bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4469: Clinical outcomes among patients treated with abiraterone acetate for advanced prostate cancer with pre-existing cardiovascular conditions
Authors: Lu-Yao Grace , Nikita Nikita , Keith Scott , Gandhi Krupa , Rebbeck Timothy R. , Cullen Jennifer , Nightingale Ginah , Mann Mark , Chapman Andrew 
Published: August 2019

Abstract
Background: Advanced prostate cancer patients with pre-existing cardiovascular diseases (CVD) are often excluded from clinical trials of abiraterone acetate (AA). Therefore, the clinical outcomes of these patients are uncertain. This study was undertaken to examine their outcomes - changes in the rate of hospitalization and short-term mortality after AA initiation by pre-existing CVD conditions.
Methods: This population-based study identified PCa patients from the linked Surveillance, Epidemiology and End Result (SEER)-Medicare files diagnosed between 1/1/1991 and 12/31/2013 and treated with AA in 2011-2014. The primary endpoints were 6-month overall mortality and changes in hospitalization rates following AA initiation. Major pre-existing conditions are listed in the Table 1. The changes in hospitalization rate were measured by the incidence rate ratios (IRR), post treatment rate divided by pre-treatment rate.
Results: Among 2,845 patients treated with AA (median age 75 years), 1,924 (67.6%) of these patients had at least one pre-existing CVD condition. Compared to pre-treatment period, the hospitalization incidence post-AA increased by 58% to 88%. The crude risk of 6-month overall mortality was between 21.4% to 25.6%.
Table 1:Risk of Hospital Visits and 6-month Overall Mortality among AA Patients by Pre-Existing CVD condition.Pre-existing CVD conditionNo. hospitalizations per 6-months prior to AAIRR for hospitalizations (95% CI)Crude 6-month post AA MortalityAcute Myocardial Infraction0.651.88 (1.48-2.40)25.6%Atrial Fibrillation0.561.58 (1.36-1.83)24.4%Congestive Heart Failure0.591.72 (1.54-1.92)23.4%Stroke0.521.67 (1.40-2.01)22.1%Ischemic Heart Disease0.471.78 (1.63-1.95)21.4%No CVD0.251.87 (1.59-2.20)15.8%
Conclusion: All patients experienced significant increase in hospitalization after initiation of AA. Our study highlights the importance of carefully monitoring patients after prescribing AA.
Citation Format: Grace Lu-Yao, Nikita Nikita, Scott Keith, Krupa Gandhi, Timothy R. Rebbeck, Jennifer Cullen, Ginah Nightingale, Mark Mann, Andrew Chapman. Clinical outcomes among patients treated with abiraterone acetate for advanced prostate cancer with pre-existing cardiovascular conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4469.
Abstract 4472: The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma
Authors: Yang Wen-Hsuan , Chi Jen-Tsan 
Published: August 2019

Abstract
Ferroptosis is a newly appreciated lipid peroxidation-dependent regulated cell death with relevance for many human diseases, which may be a tumor suppression mechanism and may have antitumor potential. Elucidation of the mechanism is therefore important. Here, we reported that ferroptosis sensitivity is significantly influenced by cell density. The effectors of the Hippo pathway, YAP/TAZ, are the molecular sensors of cell density that regulate cell proliferation, survival, and organ size determination. Therefore, we determined the potential role of YAP/TAZ in regulating ferroptosis sensitivities. RCC cell lines and RCC PDX tumor cells mainly express TAZ that undergoes density-dependent nuclear translocation. Importantly, the removal of TAZ confers ferroptosis resistance, while the expression of constructively active TAZ sensitizes cells to ferroptosis. Mechanistically, we found that TAZ knockdown reduced ferroptosis through the repression of its target gene, EMP1. EMP1 affects ferroptosis through the regulation of NOX4 and lipid peroxidation. Collectively, we have shown that the ferroptosis can be regulated by non-genetic factors, such as cell density, through the Hippo pathway and suggest the therapeutic potential of ferroptosis-inducing agent, such as erastin, for TAZ-activated tumors.
Citation Format: Wen-Hsuan Yang, Jen-Tsan Chi. The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4472.
