bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2366: Malignant ascites-derived extracellular vesicles promote metastasis of ovarian cancer by transferring miR-1246 and miR-1290
Authors: Wang Wenyu , Jo HyunA , Song Yong Sang 
Published: July 2021

Abstract
Background and purpose: Ovarian cancer is the most lethal gynecologic cancer in females worldwide. The high mortality rate is due primarily to the lack of early diagnosis strategies and the high rate of recurrence. Ascites is detected in over one-third of ovarian cancer patients at initial diagnosis and present in almost all the patients with recurrence. Extracellular vesicles (EVs) are double-membrane particles secreted by cells into extracellular space. EV-mediated intercellular communication in the tumor microenvironment is crucial in cancer progression. Additionally, EVs are present in various body fluids, serving as fine analytes for liquid biopsy. Our research is aimed to explore the role of malignant ascites-derived EVs in ovarian cancer metastasis and the underlying mechanisms focusing on the miRNA cargos.
Methods: Patient-derived samples were collected from Seoul National University Hospital with the approval of the Institutional Review Board. EVs were isolated from ascites using the commercial kit and identified through transmission electron microscopy, nanoparticle tracking analysis and western blotting. Transwell assay was performed to investigate the effects of ascites-derived EVs on ovarian cancer cells. MiRNA sequencing was carried out in EVs derived from malignant ascites(n=10) and benign peritoneal fluids(n=9).
Results: Malignant ascites-derived EVs were characterized as double-membrane particles sizing ranging from 30nm to 150nm with the expression of CD63 and CD81. Those EVs significantly promoted the invasion and migration ability of ovarian cancer cells. MiRNA sequencing data showed that 118 miRNAs were upregulated and 44 miRNAs were downregulated in the ascites-derived EVs compared with benign peritoneal fluid-derived EVs. Among those, miR-1246 and miR-1290 were the top two upregulated miRNAs, which were negatively associated with the overall survival of ovarian cancer patients. Moreover, miR-1246 and miR-1290 could enhance the invasion and migration ability through activating Wnt/β-catenin signaling pathway via binding to RAR-related orphan receptor alpha (RORα).
Conclusion: Malignant ascites-derived EVs could facilitate the metastatic potential of ovarian cancer cells through transferring miR-1246 and miR-1290. Targeting miR-1246 and miR-1290 might be a promising therapeutic strategy in ovarian cancer treatment.
Citation Format: Wenyu Wang, HyunA Jo, Yong Sang Song. Malignant ascites-derived extracellular vesicles promote metastasis of ovarian cancer by transferring miR-1246 and miR-1290 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2366.
Abstract 2375: Comprehensive analysis of immunotherapy-related biomarkers in Chinese patients with gastric adenocarcinoma
Authors: Zhao Qun , Guo Yuntong , Cui XiaoLong , Peng LiangBiao , Li Junying , Wang Fei , Zhang Lin 
Published: July 2021

Abstract
Background: Gastric adenocarcinoma (GAC) is a deadly disease in need for new therapies. Recently, the most exciting developments in oncology are immune checkpoint inhibitors (ICIs) such as inhibitors of programmed cell death protein 1 (PD-1) which has shown response rates of 11-16% in unselected GAC patients. This study aimed to characterize the distributions of immunotherapy-related biomarkers in Chinese patients with gastric adenocarcinoma.
Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples and matched peripheral blood samples of 497 Chinese gastric adenocarcinoma patients were collected for YuansuTM NGS-panel assay (OrigiMed, Shanghai). Genomic alterations (GAs) including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. Microsatellite instability (MSI), PD-L1 expression and tumor mutational burden (TMB) were assessed in 467(94%), 208(42%) and 467(94%) patients, respectively.
