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Nicholson, L P, 5680
No full textThis record was harvested from a previous catalogue system and will be withdrawn in 2025. Information in this record may be superseded or incomplete. Visit this record in UMA's new catalogue at: https://archives.library.unimelb.edu.au/nodes/view/407744Surname: NICHOLSON. Given Name(s) or Initials: L P. Military Service Number or Last Known Location: 5680. Missing, Wounded and Prisoner of War Enquiry Card Index Number: V-1265.236556
Item: [2016.0049.40019] "Nicholson, L P, 5680
Prevalence of anemia among women (n = 5680) based on BMI category.
No full textPrevalence of anemia among women (n = 5680) based on BMI category.</p
Abstract 5680: TRK xDFG mutations trigger a sensitivity switch from type I to II kinase inhibitors
No full textAbstract
Background: TRK inhibition is the standard of care for patients with TRK fusion-positive solid tumors. TRK kinase domain mutations that impair drug binding are common mechanisms of resistance to 1st-generation TRK inhibitors. While 2nd-generation TRK inhibitors were designed to maintain kinase inhibition in this setting, the resistance to these agents is still poorly characterized.
Methods and Results: We sequenced paired tumor biopsies and serial cell-free DNA (cfDNA) collected before therapy and at progression from patients treated with 2nd-generation TRK inhibitors (selitrectinib or repotrectinib). We identified 5 cases in which the acquisition of xDFG (G667) TRKA mutations was associated with resistance. Two patients whose tumors carried these substitutions pre-selitrectinib never responded to therapy, while three additional cases acquired these mutations upon progression to either selitrectinib or repotrectinib.
In-silico molecular modeling combined with molecular dynamic simulations predicted that TRKA xDFG substitutions can confer resistance to 2nd-generation TRK inhibitors by generating steric hindrance that compromises drug binding. Accordingly, in vitro kinase assays showed that the IC50 for selitrectinib of TRKA xDFG mutants was >12 to >8000 fold higher compared to the IC50 of either TRKA wild type or the selitrectinib-sensitive TRKA G595R solvent front mutant.
Interestingly, our data also suggest that TRKA xDFG substitutions induce conformational changes that stabilize the inactive (xDFG-out) conformation of the kinase, thus sensitizing it to type II inhibition. In vitro microscale thermophoresis revealed that the binding affinity of type II TRK inhibitors (cabozantinib or foretinib) to the TRKA G667C-mutant kinase was 8-10-fold higher compared to the type I inhibitor selitrectinib. We then tested the efficacy of type II TRK inhibitors against TRKA xDFG mutants in different cell models. A Bcan-Ntrk1-driven mouse model knocked in by CRISPR Cas9 to express the xDFG mutations was sensitive to type II but not to type I TRK inhibitors. Similar results were obtained using an LMNA-NTRK1-positive colorectal cell line that acquired the G667C substitution upon chronic selitrectinib treatment.
Type II TRK inhibitor therapy achieved complete and durable responses also in patient-derived models with TRKA xDFG-mediated resistance to type I 2nd-generation agents.
Conclusions: Our study uncovers a molecular switch induced by xDFG mutations that limits the sensitivity to type I kinase inhibitors by conformational changes that favor the inactive xDFG-out kinase state. This same switch in turn sensitizes these mutant kinases to type II inhibitors that effectively engage this inactive conformation. These results provide a paradigm for the rational development of 3rd-generation TKIs that address the problem of conformational resistance in tumors that are driven by oncogenic kinases.
Citation Format: Emiliano Cocco, Ji Eun Lee, Srinivasaraghavan Kannan, Alison M. Schram, Helen H. Won, Sophie Shifman, Amanda Kulick, Laura Baldino, Eneda Toska, Sabrina Arena, Benedetta Mussolin, Ram Kannan, Neil Vasan, Alexander N. Gorelick, Michael F. Berger, Yi Liao, Uwe Rix, Alberto Bardelli, Jacklyn Hechtman, Elisa de Stanchina, David M. Hyman, Chandra Verma, Andrea Ventura, Alexander Drilon, Maurizio Scaltriti. TRK xDFG mutations trigger a sensitivity switch from type I to II kinase inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5680
Blood hemoglobin level of women (n = 5680) based on BMI category and pregnancy status.
No full textBlood hemoglobin level of women (n = 5680) based on BMI category and pregnancy status.</p
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
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