1,720,963 research outputs found
Transformation Mechanisms of the Nfia-ETO2 Fusion Gene Associated with Pediatric Pure Acute Erythroleukemia
No full textPure erythroleukemia (PEL) is a very aggressive, but poorly understood form of acute myeloid leukemia characterized by malignant accumulation of erythroid progenitor cells. A novel t(1;16)(p31;q24) chromosomal translocation leading to expression of a fusion between the nuclear factor I A (NFIA) and the ETO2 transcriptional co-regulator (a.k.a. CBFA2T3 or MTG16) has been identified in pediatric patients with PEL. Based on the function of the fusion partners, we hypothesized that NFIA-ETO2 (N-E) might initiate PEL by interfering with erythroid differentiation. To investigate its function, we cloned a full-length ORF and retrovirally expressed N-E in primary mouse bone marrow (BM)- and fetal liver (FL)-derived erythroblasts (EB). N-E expression significantly increased proliferation and blocked differentiation of EB. N-E expressing BM-derived hematopoietic stem and progenitor cells (HSPC) could be plated in erythropoietin (EPO)-containing methylcellulose (MC) for up to 3 rounds. Expression of N-E deletion mutants lacking the NFIA DNA-binding, the ETO2 NHR2 or NHR4 (ΔNHR4) transcriptional repression domains were unable to block erythroid differentiation. Notably, interfering with the ETO2-NHR2 oligomerization domain by overexpressing a competing peptide overcame the N-E-mediated differentiation block. Transplantation of N-E-expressing BM-derived HSPC into irradiated syngenic mice did not induce any disease suggesting the need of genetic cooperation. As TP53 gain-of-function (GOF) mutations are molecular hallmarks of PEL, we explored functional cooperation by using a conditional TP53R248Q allele. Interestingly, the TP53 status did not affect EB in vitro proliferation or differentiation. However, N-E expression increased proliferation of TP53R248Q+ EB and resulted in the formation of abnormal round and dense colonies in MC that could be serially propagated. In addition, transplantation of N-E-expressing TP53R248Q+ EB into irradiated recipients induced a transplantable PEL-like disease after a median latency of 4 months. Symptomatic mice presented with anemia, thrombocytopenia, multi-organ tumor cell infiltration and increased white blood cell counts. To better understand the molecular mechanism, we compared the gene expression signatures before and 24 hours after induced differentiation of FL-derived EB expressing WT or the inactive ΔNHR4 N-E mutant, in presence or absence of TP53R248Q. Principal component analysis (PCA) revealed a clear separation between the transcriptomes of WT EB expressing either the active or the inactive ΔNHR4 N-E (PC1:54.7%) and by their erythroid differentiation stage (PC2:9.07%). Overall, we observed 3753 (FDR<0.05, logFC>1.5) differentially expressed genes. Many of the significantly higher expressed genes (2313/3753) were related to hematopoietic stemness (GSEAs, p<0.001). Almost 10% of the significantly lower expressed genes (92/1440) were linked to the erythroid lineage development and to erythropoietic targets of NFIA or the erythroid master regulator GATA1. Interestingly, we also found reduced expression of genes encoding for ETO2-interacting transcription factors including TAL1 and KLF1. Despite a critical role on disease progression, PCA showed only minimal changes in the N-E expression signature in presence or absence of TP53R248Q with only 12 genes differently expressed (FDR<0.05, logFC>1). These genes were previously shown to be oncogenic mediators of TP53-GOF mutations, related to metabolism and transcriptional regulation. Interestingly, the signature of differentially expressed genes in N-E transformed FL-derived EB were significantly differentially expressed in tumor cells from pediatric but not adult PEL patients (p=0.00045), indicating the pediatric origin of the fusion. Collectively, we found that the PEL-associated N-E fusion blocks erythroid differentiation, and cooperates with a TP53-GOF mutation to induce a PEL-like disease in mice that phenocopies the human disease. Mechanistically, its activity seems to correlate with repression of erythroid regulatory genes controlled by the fusion partners NFIA, ETO2, and the erythroid master regulator GATA1. Disclosures No relevant conflicts of interest to declare
The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53
No full textThe NFIA-ETO2 fusion is the product of a t(1;16)(p31;q24) chromosomal translocation so far exclusively found in pediatric patients with pure erythroid leukemia (PEL). To address the role for the pathogenesis of the disease, we expressed the NFIA-ETO2 fusion in murine erythroblasts. We observed that NFIA-ETO2 significantly increased proliferation and impaired erythroid differentiation of murine erythroleuemia (MEL) cells and of primary fetal liver-derived erythroblasts. However, NFIA-ETO2-expressing erythroblasts acquired neither aberrant in vitro clonogenic activity nor disease-inducing potential upon transplantation into irradiated syngenic mice. In contrast, in the presence of one of the most prevalent erythroleukemia-associated mutations, TP53R248Q, expression of NFIA-ETO2 resulted in aberrant clonogenic activity, and induced a fully penetrant transplantable PEL-like disease in mice. Molecular studies support that NFIA-ETO2 interferes with erythroid differentiation by preferentially binding and repressing erythroid genes that contain NFI binding sites and/or are decorated by ETO2, resulting in a activity shift from GATA- to ETS-motif-containing target genes. In contrast, TP53R248Q does not affect erythroid differentiation but provides self-renewal and survival potential, mostly via downregulation of known TP53 targets. Collectively, our work indicates that NFIA-ETO2 initiates PEL by suppressing gene expression programs of terminal erythroid differentiation and cooperates with TP53 mutation to induce erythroleukemia
