1,721,099 research outputs found
Identification and characterization of the role of CALR protein and 3’untranslated region in normal and neoplastic hematopoiesis
Full text linkMyeloproliferative Neoplasms (MPNs) are hematopoietic stem cell-derived clonal disorders including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), with an overproduction of red blood cells, platelets and bone marrow fibrotic tissue, respectively. MPNs are triggered by JAK2, MPL and CALR (CALR) somatic mutations, all deregulating JAK/STAT signalling. CALR mutations, which are exclusively associated to ET and PMF, generally arise from a +1 frameshift converting the first 31 nucleotides of CALR-3’UTR, into coding sequence. However, the physiologic role of CALR and such CALR-3’UTR region in hematopoiesis are unknown.
This thesis was aimed to: i) investigate the role of CALR in physiological hematopoiesis and the context of MPN; ii) elucidate the function of novel mutated variants of CALR 3’UTR that we identified; iii) realize a model in vitro to study the functional consequences of CALR 3’UTR disruption in myelopoiesis.
Results and conclusions. We observed a hematopoietic lineage- specific regulation of CALR. Moreover, in a cohort of MPN patients, we detected two non-canonical CALR mutations associated to enhanced erythropoiesis in patients diagnosed as JAK2V617F-negative PVs. One was an in frame mutation (c.1214_1225del/del12), whereas the other occurred in the 3’UTR (c.1254+10_+33del/del24). Interestingly, the RNA folding prediction of del24, and even more of del12 indicated a structural impairment of this 3’UTR region. Primary CD34+ cells from such patients exhibited an erythroid growth push on unilineage culture and colony assays, associated with JAK/STAT activation and increase of CALR expression. Strikingly, CALR 3’UTR disruption in myeloid progenitors by CRISPR-CAS9 technology increased CALR levels and JAK/STAT activation, and, more surprisingly, induced erythropoiesis. Overall, these results suggest a novel role for CALR-3’UTR in lineage fate decision of myeloid progenitors. Its disruption might induce a PV-phenotype in vitro and in vivo
The acute promyelocytic leukemia-specific PML/RAR alpha fusion protein reduces the frequency of commitment to apoptosis upon growth factor deprivation of GM-CSF-dependent myeloid cells
No full textPML/RAR alpha is the putative transforming sequence of acute promyelocytic leukemias. We investigated the effects of PML/RAR alpha on cell survival by expressing the fusion protein in the growth factor-dependent TF-1 cell line and analyzing the kinetics of cell death after GM-CSF deprivation. Results showed that PML/RAR alpha expression markedly delayed apoptotic cell death (3 weeks vs 1 week) without inducing growth factor independence. Growth factor deprivation caused rapid and massive apoptosis of control TF-1 cells (>95% apoptotic cells after 4-5 days). Factor-deprived control cells were synchronously and irreversibly committed to apoptosis as shown by their inability to re-enter the cell cycle after GM-CSF re-addition. The percentage of apoptotic cells in the PML/RAR alpha expressing cells was low (approximately 30-35%) and constant over the 4 weeks of factor deprivation. GM-CSF re-addition produced rapid increase in cell number at all time points during the 4 weeks of factor deprivation, suggesting that commitment to apoptosis was asynchronous and delayed in PML/RAR alpha-expressing TF-1 cells. We conclude that PML/RAR alpha interferes with the genetic pathways which regulate survival by reducing the frequency of commitment to apoptosis. This biological effect of PML/RAR alpha may contribute to its leukemogenetic potential
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
The prognostic value of cell proliferation in non-small cell lung cancer assessed with tritiated thymidine and anti-PCNA antibodies
No full textVariations 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
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