462 resultados para positionnement multidimensionnel (MDS)


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The diagnosis of patients with myelodysplastic syndromes (MDS) is largely dependent on morphologic examination of bone marrow aspirates. Several criteria that form the basis of the classifications and scoring systems most commonly used in clinical practice are affected by operator-dependent variation. To identify standardized molecular markers that would allow prediction of prognosis, we have used gene expression profiling (GEP) data on CD34+ cells from patients with MDS to determine the relationship between gene expression levels and prognosis.

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Introduction: Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown.

Materials and methods: Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n=8489), CML (n=3626) diagnosed 1992-2005; MDS (n=3072) and MPNs (n=2001) diagnosed 2001-2005; and controls (200,000 for AML/CML and 97,681 for MDS/MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13-month period prior to selection to reduce reverse causality.

Results: Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14-1.26], 1.25 [95% CI: 1.16-1.36]), influenza (ORs 1.16 [95% CI: 1.07-1.25], 1.29 [95% CI: 1.16-1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06-1.21], 1.22 [95% CI: 1.11-1.35]), pneumonia (ORs 1.28 [95% CI: 1.21-1.36], 1.52 [95% CI: 1.40-1.66]), sinusitis (ORs 1.23 [95% CI: 1.16-1.30], 1.25 [95% CI: 1.15-1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07-1.18], 1.26 [95% CI: 1.17-1.36]). Cellulitis (OR 1.51 [95% CI: 1.39-1.64]), herpes zoster (OR 1.31 [95% CI: 1.14-1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17-1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12-1.31]), pneumonia (OR 1.49 [95% CI: 1.37-1.62]), sinusitis (OR 1.19 [95% CI: 1.09-1.29]) and cellulitis (OR 1.43 [95% CI: 1.32-1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21-1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded.

Discussion: Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration.

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Solid organ transplant recipients have elevated cancer risks, owing in part to pharmacologic immunosuppression. However, little is known about risks for hematologic malignancies of myeloid origin. We linked the US Scientific Registry of Transplant Recipients with 15 population-based cancer registries to ascertain cancer occurrence among 207 859 solid organ transplants (1987–2009). Solid organ transplant recipients had a significantly elevated risk for myeloid neoplasms, with standardized incidence ratios (SIRs) of 4.6 (95% confidence interval 3.8–5.6; N=101) for myelodysplastic syndromes (MDS), 2.7 (2.2–3.2; N=125) for acute myeloid leukemia (AML), 2.3 (1.6–3.2; N=36) for chronic myeloid leukemia and 7.2 (5.4–9.3; N=57) for polycythemia vera. SIRs were highest among younger individuals and varied by time since transplantation and organ type (Poisson regression P<0.05 for all comparisons). Azathioprine for initial maintenance immunosuppression increased risk for MDS (P=0.0002) and AML (2–5 years after transplantation, P=0.0163). Overall survival following AML/MDS among transplant recipients was inferior to that of similar patients reported to US cancer registries (log-rank P<0.0001). Our novel finding of increased risks for specific myeloid neoplasms after solid organ transplantation supports a role for immune dysfunction in myeloid neoplasm etiology. The increased risks and inferior survival should heighten clinician awareness of myeloid neoplasms during follow-up of transplant recipients.

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Dietary pattern (DP) analysis allows examination of the combined effects of nutrients and foods on the markers of CVD. Very few studies have examined these relationships during adolescence or young adulthood. Traditional CVD risk biomarkers were analysed in 12-15-year-olds (n 487; Young Hearts (YH)1) and again in the same individuals at 20-25 years of age (n 487; YH3). Based on 7 d diet histories, in the present study, DP analysis was performed using a posteriori principal component analysis for the YH3 cohort and the a priori Mediterranean Diet Score (MDS) was calculated for both YH1 and YH3 cohorts. In the a posteriori DP analysis, YH3 participants adhering most closely to the 'healthy' DP were found to have lower pulse wave velocity (PWV) and homocysteine concentrations, the 'sweet tooth' DP were found to have increased LDL concentrations, systolic blood pressure, and diastolic blood pressure and decreased HDL concentrations, the 'drinker/social' DP were found to have lower LDL and homocysteine concentrations, but exhibited a trend towards a higher TAG concentration, and finally the 'Western' DP were found to have elevated homocysteine and HDL concentrations. In the a priori dietary score analysis, YH3 participants adhering most closely to the Mediterranean diet were found to exhibit a trend towards a lower PWV. MDS did not track between YH1 and YH3, and nor was there a longitudinal relationship between the change in the MDS and the change in CVD risk biomarkers. In conclusion, cross-sectional analysis revealed that some associations between DP and CVD risk biomarkers were already evident in the young adult population, namely the association between the healthy DP (and the MDS) and PWV; however, no longitudinal associations were observed between these relatively short time periods.

