bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2563: LSD1 maintains differentiation and survival of mammary luminal cells and suppresses invasion of luminal breast cancer cells via GATA3
Authors: Hu Xin , Xiang Dongxi , Tao Luwei , Xie Ying , Jin Yue , Guo Yidi , Pinello Luca , Yuan Guo-Cheng , Li Zhe 
Published: July 2017

Abstract
LSD1 (also known as KDM1A) is a histone demethylase that has been shown to play both oncogenic and tumor suppressor roles in breast cancer. However, the exact context under which it functions as a tumor suppressor or oncoprotein remains largely elusive. To address this, we characterized its role in normal mammary epithelial cells (MECs) and found MEC-specific ablation of Lsd1 largely phenocopied that of Gata3, which encodes a master regulatory transcription factor for luminal MECs. In the luminal lineage, LSD1-loss led to reduction in both mature ductal and alveolar luminal subpopulations. In human luminal breast cancer cells, we found LSD1 interacts with GATA3 and their common target genes are highly related to breast cancer. In particular, we found LSD1 might be recruited by GATA3 to the GATA3 promoter region, to positively regulate GATA3 expression via demethylation of H3K9me2. Knockdown of LSD1 led to increased invasion of luminal breast cancer cells, in part via downregulation of GATA3 and multiple cell junction genes (e.g., CDH1, VCL, CTNNA1), as well as upregulation of mammary stem/progenitor cell genes (e.g., ELF5, ITGB1). However, LSD1 knockdown also led to reduced proliferation of luminal breast cancer cells, in part via downregulation of RBBP4 (encoding a Histone-binding protein) and upregulation of CDKN1A (encoding p21). Collectively, our data suggest that LSD1 is required for maintaining luminal MEC differentiation and survival and for suppressing luminal breast cancer cell invasion, in part via GATA3. As inhibitors of LSD1 are currently under clinical trials (e.g., in leukemia), our data suggest that although treatment of luminal breast cancer by the LSD1 inhibitor may lead to reduced tumor cell proliferation (and thus tumor shrinkage), the treatment may also lead to increased invasion of surviving breast cancer cells. Thus, our study is expected to have important implications for developing better epigenetic therapy in an individualized, context-dependent fashion.
Citation Format: Xin Hu, Dongxi Xiang, Luwei Tao, Ying Xie, Yue Jin, Yidi Guo, Luca Pinello, Guo-Cheng Yuan, Zhe Li. LSD1 maintains differentiation and survival of mammary luminal cells and suppresses invasion of luminal breast cancer cells via GATA3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2563. doi:10.1158/1538-7445.AM2017-2563
Abstract 2584: The UCSC Xena system for cancer genomics data visualization and interpretation
Authors: Goldman Mary , Craft Brian , Zhu Jingchun , Haussler David 
Published: July 2017

Abstract
The UCSC Xena platform (http://xena.ucsc.edu/) allows biologists and bioinformaticians to securely analyze and visualize their private functional genomics data in the context of public genomic and clinical data sets. The Xena platform consists of a set of federated data hubs and the Xena browser, which integrates across hubs, providing one location to analyze and visualize all data. Our expanding public Xena Data Hubs currently hosts 1400+ data sets from more than 35 cancer types, as well as Pan-Cancer data sets. Our public data hubs serve seminal cancer genomics and functional genomics data set to the scientific community, including the latest TCGA, TARGET, ICGC, and GTEx data sets. We support most data types including somatic and germline SNPs, INDELs, large structural variants, CNV, gene-, transcript-, exon- protein-, miRNA-expression, DNA methylation, phenotypes, clinical data, subtype classifications and genomic biomarkers. Additionally, investigators’ own functional genomics data can be hosted on private hubs running on their laptop or behind the firewall. Data is integrated on the UCSC Xena Browser, allowing biologists to view and interpretation of their genomic data in the context of a large collection of cancer genomics data sets such as TCGA. The lightweight Xena data hubs are straightforward to install on Windows, Mac and Linux operating systems and loading data is easy using either our application or command line interface. This system of the browser and hubs helps researchers combine new or preliminary results from their laptops or internal servers, or even data from a new paper, securely with vetted data from the public sphere.
Visualizations and analyses include dynamic Kaplan-Meier survival analysis to assess survival stratification by any information in addition to our visual spreadsheet, scatter plots and bar graphs. We seek feedback at our poster on new visualizations and functionalities.
Citation Format: Mary Goldman, Brian Craft, Jingchun Zhu, David Haussler. The UCSC Xena system for cancer genomics data visualization and interpretation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2584. doi:10.1158/1538-7445.AM2017-2584
Abstract 2628: BGB-A425: a humanized anti-human Tim-3 antibody that exhibits strong immune cell activation
Authors: Zhang Tong , Xue Liu , Zhang Jing , Liu Qi , Ma Jie , Zhang Yi , Shi Yingdi , Hou Hongjia , Peng Hao , Liu Ning , Zhang Yilu , Song Xiaomin , Li Yucheng , Song Jing , Wang Lai , Wei Min , Li Kang 
Published: July 2017

