1,721,266 research outputs found
Abstract 3967: High microsomal PGE2synthase-1 levels associate with low CD8 T cells and poorer melanoma patient survival
No full textAbstract
COX-2 and its product PGE2 are reported to enhance carcinogenesis and tumor progression and to support immunosuppression, as reported by others in melanoma and other cancers. As most COX-2 inhibitors result in cardiotoxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is now also an alternative consideration for therapeutic targeting. Our previously published results (Kim, et al., 2016) showed that mPGES1 protein increased with melanoma patient clinical stage and that its intense expression was associated with reduced patient survival. We also reported that mPGES1 inhibition attenuated cell survival and increased apoptosis in human melanoma cells and significantly suppressed tumor growth in melanoma xenografts. This current study was designed to evaluate whether expression of mPGES1 contributes to immune evasion. Tumors in a Stage III melanoma TMA analysis demonstrated that high mPGES1 expression (intensity 3) was significantly associated with low CD8 levels (lower than median CD8 percent value) (r=-0.2722, p=0.0128). Importantly, stage III melanoma patients with this high mPGES1 and low CD8 signature had significantly increased risk of death as determined by Kaplan-Meier method and Univariate Cox proportional hazards regression models, and compared with patients with low mPGES1/low CD8 and low mPGES1/high CD8. Furthermore, the differential levels of several chemokines including CXCL1 and CXCL2 to regulate T cell migration were correlated the mPGES1 expression in the TCGA melanoma data set. Collectively, our study continues to resolve the potential role of mPGES1 in regulation of immune evasion and is designed as a preclinical approach to develop a rational therapeutic strategy targeting PGE2-driven inflammatory mediators as useful adjuvants for immune-based therapy.
Citation Format: Sun-Hee Kim, Jason Roszik, Weiyi Peng, Suhendan Ekmekcioglu, Elizabeth A. Grimm. High microsomal PGE2synthase-1 levels associate with low CD8 T cells and poorer melanoma patient survival [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 3967. doi:10.1158/1538-7445.AM2017-3967</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
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
Abstract 5602: Regulation of immune checkpoint genes revealed by a melanoma tumor cancer genome atlas (TCGA) analysis - potential implications for improving immunotherapy
No full textAbstract
Introduction: The interface between T lymphocytes and cancer or antigen presenting cells (C/APCs) is multi-faceted and complex. This interface, now designated 'the immunological synapse', comprises of both co-inhibitory and co-stimulatory transmembrane protein pairs ('checkpoint proteins') that all serve to modulate the signal transmitted to the T lymphocyte, leading to either activation, anergy or exhaustion. Immune checkpoint inhibitors have anti-neoplastic activity in a wide range of malignancies, but not all cancers and not all patients with a given cancer respond to the currently available checkpoint inhibitors. Micro-RNAs (miRNAs) are short intracellular RNA molecules known to be master regulators of gene expression. Our aim was to study the associations between a miRNA that was previously implicated in cancer and immune checkpoint genes.
Methods: Bioinformatic analyses of the expression of mRNAs and miRNAs from 451 samples was performed using the melanoma TCGA database. Correlation coefficients between the expression of mRNAs or mRNAs/miRNAs were calculated using the Spearman rho method. Survival analysis was performed using the Kaplan-Meier method. Potential 3'UTR binding sites of miRNAs were found using the web-based tool www.targetscan.org.
Results: Of 22 mRNAs of checkpoint genes assessed, the expression of 19 was highly positively correlated to each other. These mRNAs code for both co-inhibitory and co-stimulatory proteins at the T cell and the C/APC sides of the immunological synapse, suggesting that there is joint transcriptional regulation on the expression of these checkpoint genes. The expression of one specific miRNA was also significantly positively correlated with the expression of eight of these checkpoint mRNAs (PD1L, PD1L, B7.1, ICOS, BTLA, LAG3, CTLA4, TNFRSF9). The significant positive correlation between this miRNA and B7.1 and PD1L was verified in 18 cell lines in vitro, with rho correlation coefficients of 0.72 and 0.61, respectively (p=0.001 and 0.01, respectively). This possibly indicates a joint transcriptional regulation on this miRNA and the mRNAs. Bioinformatic analyses suggest that this miRNA may potentially target the 3'UTR of 6 of these mRNAs (PD1, PD1L, B7.1, ICOS, BTLA, TNFRSF9). Data from 163 stage III melanoma patients with documented survival data show that a high expression level of this miRNA and a low expression level of either B7.1, B7.2, CD28, ICOS, ICOSL, OX40, OX40L, TNFRSF18 or PD1L was each significantly associated with poor prognosis relative to all other expression groups. Eight of these nine mRNAs are co-stimulatory.
Conclusions: It is tempting to speculate that aberrant co-regulation of the miRNA-mRNAs, leading to high levels of the miRNA and low levels of co-stimulatory checkpoint genes is associated with worse outcome, potentially as a result of 'immune evasion' due to decreased co-stimulation at the synapse.
Citation Format: Raya Leibowitz-Amit, Jason Roszik, Dror Avni, Elizabeth Grimm. Regulation of immune checkpoint genes revealed by a melanoma tumor cancer genome atlas (TCGA) analysis - potential implications for improving immunotherapy [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 5602. doi:10.1158/1538-7445.AM2017-5602</jats:p
Abstract 1528: Forecasting novel therapies by understanding the role BRD4 in regulating the Notch3 signaling in ovarian cancer
No full textAbstract
Advances in cancer research have led to the rapid development of novel drug therapies designed for optimal personalized patient care. Despite this surge of treatments, there is still a challenge in accurately predicting the most effective targeted therapy for a specific cancer. Additionally, the potential of systematically identifying and re-purposing currently existing therapeutics designed for one specific cancer to treat other malignancies remains understudied. To address this problem, our group has developed an integrative computational therapy-forecasting algorithm. This algorithm incorporates data from The Cancer Genome Atlas (TCGA) as well as molecular and survival correlations to identify candidate anti-tumor drugs that can be re-purposed for other malignancies by targeting novel pathways. Our computational analysis predicted that bromodomain inhibitors, which inhibit bromodomain-containing proteins such as BRD4, would target the Notch3 pathway in high-grade serous ovarian carcinoma (HGSC). Upregulation of Notch3 plays a crucial role in HGSC tumorigenesis and is associated with worse patient survival. Current Notch3 targeted therapies are not effective, thus designing therapeutic strategies to target Notch3 are critical for HGSC. We hypothesize that inhibition of BRD4 is an effective therapeutic target in HGSC by downregulating the Notch3 pathway. Current in vitro results demonstrated that BRD4 inhibition either by using chemical inhibitors or siRNA results in a decrease in HGSC cell viability by both MTT and 2-D colony formation assays. Furthermore, inhibition of BRD4 resulted in a decrease in both Notch3 transcription and protein levels. Given that BRD4 regulates gene transcription, we performed chromatin immunoprecipitation (ChIP) and observed that BRD4 was present in the Notch3 gene promoter. These findings suggest that by inhibiting BRD4 in HGSC, we can target Notch3 and biologically validates our initial in sillico analysis. The successful completion of this project could have major implications for development of personalized therapies not only for HGSC but for other cancers as well.
Note: This abstract was not presented at the meeting.
Citation Format: Alejandro Villar-Prados, Sherry Y. Wu, Jason Roszik, Anil K. Sood, Margaret I. Engelhardt. Forecasting novel therapies by understanding the role BRD4 in regulating the Notch3 signaling in ovarian cancer [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 1528. doi:10.1158/1538-7445.AM2017-1528</jats:p
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