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Modifying induction therapy in AML may improve the remission rate and reduce the risk of relapse thereby improving survival. Escalation of the daunorubicin dose to 90mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45mg/m(2) and has been recommended as a standard of care. However 60mg/m(2) is widely used and has never been directly compared to 90mg/m(2). As part of the UK NCRI AML17 trial 1206 adults with untreated AML or high risk MDS, mostly under 60 years of age, were randomised to a first induction course of chemotherapy which delivered either 90mg/m(2) or 60mg/m(2) on days 1,3 and 5 combined with cytosine arabinoside. All patients then received a second course which included daunorubicin 50mg/m(2) on days 1,3 and 5. There was no overall difference in complete remission rate (CR) (73% vs 75%, OR1.07 (0.83-1.39), p=0.6) or in any recognised subgroup. The 60 day mortality was increased in the 90mg/m2 arm (10% vs 5% (HR 1.98(1.30-3.02) p=0.001)), which resulted in no difference in overall 2 year survival (59% vs 60%, HR 1.16(0.95-1.43), p=0.15). In exploratory subgroup analysis there was no subgroup which showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. The trial is registered to www.isrctn.com as ISRCTN55675535.

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The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34 + cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript andor exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicingprocessing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expressionsplicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34 + cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processespathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

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The presence of SF3B1 gene mutations is a hallmark of refractory anemia with ring sideroblasts (RARS). However, the mechanisms responsible for iron accumulation that characterize the Myelodysplastic Syndrome with ring sideroblasts (MDS-RS) are not completely understood. In order to gain insight in the molecular basis of MDS-RS, an integrative study of the expression and mutational status of genes related to iron and mitochondrial metabolism was carried out. A total of 231 low-risk MDS patients and 81 controls were studied. Gene expression analysis revealed that iron metabolism and mitochondrial function had the highest number of genes deregulated in RARS patients compared to controls and the refractory cytopenias with unilineage dysplasia (RCUD). Thus mitochondrial transporters SLC25 (SLC25A37 and SLC25A38) and ALAD genes were over-expressed in RARS. Moreover, significant differences were observed between patients with SF3B1 mutations and patients without the mutations. The deregulation of genes involved in iron and mitochondrial metabolism provides new insights in our knowledge of MDS-RS. New variants that could be involved in the pathogenesis of these diseases have been identified.

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The Pan-STARRS1 (PS1) survey has obtained imaging in five bands (grizyP1) over 10 Medium Deep Survey (MDS) fields covering a total of 70 square degrees. This paper describes the search for apparently hostless supernovae (SNe) within the first year of PS1 MDS data with an aim of discovering superluminous supernovae (SLSNe). A total of 249 hostless transients were discovered down to a limiting magnitude of MAB ∼ 23.5, of which 76 were classified as Type Ia supernovae (SNe Ia). There were 57 SNe with complete light curves that are likely core-collapse SNe (CCSNe) or type Ic SLSNe and 12 of these have had spectra taken. Of these 12 hostless, non-Type Ia SNe, 7 were SLSNe of type Ic at redshifts between 0.5 and 1.4. This illustrates that the discovery rate of type Ic SLSNe can be maximized by concentrating on hostless transients and removing normal SNe Ia. We present data for two possible SLSNe; PS1-10pm (z = 1.206) and PS1-10ahf (z = 1.1), and estimate the rate of type Ic SLSNe to be between 3+3−2×10−53+3−2×10−53+3−2×10−5 and 8+2−1×10−58+2−1×10−58+2−1×10−5 that of the CCSN rate within 0.3 ≤ z ≤ 1.4 by applying a Monte Carlo technique. The rate of slowly evolving, type Ic SLSNe (such as SN2007bi) is estimated as a factor of 10 lower than this range.