Abstract
Background: Tim-3 (T-cell immunoglobin and mucin-domian containing-3) is a “checkpoint” inhibitory receptor, which is primarily expressed in activated or “exhausted” T cells, NK cells, macrophages and DCs. Engagement of Tim-3 receptor by its ligand phosphatidylserine (PtdSer) or galectin-9 leads to activation of negative regulatory signaling in T-cells, promoting functional exhaustion of tumor-infiltrating T-lymphocytes. BGB-A425 is a novel humanized IgG1 (variant) anti-Tim-3 antibody under preclinical development. The immunomodulatory activity of BGB-A425 was evaluated both in vitro and in vivo.
Materials and methods: BGB-A425 was generated through hybridoma fusion, humanized by CDR grafting and structural simulation. The Fc region (IgG1) of BGB-A425 was engineered to remove Fc gamma receptor (FcγR) binding. The binding affinity and specificity were studied by ELISA, FACS and SPR (Biacore). The immunomodulatory functions of BGB-A425 were evaluated using primary immune cells as well as cell lines.
Results: BGB-A425 binds to the extracellular domain of human Tim-3 with high affinity (KD = 0.36 nM) and specificity. In a competition assay, BGB-A425 efficiently blocks the interactions between Tim-3 and PtdSer. In vitro, BGB-A425 significantly enhances IFN-γ production of primary T cells and NK-mediated cytotoxicity against tumor cells. In a MLR assay, BGB-A425 augments T-cell response to allogeneic antigens either alone or in combination with an anti-PD-1 antibody BGB-A317. Besides blocking Tim-3, BGB-A425 can also induce the internalization of Tim-3 receptor on cell surface. In vivo, BGB-A425 in combination with BGB-A317 inhibits tumor growth in a mouse xenograft cancer model.
Conclusions: BGB-A425 demonstrates potent activity to stimulate immune cell function both in vitro and in vivo, supporting its clinical development for the treatment of human cancers.
Citation Format: Tong Zhang, Liu Xue, Jing Zhang, Qi Liu, Jie Ma, Yi Zhang, Yingdi Shi, Hongjia Hou, Hao Peng, Ning Liu, Yilu Zhang, Xiaomin Song, Yucheng Li, Jing Song, Lai Wang, Min Wei, Kang Li. BGB-A425: a humanized anti-human Tim-3 antibody that exhibits strong immune cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2628. doi:10.1158/1538-7445.AM2017-2628
Abstract 3083: Prior irradiation results in elevated programmed death 1 (PD-1) in T cells
Authors: Chen Renxiang , Li Deguan , Fornace Albert J. , Li Henghong 
Published: July 2017

