1,721,035 research outputs found
CHARACTERIZATION OF THE UNFOLDED PROTEIN RESPONSE ROLE IN DIFFERENTIATION THERAPY OF ACUTE MYELOID LEUKEMIAS
No full textIntroduction. Acute myeloid leukemia (AML) is caused by the clonal
expansion of hematopoietic myeloid precursors blocked at different
stages of differentiation. A subtype of AML, acute promyelocytic
leukemia (APL), is a paradigm of differentiation therapy since all-transretinoic
acid (ATRA)-based treatments are able to induce leukemic blast
terminal differentiation, leading to clinical remission in the majority of
APL patients. However, ATRA can lead to systemic toxicity and relapses
after initial remission followed by resistance. Furthermore APL
accounts for about 10-15% of AML cases and non-APL AML respond
only very slightly to ATRA. Thus the search for a strategy to further sensitize
AML cells to ATRA is highly needed. ATRA induces differentiation
of APL blasts to granulocytes that are secretory cells since they are
characterized by the presence of secretory granules containing peptides
indispensable for their role in the immune response. The majority of
proteins secreted or reside
Building and operating an antibody factory: Redox control during B to plasma cell terminal differentiation
No full textAbstractWhen small B lymphocytes bind their cognate antigens in the context of suitable signals, a dramatic differentiation program is activated that leads to the formation of plasma cells. These are short-lived specialized elements, each capable of secreting several thousands antibodies per second. The massive increase in Ig synthesis and transport entails a dramatic architectural and functional metamorphosis that involves the development of the endoplasmic reticulum (ER) and secretory organelles. Massive Ig secretion poses novel metabolic requirements, particularly for what concerns aminoacid import, ATP synthesis and redox homeostasis. Ig H and L chains enter the ER in the reduced state, to be rapidly oxidised mainly via protein driven relays based on the resident enzymes PDI and Ero1. How do plasma cells cope with the ensuing metabolic and redox stresses? In this essay, we discuss the physiological implications that increased Ig production could have in the control of plasma cell generation, function and lifespan, with emphasis on the potential role of ROS generation in mitochondria and ER
Targeting the miRNA pathway with small-molecule modulators of Argonaute protein
No full textThe deregulation of miRNAs expression and activity is associated with a variety of human pathologies, especially hematological malignancies. Because targeting miRNA expression can modify the disease phenotype, the understanding of the role of miRNAs in pathological processes is currently spurring the development of specific oligonucleotides or plasmid- and virus-based constructs able to modulate miRNA levels. In this context, the usage small-molecules may constitute an improved strategy to circumvent problems of delivery and immunogenic response as well as a very attractive way to devise new therapeutic tools. Here we present a new lead-like modulator of Argonaute 2 (Ago2) protein, which is a component of the RNA-induced silencing complex (RISC) with a central role in RNA silencing. We show that a specific small-molecule is able to interfere with the miRNAs-loading into the Ago2 complex and that the disruption of this binding results in an improvement of the differentiation capabilit
The methylated DNA immunoprecipitation [MeDIP] to investigate the epigenetic remodeling in cell fate determination and cancer development
No full textEpigenetic mechanisms such as DNA methylation, posttranslational modifications of histone proteins, remodeling of nucleosomes, and the expression of noncoding RNAs contribute to the regulation of gene expression for the cell fate determination and tissue development. The disruption of these epigenetic mechanisms, in conjunction with genetic alterations, is a decisive element for cancer development and progression. The cancer phenotype is characterized by global DNA hypomethylation and gene-specific hypermethylation. The methylated DNA immunoprecipitation [MeDIP] is a useful approach currently used to clarify the functional consequences of DNA methylation on cell fate determination and cancer development
Antisense to Epstein Barr virus-encoded LMP1 does not affect the transcription of viral and cellular proliferation-related genes, but induces phenotypic effects on EBV-transformed B lymphocytes
Full text linkIt is generally accepted that Epstein-Barr virus (EBV) latent genes EBNA-2, EBNA-3A, -3C, EBNA-LP and LMP1 are essential for growth transformation and immortalization of B lymphocytes. Among these genes, LMP1 plays a key role in the survival and dissemination of the infected B cells by inducing anti-apoptotic genes and surface expression of several activation antigens and adhesion molecules. We have previously shown that antisense oligodeoxynucleotides directed to LMP1 mRNA, effectively suppress LMP1 gene expression and substantially reduce B95.8 cell proliferation. In this study, we have used antisense LMP1 oligomers to investigate whether LMP1 suppression might influence the expression of latent EBV genes with oncogenic potential, anti-apoptotic genes, or affect the phenotype of EBV-infected B95.8 cells. Our data show that LMP1 suppression does not affect the transcription of EBNA-2, EBNA-3A, -3B and -3C genes, or that of bcl-2 and mcl-1 anti-apoptotic genes. In contrast, consistent modifications in the expression of CD39, CD54, CD23, CD11 and CD10 molecules were observed in B95.8 cells after treatment with antisense LMP1. Our findings support the possibility for using LMP1 antisense oligomers as therapeutics in EBV-associated tumors
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
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
ARGONAUTE-2 AS NOVEL MOLECULAR TARGET FOR THE DIFFERENTIATION THERAPY OF ACUTE MYELOID LEUKEMIA CELLS
No full textIntroduction. In hematopoietic stem cells, growth and maturation of erythroid,
granulocytic, monocytic and megakaryocytic lineages are largely
controlled by unique combinations of transcription factors that cooperatively
regulate promoters and enhancers present on specific target genes.
miRNAs provide an additional level of control beyond the transcription
factors and play a central role in hematopoietic differentiation through the
establishment of complex regulatory circuitries. These small RNAs, to
exert their function, are assembled in the functional RNA-induced silencing
complexes (RISCs), where a member of Argonaute (Ago) family of
proteins, Ago1-4, provides a unique platform for target recognition and
gene silencing. Alteration of miRNAs levels and functional activity may
affect proliferation, differentiation and genetic stability of hematopoietic
stem/progenitor cells (HPCs), resulting in myeloproliferative disorders
and leukaemia. Methods. By using myeloid cell lines and prima
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