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We present a novel method for the light-curve characterization of Pan-STARRS1 Medium Deep Survey (PS1 MDS) extragalactic sources into stochastic variables (SVs) and burst-like (BL) transients, using multi-band image-differencing time-series data. We select detections in difference images associated with galaxy hosts using a star/galaxy catalog extracted from the deep PS1 MDS stacked images, and adopt a maximum a posteriori formulation to model their difference-flux time-series in four Pan-STARRS1 photometric bands gP1, rP1, iP1, and zP1. We use three deterministic light-curve models to fit BL transients; a Gaussian, a Gamma distribution, and an analytic supernova (SN) model, and one stochastic light-curve model, the Ornstein-Uhlenbeck process, in order to fit variability that is characteristic of active galactic nuclei (AGNs). We assess the quality of fit of the models band-wise and source-wise, using their estimated leave-out-one cross-validation likelihoods and corrected Akaike information criteria. We then apply a K-means clustering algorithm on these statistics, to determine the source classification in each band. The final source classification is derived as a combination of the individual filter classifications, resulting in two measures of classification quality, from the averages across the photometric filters of (1) the classifications determined from the closest K-means cluster centers, and (2) the square distances from the clustering centers in the K-means clustering spaces. For a verification set of AGNs and SNe, we show that SV and BL occupy distinct regions in the plane constituted by these measures. We use our clustering method to characterize 4361 extragalactic image difference detected sources, in the first 2.5 yr of the PS1 MDS, into 1529 BL, and 2262 SV, with a purity of 95.00% for AGNs, and 90.97% for SN based on our verification sets. We combine our light-curve classifications with their nuclear or off-nuclear host galaxy offsets, to define a robust photometric sample of 1233 AGNs and 812 SNe. With these two samples, we characterize their variability and host galaxy properties, and identify simple photometric priors that would enable their real-time identification in future wide-field synoptic surveys.

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In the past decade, several rapidly evolving transients have been discovered whose timescales and luminosities are not easily explained by traditional supernovae (SNe) models. The sample size of these objects has remained small due, at least in part, to the challenges of detecting short timescale transients with traditional survey cadences. Here we present the results from a search within the Pan-STARRS1 Medium Deep Survey (PS1-MDS) for rapidly evolving and luminous transients. We identify 10 new transients with a time above half-maximum (t1/2) of less than 12 days and -16.5 > M > -20 mag. This increases the number of known events in this region of SN phase space by roughly a factor of three. The median redshift of the PS1-MDS sample is z = 0.275 and they all exploded in star-forming galaxies. In general, the transients possess faster rise than decline timescale and blue colors at maximum light (gP1-rP1 ≲ -0.2). Best-fit blackbodies reveal photospheric temperatures/radii that expand/cool with time and explosion spectra taken near maximum light are dominated by a blue continuum, consistent with a hot, optically thick, ejecta. We find it difficult to reconcile the short timescale, high peak luminosity (L > 1043erg s-1), and lack of UV line blanketing observed in many of these transients with an explosion powered mainly by the radioactive decay of 56Ni. Rather, we find that many are consistent with either (1) cooling envelope emission from the explosion of a star with a low-mass extended envelope that ejected very little (<0.03 M) radioactive material, or (2) a shock breakout within a dense, optically thick, wind surrounding the progenitor star. After calculating the detection efficiency for objects with rapid timescales in the PS1-MDS we find a volumetric rate of 4800-8000 events yr-1Gpc-3(4%-7% of the core-collapse SN rate at z = 0.2).

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Malignant initiation, leukaemic transformation, and disease progression in haematological malignancies involves a series of mutational events in genes involved in normal housekeeping functions of the cell. These acquired genetic changes can lead to either increased proliferation or a decreased rate of apoptosis, thus allowing expansion of the malignant clone. Although leukaemia can arise as a de novo disease, it has become increasingly clear that therapies, including the use of irradiation and/or chemotherapy, can give rise to malignancy. Therapy-associated myelodysplasia (t-MDS) and therapy-associated acute myeloid leukaemia (t-AML) account for 10-20% of new cases of these diseases. Although these secondary malignancies have been recognised as a clinical entity for nearly 30 years, molecular studies are now pinpointing various regions of the genome that are susceptible to DNA damage by these chemotherapeutic/radiotherapeutic strategies. The detection of new malignancies (both solid tumours and haematological tumours) following allogeneic bone marrow transplantation (BMT) is also providing us with some clues to the nature of leukaemogenesis, particularly with the observation that leukaemia can occur in donor cells postallogeneic BMT.

