bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-205: A lipoplex-based mRNA nanovaccine for cancer immunotherapy
Authors: Hongxia Zhang , Xinru You , Xiaojuan Wang , Zining Wang , Feifei Xu , Jun Wu , Xiaojun Xia 
Published: August 2019

Abstract
Intracellular delivery of messenger RNA (mRNA)-based cancer vaccines have shown great potential to activate antitumor immune response for cancer prevention and therapy. In vivo delivery efficiency of mRNA has been greatly improved by various nucleotide chemical modifications and nanovector formulations, but the efficacy of mRNA vaccine remains unsatisfied. Here, we report a lipoplex-based mRNA nanovaccine that can markedly improve mRNA delivery in antigen presenting cells, activate T cell response, and induce robust antitumor immunity. The nanovaccine formulation contains three components: cationic polymer/lipid(poly(amidoamine)/alkylene oxide), DSPE-PEG2000, and epitope-encoding mRNA. With appropriate ratio, the optimized nanovaccine show effective mRNA delivery in dendritic cells, and strongly active antigen-specific immune response in vitro and in vivo. The mRNA@lipoplex nanovaccine enhanced mRNA uptake by dendritic cells, and significantly increased T cell activation reflected by IL-2 and IFN-γsecretion in an in vitro antigen presentation assay. Besides enhancing cross-presentation, nanoparticle itself can promote the expression of inflammatory cytokines such as IL-12 via stimulating NF-κB signal pathway in dendritic cells. In a tumor prevention setting, mRNA@lipoplex nanovaccine produced strong CD8+ T cell activation and great efficacy in preventing tumor development. Furthermore, treatment of established B16 and B16-OVA melanoma and MC38-OVA colon tumors with nanovaccine containing mRNA encoding cancer-associated antigen resulted in great therapeutic efficacy and prolonged survival. Re-challenge of tumor-free mice with MC38-OVA cells led to complete tumor rejection, suggesting long-term antitumor memory. In conclusion, our work presents a new means to deliver mRNA cancer vaccine, which in principle may be applied for immunotherapy for a wide range of tumor types.
Citation Format: Zhang Hongxia, You Xinru, Wang Xiaojuan, Wang Zining, Xu Feifei, Wu Jun, Xia Xiaojun. A lipoplex-based mRNA nanovaccine for cancer immunotherapy [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 LB-205.
Abstract LB-209: Novel pathway prediction for colorectal cancer to liver metastasis through bioinformatics
Authors: Makondi Precious Takondwa , Huang Chien-Yu , Chang Yu-Jia 
Published: August 2019

Abstract
Background: Liver metastases are the most common cause of colorectal cancer (CRC) related deaths, with no reliable clinical predictors. Therefore, identifying potential candidate predictors is crucial for clinical application and management.
Methodology: The Gene Expression Omnibus (GEO) datasets GSE49355, GSE41258 and GSE81558 for genes and GSE54088 and GSE56350 for miRNAs were used to identify common differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) between paired primary CRC tissues and the corresponding liver metastatic tissues. Then, DEMs targets were identified from DEGs. These were verified in GEO datasets comprising gene, miRNA and miRNA exosome profiles of CRC patients with no distant metastases (M0) and distant metastases (M1); the interaction networks and pathways were also mapped.
Results: There were 49 upregulated and 13 downregulated DEGs, and 16 downregulated and 14 upregulated DEMs; between DEGs and DEMs targets, there were five upregulated and four downregulated genes. MiR-20a was significantly high in M1, with the combination of MiR-20a, -495, -576-5p and -449a offering a superior prediction value (sensitivity of 83.3%, specificity of 63.8%, AUC of 0.725). In miRNA exosomes, MiR-576-5p was significantly low in M1, while MiR-20a and -449a were highly expressed, and combination of miR-20a, -495, -576-5p, -449a, -619 and -382 provided best predictive value (sensitivity=75.0%, specificity=88.2%, AUC=0.875). The miRNA target CDH2 was significantly highly expressed in M1 while KNG1 and MMP2 were lowly expressed. The miRNA to gene interaction model was demonstrated, and enriched pathways were; regulation of IGF transport and uptake by IGFBPs, extracellular matrix organization, signal transduction and immune system.
Conclusion: This model predicts novel pathway for predicting CRC to liver metastases. This may be clinically applicable.
Citation Format: Precious Takondwa Makondi, Chien-Yu Huang, Yu-Jia Chang. Novel pathway prediction for colorectal cancer to liver metastasis through bioinformatics [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 LB-209.
Abstract LB-212: FCRF: An efficient algorithm for detecting circular fusion transcript from RNA-Seq data
Authors: Yu Han , Zhang Xuanping , Guan Yanfang , Chen Yongsheng , Xiao Xiao , Wang Jiayin 
Published: August 2019

