1,720,958 research outputs found
Abstract 2600: Analysis of drug resistance mechanisms and strategies for overcoming resistance in cancer therapy using a curated clinical knowledgebase
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Emergence of resistance to targeted therapies is a critical problem in cancer therapy, and understanding both the mechanisms of resistance and strategies for overcoming resistance are crucial to effective treatment of cancer patients. The JAX Clinical Knowledgebase (JAX-CKB), which incorporates data on therapeutic efficacy in the context of molecular alterations, enables rapid analysis of known therapy resistance mechanisms and current data surrounding strategies for overcoming resistance, both in the preclinical and clinical setting. Using the JAX-CKB, we have identified over 1250 lines of evidence corresponding to therapy resistance across tumor types. Of those lines, 147 correspond to therapy resistance in lung cancer. The JAX-CKB contains 22 variants in ALK associated with ALK therapy resistance. Within ALK fusion-positive lung cancer, evidence lines corresponding to ALK inhibitor resistance are associated primarily with complex molecular profiles containing secondary ALK mutations, and mechanisms for overcoming resistance in this setting were associated with use of novel agents. Within EGFR mutation positive lung cancer, lines associated with resistance to EGFR inhibitor therapy included copy number alterations, primary resistance mutations, secondary resistance mutations, and expression level changes. Strategies for overcoming resistance in these settings include novel agents and/or various combination therapies. The JAX-CKB provides a unique global view into current data on resistance to targeted therapies in oncology, which may enable more rapid assessment of effective therapy options and expose opportunities for additional research into strategies for overcoming resistance.
Citation Format: Sara E. Patterson, Cara M. Statz, Taofei Yin, Susan M. Mockus. Analysis of drug resistance mechanisms and strategies for overcoming resistance in cancer therapy using a curated clinical knowledgebase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2600. doi:10.1158/1538-7445.AM2017-2600</jats:p
Abstract 2583: A model for capturing and integrating complex molecular alterations related to clinically relevant efficacy evidence
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The ability to capture data relevant to different types of oncology-related variations, including single nucleotide variations, deletions, insertions, copy number variations, and fusions in a single system is crucial to a comprehensive understanding of cancer biology. However, collectively linking these varied types of molecular alterations to capture their compound impact to clinically relevant efficacy evidence within a database can prove challenging. Thus, we have built the JAX Clinical Knowledgebase (JAX-CKB), a flexible relational database that allows curation of complex molecular profiles and provides the ability to associate these profiles with documented efficacy evidence, thereby providing a more detailed overview of therapeutic relevance. To demonstrate the utility of creating complex molecular signatures in relation to efficacy evidence, the JAX-CKB was queried to first determine the overall degree of efficacy evidence content related to complex profiles. Additionally, two specific types of complex molecular profiles were queried, which included EML4-ALK plus a missense mutation(s) and BRAF V600E plus any type of molecular alteration(s). Within the JAX-CKB, there are 1,383 unique efficacy evidence lines linked to complex molecular profiles. The complex molecular profiles consisting of EML4-ALK and one or more additional missense mutations were associated with 174 unique efficacy evidence lines. Of the 174 lines, 69 were annotated with a resistant response type, while 68 were annotated with a sensitive response type. The combination of BRAF V600E with one or more molecular alterations was linked to 229 unique efficacy evidence lines. The majority of the lines, 118, were specific to a resistant response type and 83 were associated with sensitivity. Comprehensive genomic profiling of cancer patient samples can often reveal complex molecular signatures. The JAX-CKB is an inclusive knowledgebase that allows one to interpret these complex signatures and rapidly identify appropriate targeted therapies, which could be critical in a clinical setting.
