1,720,978 research outputs found
Abstract 3844: Identification and validation of novel therapeutic targets driving clonal heterogeneity in treatment-refractory GBM
No full textAbstract
Glioblastoma (GBM) is the most common primary adult brain tumor, characterized by extensive cellular and genetic heterogeneity. Even with surgery, standard chemotherapy with temozolomide (TMZ), and radiation, tumor re-growth (or recurrence) and patient relapse are inevitable. Patients face a median survival of <15 months, with uniformly fatal outcomes upon disease progression post-therapy. Recent profiling of GBM-initiating genes has shown that evolution of cancer-driving clones or cell populations within a solid tumor may progress through (and possibly be driven by) cancer treatment, such that GBM recurrence may no longer resemble the genetic landscape of the original primary tumor. Understanding and mapping clonal evolution of the primary GBM through therapy and at recurrence will allow for the discovery of novel targets specific to treatment-refractory GBM. Here, we have developed early passage patient-derived brain tumor initiating cell (BTIC) lines that have been annotated by genomic deep-sequencing technologies to systematically characterize and describe the extent of intratumoral heterogeneity. Tagged with a red florescent protein, these BTIC lines were engrafted into immunocompromised NOD SCID mice. Following half-maximal tumor engraftment, tumor bearing mice underwent a clinically relevant chemoradiotherapy regimen, with 2 Gy gamma-irradiation on the first day and 66 mg/kg temozolomide for five consecutive days. Following therapy, mice were kept alive until tumor recurrence. Engrafted BTICs were harvested at initial tumor formation, minimal residual disease after chemoradiotherapy, and tumor recurrence. Samples were analyzed by RNA and genomic deep-sequencing technologies to map cancer progression and identify novel therapeutic targets in treatment-refractory GBM.
Potential therapeutic targets were validated by their effect on self-renewal and proliferation of patient-derived BTIC lines of human GBM in vitro and in vivo. Using CRISPR Cas9, potential targets were knocked out in patient-derived BTIC lines of human GBM in order to characterize the effect on sphere formation and proliferation in vitro, and tumor formation in vivo. Following validation of new therapeutic targets of treatment-refractor GBM, we aim to build novel biotherapeutics against highly validated cell surface targets, and establish preclinical testing protocols using our novel patient-derived and therapy-adapted xenograft model of treatment-resistant GBM.
Citation Format: Chirayu Chokshi, Nick Yelle, Parvez Vora, Chitra Venugopal, Maleeha Qazi, Mohini Singh, Minomi Subapanditha, Avrilynn Ding, Sheila K. Singh. Identification and validation of novel therapeutic targets driving clonal heterogeneity in treatment-refractory GBM [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 3844. doi:10.1158/1538-7445.AM2017-3844</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
Abstract 5831: Activated Wnt signaling for the treatment of recurrent medulloblastoma
No full textAbstract
Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current molecular subgroups of MB recognize distinct disease entities of which activated Wnt signaling (monosomy 6, exon 3 mutations in CTNNB1, and Wnt gene signature) is associated with a distinct subgroup and the best overall outcome. In contrast, only non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in patients with Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups into an ostensibly benign tumor through selective targeting by small molecules and transgenic patient-derived lines containing a stabilized beta-catenin mutant. Activated Wnt signaling by way of Wnt agonists in treatment-refractory MBs resulted in decreased in vitro self-renewal and promoted differentiation. Comparative gene expression profiling of control and transgenic lines containing a stabilized beta-catenin mutant demonstrated a reduction in stem cell self-renewal genes following beta-catenin overexpression, including Sox2 and Bmi1. In order to validate the therapy-sensitive nature of Wnt-activated cells, we developed stable patient-derived lines containing a 7XTOPFlash reporter for endogenous Wnt signaling. Rare subclonal Wnt-active cells demonstrated a reduced self-renewal and tumor-initiating capacity through in vivo limiting dilution assays when compared to bulk Wnt-inactive cells. The therapeutic relevance of these findings were demonstrated with an in vivo survival advantage in mice with orthotopic injections of cells containing a stabilized beta-catenin mutant representative of constitutively active Wnt signaling or endogenous Wnt-active cells. Xenografts generated from Wnt-activated tumors were smaller in size, maintained a lower rate of proliferation, and reduction in MB self-renewal genes. To further illustrate the clinical utility of activated Wnt signaling, we modified the Children’s Oncology Group therapy protocol for childhood MB so that xenografts may receive chemo/radiotherapy. Tumors generated from Wnt-active xenografts were much more radiosensitive and displayed a significant reduction in spinal metastasis when compared to mice receiving standard therapy without Wnt activation. To develop a rationale clinical therapeutic, we developed unique agonist antibodies that target the Wnt co-receptor LRP5. Treatment with LRP5 antibodies showed a significant reduction in tumor burden and increase in survival of patient-derived tumors that were otherwise treatment-resistant. Our work establishes for the first time activated Wnt signaling as a novel treatment paradigm in childhood MB, identifies a rationale therapeutic approach for recurrent MB, and provides evidence for the context-specific tumor suppressive function of the canonical Wnt pathway.
Note: This abstract was not presented at the meeting.
Citation Format: Branavan Manoranjan, Chitra Venugopal, Zvezdan Pavlovic, David Bakhshinyan, Michelle Kameda-Smith, Minomi Subapanditha, Sujeivan Mahendram, Jason Moffat, Bradley W. Doble, Sheila Singh. Activated Wnt signaling for the treatment of recurrent medulloblastoma [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 5831. doi:10.1158/1538-7445.AM2017-5831</jats:p
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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