bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5155: Increased longevity of continuous bone marrow cultures and radioresistance of bone marrow stromal cells from SOD193A ALS (Amyotrophic Lateral Sclerosis) mice
Authors: Henderson Andrew , Epperly Michael W. , Fisher Renee , Shields Donna , Rigatti Lora , Donnelly Christopher , Watkins Simon , Greenberger Joel S. 
Published: August 2019

Abstract
Introduction: The SOD1G93A mouse model of ALS, demonstrates hind limb paralysis beginning at 90 - 100 days of age with stage 4 paralysis at 125 days of age and progressive neuromuscular loss.
Materials and Methods: To determine whether deficiency of functional SOD1 influenced parameters of hematopoiesis, long-term bone marrow cultures were established from ALS and control mice. Bone marrow stromal cell lines derived from LTBMCs were tested for clonogenic radiation survival. We tested the effect of bone marrow transplant after total body irradiation on delay of paralysis.
Results: SOD1G93A marrow cultures demonstrated significant increase in production of hematopoietic progenitor cells (p &lt; 0.0001) and overall longevity of production of hematopoietic cells (p = 0.0354), and bone marrow stromal cell lines were significantly radioresistant (D0 = 1.33 ± 0.09, and ñ = 8.57 ± 1.8) compared to control C57BL/6J mice (D0 = 1.59 ± 0.11, p = 0.117; and ñ = 3.4 ± 0.4, p= 0.0466). Total body irradiation and bone marrow transplantation with GFP+ donor marrow demonstrated a significant increase in paralysis free interval from 129.2 ± 3.0 to 240.7 ± 21.1 days (p = 0.0010), normalization of blood/brain barrier permeability, and increase in M2 marrow origin microglial cells in proximity to degenerating anterior horn cell/motor neurons. Isolated brain and spinal cord irradiation did not prolong the paralysis free interval (129.0 ± 2.7 days, p = 0.7748).
Conclusions: The results of hematopoiesis in LTBMCs in the absence of functional SOD1 showed improved LTBMC longevity and radioresistance of marrow stromal cells both unexpected pleiotropic effects of the SOD1G93A genotype. Marrow transplant after TBI prolonged the paralysis free interval in ALS mice.
Citation Format: Andrew Henderson, Michael W. Epperly, Renee Fisher, Donna Shields, Lora Rigatti, Christopher Donnelly, Simon Watkins, Joel S. Greenberger. Increased longevity of continuous bone marrow cultures and radioresistance of bone marrow stromal cells from SOD193A ALS (Amyotrophic Lateral Sclerosis) mice [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 5155.
Abstract 5165: Secreted CCDC80 from hepatic stellate cells promote metastasis of hepatocellular carcinoma
Authors: Kim Kwang-Suck , Lee SaeHwan , Jun Nayoung , Kwon Hyog Young 
Published: August 2019

Abstract
Liver cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) and hepatic stellate cell (HSC) has pivotal role in developing cirrhosis by producing various extracellular matrix (ECM). HSC are essential mediators of tumor microenvironment of HCC through remodeling of ECM and angiogenesis. We found that CCDC80 expression is upregulated in activated HSCs from RNA-sequencing with human fetal stellate cell. However, the role of CCDC80 was not well known in hepatocarcinogenesis. First, we validated mRNA expression of CCDC80 was increased in activated HSC lines and protein expression was also increased in cultured media. Functional analysis of knockdown and over expression CCDC80 was investigated in both HCC and HSC cell lines, and HCC cell lines were analyzed for proliferation (MTT assay), migration (using transwell), invasion (using Matrigel-coated transwell), and wound healing assay with condition media of CCDC80 knockdown HSCs. Expression of epithelial-mesenchymal transition (EMT) markers in HCC was evaluated with conditioned media. Knockdown of CCDC80 resulted in significantly reduced invasion, migration and wound healing behaviors of HCC cell lines. Overexpression of CCDC80 was increased invasion and migration. Expression of E-cadherin was increased and snail and vimentin expression were decreased in HCC cell lines cultured with conditioned media of CCDC80 knockdown HSCs. The associations between CCDC80 and EMT markers were validated in CCDC80 transfected HSC cell line compared with control. The mouse xenograft model also has shown the lower tumor growth, tumor weight and metastatic tumor nodule number in CCDC80 knockdown HSC with HCC co-injection compared with normal HSC and HCC co-injected mouse. Taken together, secreted CCDC80 from HSCs affected the aggressiveness and EMT of HCC cell lines. CCDC80 might be a novel biomarker and therapeutic target for patients with HCC.
Citation Format: Kwang-Suck Kim, SaeHwan Lee, Nayoung Jun, Hyog Young Kwon. Secreted CCDC80 from hepatic stellate cells promote metastasis of hepatocellular 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 5165.
Abstract 5166: Extracellular matrix protein tenascin C increases phagocytosis mediated by CD47 loss-of-function in glioblastoma
Authors: Ma Ding , Liu Senquan , Lal Bachchu , Laterra John , Wilson Mary Ann , Xia Shuli 
Published: August 2019

