bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract POSTER-TECH-1103: Aspirin, NSAIDS, and ovarian cancer survival from electronic medical records
Authors: Beeghly-Fadiel Alicia , Holman Gwendolyn , Stansel Samantha P. , Edwards Gretchen , Baeg Edward , Berke Hannah , Delahanty Ryan J. , Khabele Dineo 
Published: August 2015

Abstract
Background: Extensive literature indicates that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are associated with reduced cancer incidence and mortality. For ovarian cancer, a pooled analysis of 12 case-control studies recently demonstrated a significantly reduced risk for regular aspirin use and a similar but non-significant reduced risk for non-aspirin NSAID use. However, studies specifically evaluating NSAIDs and ovarian cancer survival are absent from the published literature.
Purpose: To determine if aspirin and other NSAIDs are associated with ovarian cancer survival.
Methods: Ovarian cancer cases were identified from de-identified electronic medical records (EMR) from the Vanderbilt University Medical Center. Ever use of aspirin or any NSAID was determined by MedEx, a natural language processing system designed to capture medication use from EMR. Linked tumor registry data was used to generate hazard ratios (HR) and confidence intervals (CI) for overall survival using Cox proportional hazards regression; covariates included age, race, stage of disease, histologic subtype, treatments received, and year of diagnosis.
Results: The majority of 1,147 confirmed ovarian cancer cases were Caucasian (87.0%), had serous histologic subtypes (53.6%), and late stage (III/IV, 50.0%) or stage unknown (29.3%) disease. Ovarian cancer cases with any aspirin use (207, 18.1%) had significantly longer overall survival in both unadjusted (HR: 0.56, 95% CI: 0.45-0.70) and adjusted analyses (HR: 0.59, 95% CI: 0.46-0.74). Similarly, ovarian cancer cases with any non-aspirin NSAID use (248, 21.6%) had significantly longer overall survival in both unadjusted (HR: 0.60, 95% CI: 0.48-0.74) and adjusted analyses (HR: 0.69, 95% CI: 0.54-0.88). Associations between any aspirin or other NSAID use (360, 31.4%) and longer ovarian cancer survival did not significantly differ by stage of disease (P-interaction=0.650), histologic subtype (P-interaction=0.076), or treatment with a platinum-based agent (P-interaction=0.069).
Conclusions: Indication of aspirin or non-aspirin NSAID use ascertained retrospectively from EMR was associated with improved overall ovarian cancer survival. Further evaluation, including timing and duration of use, are underway; replication of this association in additional study populations is needed.
Citation Format: Alicia Beeghly-Fadiel, Gwendolyn Holman, Samantha P. Stansel, Gretchen Edwards, Edward Baeg, Hannah Berke, Ryan J. Delahanty, Dineo Khabele. Aspirin, NSAIDS, and ovarian cancer survival from electronic medical records [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1103.
Abstract POSTER-TECH-1122: Mass spectrometric imaging of ovarian cancer mouse model tissue: searching for high-grade serous carcinoma biomarkers
Authors: Paine Martin R. L. , Bennett Rachel V. , Kim Jaeyeon , Sullards M. Cameron , Matzuk Martin M. , Fernández Facundo M. 
Published: August 2015

