1,721,222 research outputs found
Abstract KP02: STARING DOWN THE BARREL OF A TUBE AT THE ORIGINS OF OVARIAN CANCER
No full textAbstract
There is an emerging consensus that a majority of high-grade serous carcinomas, the most common type of ovarian cancer, are derived from PAX8-expressing cells in the distal fallopian tube. Careful histologic examination of fallopian tubes from BRCA1/2 mutation carriers has led to the identification of a morphological continuum that begins with a benign secretory cell, transitions to identifiable precursor lesions, and culminates in serous carcinoma. We have previously demonstrated the biologic plausibility of this hypothesis by showing that dysregulation of BRCA1/2 and TP53 in PAX8-expressing mouse or human fallopian tube secretory epithelial cells (FTSECs) can induce tumors that are genomically and phenotypically identical to human high-grade serous ovarian cancers.
While PAX8 serves as the basis for many of the fallopian tube-based models we have developed, little is known about its role during neoplastic transformation. PAX8 is a lineage-defining transcription factor that directs the development of the Müllerian duct (the female reproductive tract). Its expression is retained by nearly all high-grade serous carcinomas but it remains unknown whether alterations in the PAX8 cistrome contribute to ovarian carcinomas. Using whole transcriptome shotgun sequencing (RNA-Seq) after PAX8 knockdown and ChIP-Seq, we show that FTSECs and high-grade serous carcinomas are distinguished by marked reprogramming of the PAX8 cistrome. Interestingly, the majority of PAX8 binding peaks are found in intronic and intergenic regions of the genome rather than promoters. Genes that are significantly altered between FTSECs and carcinoma lines are enriched near PAX8 binding sites. These sites are also near TEAD binding sites, and these transcriptional changes may be related to PAX8 interactions with the TEAD/YAP1 signaling pathway. These data suggest that transcriptional changes after transformation in ovarian cancer are closely related to epigenetic remodeling in lineage-specific transcription factors.
Citation Format: Ronny Drapkin. STARING DOWN THE BARREL OF A TUBE AT THE ORIGINS OF OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr KP02.</jats:p
Abstract MIP-044: FOXM1 INDUCED REPLICATION STRESS IS MITIGATED BY ITS BIDIRECTIONAL GENE PARTNER, RHNO1, IN HIGH GRADE SEROUS OVARIAN CANCER
No full textAbstract
PURPOSE: FOXM1 is located at 12p13.33, a significantly amplified locus in high-grade serous ovarian cancer (HGSC). The 12p13.33 amplicon contains ~33 genes, which may cooperate with FOXM1 to exert oncogenic function. Although FOXM1 expression is associated with cancer genomic instability, it is unclear whether FOXM1 causes this phenotype and, if so, by what mechanism. We hypothesized that FOXM1 induces replication stress, which is the slowing or stalling of replication forks. We further noted that RHNO1, a component of the 9-1-1 complex required for ATR-CHK1 signaling, is contained within the 12p13.33 amplicon, and arranged in a head-to-head orientation with FOXM1. Here, we characterized the FOXM1-RHNO1 bidirectional promoter, FOXM1 and RHNO1 expression patterns in HGSC, and determined the relationship between FOXM1 and RHNO1 in replication stress.
METHODS: We used 5' RACE and a luciferase reporter construct to characterize the FOXM1-RHNO1 bidirectional promoter. We analyzed copy number, mRNA and protein expression datasets in TCGA HGSC and additional TCGA cancers. We measured FOXM1 and RHNO1 expression in HGSC cell lines and primary HGSC tissues. We overexpressed FOXM1 in human immortalized fallopian tube epithelial (FTE) cells to determine its contribution to replication stress. We used RHNO1 knockdown to dissect its functional contribution to ATR-CHK1 signaling in HGSC cells.
RESULTS: FOXM1 and RHNO1 were co-amplified in ~12% of HGSC and their mRNA expressions were highly correlated. The FOXM1-RHNO1 bidirectional promoter showed similar activity in each direction in HGSC cells, and correlated with mRNA expression. Analysis of TCGA HGSC data revealed that FOXM1 associates with markers of DNA replication and CHK1-Ser345 phosphorylation, a canonical marker of replication stress. FOXM1 overexpression in immortalized FTE cells induced CHK1-Ser345 phosphorylation. RHNO1 knockdown attenuated CHK1-Ser345 phosphorylation in response to replication stress, and, importantly, reduced clonogenic growth in FOXM1 overexpressing HGSC cells.
CONCLUSIONS: Our data reveal that FOXM1 and RHNO1 share a bidirectional promoter resulting in their frequent co-expression. FOXM1 induces replication stress whereas RHNO1 is necessary for efficient ATR-CHK1 signaling. We hypothesize that balanced FOXM1 and RHNO1 expression promotes HGSC development and progression. Ongoing studies are characterizing the impact of FOXM1 and RHNO1 on replication stress and genomic instability. Finally, our findings suggest ATR-CHK1 signaling as a potential therapeutic vulnerability in FOXM1 activated HGSC.
Citation Format: Carter J Barger, Linda Chee, Ronny Drapkin, Kunle Odunsi, Adam R. Karpf. FOXM1 INDUCED REPLICATION STRESS IS MITIGATED BY ITS BIDIRECTIONAL GENE PARTNER, RHNO1, IN HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-044.</jats:p
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
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
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
Faculty Opinions recommendation of Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma.
No full textFaculty Opinions recommendation of Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling.
No full textAbstract IA5: Discovering the distal fallopian tube as the origin for high-grade serous ovarian cancer
No full textFaculty Opinions recommendation of A PET imaging agent for evaluating PARP-1 expression in ovarian cancer.
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