Abstract
It is well known that radiation has long-lasting effects on the immune system. In this study we address the question whether these radiation-induced adverse effects on T cell activation are associated with alterations of T cell inhibitory receptors. Expression levels of inhibitory receptors on T cells were analyzed at multiple post-radiation time points ranging from one to four weeks in mice receiving whole body irradiation. The level of the checkpoint receptor, PD-1, on different T cell subpopulations was determined. Our results showed that prior irradiation resulted in significant elevated expression of PD-1 in both CD4+ and CD8+ populations. T cells with elevated PD-1 mostly were either central memory or naïve cells. In addition, the feedback induction of PD-1 expression in activated T cells declined with time after radiation. Taken together, the elevated PD-1 level observed at weeks after radiation exposure is connected to T cell dysfunction. Similar changes were seen in samples from tumor patients receiving radiotherapy. Recent preclinical and clinical studies have shown that radiation alters the immune-modulatory microenvironment in tumor tissue, and implies that a combination of radiotherapy and T cell checkpoint blockade immunotherapy including targeting the PD-L1/PD-1 axis may potentiate the antitumor response. Therefore, understanding the dynamic changes in PD-1 levels in T cells after radiation should help in the development of a more effective therapeutic strategy.
Citation Format: Renxiang Chen, Deguan Li, Albert J. Fornace, Henghong Li. Prior irradiation results in elevated programmed death 1 (PD-1) in T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3083. doi:10.1158/1538-7445.AM2017-3083
Abstract 3127: Roles of ERKs-RSK2 signaling in human cancers
Authors: Cho Yong Yeon 
Published: July 2017

Abstract
RSK2 is a member of p90RSK superfamily consisted with RSK1-4 and MSK1-2, and has suggested involving in many cellular processes including cell proliferation, differentiation, transformation and cancer development. Accumulating data obtained by our 16-year researches strongly demonstrated that RSK2 is a key player in cell transformation and cancer metastasis. We found that ectopic expression of RSK2 induced anchorage-independent cell transformation. Notably, knockdown of RSK2 strongly suppressed constitutive active-Ras (CA-Ras)-induced foci-formation, EGF-induced cell transformation and cancer cell growth in anchorage-independent condition. The results obtained from human skin cancer tissue array demonstrated that total protein levels and RSK2 activity were higher in cancer tissues than that of normal tissues. Molecular targeting of RSK2 or ERK1 and 2 with natural compounds demonstrated that ERKs-RSK2 signaling pathway plays a key role in cell transformation and cancer development. Moreover, inhibition of ERKs-RSK2 signaling suppressed NF-κB activity in JB6Cl41 cells. The EGF-induced NF-κB activity was abrogated up-regulation of COX-2 mRNA expression and COX-2 protein levels by inhibition of ERKs-RSK2 signaling pathway. Interestingly, magnolin, a specific inhibitor of ERK1 and ERK2, suppressed ERK-mediated MMP-2 and NF-κB-mediated MMP-9 expression. In addition, we found that the protein expression of N-cadherin involved in metastasis was markedly attenuated by inhibition of ERKs-RSK2 signaling pathway. Notably, magnolin suppressed the migration and invasion of lung cancer cells in a dose-dependent manner. Taken together, these results demonstrated that targeting of ERKs-RSK2 signaling is beneficial for the chemoprevention, and anti-invasion and -migration in cancer metastasis.
Key words: MAPK pathway, Transformation, Metastasis, Molecular targets
Citation Format: Yong Yeon Cho. Roles of ERKs-RSK2 signaling in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3127. doi:10.1158/1538-7445.AM2017-3127
Abstract 3198: Using a genome-wide CRISPR-Cas9 knockout library to identify therapeutic combinations in oral cancer
Authors: Ludwig Megan , Birkeland Andrew , Nimmagadda Sai , Foltin Sue , Kulkarni Aditi , Jiang Hui , Carey Thomas , Brenner Chad 
Published: July 2017