Citation Format: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus. A model for capturing and integrating complex molecular alterations related to clinically relevant efficacy evidence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2583. doi:10.1158/1538-7445.AM2017-2583</jats:p
Abstract 2598: Paradigm to ensure curation transparency and consistency of a cancer genomic database - the JAX Clinical Knowledgebase (CKB)
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In the era of personalized medicine, comprehensive cancer genomic databases represent critical tools for interpreting gene variants and their relevant therapies. As the number of cancer genomic databases grow, it is challenging for users to compare and assess the data integrity and validity of such databases. The lack of disclosure of curation processes makes it difficult to cross reference different databases. The JAX Clinical Knowledgebase (CKB) is a comprehensive relational database providing evidence-based information on gene variants, targeted therapies, efficacy evidence, and clinical trials. At the Jackson Laboratory for Genomic Medicine, we have developed a curation paradigm to ensure curation transparency and consistency of the JAX-CKB. First, to ensure standardization of nomenclature, we have integrated standard nomenclature and ontologies, including HGNC approved nomenclatures for genes, HGVS guidelines for variants, and the Disease Ontology for indications/tumor types. Second, we implemented decision matrices to maintain uniformity of our evaluation of scientific and clinical data. For example, evaluation of the effect of gene variants on protein function is solely based on changes in the intrinsic activity of the protein instead of downstream pathway activation or the effects on pathogenesis; the response type of gene variants to therapies are classified based on the evidence of targeting specificity; and the efficacy evidence are further classified as actionable, diagnostic, prognostic, risk factor, emerging, or not active centered on the response type and the strength of the evidence. Third, to provide convenient evaluation of the clinical relevance of efficacy data, we further developed a tier ranking system based on emerging consensus guidelines, which takes response type, evidence type, and approval status into consideration. Finally, all decision matrices are clearly outlined on the JAX-CKB open access website for users’ reference. In summary, we have curated a highly structured and semantically consistent cancer genomic database following a set of specific curation guidelines. As a result, JAX-CKB open access has become a valuable resource for both the clinical and research communities, and is utilized by numerous independent groups for variant interpretation.
Citation Format: Taofei Yin, Sara E. Patterson, Cara M. Statz, Anuradha Lakshminarayana, Daniel Durkin, Susan M. Mockus. Paradigm to ensure curation transparency and consistency of a cancer genomic database - the JAX Clinical Knowledgebase (CKB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2598. doi:10.1158/1538-7445.AM2017-2598</jats:p
Abstract 541: A comprehensive analysis delineating the immunotherapeutic terrain of cancer-related clinical trials
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Technological innovations have facilitated a greater understanding of how the tumor microenvironment contributes to cancer, leading to rapid FDA approval of four immunotherapies. To assess how these therapies are being further investigated in combination with other therapies and in tumor types outside of the current FDA approval, we performed a comprehensive analysis of the curated clinical trials in the JAX Clinical Knowledgebase (JAX-CKB). In brief, clinical trials investigating Atezolizumab, Nivolumab, Pembrolizumab, and Ipilimumab, curated from clinicaltrials.gov, were queried in the JAX-CKB and then analyzed for comparison. Further analyses were executed to illustrate possible unmet needs within the field of cancer therapeutics. Of the four immunotherapies, Pembrolizumab was identified with the greatest number of clinical trials overall, with 305 compared to Atezolizumab, 79, Nivolumab, 183, and Ipilimumab, 126. Of these trials the number of trials investigating Pembrolizumab, Atezolizumab, Nivolumab, or Ipilimumab in combination with another therapy was higher than those investigating one of the four immunotherapies as a monotherapy. Phase II trials for both single therapy and combinatorial therapies were greater than both Phase I and Phase III for the same groups, regardless of therapy. On average, 12% ± 3.8% of the combined trials for all four drugs included any advanced solid tumor. Nivolumab combined with Ipilimumab demonstrated the greatest number of trials (61) investigating an immunotherapy in combination with another immunotherapy. Among those, 30 were Phase II trials, 16 were Phase I, and 14 were Phase III. Across five cancer indications (lung, pancreatic, ovarian, prostate, and colon), lung cancer was most commonly indicated in the trials, among all four drugs. Prostate was indicated in the least number of trials, with Ipilimumab ranking the highest (10). The recent success with immunotherapies has garnered significant interest in understanding how these therapies will perform in different tumor types and whether specific combinations will have a greater impact. Interrogation of the clinical trial terrain in the JAX-CKB provides a basis for determining additional investigations that might be warranted.
Citation Format: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus. A comprehensive analysis delineating the immunotherapeutic terrain of cancer-related clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 541. doi:10.1158/1538-7445.AM2017-541</jats: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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