Results: There were 334 males (67.2%) and 163 females (32.8%) with a median age of 60 (range 23-87) years in this cohort, including 440 primary tumors and 57 metastases. MSI-H was detected in 39 samples (7.8%). The rate of MSI-H in the ACVR2A mutation group was significantly higher than that in the ACVR2A wild-type group (82.1% vs 17.9%, p&lt;0.001). In addition, we found that patients with mutations of K437Rfs*5 (54.1%) or D96Tfs*54 (11.4%) of ACVR2A were all MSI-H. The frequency of ERBB2 amplification was 7.5%, which was mutually exclusive to MSI-H. PD-L1 expression levels by CPS of negative, 1-9 and ≥10 were 54%, 33% and 13%, respectively. The median value of TMB was 6.2 (0-99.3) muts/Mb and TMB ≥10 muts/Mb was seen in 27.4% tumors. The patients with ACVR2A mutations had a significantly higher TMB (ACVR2A: 5.7 vs 2.6 muts/Mb, respectively, p &lt; 0.01). In addition, the biomarkers associated with hyperprogression (HP) to immune checkpoint inhibitors (ICIs) included 11q13 amp, MDM2/MDM4 amp, and CDKN2A/B gene loss, which were identified in 4%, 2% and 2% of patients, respectively.
Conclusions: We analyzed the distribution of microsatellite status, PD-L1 expression and TMB in Chinese patients with GAC. Interestingly, our data showed that mutated ACVR2A was significantly associated with MSI-H and TMB-H. In addition, approximately 8% of patients were identified harboring hyperprogression-related gene alterations. Therefore, the application of comprehensive genomic profiling might be necessary in guiding ICI treatments in GAC.
Citation Format: Qun Zhao, Yuntong Guo, XiaoLong Cui, LiangBiao Peng, Junying Li, Fei Wang, Lin Zhang. Comprehensive analysis of immunotherapy-related biomarkers in Chinese patients with gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2375.
Abstract 2377: microRNA expression profile in urinary exosomes is dependent on non-invasive lymphoma induction in mice
Authors: Wilson Brittany , Betar Rebekah , Martin Alexander , Niazi Zackaria , Boyer Michael , Winter Lori , Babich Victor , Sole Francesca Di , Ananieva Elitsa 
Published: July 2021

Abstract
Lymphoma accounts for approximately 4% of cancers in the United States, with an estimated 20,910 number of deaths per year. The standard method of diagnosis and staging of lymphoma involves surgical biopsy of the tumor - a procedure that has many negative associated risks. Exosomes are extracellular vesicles secreted in biological fluids that can serve as “liquid biomarkers”. Identification of unique cancer-related biomarkers in urinary exosomes may provide a novel non-invasive and cost-effective tool for lymphoma diagnosis. Analyses of biomarkers obtained from urinary exosomes have been used to evaluate urological cancers, however, these methods have not yet been translated to non-urological pathologies, such as lymphomas. The objective for this study was to determine the profile of microRNAs (miRNAs) expressed in urinary exosomes of mice challenged with lymphoma and compare it to miRNAs identified in urinary exosomes of control mice. Male and female C57BL/6 mice, (tumor (+), n=12), were injected with either 2.5x105 mouse EL-4 lymphoma cells or phosphate-buffered saline (tumor (-), n=12). Tumor growth was monitored for 20 days. Urine was collected for 48 hours starting on day 17 and serum, tumor tissues, and organs were collected on day 20. Extraction of urinary exosomes was followed by total RNA isolation and RT-qPCR for which a set of PCR arrays consisting of 709 mouse-specific miRNA primers was used. Fold changes in miRNA expression were quantified using the ΔΔCt method. Mice developed tumors by day 13 with initial tumor appearance around day seven. There were no statistically significant differences between final tumor mass, body weight, or food and water intake in tumor (+) versus tumor (-) mice. RT-qPCR arrays of miRNAs extracted from urinary exosomes revealed 464 miRNAs that were differentially expressed between tumor (+) and tumor (-). 215 miRNAs were up-regulated, while 249 miRNAs were down-regulated in tumor (+) mice. These results will be compared to miRNAs from serum and tumor tissues to identify tumor-specific miRNAs that can be used for potential application in the clinical setting.
Citation Format: Brittany Wilson, Rebekah Betar, Alexander Martin, Zackaria Niazi, Michael Boyer, Lori Winter, Victor Babich, Francesca Di Sole, Elitsa Ananieva. microRNA expression profile in urinary exosomes is dependent on non-invasive lymphoma induction in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2377.
Abstract 2379: microRNA-7 replacement therapy: a promising approach for hepatocellular carcinoma
Authors: Beveridge Dianne J. , Kabir Tasnuva , Woo Andrew J. , Richardson Kirsty L. , Stuart Lisa M. , Leedman Peter J. 
