.50, CI 1.24-1.83). Mutations of U2AF1 (HR 1.29, CI 1.06-1.58) and ASXL1 (HR 1.21, CI 1.04-1.41) retained a more modest association with shorter OS. Adjustment for IPSS-R risk groups also moderated the favorable risk associated with mutations of SF3B1 (HR 0.83, CI 0.70-0.99). Patients without mutations in any of the 6 adverse genes above represented 58% of the fully sequenced cohort and had a longer median survival than patients with adverse mutations (4.8 years vs. 1.6 years respectively, p < 0.0001; Figure 2) even after correction for IPSS-R risk groups (adjusted HR 0.59, CI 0.51-0.67).
Multivariable analysis of this dataset will examine the combined contribution of mutated genes to prognosis. A mutation score based on survival risk will be proposed and internally validated. The impact of somatic mutation in patients traditionally considered lower risk will be explored.
Conclusions
This large study definitively validates the prognostic value of mutations in several MDS-associated genes while clarifying the significance of other, less frequently mutated ones. Mutations in several genes retain their prognostic significance after adjustment for IPSS-R risk groups, indicating that these select abnormalities could refine the prediction of prognosis when incorporated into a clinical scoring system such as the IPSS-RM. The results of this analysis will serve as the template with which to build an integrated molecular risk model for MDS.
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Bejar:Alexion: Other: ad hoc advisory board; Celgene: Consultancy, Honoraria; Genoptix Medical Laboratory: Consultancy, Honoraria, Patents & Royalties: MDS prognostic gene signature. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Shih:Novartis: Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incyte: Consultancy; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau. List:Celgene Corporation: Honoraria, Research Funding. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Campbell:14M genomics: Other: Co-founder and consultant. Ebert:Celgene: Consultancy; Genoptix: Consultancy, Patents & Royalties; H3 Biomedicine: Consultancy.
Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of ...mtDNA in the etiology of AD remains uncertain.
We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.
In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.
The current evidence linking common mtDNA variations with AD is not compelling.
Operation and performance of the NA60 silicon pixel telescope Banicz, K.; David, A.; Floris, M. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2005, Letnik:
539, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The NA60 experiment studies open charm and prompt dimuon production in proton–nucleus and nucleus–nucleus collisions at the CERN SPS. The high multiplicity of charged tracks produced in heavy-ion ...collisions imposes the use of silicon pixel detectors to perform an efficient tracking. This paper describes the design and assembly of the pixel telescope and performance results from three detector planes operated in the high charged particle multiplicity conditions of Pb–Pb collisions.
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