Abstract
Fusion circular RNAs (f-circRNAs) are circular RNAs derived from rearranged genome translocations. Their formation is caused by back-splicing happening to the genome regions of aberrant chromosomal translocation. Their cancer-promoting roles have been implicated in recent studies. One of them adopted both in vivo and in vitro models to demonstrate the oncogenic roles of f-circRNAs including promoting cellular transformation, cell viability and resistance to treatment. Therefore, it is suggested that accurate identification of f-circRNA will contribute to cancer diagnosis and therapy. But until now there is only one tool called Acfs (accurate circRNA finder suite) ever mentioned detecting f-circRNAs whose primary job is to detect normal circRNAs and only 10 f-circRNAs have been tested for verification without considering realistic sequencing problems. Here, we proposed the first algorithm, FCRF (Fusion CircRNA Finder), to identify f-circRNAs from RNA-Seq data. The SAM file aligned by BWA was used as input, and paired fusion junction site locations would be output. After pre-processing and correcting the original data in consideration of the sequencing fault tolerance, we divided the candidates into balance set and unbalance set according to the relative aligned length. For balance set, we extracted reads from non-homologous chromosomes owing to the fusion events and further detected the paired clipping signals specific to fusion junctions. On the other hand, for unbalance set, we could not use the paired signal because BWA only reported one alignment for them. So we handled them with local similar sequence considering that each junction read has similar sequences with the other read spanning the same junction. Finally we searched all the candidate fusion junctions in accord with the threshold window size and cyclization characteristics, and then recorded two special junction site locations for each fusion-circRNA. We conducted a series of simulation experiments to evaluate our algorithm. The proposed algorithm FCRF achieved 95% on precision and 85% on sensitivity where Acfs output nothing from our improved dataset.
Note: This abstract was not presented at the meeting.
Citation Format: Han Yu, Xuanping Zhang, Yanfang Guan, Yongsheng Chen, Xiao Xiao, Jiayin Wang. FCRF: An efficient algorithm for detecting circular fusion transcript from RNA-Seq data [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 LB-212.
Abstract LB-233: Analysis of personalised circulating tumour DNA to monitor recurrence and metastasis in multiple cancer types
Authors: Wang Guan , Wei Jinwang , Wu Angela , Dai Chun , Sun Wending , Cai Xin , Xu Qiang 
Published: August 2019