Abstract
High-grade serous carcinoma (HGSC) is the most common and deadliest ovarian cancer responsible for 90% of all ovarian cancer deaths. Studying the origin and early progression of this deadly cancer is critical in identifying biomarkers for early detection of the disease. Unfortunately, in the case of HGSC, it is virtually impossible to obtain early-stage human HGSC tissue samples because there is no diagnostic method capable of detecting early forms of HGSC. The recent breakthrough of an animal model (Dicer-Pten double-knockout mice) provides an invaluable opportunity to finally investigate the early tumor microenvironment. The model exhibits remarkable similarities to human HGSC, allowing greater insight into the biochemistry associated with nascent neoplastic changes within ovarian and fallopian tube tissues. An important aspect of determining potential biomarkers is to correlate any detected chemical changes with observed histological changes. To visualize the spatial distribution of chemical changes, tissue-based mass spectrometric imaging (MSI) can be employed as an unbiased way of visualizing the changes of proteins, metabolites, or both in cancer tissues. MSI is particularly useful for identifying molecules uniquely elevated or lowered in early tumor tissues, in which cell-type specific changes are expected to occur due to intratumoral microenvironment heterogeneity. In this study, two complementary MSI techniques – matrix-assisted laser desorption ionization (MALDI) and desorption electrospray ionization (DESI) mass spectrometry – are applied to thin tissue sections of Dicer-Pten mutant mouse ovaries and fallopian tubes. Several sulfatide lipids d18:1/C16:0, d18:1/C24:1 and d18:1/C24:0 have been implicated as potential biomarkers in human ovarian cancer. These metabolites, among others, are being included in a thorough MSI experiment to visualize molecular changes in multiple cell types in the microenvironment during early tumor progression. In addition to providing information about the early molecular changes taking place, the knowledge gained from this study will also help understand which specific cell types in the fallopian tube are more prone to early tumorigenesis.
(Grant support: Marsha Rivkin Ovarian Cancer Challenge Grant)
Citation Format: Martin R. L. Paine, Rachel V. Bennett, Jaeyeon Kim, M. Cameron Sullards, Martin M. Matzuk, Facundo M. Fernández. Mass spectrometric imaging of ovarian cancer mouse model tissue: searching for high-grade serous carcinoma biomarkers [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1122.
Abstract POSTER-THER-1409: Targeting p53-FoxM1 axis in ovarian cancer
Authors: Zhang Xuan , Cheng Lihua , Minn Kay , Waggoner Magdalena , Parelkar Nikhil K. , Jokar Iman , Vielhauer George A. , Madan Rashna , Godwin Andrew K. , Shridhar Viji , Chien Jeremy 
Published: August 2015

Abstract
FoxM1, a member of the Forkhead transfection factors, has been found to be overexpressed in many human cancers including ovarian cancer. Although FoxM1 is known to be downregulated by p53, the molecular mechanisms are not well characterized. In this study, we used the MDM2 inhibitor Nutlin-3 as a tool to modulate p53 expression and investigated the mechanism by which p53 regulates FoxM1 expression in ovarian cancer cells. We observed that Nutlin-3 upregulated p53 protein and downregulated FoxM1 mRNA and protein levels in ovarian cancer cell lines with wild type TP53, but not in cell lines with mutant TP53. This effect was at least partially blocked by cycloheximide or actinomycin D, indicating a transcription- and translation-dependent mechanism. Pulse-chase studies revealed that downregulation of FoxM1 by Nutlin-3 is due to enhanced FoxM1 mRNA decay. Knockdown of p53 using shRNAs abrogated the suppression of FoxM1 expression by Nutlin-3, indicating a p53-dependent mechanism. Furthermore, silencing of FoxM1 by shRNAs in ovarian cancer cells with or without wild-type TP53 led to a significant decrease in cell proliferation. The FoxM1 inhibitor, thiostrepton, induces cytotoxicity in ovarian cancer cell lines and enhances sensitivity to cisplatin in these cells. Thiostrepton downregulates FoxM1 expression in several ovarian cancer cell lines and enhances sensitivity to carboplatin in vivo. Finally, FoxM1 expression is elevated in nearly all (47/48) ovarian tumors. In summary, the present study provides novel evidence that p53 downregulates FoxM1 in ovarian cancer cells at least in part by destabilizing FoxM1 mRNA and that FoxM1 may be targeted for therapeutic benefits in ovarian cancer.
Citation Format: Xuan Zhang, Lihua Cheng, Kay Minn, Magdalena Waggoner, Nikhil K. Parelkar, Iman Jokar, George A. Vielhauer, Rashna Madan, Andrew K. Godwin, Viji Shridhar,, Jeremy Chien. Targeting p53-FoxM1 axis in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1409.
Abstract POSTER-THER-1411: MM-141, an IGF-1R and ErbB3 directed tetravalent bispecific antibody, inhibits ovarian cancer cell growth in vitro
Authors: Curley Michael , Czibere Akos , Lugovskoy Alexey 
Published: August 2015