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Avaliação de polimorfismos de único nucleotídeo e expressão do gene SOCS5 em pacientes com Carcinoma Hepatocelular (CHC)
Full text linkO Carcinoma Hepatocelular (CHC) é a forma mais comum de câncer primário do fígado, caracterizado por um diagnóstico geralmente tardio. Assim, estudos que identifiquem biomarcadores que auxiliem no diagnóstico precoce de tumores são necessários, como os que destacam a relação do gene SOCS5 na tumorigênese do CHC. Desse modo, o objetivo do estudo foi avaliar os polimorfismos de único nucleotídeo e expressão gênica do gene SOCS5 em pacientes com Carcinoma Hepatocelular (CHC). Este estudo transversal foi realizado com a comparação dos grupos CHC e cirrótico, ambos com diagnóstico confirmado. O DNA analisado foi extraído de amostras de sangue periférico, já o RNA total foi extraído a partir de células mononucleares do sangue periférico (PBMC), sendo o material genético submetido às metodologias de RT-PCR, sequenciamento de Sanger e qPCR para análise de polimorfismos presentes no gene e diferenças da expressão gênica relativa, respectivamente. Para as análises do sequenciamento foram utilizadas as ferramentas BioEdit e Geneious, foram executados ensaios de genotipagem e expressão gênica, sendo realizadas análises de correlação, sobrevida e regressão logística, admitindo para todas análises o nível de significância fixado em p≤ 0,05. Foram encontrados quatro polimorfismos na região gênica do SOCS5, com destaque para o rs6738426, que se apresentou de forma semelhantes entre os grupos analisados. Em relação à expressão do gene, foi observado que pacientes cirróticos com classificação Child-Pugh A apresentaram maiores níveis de SOCS5, indicando que, possivelmente nesse grupo, o gene apresenta um papel supressor de tumor, provavelmente por meio do feedback negativo das vias JAK/STAT. Já nos pacientes com CHC, foi verificada uma menor sobrevida naqueles com níveis elevados de expressão de SOCS5, indicando um papel tumorigênico, provavelmente devido ao feedback positivo da via PI3K/Akt/mTOR. Na análise multivariada, a susceptibilidade ao CHC foi associada à idade [p= 0,003 OR 0,924 IC (0,877-0,9740)] e aos níveis de HDL [(p= 0,043 OR 1,032 IC (1,001 – 1,065)], sendo o aumento da idade e a diminuição do HDL considerados fatores de risco. Deste modo, propõe-se que o gene SOCS5 pode desempenhar um importante papel no processo tumorigênico, podendo atuar de forma oncogênica ou antitumorigênica. No entanto, estudos com coorte maior de amostras são indicados para validar os resultados aqui encontrados, assim como a análise do impacto do SOCS5 dentro das vias JAK/STAT e PI3K/Akt/ mTOR, por meio de ensaios de silenciamento e superexpressão do gene.Hepatocellular Carcinoma (HCC) is the most common type of primary liver cancer, characterized by a typically late diagnosis. Therefore, studies identifying biomarkers that may help in early diagnosis of tumors are necessary, such as those highlighting the relationship of the SOCS5 gene in HCC tumorigenesis. Thus, the aim of the study was to evaluate single nucleotide polymorphisms and gene expression of the SOCS5 gene in patients with HCC. This cross-sectional study was conducted by comparing HCC and cirrhotic groups, both with confirmed diagnoses. The analyzed DNA was extracted from peripheral blood samples, while total RNA was extracted from peripheral blood mononuclear cells (PBMC), and the genetic material was subjected to RT-PCR, Sanger sequencing, and qPCR methodologies for the analysis of gene polymorphisms and relative gene expression differences, respectively. For sequencing analyses, the BioEdit and Geneious tools were used, genotyping and gene expression assays were performed, and correlation, survival and logistic regression analyzes were carried out, allowing for all analyzes the level of significance set at p≤ 0.05. Four polymorphisms were found in the SOCS5 gene region, with emphasis on rs6738426, which showed similar occurrences between the analyzed groups. Regarding gene expression, it was observed that cirrhotic patients with Child-Pugh A classification exhibited higher levels of SOCS5, indicating that in this group, the gene may play a tumor-suppressive role, possibly through negative feedback of the JAK/STAT pathways. In HCC patients, a lower survival rate was observed in those with elevated levels of SOCS5 expression, suggesting a tumorigenic role, likely due to positive feedback from the PI3K/Akt/mTOR pathway. In multivariate analysis, susceptibility to HCC was associated with age [p= 0.003, OR 0.924, CI (0.877-0.9740)] and HDL levels [p= 0.043, OR 1.032, CI (1.001 – 1.065)], with increased age and decreased HDL considered risk factors. Thus, it is proposed that the SOCS5 gene may play a significant role in the tumorigenic process, potentially acting in an oncogenic or antitumorigenic manner. However, larger cohort studies are recommended to validate the results found here, as well as the analysis of the impact of SOCS5 within the JAK/STAT and PI3K/Akt/mTOR pathways through gene silencing and overexpression assays.2025-05-0
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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