Published: July 2021

Abstract
Hepatocellular carcinoma (HCC) is increasing in incidence, has a very poor prognosis and presents massive global unmet clinical need. Current treatment of advanced HCC with sorafenib and other targeted therapies offers short-term relief with little significant clinical advantage. New approaches to the treatment of HCC are urgently needed. Non-coding RNAs, including small interfering RNAs (siRNAs) and microRNAs (miRNAs), are gaining prominence in clinical medicine as potential diagnostics and therapeutics. The introduction of 2nd generation synthetic chemistry has led to dramatic stabilization of siRNAs and miRNAs producing prolonged effects on target gene expression. This has led the FDA to approve multiple RNA-mediated drugs starting in 2018, the first being a siRNA drug, Patisiran. A second major advance in the RNA-therapeutics field is the specific targeting of the liver by conjugating a galactose moiety (GalNAc) to the passenger RNA strand. This enables the dsRNA to be selectively and efficiently taken up by the asialoglycoprotein receptor (ASGPR) on the hepatocyte. The recent FDA approval of Givosiran, based on its clinical success in patients with porphyria using an ALAS-1 siRNA-GalNAc, illustrates the clinical utility of this system. We have shown that miRNA-7 (miR-7), a tumor suppressor miRNA, is a powerful inhibitor of HCC cell viability, via marked inhibition of EGFR, TYRO3, P-Akt and caveolin-1 signaling pathways. In vivo, miR-7 is a potent inhibitor of HCC tumor growth. In addition, miR-7 readily overcomes sorafenib resistance in multiple HCC cell lines. We utilized 2nd generation synthetic chemistry to develop a novel mimic of miR-7, mRx-7, for the treatment of HCC. mRx-7 is a significant inhibitor of HCC in vitro and is also substantially more stable than commercially available miR-7. In addition, we have engineered a liver-specific version of mRx-7 (mRx-7-GalNAc), which is a conjugate of mRx-7 plus GalNAc, and is a potent inhibitor of multiple signaling pathways, including P-Akt. Taken together, these data suggest that mRx-7 and mRx-7-GalNAc hold promise as novel HCC therapeutics.
Citation Format: Dianne J. Beveridge, Tasnuva Kabir, Andrew J. Woo, Kirsty L. Richardson, Lisa M. Stuart, Peter J. Leedman. microRNA-7 replacement therapy: a promising approach for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2379.
Abstract 2388: p73 - lncRNA Fer1l4 axis plays a critical role in suppression of cancer cell migration, invasion and metastasis in a p73-dependent manner via inhibition of miR-1273g-3p
Authors: Uboveja Apoorva , Satija Yatendra Kumar , Siraj Fouzia , Bareja Chanchal , Saluja Daman 
Published: July 2021

Abstract
p73 is a member of the p53 tumor suppressor family and exerts its tumor suppressor functions by suppressing metastasis. It is increasingly evident that long noncoding RNAs (lncRNAs) play a significant role in tumor suppression. The present study is aimed to identify novel lncRNAs that play a role in p73-mediated suppression of metastasis in colorectal cancer cells. Transcriptome analysis was performed to detect the differentially expressed lncRNAs in presence and absence of p73. Out of these, FER1L4 lncRNA was found to be significantly induced in a p73-dependent manner. p73 binding to FER1L4 promoter was confirmed through bioinformatic analysis, luciferase reporter, ChIP and site-directed mutagenesis assays. Knockdown of FER1L4 and p73 significantly increased the invasion and migration rate of colorectal cancer cells as confirmed by wound-healing assay. Knockdown of FER1L4 decreased the expression of E-cadherin and increased the expression of prominent EMT markers such as N-cadherin, Snail, Vimentin and Fibronectin. FER1L4 causes a G2/M cell cycle arrest in a p73-dependent manner in HCT116p53-/-p73+/+ cells and upon FER1L4kd, normal cell cycle progression was observed. Annexin V/PI and TUNEL apoptosis assays revealed that FER1L4 induced apoptosis in HCT116p53-/-p73+/+ cells with increase in time-dependent treatment of etoposide and FER1L4kd inhibited apoptosis even in the presence of p73. The protein expression level of pro-apoptotic genes such as Bad, Bax, Bik, Bim, BID, Bak and PUMA decreased upon FER1L4kd and p73kd, confirming that FER1L4 plays a role in p73 mediated apoptosis and cell cycle arrest. FER1L4 also sponges the expression of miR-1273g-3p, thus inhibiting its oncogenic role. RNA-In situ hybridization (RNA-ISH) confirmed the decreased expression of p73 and FER1L4 mRNA in 30 human metastatic CRC tissues as compared to 30 human non-metastatic CRC tissues. Taken together, we provide conclusive proof that p73 exerts its anti-metastatic function by inducing the expression of lncRNA FER1L4 in response to genotoxic stress.