Abstract
PURPOSE OF STUDY: Insulin-like growth factor receptor 1 (IGF-1R) signaling has been implicated in the pathogenesis of ovarian cancer. However, IGF-1R inhibitors have had limited efficacy in clinical trials to date. ErbB3, a member of the ErbB receptor tyrosine kinase family, can activate AKT survival signaling through binding of its ligand heregulin (HRG) in a majority of IGF-1 sensitive human cancer cell lines. ErbB3 and pAKT expression are upregulated following IGF-1R blockade and thus activated ErbB3 signaling may represent a potential escape route in the development of resistance to therapy. MM-141, an IGF-1R and ErbB3 directed bispecific antibody, blocks and degrades IGF-1R and ErbB3 containing receptor complexes leading to inhibition of downstream tumor pro-survival signaling to a greater extent as compared to anti-IGF-1R and ErbB3 antibodies. Here we explore the activity of MM-141 in ovarian cancer cell lines in vitro.
EXPERIMENTAL PROCEDURES: Growth inhibitory activity of MM-141 was tested on a panel of established ovarian cancer cell lines in vitro. The ability of MM-141 to inhibit basal and IGF-1- and HRG-induced signaling was explored by ELISA and western blotting analyses.
DATA SUMMARY: Inhibition of cell proliferation mediated by MM-141 varied among the ovarian cancer cell lines profiled in vitro. Furthermore, MM-141 treatment inhibited basal and ligand-activated IGF-1R, ErbB3 and downstream signaling in a selection of these ovarian cell lines.
CONCLUSIONS: Our findings suggest that co-inhibition of IGF-1R and ErbB3 signaling with MM-141 has the potential to be an effective therapy for ovarian cancer patients by blocking redundant survival pathway activation.
Citation Format: Michael Curley, Akos Czibere, Alexey Lugovskoy. MM-141, an IGF-1R and ErbB3 directed tetravalent bispecific antibody, inhibits ovarian cancer cell growth in vitro [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1411.
Abstract POSTER-THER-1421: Epigenetic targeting of ovarian cancer stem cells
Authors: Wang Yinu , Cardenas Horacio , Fang Fang , Condello Salvatore , Taverna Pietro , Segar Matthew , Liu Yunlong , Matei Daniela , Nephew Kenneth P. 
Published: August 2015

Abstract
In ovarian and other cancers, emerging data indicate that cancer stem cells contribute to chemoresistance and that their persistence alters clinical outcome. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may play a critical role in targeting this subpopulation. Epigenetic aberrations, especially DNA methylation, result in silencing of tumor suppressor and differentiation-associated genes and regulate ovarian cancer stem cell (OCSCs) survival. To test the hypothesis that DNA hypomethylating agents “reset” OCSCs towards differentiation, we investigated the effect of the new DNA methytransferase inhibitor SGI-110 on OCSCs, defined as aldehyde dehydrogenase 1 (ALDH)(+) cells. We demonstrated that ALDH(+) OC cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low dose SGI-110 reduced the stemness properties of ALDH(+) cells, including their tumor initiating capacity, resensitized these OCSCs to platinum, and induced re-expression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSCs, caused profound global tumor hypomethylation, and delayed tumor progression, supporting epigenomic targeting as a novel strategy after platinum-based therapy in OC. Collectively, our data suggest that a strategy targeting DNA methylation in OC exerts potent anti-tumor activity by allowing elimination of OCSCs enriched in residual, platinum resistant tumors. Our study provides the first evidence that epigenome targeting strategies delay tumor progression by targeting and reprogramming residual cancer stem cells, suggesting that SGI-110 in combination with platinum has the potential to prevent recurrent and chemoresistant OC.
Citation Format: Yinu Wang, Horacio Cardenas, Fang Fang, Salvatore Condello, Pietro Taverna, Matthew Segar, Yunlong Liu, Daniela Matei, Kenneth P. Nephew. Epigenetic targeting of ovarian cancer stem cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1421.
Abstract POSTER-THER-1427: Epidermal growth factor receptor mediated alterations in DNA methylation associated with the development of platinum resistance in ovarian cancer cells
Authors: Samudio-Ruiz Sabrina L. , Granados Michaela L. , Hudson Laurie G. 
Published: August 2015

