1,720,994 research outputs found
Abstract 4255: Rational targeting of the Androgen receptor interactome in prostate cancer
No full textAbstractAbstract
Background: The Androgen receptor (AR) is the central driver of prostate cancer and AR signaling is intact across all stages of disease. The interaction of AR with protein cofactors is critical for its signaling: targeted disruption of these interactions may enable shutdown of AR signaling.
Methods: Using known crystal structure, modeled structure and imputed structure based models, peptide agents were rationally designed to block the interface between AR and critical cofactors in its interactome and tested for physiologic activity using prostate cancer cell lines, xenografts and primary tumor explants.
Results: Knowledge of the protein cofactors, their interacting motifs and structure of the interface are needed for optimal targeting of protein-protein interactions. Using an iterative rational design approach, we have been able to successfully disrupt three classes of the AR interactome:
1. Interactions where the protein cofactor, the motifs and the structure of the interface is known, (targeting AR-PELP1 interface through a helical LxxLL motif)
2. Interactions where the protein cofactor is known but the motifs and the structure of the interface is not known, (targeting AR-FoxA1 interaction) and
3. Interactions where the motif is known, but neither the protein cofactor nor the structure of the interface are known (only known is a critical motif on AR).
The design of initial compounds targeting the interactions in Class 1 was based on crystal structures, while those for Class 2 and Class 3 were based on either predicted or imputed (motif in different context) structures. The interaction between AR and proteins in each of these classes is disrupted by a targeted agent as evidenced by co-immunoprecipitation of endogenous protein cofactors and AR. The functional utility of these agents blocking the AR interactome on AR driven gene expression and proliferation has been validated for agents in Class 1, but is being validated for agents in Classes 2 and 3. In each case, using significant structural modeling, active agents were synthesized with a minimal use of synthesis of analogues.
Conclusions: The rational targeting of the AR interactome is feasible and may be a useful complement to traditional screening campaigns. We have demonstrated the utility of this approach to blocking the interface in three distinct classes of protein-protein interactions. Further validation/optimization of these drugs is needed prior to their clinical implementation.
Citation Format: Preethi Ravindranathan, Wayne Tilley, Ganesh V. Raj. Rational targeting of the Androgen receptor interactome in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4255. doi:10.1158/1538-7445.AM2014-4255Preethi Ravindranathan, Wayne Tilley and Ganesh V. Ra
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
Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update
No full textCyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.Solomon Tadesse, Elizabeth C. Caldon, Wayne Tilley and Shudong Wan
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
Early life exposure to a high fat diet results in histological and molecular changes in the rat prostate which are transmitted paternally to the second generation
No full textAbstract: Oral presentationsTina Bianco-Miotto, Karen Chiam, Shalini Jindal, Natalie Ryan, Siti Zulkifli, Simon Moretta, Miles De Blasio, Karen Kind, Wayne Tilley, Julie Owen
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
Parthenolide as a selective radiosensitiser in the treatment and prevention of prostate cancer
No full textAbstract: Prostate Cancer World Congress & 14th Australasian Prostate Cancer Conference, Melbourne, Australia, 6–10 August 2013Katherine Morel, Rebecca Ormsby, Eva Bezak, Wayne Tilley, Mark Lawrence, and Pamela Syke
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe 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
- …