Abstract 4502: The role of A-to-I RNA editing in diversifying the microRNA functions in cancer
Authors: Liang Han 
Published: August 2019

Abstract
Both miRNAs and A-to-I RNA editing, a widespread nucleotide modification mechanism, have recently emerged as key players in cancer pathophysiology. However, the functional impact of RNA editing of miRNAs in cancer remains largely unexplored. Here, we systematically characterized the miRNA editing profiles of ~9000 samples across 20 cancer types from miRNA sequencing data of The Cancer Genome Atlas and identified adenosine-to-inosine (A-to-I) RNA editing hotspots. Focusing on the RNA editing hotspot in miR-200b, a key tumor metastasis suppressor, we found that the miR-200b editing level correlates with patient prognosis opposite to that pattern for the wild-type miR-200b expression. We further experimentally showed that in contrast to wild-type miRNA, the edited miR-200b can promote cell invasion and migration through its impaired ability to inhibit ZEB1/ZEB2 and acquired concomitant ability to repress new targets including LIFR, a well-characterized metastasis suppressor. In another example, an ADAR2-catalyzed RNA editing site within the miR-379 is under-edited in tumors relative to normal tissues, with a high editing level being correlated with better patient survival times across cancer types. We demonstrate that in contrast to wild-type miRNA, edited miR-379 inhibited cell proliferation and promoted apoptosis in diverse tumor contexts in vitro. Importantly, through nanoliposomal delivery, edited miR-379 mimics significantly inhibited tumor growth and extended survival of mice. Our study indicates a role of RNA editing in diversifying miRNA function during cancer progression and highlights the translational potential of edited miRNAs as new class of cancer biomarkers and therapeutics.
Citation Format: Han Liang. The role of A-to-I RNA editing in diversifying the microRNA functions in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4502.
Abstract 4506: MDM2 alternative splicing is regulated by microRNA binding to control p53 activity
Authors: Montes Matias , Goodwin Andrew , Chandler Dawn S. 
Published: August 2019

Abstract
Alternative splicing of the MDM2 is an important means by which p53 is upregulated to combat the deleterious effects of genotoxic stress. One splice variant, MDM2-ALT1, is activated in response to genotoxic stress and is comprised of only the two terminal coding exons 3 and 12 and therefore lacks a p53 binding domain. This variant has been identified in a number of human tumors, including invasive carcinoma of the breast and lung, as well as soft tissue sarcomas. Despite its pervasiveness in tumors and the therapeutic possibilities it presents, there is very little known about the regulators of that govern this alternative splicing event.
Our lab has identified a specific microRNA that is expressed at high levels in normal cells but decreased under conditions of genotoxic stress and in rhabdomyosarcoma cells, both of which are characterized by the expression of the MDM2 spliced isoform. Hence, expression of the microRNA is inversely correlated with the splice variant MDM2-ALT1. Though recent studies have shown that splicing factors can be regulated through miRNA-mediated gene silencing and indirectly influence splicing choices, we were unable to identify any splicing regulators of MDM2 to be targeted by the microRNA. Interestingly, the microRNA has been reported as one of the miRNAs that is reimported to the nucleus but has not been ascribed a role in the nuclear space. We therefore wanted to test the hypothesis that the microRNA can directly bind to the MDM2 pre-mRNA to drive splicing choices in a regulated fashion. To this end, we have identified predicted binding sites for the microRNA in the regulated region of MDM2, within and near exons 3 and 12. We have shown that the microRNA binds specifically to these regions in MDM2 in normal cells and has decreased binding after genotoxic stress. Furthermore, we have shown that overexpression of the pre-microRNA can alleviate the induction of the MDM2-ALT1 isoform in response to genotoxic stress. We propose that microRNA binding to the MDM2 pre-mRNA regulates its splicing and plays a role in the DNA damage response and the pathway to tumorigenesis.
Our work implicates for the first time that a miRNA would be acting as a splicing factor, a novel function for this class of non-coding RNAs and a novel method of regulation of the p53-MDM2 axis. Furthermore, our discoveries reveal miR-regulated splicing as a possible strategy to activate p53 and sensitize cancer cells to conventional cancer therapies.