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Myelodysplastic syndromes (MDS) represent a broad spectrum of diseases characterized by their clinical manifestation as one or more cytopenias, or a reduction in circulating blood cells. MDS is predominantly a disease of the elderly, with a median age in the UK of around 75. Approximately one third of MDS patients will develop secondary acute myeloid leukemia (sAML) that has a very poor prognosis. Unfortunately, most standard cytotoxic agents are often too toxic for older patients. This means there is a pressing unmet need for novel therapies that have fewer side effects to assist this vulnerable group. This challenge was tackled using bioinformatic analysis of available transcriptomic data to establish a gene-based signature of the development and progression of MDS. This signature was then used to identify novel therapeutic compounds via statistically-significant connectivity mapping. This approach suggested re-purposing an existing and widely-prescribed drug, bromocriptine as a novel potential therapy in these disease settings. This drug has shown selectivity for leukemic cells as well as synergy with current therapies.

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Este relatório foi elaborado no âmbito do lote 7 (Inserção Curricular da Intercompreensão) do projeto MIRIADI. Trata-se de um lote cujo objetivo é desenvolver processos de integração curricular da Intercompreensão (IC) à distância em grupos plurilingues, a partir de trabalhos experimentais levados a cabo no terreno e realizados numa lógica de investigação-ação, tendo em vista compreender as “condições de exequibilidade” desta abordagem didática nos curricula de aprendizagem de línguas e de formação. Procura-se, em particular, identificar empiricamente permeabilidades e resistências dos contextos e dos atores educativos face à IC como conceito prático com relevância profissional, bem como vantagens e limites do ponto de vista da aprendizagem linguística que possam justificar o seu valor educativo. A Intercompreensão tem vindo, nas últimas décadas, a percorrer um percurso de destaque em Didática de Línguas (sobretudo Estrangeiras) na Europa e fora dela, em particular no âmbito das atuais abordagens plurais, ocupando um lugar de visibilidade nos discursos e práticas de investigação e formação desta disciplina e contribuindo para a tonalidade da sua voz mais propriamente politico-ideológica (Alarcão, Andrade, Araújo e Sá, Melo-Pfeifer & Santos, 2009). Contudo, a presença do conceito nos espaços concretos de educação em línguas (tais como escolas, liceus, universidades e outras instituições) é extremamente débil, limitando-se a algumas experiências pontuais, sob o impulso (e mesmo a condução), na maior parte dos casos, dos investigadores e tendo como finalidade principal a produção de conhecimento didático (Degache & Tavares, 2011). Assim, pouco se sabe ainda do que pode ser efetivamente o contributo da IC para o projeto educativo das instituições, e muito menos do modo como o conceito pode ser integrado em práticas curriculares continuadas e sistemáticas de educação em línguas, sabendo-se que estas mesmas práticas são reguladas por múltiplas instâncias, internas e externas, objetivas e subjetivas, que atuam a vários níveis (macro, meso, micro) e que não podem deixar de ser consideradas. O lote 7 de Miriadi propõe abordar estas questões, relativas à integração curricular da IC, a partir de uma outra lógica epistemológica, uma lógica que não busca propostas desenhadas a partir dos resultados da investigação e orientadas para a transferência do conhecimento, ou seja, que não reflete uma perspetiva aplicacionista do saber didático. Ao invés, o trabalho realizado por este lote entende o currículo como uma construção dinâmica que se (re)define e se (re)negocia em função dos contextos específicos em que ocorre, atribuindo-lhe por conseguinte uma natureza contingente, situada, intersubjetiva e local. Nesta perspetiva sócio-construtivista, em que o currículo é uma co-construção que ocorre entre sujeitos precisos nas suas ações educativas quotidianas, a integração curricular da IC produz-se no âmbito destas ações, ou, dito de outra forma, através de práticas situadas nas especificidades e possibilidades que oferecem os contextos concretos, em particular os sujeitos que deles fazem parte. Esta perspetiva de trabalho do lote 7 parece-nos ser a mais coerente com o posicionamento teórico relativamente à IC enquanto conceito didático do projeto MIRIADI. Com efeito, está amplamente estudado que a IC tem vindo a ser tratada segundo diferentes pontos de vista, de acordo com as escolas epistemológicas e as proveniências e ancoragens disciplinares dos seus autores (para uma revisão recente, ver Araújo e Sá, 2013; Olliver, 2013). No âmbito do percurso específico de investigação/formação/intervenção do grupo e-Gala (www.e-gala.eu), no