Abstract
Oral squamous cell carcinoma (OSCC) has remained a disease with poor survival for decades with few novel treatment options. We anticipate great potential for personalized targeted therapies, facilitated by recent characterizations of the mutational landscape of OSCCs. Combinations of targeted therapies may have greater efficacy through inhibiting compensatory pathways. For example, targeting EGFR has had limited success. To identify synergistic combinations with EGFR-targeted therapy, we introduced Genome-scale CRISPR-Cas9 Knock-Out (GeCKO) libraries into OSCC cell lines. CRISPR-Cas9 generates individual genetic knockouts through targeted gene editing. We used a pool of CRISPRs targeting over 18,000 genes to perform genome-scale screening for drivers of sensitivity to EGFR-targeted therapy. Upon selection of the OSCC GeCKO pool, we identified gene knockouts in the FGFR pathway that increased sensitivity to the EGFR inhibitor gefitinib. Using resazurin viability assays we tested combinations of EGFR and FGFR inhibitors in 14 OSCC cell lines. Six/14 (43%) of the cell lines were responsive to the combination, indicating that the FGFR pathway is an alternate mechanism of resistance to EGFR-targeted therapy in some tumors. In complement, we again used CRISPR-Cas9 to generate a syngeneic EGFR knockout (KO) OSCC cell line. The parent OSCC cell line is responsive to the EGFR and FGFR dual inhibition, and the EGFR KO derivative retains sensitivity to FGFR-targeted monotherapies. We expect that this EGFR KO cell line will be a useful tool in further evaluating the compensatory mechanism of the FGFR pathway. OSCC remains a common and frequently lethal cancer with great potential for the development of personalized targeted therapies. Here, we describe the use of genome-wide CRISPR-Cas9 library to discover the synergistic combination of EGFR and FGFR inhibition. Further investigation suggests the FGFR pathway is a common compensatory mechanism to EGFR inhibition. We hope to use this approach to identify additional compensatory mechanisms of resistance to targeted therapies with the eventual goal of translating these findings to clinic.
Citation Format: Megan Ludwig, Andrew Birkeland, Sai Nimmagadda, Sue Foltin, Aditi Kulkarni, Hui Jiang, Thomas Carey, Chad Brenner. Using a genome-wide CRISPR-Cas9 knockout library to identify therapeutic combinations in oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3198. doi:10.1158/1538-7445.AM2017-3198
Abstract 3498: Characterization of a novel metastatic lung cancer associated lncRNA
Authors: White Nicole M. , Rozycki Emily B. , Dang Ha X. , Maher Christopher A. 
Published: July 2017

Abstract
Lung cancer is the leading cause of death worldwide with the majority of patients presenting with metastasis and moreover, developing resistance to current treatments. One promising therapeutic area is the novel class of long noncoding RNAs (lncRNAs). While emerging evidence implicates them in cancer, lncRNA biology is still largely unexplored in tumor metastasis. To elucidate the function of lncRNAs in lung cancer, our lab used transcriptome sequencing (RNA-Seq) to discover 120 long non-coding RNAs (lncRNAs) that are enriched in metastatic tumors compared to their corresponding primary lung tumors, which we have named Metastasis Associated Lung cancer LncRNAs (MALLs). Notably, metastatic tumors were enriched for differentially expressed protein-coding genes targeted by Polycomb Repressive Complex 2 (PRC2). In lung cancer studies show that the catalytic subunit of PRC2, EZH2 (an H3K27 methylase), is overexpressed, associates with poor prognosis, promotes tumor progression, and epigenetically represses genes to promote metastasis. Specifically, we have found MALL-1 to be (i) highly up-regulated in lung cancer; (ii) promotes proliferation and migration/invasion, hallmarks of oncogenic phenotypes; (iii) binds to EZH2; and (iv) cooperatively represses well-known PRC2 target genes associated with metastasis in patients. Further, we found MALL-1 to be altered in multiple solid tumors thus suggesting a critical conserved oncogenic role of MALL-1 in solid tumor progression. We believe MALL-1 promotes aggressive disease through its interactions with, and recruitment of the PRC2 complex to chromatin, to epigenetically modify genes associated with metastasis.
Citation Format: Nicole M. White, Emily B. Rozycki, Ha X. Dang, Christopher A. Maher. Characterization of a novel metastatic lung cancer associated lncRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3498. doi:10.1158/1538-7445.AM2017-3498
Abstract 3589: A systematic approach toward gene annotation of the hallmarks of cancer
Authors: Kiefer Jeff , Nasser Sara , Graf John , Kodira Chinnappa , Ginty Fiona , Newberg Lee , Sood Anup , Berens Michael E. 
Published: July 2017