Citation Format: Matias Montes, Andrew Goodwin, Dawn S. Chandler. MDM2 alternative splicing is regulated by microRNA binding to control p53 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4506.
Abstract 4515: Utilizing nucleic-acid scavengers (NASs) to inhibit proinflammatory and proinvasive signaling in triple-negative breast cancer
Authors: Eteshola Elias O. , Naqvi Ibtehaj A. , Gunaratne Ruwan , Moreno Angelo , Nair Smita K. , Sullenger Bruce A. 
Published: August 2019

Abstract
Breast cancers (BC) remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortalities in the US. Subtype heterogeneity and aggressive invasive potential are believed to be the major contributors of these outcomes. BC lacking canonical histological receptors (i.e. ER/PR/HER2), called triple-negative (TNBC), are notoriously aggressive, difficult-to-treat, and metastatic. It has been observed that the degree of inflammation-driven tumorigenesis tends to correlate with increased levels of cell-free DNA (cfDNA) in cancer patient sera. Our lab had previously shown that nucleic-acid scavengers (NASs) could be used to block the pro-inflammatory and pro-invasive/metastatic signals (e.g. DAMPs) elicited by these cfDNA/RNA likely through innate immune sensors such as of the toll-like receptors (TLRs). Recently, we showed that treatment with the cationic polymer NAS, PAMAM-G3, elicited a drastic reduction in metastatic tumor burden to the liver in an immune-competent murine model of pancreatic cancer (I. Naqvi & R. Gunaratne et al., Molecular Therapy 26, 2018). Ongoing work has shown that both chemotherapy-derived TNBC conditioned media and a TLR9 agonist greatly increased TNBC in vitro invasion and was significantly inhibited upon treatment with PAMAM-G3. To elucidate the mechanism by which this NAS works in these tumor settings, our lab has developed several PAMAM-G3 derivatives, including biotin, IR-, and near-IR fluorophore labeled molecules. These molecules will allow us to conduct DAMP capture and characterization experiments, as well as perform in vitro and in vivo live imaging experiments to gain better insights into NAS PK/PD properties. Mechanistic insight into NAS anti-metastatic and anti-inflammatory capabilities will enhance our basic understanding of metastatic progression and its interplay with the immune system. Moreover, these principles will aid in the development of novel of anti-metastatic therapies to improve TNBC patient outcomes.
Citation Format: Elias O. Eteshola, Ibtehaj A. Naqvi, Ruwan Gunaratne, Angelo Moreno, Smita K. Nair, Bruce A. Sullenger. Utilizing nucleic-acid scavengers (NASs) to inhibit proinflammatory and proinvasive signaling in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4515.
Abstract 4521: Mutant Kras expression triggers clonal acinar cell expansion as an early step in pancreas cancer
Authors: Artandi Steven E. , Neuhöfer Patrick , Roake Caitlin M. , Kim Stewart , Lu Ryan , Charville Greg 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States with the lowest 5-year survival rate of any major cancer, in part due to late detection of the disease. Studies indicate that pre-invasive lesions - pancreatic intraepithelial neoplasias (PanINs) - progress to PDA. The cell of origin for PDA is still under debate. While lineage-tracing experiments in mice indicate that PanINs originate from acinar cells, cell culture studies suggest that ductal cells can give rise to PanINs. In addition to these important questions regarding cancer initiation, mechanisms of cellular renewal in the exocrine pancreas remain poorly understood. The enzyme telomerase is intimately associated with cancer, and with stem cells and tissue renewal. Telomerase is required for long-term cell proliferation through its critical role in maintaining telomeres. The core enzyme consists of the RNA component TERC and the reverse transcriptase TERT. Moreover, telomerase is activated in over 90% human cancers and genome wide association studies have linked polymorphisms in the Tertgene with an increased risk of pancreas cancer. To analyze the role of TERT-expressing cells in the pancreas during homeostasis, regeneration and tumorigenesis, we generated a mouse line that expresses the regulated CreERT2 recombinase under the endogenous TERT promoter (TertCreERT2/+). Crossing these mice to a reporter strain enables the permanent labeling of TERT-expressing cells and their progeny upon tamoxifen injection. We find that rare TERT+ cells exist throughout the pancreas within the acinar and islet cell populations, but not in ductal cells. We show that rare TERT+ acinar cells clonally expand to renew the acinar compartment during homeostasis and during pancreas injury. To understand how these TERT+ acinar progenitor cells respond to mutant Kras, we crossed TertCreERT2/+mice with KrasLoxStopLox-G12D/+mice. We find that activation of KrasG12D in TERT-expressing cells in adult mice promotes accelerated acinar clone formation and these acinar lesions ultimately convert to PanIN pre-invasive lesions. Our data indicate that TERT-expressing cells represent an acinar progenitor cell population. Furthermore, these progenitor cells respond to mutant Kras first through a regenerative response yielding expanding acinar clones, followed by conversion to ductal PanIN lesions. We propose that acinar cell expansion is an early step in pancreatic tumorigenesis that precedes ADM and PanIN formation.
