1,721,016 research outputs found
Signal transduction therapy in haematological malignancies: identification and targeting of tyrosine kinases
No full textTyrosine kinases play key roles in cell proliferation, survival and differentiation. Their aberrant activation, caused either by the formation of fusion genes by chromosome translocation or by intragenic changes, such as point mutations or internal duplications, is of major importance in the development of many haematological malignancies. An understanding of the mechanisms by which BCR-ABL contributes to the pathogenesis of chronic myeloid leukaemia led to the development of imatinib, the first of several tyrosine kinase inhibitors to enter clinical trials. Although the development of resistance has been problematic, particularly in aggressive disease, the development of novel inhibitors and combination with other forms of therapy shows promise.Abbreviations: ALK, anaplastic lymphoma kinase; ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CEL, chronic eosinophilic leukaemia; CML, chronic myeloid leukaemia; CMML, chronic myelomonocytic leukaemia; EGFR, epidermal growth factor receptor; EMS, Eight p11 myeloproliferative syndrome; EPO, erythropoietin; FGFR, fibroblast growth factor receptor; FIP1L1, Fip1-like 1; FLT3, Fms-like tyrosine kinase 3; FISH, fluorescence in situ hybridization; HES, hypereosinophilic syndrome; IFNa, interferon a; IL3, interleukin 3; IRIS, International Randomized study of Interferon and STI571; ITD, internal tandem duplication; JAK, Janus kinase; MDS, myelodysplastic syndrome; MPD, myeloproliferative disorder; NTRK, neurotrophin receptor kinase; PDGFR, platelet-derived growth factor receptor; Ph, Philadelphia chromosome; PV, polycythaemia vera; RT, reverse transcription; SCT, stem cell transplantation; TK, tyrosine kinase
Aberrations of EZH2 in cancer
No full textControl of gene expression is exerted at a number of different levels, one of which is the accessibility of genes and their controlling elements to the transcriptional machinery. Accessibility is dictated broadly by the degree of chromatin compaction, which is influenced in part by polycomb group proteins. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2) which catalyses trimethylation of histone H3 lysine 27 (H3K27me3). PRC2 may recruit other polycomb complexes, DNA methyltransferases and histone deacetylases resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci. Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumours including prostate and breast cancer. Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity whilst inactivating mutations are seen in poor prognosis myeloid neoplasms. No histone demethylating agents are currently available for treatment of patients but 3-deazaneplanocin (DZNep) reduces EZH2 levels and H3K27 trimethylation resulting in reduced cell proliferation in breast and prostate cancer cells in vitro. Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors opening up the possibility of refined epigenetic treatments in the future. <br/
A common constitutional JAK2 haplotype predisposes to Myeloprolifrative Neoplasms
No full textMeeting Abstract: 0555<br/
A high-throughput candidate gene mutation screen in lymphoproliferative and myeloproliferative neoplasias
No full textTKI258 (CHIR-258) selectively inhibits FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome
No full textPonatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome
No full textThe 8p11 myeloproliferative syndrome is a rare, aggressive myeloproliferative neoplasm characterised by constitutively active FGFR1 fusion proteins that arise from specificchromosomal translocations and which drive aberrant proliferation. Although FGFR1 inhibitors have shown in vitro activity against FGFR1 fusions, none are in use clinically and there is a need to assess additional compounds as potential therapy. Here we use cell linesand primary cells to investigate ponatinib (AP24534). Ponatinib-treated Ba/F3 cells transformed by ZMYM2-FGFR1 and BCR-FGFR1 and the FGFR1OP2-FGFR1 positiveKG1A cell line showed reduced proliferation and decreased survival when compared to control cells. Inhibition induced apoptosis and reduced phosphorylation of the FGFR1 fusionproteins and substrates. Ponatinib-treated cells from five 8p11 myeloproliferative syndrome patients showed reduced colony growth compared to controls. In one evaluable patient, ponatinib specifically reduced numbers of FGFR1-fusion gene positive colonies. Ponatinib therefore shows considerable promise for the treatment of patients with 8p11myeloproliferative syndrome
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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