Abstract
Acquisition of platinum resistance following first line platinum-taxane therapy occurs in a large portion of ovarian cancer patients and continues to be a major challenge in clinical effectiveness. To date, there are limited interventions available to prevent or reverse platinum resistance; however, there has been some advances in the use of demethylating agents in the resensitization of patients to platinum based therapy. This highlights epigenetic alterations, in particular DNA methylation, as critical contributors to the acquisition of drug resistance in ovarian cancer. The Epidermal Growth Factor Receptor (EGFR) has also been linked to chemoresistance and is known to be activated by cisplatin treatment. We previously published that activation of the EGFR can increase DNA methyltransferase (DMNT) activity and, over extended activation, can significantly increase global DNA methylation in ovarian cancer cells. We hypothesized that cisplatin induced activation of the EGFR could mediate changes in DNA methylation associated with the development of platinum resistance. To investigate this, we used an in vitro model of platinum resistance and evaluated EGFR signaling and DNMT activity after acute cisplatin and in platinum resistant cells. We found that cisplatin treatment activates the EGFR and downstream signaling pathways JAK and AKT. Cisplatin also increased DNMT activity and this increase was dependent on EGFR activation. Over repeated sequential treatments of cisplatin, we successfully developed platinum resistant cells that possessed significant increases in DNMT activity and had moderate, but significant, increases in global DNA methylation. Preliminary data using the EGFR inhibitor Erlotinib during the development of platinum resistant cells suggest that the EGFR plays an integral role in the acquisition of platinum resistance. This work implicates EGFR driven alterations to DNMT activity and DNA methylation as a novel mechanism for development of platinum resistance. Further studies are currently being done to evaluate potential alterations in activation of downstream signaling pathways, levels of DNA methyltransferases and other changes in expression associated with platinum resistance.
Citation Format: Sabrina L. Samudio-Ruiz, Michaela L. Granados, Laurie G. Hudson. Epidermal growth factor receptor mediated alterations in DNA methylation associated with the development of platinum resistance in ovarian cancer cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1427.
Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18
Authors: Hamad Osama A. , Mitroulis Ioannis , Fromell Karin , Kozarcanin Huda , Chavakis Triantafyllos , Ricklin Daniel , Lambris John D. , Ekdahl Kristina N. , Nilsson Bo 
Published: August 2015

SummaryComplement component C3 has a potential role in thrombotic pathologies. It is transformed, without proteolytic cleavage, into C3(H2O) upon binding to the surface of activated platelets. We hypothesise that C3(H2O) bound to activated platelets and to platelet-derived microparticles (PMPs) contributes to platelet-PMN complex (PPC) formation and to the binding of PMPs to PMNs. PAR-1 activation of platelets in human whole blood from normal individuals induced the formation of CD16+/CD42a+ PPC. The complement inhibitor compstatin and a C5a receptor antagonist inhibited PPC formation by 50 %, while monoclonal antibodies to C3(H2O) or anti-CD11b inhibited PPC formation by 75–100 %. Using plasma protein-depleted blood and blood from a C3-deficient patient, we corroborated the dependence on C3, obtaining similar results after reconstitution with purified C3. By analogy with platelets, PMPs isolated from human serum were found to expose C3(H2O) and bind to PMNs. This interaction was also blocked by the anti-C3(H2O) and anti-CD11b monoclonal antibodies, indicating that C3(H2O) and CD11b are involved in tethering PMPs to PMNs. We confirmed the direct interaction between C3(H2O) and CD11b by quartz crystal microbalance analysis using purified native C3 and recombinant CD11b/CD18 and by flow cytometry using PMP and recombinant CD11b. Transfectants expressing CD11b/CD18 were also shown to specifically adhere to surface-bound C3(H2O). We have identified contact-activated C3(H2O) as a novel ligand for CD11b/CD18 that mediates PPC formation and the binding of PMPs to PMNs. Given the various roles of C3 in thrombotic reactions, this finding is likely to have important pathophysiological implications.
Post-Transcriptional Regulation of Endothelial Nitric Oxide Synthase Expression by Polypyrimidine Tract–Binding Protein 1
Authors: Yi Bing , Ozerova Maria , Zhang Guan-Xin , Yan Guijun , Huang Shengdong , Sun Jianxin 
Published: August 2015

Objective—
Endothelial nitric oxide synthase (eNOS) is an important regulator of vascular function and its expression is regulated at post-transcriptional levels through a yet unknown mechanism. The purpose of this study is to elucidate the post-transcriptional factors regulating eNOS expression and function in endothelium.