Citation Format: Steven E. Artandi, Patrick Neuhöfer, Caitlin M. Roake, Stewart Kim, Ryan Lu, Greg Charville. Mutant Kras expression triggers clonal acinar cell expansion as an early step in pancreas cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4521.
Abstract 4522: An in vitro 3D immune exclusion tumor model engineered in a layer-by-layer fashion
Authors: Hribar Kolin C. , Kleinheinz Tracy , Klementowicz Joanna , Kaufman Susan , Blake Robert A. , Eidenschenk Celine 
Published: August 2019

Abstract
Recent immunotherapy failures in clinical trials have elucidated the affects of the tumor stroma on attenuating therapeutic response. In some cancers, the stroma consists of a collagen-rich fibrotic zone on the tumor periphery that traps infiltrating CD8+ T cells, allowing the tumor to evade immune cell-mediated death. Typically, animal models are employed to study complex physiology. However, known challenges to these methods include cost, duration and throughput. Thus, we sought to develop a 3D in vitro model that recapitulates the immune exclusion phenotype in a high throughput manner. We utilized a novel 3D cell culture platform, VersaGel and Symphony, to pattern tumor-stroma-immune compartments in a layer-by-layer fashion in 96-well plates. VersaGel is a chemically modified extracellular matrix that is amenable to light-induced crosslinking using the Symphony apparatus. Moreover, Symphony allows for discrete layers to be formed with any VersaGel/cell mixture, with defined 3D gel thicknesses (eg. 100µm, 250µm, 500µm) and areas in the plate (eg. 2mm, 4mm, or 8mm diameter discs).
GFP-labeled MC38-ova (ovalbumin antigen) colon carcinoma cells were grown in 100µm thick 3D VersaGel with or without CFP-labeled mouse embryonic fibroblasts (MEF) layered on top for 4 days. After, OT-1-RFP CD8+ cells were added to the culture medium to assess their penetration depth and tumor cell death over 3 days. 3D cell analysis through the optically clear VersaGel was performed in situ using high content confocal microscopy, effectively quantifying RFP/CFP/GFP-labeled cells and DRAQ7-labeled dead cells using Z-stack analysis. In the control (tumor-only condition), OT-1 cells fully penetrated the tumor layer and induced cell death. In the experimental condition (with fibroblasts), it was found that the fibrotic stromal layer limited OT-1 penetration to the periphery of the 3D tumor, and, moreover, the total OT-1 cells increased relative to the control. Future analysis may include the utility of wild-type T cells and novel therapeutics targeting the stroma to activate the immune response. The results suggest a novel 3D immune exclusion model that integrates with high content confocal analysis and is amenable to immunotherapeutic screening and translational assessment.
Citation Format: Kolin C. Hribar, Tracy Kleinheinz, Joanna Klementowicz, Susan Kaufman, Robert A. Blake, Celine Eidenschenk. An in vitro 3D immune exclusion tumor model engineered in a layer-by-layer fashion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4522.
Abstract 4532: Differential protein and metabolite regulation in urothelial carcinoma highlights changes in immunity and receptor signaling pathways
Authors: Gethings Lee , King Adam , Peck Andrew J. , Plumb Robert S. 