Abstract
Purpose: The evaluation of circulating tumour DNA (ctDNA) is a promising tool to monitor tumour progression and guide personalised treatments. We evaluated ctDNA in plasma samples from 521 Chinese patients with more than 12 tumour types and explored ctDNA’s ability to predict tumour status, especially recurrence and metastasis.
Methods: We established a personalised ctDNA panel sequencing, which targeted trunk clonal somatic mutations of each patient calculated by CSMT-tools (monitors tumour load tools based on paired whole exon and cell-free DNA next generation sequencing data, PCT/CN2016/106284) and drug-resistant mutations. The ctDNA content fraction of all somatic mutations was then evaluated. Furthermore, 209 patients were followed up for ctDNA detection and routine examination.
Results: Whole exome sequencing was performed on 1121 patients, and 97% of patients were successfully designed personalised ctDNA assays using CSMT-tools. Currently, 521 Chinese patients mainly with colorectal, liver, lung, gastric cancer, glioma or cholangiocarcinoma received at least one ctDNA detection. 66.79%, 50.86%, 42.99%, and 25.72% of these patients had detectable ctDNA with ctDNA content fractions above 0.25%, 0.5%, 1%, and 5%, respectively. At ctDNA content fraction above 0.25%, the detection rate of ctDNA in major cancer types, excluding liver, pancreatic cancer and glioma, was higher than 70%. In glioma, the rate of ctDNA detection in blood was much lower than in cerebrospinal fluid (24.29% vs 80%). Moreover, dynamic changes of ctDNA were significantly correlated with clinical outcomes for patients, with a consistency rate of 89.51%. The consistency rate of most major cancer types was above 90%, but that of glioma (71.43%) and pancreatic cancer (60%) were lower. ctDNA content fraction increased in all patients with recurrence and metastasis, from 2.72 to 59.8 fold. We also detected a drug-resistance process in a lung cancer patient with EGFR_p.E746_A750del. EGFR_p.T790M was first detected after the patient was administered gefitinib for more than a year, 3 months earlier than radiologic progression. Conclusions: Our personalised ctDNA analysis can effectively detect ctDNA. Hence, it can predict tumour progression and guide precise treatment.
Citation Format: Guan Wang, Jinwang Wei, Angela Wu, Chun Dai, Wending Sun, Xin Cai, Qiang Xu. Analysis of personalised circulating tumour DNA to monitor recurrence and metastasis in multiple cancer types [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 LB-233.
Abstract LB-248: A novel multiplex assay for detection and quantitation of fatty acid synthase (FASN) in serum or plasma samples
Authors: Venkateswaran Neeraja , Nelson William M. 
Published: August 2019

Abstract
Many cancers overexpress FASN which catalyzes the final synthetic step of de novo fatty acid synthesis pathway. FASN has been considered as a potential drug target for several decades now. Many publications provide evidence of the elevated FASN with aggressive tumors, but still, there are very few inhibitors of FASN that have successfully been utilized as therapeutics in the clinical arena. An accurate measurement of FASN in association with tumor-specific markers in solid tumors and serum may help to propel forward the therapeutic significance of FASN inhibitors. With this objective in mind, we are currently working on the development of a multiplex assay for detection and quantitation of FASN and Cripto-1 in serum samples. We have optimized a magnetic fluorescent bead based multiplex sandwich immunoassay for detection and quantitation of FASN and Cripto-1 (CR-1) in human serum and plasma samples. We selected Cripto-1 to pair with FASN because it is an EGF-like domain carrying growth factor associated with a number of different types of human carcinomas. We use two different monoclonal antibodies for FASN and one for CR-1 as capture antibodies covalently coupled to magnetic fluorescent beads and a mixture of two biotin-labeled detection antibodies in this assay. The streptavidin-phycoerythrin (SAPE) conjugate is used to report the positive capture of a target in this assay. We have also included various internal controls in this assay to monitor the assay performance and assure quality of the reagents used in each well. The dynamic range of this assay was determined to be 100pg/mL to 100 ng/mL using recombinant FASN and Cripto-1 from commercial sources. The R2 values were 0.98 and above for each of the analytes and recovery of each standard were between 90 % and 125%. We spiked recombinant FASN and Cripto-1 in normal human serum and plasma at different concentrations and spike recovery was between 70 % and 130 %. We further evaluated this assay with some commercially obtained clinical samples. This presentation includes detailed results of this study.
Citation Format: Neeraja Venkateswaran, William M. Nelson. A novel multiplex assay for detection and quantitation of fatty acid synthase (FASN) in serum or plasma samples [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 LB-248.
Abstract LB-265: ARAF activates RAS by antagonizing its interaction with NF1
Authors: Su Wenjing , Yaeger Rona , Na Na , Hechtman Jaclyn , Paroder Viktoriya , Misale Sandra , Han Sae-Won , Abdel-Wahab Omar I. , McCormick Frank , Rosen Neal , Yao Zhan 
Published: August 2019