Abstract
The hallmarks of cancer consist of ten categories that serve as an organizing principle and framework for understanding neoplastic disease. The ten hallmarks include activating invasion and metastasis, avoiding immune destruction, deregulating cellular energetics, enabling replicative immortality, evading growth suppressors, genome instability and mutation, inducing angiogenesis, resisting cell death, sustaining proliferative signaling, and tumor-promoting inflammation. In order to facilitate the use of the hallmarks of cancer in genomic studies, we have undertaken a systematic methodology to map genes to each individual hallmark of cancer. Assignment of genes to the individual hallmarks was performed leveraging gene ontology (GO) annotations. Specifically, for each hallmark, a term list was generated by cancer research experts, with biological terms associated with each hallmark. This term list was used to search and identify matching GO terms. Matched terms were then mapped to the highest, most specific, representative, non-redundant GO term in the GO hierarchy. Genes for each term were restricted by selecting only human taxon, and high confidence experimental evidence codes. For specific GO terms, where present, the Regulation of ‘GO term’ category was included. The genes for each GO term for each hallmark were combined in a non-redundant list of genes for each hallmark. In the case of the evading growth suppressors category, a different strategy was employed. In this instance, genes were identified through ‘tumor suppressor’ gene/protein annotation in the DGIdb resource and UniProt. Additionally, text-mining methods on biomedical research literature were used to defined a high confidence list of genes for this hallmark. As an example use case of the hallmarks we applied them to the analysis of the TCGA Pan-Cancer RNAseq data set. Clustering across the individual hallmarks led to interesting differences within particular tumor tissue types, as well as shared hallmarks for other tumor types. For example, use of the genome instability and mutation hallmark for Pan-Cancer clustering, revealed a tight tissue-based cluster of low-grade gliomas and GBMs. This result suggests the importance of this hallmark expression in this tumor type. This high confidence mapping of genes to hallmarks of cancer provides a unique dataset to facilitate analyses of cancer genome data.
Citation Format: Jeff Kiefer, Sara Nasser, John Graf, Chinnappa Kodira, Fiona Ginty, Lee Newberg, Anup Sood, Michael E. Berens. A systematic approach toward gene annotation of the hallmarks of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3589. doi:10.1158/1538-7445.AM2017-3589
Abstract 3921: Detection of circulating tumor cells in osteosarcoma: A validation study using a translational model
Authors: Takada Marilia , Yang Ya-Ting , Piegols Hunter , Saavedra Paulo Vilar , Tang Cha-Mei , Amstutz Pete , Yuzbasiyan-Gurkan Vilma 
Published: July 2017

Abstract
Osteosarcoma (OS) is the most common primary bone cancer in humans, and most frequently seen in pediatric patients. Metastasis to distant organs via hematogenous route is the leading cause of mortality in OS. Current methods to detect metastasis and to monitor response to treatment largely depend on imaging systems with low sensitivity to micrometastases. The value of circulating tumor cells (CTCs) as prognostic marker has been demonstrated in several types of malignancies, including cancer of breast, prostate and colorectal. The objective of this study was to establish a protocol to quantify CTC in patients with OS, as a biomarker for the presence of micrometastases and early detection of tumor relapse. We used dogs with spontaneous OS as a unique translational model. OS occurs in dogs with a 15-fold higher incidence than in humans. Our experimental method consisted of the isolation of CTCs using the microfiltration system CellSieve™, and further enumeration of tumor cells by immunostaining. Normal blood cells were spiked with cultured OS cells and processed using the CellSieve™ system where the CTCs are captured on a microfilter and then incubated with an antibody mixture consisting of fluorescent dye-conjugated antibodies against Osteocalcin, Vimentin, and CD45R. We demonstrated that osteosarcoma tumor cells could be recovered from the blood and characterized by 4-channel immunofluorescence assay as Osteocalcin+ / Vimentin+ / DAPI + and CD45R-, where CD45 serves as a differential marker of normal blood cells. In addition, we were able to demonstrate that the system has a 98% yield of recovery of spiked tumor cells. When this protocol was applied to 7.5 ml of blood sample from a naïve large breed dog diagnosed with OS, we were able to detect one CTC with the predicted staining pattern. Ongoing studies evaluating CTC throughout the clinical course of dogs with OS will determine the value for prognosis as well as for evaluating response to therapy. In conclusion, the CellSieve™ microfiltration platform applied with a set of 4 immunofluorescent antibodies is an effective method for detection of CTCs in canine OS.
Citation Format: Marilia Takada, Ya-Ting Yang, Hunter Piegols, Paulo Vilar Saavedra, Cha-Mei Tang, Pete Amstutz, Vilma Yuzbasiyan-Gurkan. Detection of circulating tumor cells in osteosarcoma: A validation study using a translational model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3921. doi:10.1158/1538-7445.AM2017-3921