Approaches and Results—
To elucidate the molecular basis of tumor necrosis factor (TNF)-α–mediated eNOS mRNA instability, biotinylated eNOS 3′-untranslational region (UTR) was used to purify its associated proteins by RNA affinity chromatography from cytosolic fractions of TNF-α-stimulated human umbilical vein endothelial cells (HUVECs). We identified 2 cytosolic proteins, with molecular weight of 52 and 57 kDa, which specifically bind to eNOS 3′-UTR in response to TNF-α stimulation. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis identified the 57-kDa protein as polypyrimidine tract–binding protein 1 (PTB1). RNA gel mobility shift and UV cross-linking assays demonstrated that PTB1 binds to a UCUU-rich sequence in eNOS 3′-UTR, and the C-terminal half of PTB1 is critical to this interaction. Importantly, PTB1 overexpression leads to decreased activity of luciferase gene fused with eNOS 3′-UTR as well as reduced eNOS expression and activity in human ECs. In HUVECs, we show that TNF-α markedly increased PTB1 expression, whereas adenovirus-mediated PTB1 overexpression decreased eNOS mRNA stability and reduced protein expression and endothelium-dependent relaxation. Furthermore, knockdown of PTB1 substantially attenuated TNF-α-induced destabilization of eNOS transcript and downregulation of eNOS expression.

Conclusions—
These results indicate that PTB1 is essential for regulating eNOS expression at post-transcriptional levels and suggest a novel therapeutic target for treatment of vascular diseases associated with inflammatory endothelial dysfunction.
Monocyte-Derived Dendritic Cells Upregulate Extracellular Catabolism of Aggregated Low-Density Lipoprotein on Maturation, Leading to Foam Cell Formation
Authors: Haka Abigail S. , Singh Rajesh K. , Grosheva Inna , Hoffner Haley , Capetillo-Zarate Estibaliz , Chin Harvey F. , Anandasabapathy Niroshana , Maxfield Frederick R. 
Published: August 2015

Objective—
Although dendritic cells are known to play a role in atherosclerosis, few studies have examined the contribution of the wide variety of dendritic cell subsets. Accordingly, their roles in atherogenesis remain largely unknown. We investigated the ability of different dendritic cell subsets to become foam cells after contact with aggregated low-density lipoprotein (LDL; the predominant form of LDL found in atherosclerotic plaques).

Approach and Results—

We demonstrate that both murine and human monocyte-derived dendritic cells use exophagy to degrade aggregated LDL, leading to foam cell formation, whereas monocyte-independent dendritic cells are unable to clear LDL aggregates by this mechanism. Exophagy is a catabolic process in which objects that cannot be internalized by phagocytosis (because of their size or association with extracellular structures) are initially digested in an extracellular acidic lytic compartment. Surprisingly, we found that monocyte-derived dendritic cells upregulate exophagy on maturation. This contrasts various forms of endocytic internalization in dendritic cells, which decrease on maturation. Finally, we show that our in vitro results are consistent with dendritic cell lipid accumulation in plaques of an ApoE
−/−
mouse model of atherosclerosis.

Conclusions—
Our results show that monocyte-derived dendritic cells use exophagy to degrade aggregated LDL and become foam cells, whereas monocyte-independent dendritic cells are unable to clear LDL deposits. Furthermore, we find that exophagy is upregulated on dendritic cell maturation. Thus, exophagy-mediated foam cell formation in monocyte-derived dendritic cells could play a significant role in atherogenesis.
Prediction of Causal Candidate Genes in Coronary Artery Disease Loci
Authors: Brænne Ingrid , Civelek Mete , Vilne Baiba , Di Narzo Antonio , Johnson Andrew D. , Zhao Yuqi , Reiz Benedikt , Codoni Veronica , Webb Thomas R. , Foroughi Asl Hassan , Hamby Stephen E. , Zeng Lingyao , Trégouët David-Alexandre , Hao Ke , Topol Eric J. , Schadt Eric E. , Yang Xia , Samani Nilesh J. , Björkegren Johan L.M. , Erdmann Jeanette , Schunkert Heribert , Lusis Aldons J. 
Published: August 2015

Objective—
Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes.

Approach and Results—
All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters. The latter included expression quantitative trait loci, tissue specificity, and miRNA binding. High priority candidate genes were further identified based on literature searches and our experimental data. We conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, we obtained evidence that genetic variants at CAD loci affect 98 genes which had not been linked to CAD previously.

Conclusions—
Our results substantially revise the list of likely candidates for CAD and suggest that genome-wide association studies efforts in other diseases may benefit from similar bioinformatics analyses.