seio do qual emergiu MIRIADI, em particular das suas mais disseminadas realizações – as plataformas Galanet (www.galanet.eu) e Galapro (www-galapro.eu/sessions) -, a IC é abordada numa perspetiva socio-construtivista do saber e da relação comunicativa. Dito de outra forma, MIRIADI define a IC como um processo e uma prática interacional que ocorre entre sujeitos, atores sociais que vivem em diferentes línguas e que se implicam coletivamente num quadro dialógico “où le grand enjeu devient la construction d’un territoire de parole partagé” (Araújo e Sá, Degache & Spita, 2010: 26). Esta aceção interacionista (e plurilingue e intercultural) é complementada pelo recurso a meios de comunicação tecnológicos. Definido o enquadramento conceptual e metodológico do lote7, importa agora explicitar como se desenvolveu o trabalho ao longo dos seus 36 meses de execução. O lote organizou-se em 3 grandes etapas, que envolveram toda a equipa: Etapa 1. Identificação e caracterização de contextos de ensino e formação linguística suscetíveis de poderem beneficiar de uma integração curricular da IC (plurilingue e à distância) (os resultados desta etapa encontram-se na Prestation 7.1. do projeto, referida na nota anterior). Etapa 2. Planificação e desenvolvimento de múltiplas e diversificadas iniciativas de divulgação da IC nesses mesmos contextos, destinadas à comunidade educativa na generalidade (públicos, professores/formadores, órgãos de gestão, funcionários, etc.), tendo em vista a sua familiarização com a IC enquanto conceito didático e prática de educação em línguas, de modo a criar condições (e aberturas) para a sua integração curricular; uma atenção especial foi dada à formação dos agentes educativos. Etapa 3. Planificação, experimentação e avaliação, numa lógica de investigação-ação e em rede (aproveitando-se as potencialidades das plataformas Galapro e Galanet), de propostas de integração curricular da IC; pretendia-se, em especial, com estas propostas, identificar contributos da IC para a qualidade dos projetos educativos dos contextos de integração caracterizados (na etapa 1), mas também constrangimentos, fragilidades, obstáculos e resistências, numa abordagem crítica do conceito que fosse sensível às propriedades dos espaços-alvo de educação em línguas. Neste sentido, foram recolhidos, analisados e discutidos, em função das suas características contextuais (definidas na etapa 1), dados empíricos de natureza diversa (produções dos alunos, transcrições de excertos de aulas, testemunhos espontâneos de alunos e professores, respostas a questionários, entre outros). Este Rapport é um produto da Etapa 3. Trata-se de um documento multimédia, que pretende dar acesso sistematizado e crítico aos discursos e vozes de sujeitos reais que experienciaram propostas didáticas concretas de IC elaboradas durante esta etapa do lote. Mais concretamente, este relatório oferece 6 narrativas de estudos de caso (3 em contexto de ensino secundário e outros 3 no ensino superior), realizados em vários países (Brasil, França, Itália Portugal e República da Maurícia), contendo uma descrição detalhada das situações educativas experimentadas e uma análise dos dados recolhidos, com apresentação dos recursos e materiais utilizados e testemunhos dos sujeitos concretos (professores e alunos). Incluem-se igualmente os instrumentos de recolha de dados e alguns exemplos dos mesmos. Cada narrativa obedece a uma mesma estrutura discursiva, de forma a mais facilmente poderem ser comparáveis, permitindo a extração de conclusões transversais aos vários estudos: introdução; descrição do contexto de intervenção; descrição da intervenção (objetivos, atividades, com acesso aos recursos utilizados, e avaliação); resultados obtidos; conclusões e implicações A secção final, “Témoignages”, apresenta-se sob a forma de um conjunto de vídeos e podcasts, identificados de acordo com a instituição parceira do projeto que os recolheu e organizados segundo três critérios: • as línguas dos locutores (espanhol, francês, italiano e português); • os contextos de formação onde decorreram as experiências de IC (ensino secundário e ensino universitário); • o tipo de intervenientes nas experiências de IC (alunos ou professores). Assume-se mais uma vez, neste Rapport, as dinâmicas de trabalho plurilingue da equipa Miriadi, cuja rentabilidade para a produção do conhecimento didático foi analisada e evidenciada no âmbito de projetos anteriores (ver Melo-Pfeifer, 2014) e se encontra ilustrada, numa outra linguagem, nos nossos postais (disponíveis no Facebook). Assim, com exceção desta introdução, que foi traduzida para francês (ver acima), o documento encontra-se nas línguas de trabalho dos membros da equipa que o redigiram.

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Dissertação de Mestrado, Aquacultura e Pescas, Faculdade de Ciências do Mar e do Ambiente, Universidade do Algarve, 2008