Citation Format: Apoorva Uboveja, Yatendra Kumar Satija, Fouzia Siraj, Chanchal Bareja, Daman Saluja. p73 - lncRNA Fer1l4 axis plays a critical role in suppression of cancer cell migration, invasion and metastasis in a p73-dependent manner via inhibition of miR-1273g-3p [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2388.
Abstract 2405: Metabolic plasticity of ovarian metastases in response to adherence and physiologically relevant culture conditions
Authors: Compton Stephanie Edwards , Grieco Joseph , Schmelz Eva M. 
Published: July 2021

Abstract
Ovarian cancer is typically diagnosed at late stages with a poor prognosis due to high recurrence. Exfoliation from the primary tumor results in aggregation of ovarian cancer cells into spheroids in the peritoneal cavity, which then adhere to secondary sites to form metastatic outgrowth. Spheroids in the peritoneal cavity are exposed to hypoxic, low glucose conditions. Sphingosine-1-phosphate (S1P), increased in the ascites fluid of ovarian cancer patients, has been shown to increase tumor cell survival and tumorigenesis through changes in mitochondrial function. However, little is known about these effects in ovarian cancer spheroids, particularly upon secondary adherence and outgrowth in physiological conditions. Changes in spheroid metabolism in response to treatment with S1P, hypoxia, low glucose, and obese peritoneal serous fluid (PSF) in both free and adherent states was investigated. Using a late-stage and tumor-initiating murine ovarian cancer model, spheroids were subjected to treatment with S1P or obese PSF as free or adherent spheroids. Using a Seahorse XFe96, we investigated changes in metabolism over time trials measured after 24 hour treatment for free spheroids and after different time points of adherence (4, 8, 12, and 24 hours). Data show changes in basal respiration, maximal oxygen consumption rate, and spare respiratory capacity of spheroids over adherence time when treated with S1P and PSF. This suggests that the cells respond to energetic demand with metabolic flexibility as the spheroids adhere to new surfaces. The identification of the regulation of these events may help elucidate the flexibility that takes place during metastasis in culture that more closely mimics physiological conditions, providing a foundation for future interventions for preventative therapies for ovarian cancer with dietary sphingolipids and possible treatment targets.
Citation Format: Stephanie Edwards Compton, Joseph Grieco, Eva M. Schmelz. Metabolic plasticity of ovarian metastases in response to adherence and physiologically relevant culture conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2405.
Abstract 2408: Targeted bioinformatics analysis identifies high ABAT transcript expression as a multi-cancer marker of favorable patient prognosis
Authors: Knott Erika L. , Leidenheimer Nancy J. 