Abstract
ARAF, BRAF and CRAF protein kinases are RAS effectors required for activation of ERK signaling. ARAF has relatively modest kinase activity and its biological functions are largely unknown. Here, we show that ectopic expression of ARAF but not B- or CRAF, leads to induction of RAS activation in cells with WT RAS. This phenomenon requires the binding of ARAF to RAS but not its kinase activity. ARAF was found to reduce inactivation of RAS by antagonizing its binding to the major RAS-GAP NF1. By this mechanism, the abundance of ARAF in cells determines cellular RAS-GTP levels, the dynamics of RTK-induced RAS activation and the biological consequences of RAS signaling. We find that a certain expression level of ARAF is required for growth factors induced proliferating or neural differentiation in PC12 cells. In RTK-dependent tumor cells, knocking down of ARAF leads to a reduction of RAS-GTP, thus impairs RAS signaling and the tumor growth. Furthermore, by investigating the tumor samples from MSK patients who are diagnosed with progressing disease after EGFR inhibitor treatment, we find the up-regulation of ARAF (including the ARAF gene amplification) is associated with EGFR inhibitor resistance in the lung cancer patients. We confirmed in cell line and xenograft models that a 5-fold elevation of ARAF expression is sufficient to eliminate RAS inhibition by EGFR inhibition and to cause resistance. Resistance in these cells could be overcome by combining EGFR and SHP2 inhibitors. The latter prevents EGFR activation of RAS-GTP exchange and thus would be expected with weaking the effects of NF1 inhibition by ARAF. Taken together, our work shows that ARAF directly activates RAS by antagonizing its interaction with NF1 and thus affects the duration and cellular response of growth factor activation and sensitivity of tumors to pharmacological inhibition of RTK-RAS signaling.
Citation Format: Wenjing Su, Rona Yaeger, Na Na, Jaclyn Hechtman, Viktoriya Paroder, Sandra Misale, Sae-Won Han, Omar I. Abdel-Wahab, Frank McCormick, Neal Rosen, Zhan Yao. ARAF activates RAS by antagonizing its interaction with NF1 [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 LB-265.
Abstract LB-273: Development of small molecule MYC inhibitors that impair tumor growth and enhance anti-PD1 immunotherapy
Authors: Han Huiying , Jain Atul , Sargar Vinay , Anker Jonathan , Mishra Rama , Schiltz Gary , Abdulkadir Sarki A. 
Published: August 2019

Abstract
Small molecules MYC inhibitors that are efficacious and tolerated in vivo will provide invaluable chemical probes and potential therapeutic agents. We have used in silico screening coupled to a rapid in vivo screen in mice to develop a series of novel small molecule MYC inhibitors (MYCi) which engage MYC inside cells, disrupt MYC/MAX heterodimerization and inhibit MYC-regulated gene expression. The compounds enhanced MYC phosphorylation on threonine-58, leading to increased proteasome-mediated degradation of MYC. The initial lead, MYCi361, showed excellent in vivo anti-tumor efficacy in mice, inhibiting proliferation and inducing immunogenic cell death of tumor cells. MYCi361 treatment increased tumor infiltrating lymphocytes and induced tumor PD-L1 expression. Accordingly, treatment with MYCi361 sensitized tumors to anti-PD1 immunotherapy. MYCi361 however showed a narrow therapeutic index. We therefore undertook additional medicinal chemistry optimization, which yielded the related molecule, MYCi975, which combined in vivo efficacy with remarkable tolerability. These findings support the potential of small molecule MYC inhibitors as chemical probes and possible therapeutic leads.
Citation Format: Huiying Han, Atul Jain, Vinay Sargar, Jonathan Anker, Rama Mishra, Gary Schiltz, Sarki A. Abdulkadir. Development of small molecule MYC inhibitors that impair tumor growth and enhance anti-PD1 immunotherapy [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 LB-273.
Abstract LB-285: SAGA functions in development and disease
Authors: Dent Sharon Y. , Farria Aimee , Koutelou Evangelia 
Published: August 2019

