1,721,283 research outputs found
Tyrosine kinases as therapeutic targets in BCR-ABL negative chronic myeloproliferative disorders
No full textAcquired constitutive activation of protein tyrosine kinases is a central feature in the pathogenesis of chronic myeloproliferative disorders (CMPDs). The most commonly involved genes are the receptor tyrosine kinases PDGFRA, PDGFRB, FGFR1 or c-KIT and the non-receptor tyrosine kinases JAK2 and ABL. Activation occurs as a consequence of specific point mutations or fusion genes generated by chromosomal translocations, insertions or deletions. Mutant kinases are constitutively active in the absence of the natural ligands resulting in deregulation of haemopoiesis in a manner analogous to BCR-ABL in chronic myeloid leukaemia. With the advent of targeted signal transduction therapy with tyrosine kinase inhibitors, an accurate diagnosis of CMPDs by morphology, karyotyping and molecular genetics has become increasingly important. Imatinib induces high response rates in patients associated with constitutive activation of ABL, PDGFRalpha, PDGFRbeta and some KIT mutants. Other inhibitors under development are promising candidates for effective treatment of patients with constitutive activation of JAK2, FGFR1 and imatinib-resistant KIT mutants
How I (diagnose and) treat myeloid / lymphoid neoplasms with tyrosine kinase gene fusions
No full textThe fifth edition of the World Health Organization (WHO) classification and the International Consensus Classification (ICC) both include a category "myeloid/lymphoid neoplasms (MLN) with eosinophilia (eo) and tyrosine kinase (TK) gene fusions” (WHO, MLN-TK; ICC, M/LN-eo-TK). This rare group comprises phenotypically and prognostically heterogeneous disorders, which present a significant diagnostic challenge. The rapid and reliable identification of patients with MLN-TK may be delayed due to genetic complexity and significant phenotypic differences, including the chronic phase and primary/secondary blast phase (BP) of myeloid, lymphoid, or mixed phenotype in the bone marrow (BP-BM) and/or at extramedullary sites (extramedullary disease [EMD]). As a result, the entire armamentarium of conventional molecular genetic and cytogenetic techniques complemented by modern sequencing technologies, such as RNA sequencing or whole-genome sequencing, are often required to identify an underlying TK fusion. TK inhibitors (TKIs) with variable efficacy are available for all fusion genes, but a long-term favorable clinical course under TKI monotherapy is currently only observed in MLN-PDGFRA/PDGFRB fusion genes on imatinib. Because primary/secondary BP-BM/EMD occurs more frequently in MLN-FGFR1/JAK2/FLT3/ETV6::ABL1, a sequential combination of selective TKIs with or without prior intensive chemotherapy, rarely local radiotherapy, and/or subsequent allogeneic hematopoietic cell transplantation should be considered.</p
Diagnostic and therapeutic management of eosinophilia-associated chronic myeloproliferative disorders
Full text linkEosinophilia is commonly observed in a wide range of disparate non-clonal and clonal disorders.1,2 In the majority of cases it is reactive, associated with atopic conditions, autoimmune disorders, infections or malignancies. In rare cases, a hematologic disorder underlies sustained eosinophilia which can be either non-clonal or clonal. The former (secondary eosinophilia) can be found in a variety of hematologic malignancies including Hodgkin’s disease and lymphomas, predominantly of T-cell phenotype. Hypereosinophilic syndrome (HES) is diagnosed when the blood eosinophil count is persistently greater than 1500/µL for at least 6 months with no evidence of a reactive condition or clonality. HES is a potentially life-threatening condition associated with end-organ damage to heart, gastrointestinal tract, skin, joints or nervous system due to release of granular contents from infiltrating eosinophils. In the lymphocytic variant (L-HES), clonal T-lymphocytes induce non-clonal eosinophil proliferation through overproduction of eosinophilopoietic cytokines such as IL-3, IL-5 or GM-CSF. Clonal or primary eosinophilia is generally associated with chronic myeloproliferative disorders (Eos-MPD), including atypical chronic myeloid leukemia (aCML), myeloproliferative variant of HES (M-HES), chronic myelomonocytic leukemia (CMML), unclassifiable overlap syndromes of myelodysplastic syndrome/myeloproliferative disorders (MDS/MPD) and systemic mastocytosis (SM). Chronic eosinophilic leukemia (CEL) is diagnosed in the presence of increased numbers of blasts and/or proof of clonality through cytogenetic or molecular analyses
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
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