Published: July 2021

Abstract
Unsupervised analysis of γ-aminobutyric acid (GABA) system genes has identified some genes as correlated with indicators of severity in several cancers. Central to GABA system function is the GABA shunt, a series of reactions bypassing two steps of the tricarboxylic acid (TCA) cycle, which encompasses the synthesis and metabolism of the non-proteinaceous amino acid GABA. Here, we have undertaken a targeted bioinformatics study utilizing publicly available databases - including cBioPortal, UALCAN, the Human Protein Atlas, and the Human Cancer Metastasis Database - to evaluate the expression of transcripts encoding GABA shunt enzymes, and their correlation with clinical outcomes, across nearly three dozen cancers from The Cancer Genome Atlas (TCGA) Pan-Cancer Atlas initiative dataset. Of the three genes encoding enzymes of the GABA shunt, we have focused on ABAT, which encodes the GABA-catabolizing enzyme γ-aminobutyrate aminotransferase (ABAT; aka GABA-transaminase or GABA-T). ABAT is widely expressed across all 32 TCGA studies, ranging from moderate to high expression in skin cutaneous melanoma and low-grade glioma (average ± SEM = 6.5 ± 0.08; 13.3 ± 0.03 log2 RSEM), respectively. For the majority of these tissues, the expression of ABAT in tumor is lower than its expression in adjacent normal tissue. Importantly, ABAT expression is prognostic in 11 cancers: upregulation is favorably prognostic for ACC, BLCA, BRCA, and PAAD, while downregulation is unfavorably prognostic for KIRC, KIRP, LGG, LIHC, LUAD, MESO, and SKCM (Kaplan-Meier survival estimates, z-score = 0.5, p &lt; 0.05). A subset of these cancers, as well as 4 other TCGA cancers, show a decrease in ABAT transcript expression with increasing tumor stage (p &lt; 0.05). Furthermore, 7 cancers express lower levels of ABAT transcripts in the primary tumors of patients with metastases vs the primary tumors of patients without metastases. Additionally, metastases of 4 cancers express elevated levels of ABAT transcripts vs their respective primary tumors. These results imply a dynamic regulation of ABAT expression throughout cancer progression. As very few studies have directly addressed the role of ABAT in cancer progression, the identification of ABAT transcript expression as a broadly applicable multi-cancer prognostic marker may ultimately benefit a wide variety of patients. We would like to thank the Feist-Weiller Cancer Center and LSU Health, Shreveport for supporting this work.
Citation Format: Erika L. Knott, Nancy J. Leidenheimer. Targeted bioinformatics analysis identifies high ABAT transcript expression as a multi-cancer marker of favorable patient prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2408.
Abstract 2410: The mutant p53 C-terminal domain assists in DNA interactions and cell cycle promotion
Authors: Lundine Devon , Syed Zafar , Ellison Viola , Annor George , Xiao Gu , Bargonetti Jill 
Published: July 2021

Abstract
Introduction: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer and has the worst prognosis of any breast cancer sub-type. More than 80% of TNBC patients harbor mutated TP53. Some mutant p53 proteins (mtp53) exhibit gain-of function (GOF) oncogenic characteristics, contributing to the decreased prognosis for TNBC patients, but also providing a potential therapeutic target for this aggressive disease. Our group previously found mtp53 R273H interacts with replicating DNA, and increases chromatin-bound replication proteins MCM2-7, PCNA, and PARP1. Mutant p53 retains an intact C-terminal domain (CTD), the domain which facilitates non-specific DNA binding. We hypothesize that the CTD of mtp53 facilitates increased DNA replication processivity.
Methods: To test this hypothesis, we have transiently transfected human cells to compare wild-type p53, and R273H mtp53 full-length and CTD-truncated variants. We used CRISPR/Cas9 to generate endogenous CTD truncations of mtp53 R273H in the breast cancer cell line MDA-MB-468. Specifically, clones were used which have mtp53 CTD truncations (R273HΔ381-388 and R273HΔ347-393) and one clone with a frameshift resulting in no detectable mtp53 protein (R273Hfs387). Various western blotting techniques were used to assess protein level and sub-cellular localization, including the iPOND (isolation of proteins on nascent DNA) assay. Several microscopy techniques were used to visualize protein-protein interactions in cells including immunofluorescence, proximity ligation, and DNA fiber assays.
Results: Our data show mtp53 R273H and wild-type p53 proteins with CTD truncations tether less to chromatin than their full-length counterparts. Also, our data shows that the truncated R273HΔ381-388 mtp53 is in close proximity to PARylated proteins (and potentially even PARylated itself), but the R273HΔ347-393 truncation is not in close proximity to PARylated proteins. Additionally, R273HΔ381-388 and R273HΔ347-393 demonstrate delayed cell cycle progression and reduced proliferation compared to MDA-MB-468 cells. We observe DNA replication processivity is decreased in 468 R273HΔ381-388 and R273Hfs387 cells. Processivity, but not proliferation rate, is rescued in 468 R273HΔ347-393 cells.
Conclusions: The combination of reduced cell proliferation in all CTD-truncated cells, and reduced DNA replication processivity in R273HΔ381-388 and R273Hfs387 cells, but not in R273HΔ347-393 indicates a nuanced role for the CTD in DNA replication and S-phase progression.
Citation Format: Devon Lundine, Zafar Syed, Viola Ellison, George Annor, Gu Xiao, Jill Bargonetti. The mutant p53 C-terminal domain assists in DNA interactions and cell cycle promotion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2410.