Abstract
Our research is focused on defining the functions of histone modifying enzymes in normal cells, so that we can understand how alterations in these activities contribute to tumor development or progression. Our recent studies on the SAGA complex, which houses both histone acetyltransferase (HAT) and deubiquitylase (DUB) activities, revealed that the Gcn5 HAT, is an important co-activator for Myc in regulating self-renewal of mouse ES cells. Gcn5 is also important for Myc functions as a Yamanaka factor in stimulating conversion of differentiated cells towards an induced pluripotent state. These developmental functions predict that Gcn5 will also be important during Myc functions as an oncogene. In support of this idea, recent studies reveal that deletion of Gcn5 delays lymphoma onset and more than doubles survival of Eμ-Myc mice. The SAGA DUB module is also implicated in cancer, as the USP22 catalytic subunit is overexpressed in several highly aggressive human tumors. We have created USP22 knock out mice to probe the functions of this DUB. Our data indicate that USP22 drives TGF-beta and receptor tyrosine kinase signaling pathways that are critical both to normal developmental processes and to oncogenesis. Altogether, our studies indicate that both Gcn5 and USP22 may provide unique targets for development of new cancer therapies.
Note: This abstract was not presented at the meeting.
Citation Format: Sharon Y. Dent, Aimee Farria, Evangelia Koutelou. SAGA functions in development and disease [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 LB-285.
Abstract LB-290: Telomere dysfunction is a driver of inflammatory bowel disease
Authors: Chakravarti Deepavali , Multani Asha , Dey Prasenjit , Hu Baoli , Zhao Di , Chang Kyle , Xizeng Mao , Wang Guocan , Terranova Christoper , Liao Wen-ting , Spring Denise , Hou Pingping , Zhang Jianhua , Okhuysen Pablo , Vilar Eduardo , Estes Mary K. , blutt Sarah , Wang Alan , DePinho Ronald 
Published: August 2019

Abstract
The molecular instigators and therapeutic strategies for inflammatory bowel disease (IBD) are limited. Here, telomere dysfunction is shown to activate pAtm/c-Abl-mediated phosphorylation and stabilization of Yap1 up-regulates pro-IL-18 expression, a major pro-inflammatory factor in IBD. This signaling axis cooperates with gut microbiome which stimulates cytosolic receptors causing activation of caspase-1, which in turn cleaves pro-IL-18 into its mature IL-18 form. Epithelial-derived IL-18 leads to recruitment of IFNγ-secreting T cells and other immunocytes to provoke classical IBD pathology. Consistent with a role for DNA damage signaling as a driver of IBD, newly diagnosed IBD patient samples exhibited elevated expression of pγH2AX, YAP1, Caspase-1 and IL-18 along with significantly reduced telomere lengths compared to healthy tissue controls. Alleviation of IBD pathology can be achieved in mice via telomerase reactivation in intestinal epithelium or pharmacological inhibition of Atm, Yap1, or caspase-1 as well as antibiotic treatment - each intervention dramatically reducing pro-IL-18 cleavage and inflammation. Thus, telomere dysfunction-induced activation of the Atm-Yap1-pro-IL-18 pathway identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating several novel therapeutic strategies for disease interception and management.
Note: This abstract was not presented at the meeting.
Citation Format: Deepavali Chakravarti, Asha Multani, Prasenjit Dey, Baoli Hu, Di Zhao, Kyle Chang, Mao Xizeng, Guocan Wang, Christoper Terranova, Wen-ting Liao, Denise Spring, Pingping Hou, Jianhua Zhang, Pablo Okhuysen, Eduardo Vilar, Mary K. Estes, Sarah blutt, Alan Wang, Ronald DePinho. Telomere dysfunction is a driver of inflammatory bowel disease [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 LB-290.