Published: August 2019

Abstract
Bladder cancer is ranked as one of the tumours posing high morbidity and mortality, with a pathogenesis which is still not well understood. A combination of genetic and lifestyle factors, including smoking, are known to contribute towards increasing the probability of encountering cancer. Here, we describe a multi-omic approach to reveal molecular factors that may be involved in these biomolecular processes. Plasma samples consisting of healthy controls and those from patients diagnosed with bladder cancer were prepared for proteomic, metabolomic and lipidomic analyses. Label-free LC-MS data were acquired using a QTof platform utilizing a data independent (DIA) workflow termed SONAR. Small molecule analysis consisted of using Progenesis QI for data processing to provide normalised values prior to statistical analysis. Unsupervised MVA of the data showed clear distinction between cohorts. OPLS-DA was used to filter for features of significant correlation and covariance prior to identification using metabolite and lipid specific databases. Identifications matching the following criteria, mass accuracy &lt;5 ppm, ANOVA p &lt;0.05, %CV &lt;30 and fold change &gt;2 were considered for further interrogation. SONAR-based analysis indicates that this method of data acquisition enabled over an order of magnitude more specificity than equivalent methodologies with the same resolution. Proteomic data were processed and searched against a Uniprot Homo sapien database, containing reviewed entries and limited to 1% FDR. Additionally, we also searched the data against a spectral library and comparatively analysed the results from both workflows. A number of significant proteins with differential regulation were exhibited for a number of protein groups involved in antigen and lipid binding. Proteins occurring in a minimum of two out of three replicates and with ANOVA p &lt;0.05 were considered. Biological significance of the results was established by merging data from all three omic experiments and performing pathway analysis. A number of significant pathways including complement activation, B cell mediated immunity and receptor signalling were identified as key pathways.
Citation Format: Lee Gethings, Adam King, Andrew J. Peck, Robert S. Plumb. Differential protein and metabolite regulation in urothelial carcinoma highlights changes in immunity and receptor signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4532.
Abstract 4535: The mTOR complex 2 promotes glioblastoma migration via the interactions with multiple actin-binding and microtubule-associated proteins
Authors: Chantaravisoot Naphat , Wongkongkathep Piriya , Pacharakullanon Narawit , Tamanoi Fuyuhiko , Loo Joseph A. , Pisitkun Trairak 
Published: August 2019

Abstract
The mechanistic target of rapamycin complex 2 (mTORC2) is one of the two multiprotein complexes in the mTOR signaling pathway. It regulates several cellular activities such as cell survival, lipid metabolism, DNA damage control, and cell motility. The mTORC2 has been reported to be involved in the promotion of metabolic reprogramming, cancer migration, and cancer invasiveness in glioblastoma. However, underlying mechanisms and roles of this particular complex in glioblastoma migration has not been completely elucidated. Previously, we characterized the mTORC2-associated interactome by affinity purification-mass spectrometry (AP-MS) technique, identifying new RICTOR-interacting partners. In addition, we also investigated the localization of RICTOR under different culture conditions and found that it correlates with migration ability of the cancer cells. When mTORC2 activity is high resulting in increased migration, RICTOR tends to localize around the cell membrane. In this work, we further determined crucial players that interact with mTORC2 to control actin cytoskeleton and microtubule dynamics to promote migration. The results from quantitative proteomic analysis of mTORC2-associated interactome suggested that the amount of certain actin-binding proteins and microtubule-associated proteins significantly changed depending on mTORC2 activity level including Gelsolin, Myosin-9, Plectin, and MAP1B. When mTORC2 signaling was inhibited resulting in reduced migration, these proteins were found to be less interacting with mTORC2. Moreover, the results also indicated that active mTORC2 links both actin cytoskeleton and microtubules together to promote migration in glioblastoma cells. Depletion of RICTOR and inhibition of mTORC2 disrupted the connection between microtubules and cell membrane. Taken together, this work provided a plausible mechanism underlying the regulation of enhanced migration in brain cancer cells.
Citation Format: Naphat Chantaravisoot, Piriya Wongkongkathep, Narawit Pacharakullanon, Fuyuhiko Tamanoi, Joseph A. Loo, Trairak Pisitkun. The mTOR complex 2 promotes glioblastoma migration via the interactions with multiple actin-binding and microtubule-associated proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4535.