1,720,983 research outputs found
Evaluating the Role of Bone Marrow Microenvironment in the Pathogenesis of Therapy-related Myeloid Neoplasms
Get PDFTherapy-related myeloid neoplasm (tMN), lethal blood cancer developing in long-term cancer survivors, is considered to be direct consequence of cytotoxic therapy-induced DNA damage in haematopoietic stem cells. Despite increased recognition that altered bone marrow stroma can also drive leukemogenesis, the functional biology of tMN bone marrow microenvironment remains unknown. Comprehensive multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterisation of bone marrow stromal cells from tMN was performed and compared with (i) patients with myeloid neoplasm and a history of another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm and (iii) agematched controls, to decipher bone marrow microenvironmental changes induced by cytotoxics from that age related and myeloid neoplasm induced changes. tMN bone marrow mesenchymal stromal cells exhibited profound senescence with CDKN1A induction, high levels of β-Galactosidase, aberrant morphology, defective proliferation, differentiation and haematopoietic stem cell supportive capacity. Highly senescence phenotype is probably driven by defective DNA repair capacity. Strikingly, despite their dormant state, tMN stromal cells were metabolically highly active with a switch towards glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. This thesis provides novel insight into role of pro-inflammatory and senescent stromal milieu to tMN pathogenesis and provide a valuable resource for future strategies to delay/prevent the tMN.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202
Evaluation of anti-proliferative and pro-apoptotic effects of tyrosine kinase inhibitors on CML-CD34+ cells.
Get PDFAlthough imatinib (IM) has revolutionalised CML management, 30 to 40% patients fail IM therapy. Many of these patients can be rescued with second generation tyrosine kinase inhibitors (TKI), dasatinib, nilotinib and bosutinib. This research elucidates the dasatinib cellular transport pathways and its role in mediating dasatinib resistance. It also assesses dynamics of Bcr-Abl kinase inhibition and apoptosis in CML lines and CML-CD34+ progenitors. Lastly it addresses the role of cytokines in mediating TKI resistance and possible combination therapy to circumvent cytokine mediated TKI resistance. The organic cation transporter (OCT-1) mediates IM influx and low OCT-1 activity is a major contributor to suboptimal response in CML patients treated with IM. In the current study the relevance of OCT-1
activity and efflux pumps in determining intracellular concentration (IUR) of dasatinib were assessed. In contrast to IM, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of efflux proteins, ABCB1 and ABCG2. Overexpression of these proteins can mediate dasatinib resistance. There is increasing evidence that nilotinib is an ABCB1 inhibitor. These different interactions of dasatinib and nilotinib with ABCB1 were exploited for combination therapy. Nilotinib increased 14CDasatinib IUR and had synergistic effect in inducing cell death in ABCB1 overexpressing cells. These data suggest that combinations of these two TKI can overcome ABCB1 mediated dasatinib resistance and may allow the use of lower concentrations of each drug. In contrast to IM, dasatinib cellular influx is predominantly passive and maximum intracellular concentration is achieved within a few minutes. This was further confirmed by the observation of maximum Bcr-Abl kinase inhibition within 30 minutes of culture with dasatinib. Despite reactivation of Bcr-Abl kinase within 30 minutes of drug washout, short-term (30 minutes) intense (>90%) Bcr-Abl kinase inhibition with dasatinib triggers apoptosis in CML cell lines. This is in contrast to the previously established paradigm that continuous kinase inhibition is required for optimal response to IM. These results were further supported by a recently published dasatinib dose optimisation study. Further work in this thesis demonstrated that although Bcr-Abl kinase reactivates within 30 minutes of drug washout, the prosurvival proteins Erk, AKT and STAT5 dephosphorylated rapidly while the apoptotic proteins remained phosphorylated. This differential degradation of prosurvival and apoptotic proteins might be responsible for a state of “oncogenic-shock”, as described by Sharma et al. Subsequent studies demonstrated that in the absence of cytokines, short-term intense Bcr-Abl kinase inhibition with therapeutically achievable concentration of dasatinib (100 nM dasatinib) eliminated 70 to 80% of CML-CD34+ progenitors. However, in the presence of cytokines despite >90% Bcr-Abl kinase
inhibition it did not trigger cell death in CML progenitors. These results suggest that intense Bcr-Abl kinase inhibition alone may not be adequate to trigger cell death in CML progenitors. Further studies demonstrated that cytokines mediate TKI resistance by activating JAK2-STAT5 pathway and that the combination of JAK2 inhibitor and TKI can circumvent cytokine mediated TKI resistance.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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