Abstract
Glioblastomas (GBMs) are highly infiltrated by myeloid-derived innate immune cells that contribute to an immunosuppressive nature of the brain tumor microenvironment (TME). CD47 has been shown to mediate immune evasion as the CD47-SIRPα axis prevents phagocytosis of tumor cells by macrophages and other myeloid cells. In this study, we established CD47 homozygous deletion (CD47-/-) in human and mouse GBM cells by genome editing to investigate the impact of eliminating the “don’t eat me” signal on tumor growth and tumor-TME interactions. CD47 knockout (KO) did not significantly alter tumor cell proliferation in vitro, but significantly increased phagocytosis of tumor cells by macrophages in co-cultures. Compared with CD47 wild type xenografts, orthotopic xenografts derived from CD47-/- tumor cells grew much slower with enhanced tumor cell phagocytosis and increased recruitment of M2-like tumor associated microglia/macrophages (TAMs). CD47 KO increased tumor-associated extracellular matrix protein tenascin C (TNC) in xenografts, which was further examined in vitro. CD47 loss-of-function upregulated TNC expression in tumor cells via a Notch pathway mediated mechanism. ShRNA-based TNC knockdown in tumor cells enhanced the growth of CD47-/-xenografts in vivo, and decrease the number of TAMs. TNC knockdown inhibited phagocytosis of CD47-/- tumor cells in co-cultures. Furthermore, TNC stimulated release of pro-inflammatory factors including TNF-α via a toll-like receptor 4 (TLR4) and STAT3-dependent mechanism in human macrophage cells. These results reveal a vital immunomodulation role of TNC in brain tumor biology and demonstrate the prominence of the TME extracellular matrix in affecting the anti-tumor function of brain innate immune cells.
Citation Format: Ding Ma, Senquan Liu, Bachchu Lal, John Laterra, Mary Ann Wilson, Shuli Xia. Extracellular matrix protein tenascin C increases phagocytosis mediated by CD47 loss-of-function in glioblastoma [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 5166.
Abstract 5181: Global alteration of CTCF binding in the cancer genome
Authors: Fang Celestia , Wang Zhenjia , Martinez Carlos A. , Ntziachristos Panagiotis , Zang Chongzhi 
Published: August 2019

Abstract
The goal of this study is to understand the functions of altered CTCF binding in the cancer genome and its role in tumorigenesis. CTCF is a zinc finger protein that binds to DNA and functions as a transcriptional factor (TF) or a chromatin insulator. Disruption of individual CTCF bindings have been reported in several systems that associate with DNA methylation changes and result in aberrant chromatin interaction and differential expression of genes associated with the topological associated domains (TADs). We systematically analyzed over 500 CTCF ChIP-seq datasets across different human tissues and identified cancer-specific aberrant (gained) and disrupted (lost) CTCF binding sites in several cancer types. Through integrative analysis with other genomic data including RNA-seq, hi-C and DNA methylation profiles, we found that CTCF binding alterations correlate with differential chromatin interaction in the TADs, but most altered binding sites do not have DNA methylation changes. Instead, lost CTCF bindings at gene promoter regions associate with transcriptional repression, while gained bindings primarily occur in the distal enhancer regions bound by oncogenic transcription factors inducing gene expression. We validated these findings in T-cell acute lymphoblastic leukemia (T-ALL) using patient derived samples and identified NOTCH1 among oncogenic TFs bound at enhancers co-occupied with T-ALL-specific gained CTCF binding. These findings indicate that alteration of CTCF binding is an epigenomic signature of cancer cells, and our approach demonstrates a framework of integrating existing multi-omics data for mechanistic studies of cancer gene regulation.
Citation Format: Celestia Fang, Zhenjia Wang, Carlos A. Martinez, Panagiotis Ntziachristos, Chongzhi Zang. Global alteration of CTCF binding in the cancer genome [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 5181.
Abstract 5188: Epigenetic changes mediated by polycomb repressive complex 2 are associated with cisplatin acquired resistance in testicular germ cell tumor
Authors: Singh Ratnakar , Fazal Zeeshan , Bikorimana Emmanuel , Corbet Andrea , Rodriguez Jennifer , Steege Alyssa , Freemantle Sarah J. , Spinella Michael J. 
Published: August 2019

Abstract
Testicular germ cell tumors (TGCTs) represent the most common carcinoma affecting young men. TGCTs serve as a paradigm of chemo-sensitive tumors as more than 80% of metastatic disease can be cured with cisplatin-based chemotherapy. However, therapy resistance can occur, which results in poor patient outcomes. The mechanisms of cisplatin resistant in these tumors remain largely undefined. To study the mechanism of cisplatin acquired resistance we generated several independent, acquired resistant clones of parental NT2/D1, 833K and 2102EP testicular cancer cells employing an in vitro protocol designed to mimic the standard-of-care cisplatin regimen used to treat TGCT patients. We further characterized 10 of these clonal lines and confirmed stable cisplatin resistance ranging from 5- to 30-fold. After confirming the cisplatin resistance, we performed RNA seq transcriptomic profiling, differential gene expression analysis, DAVID and GSEA. Remarkably, RNA-seq based transcriptional profiling revealed highly significant alterations shared between the majority of the resistant cells regardless of their parental cell of origin. This includes apparent amplification of chromosomal region 17q21-25 in 8 of 10 lines. Unexpectedly, 7 of 10 lines had a highly significant enrichment of genes regulated by H3K27 methylation and polycomb repressive complex 2 (PRC2). Transcription factor prediction analysis of genes differentially expressed between resistant and parental cells revealed that polycomb complex members were among the most highly ranked predicted transcription factors responsible for the gene expression changes. These include EZH2, SUZ12, JARID2 and BMI1. We will present our ongoing studies investigating the role of PRC2 and H3K27 methylation in mediating cisplatin resistance in these cells and in patient samples. Together our data suggests that repression of H3K27 methylation may be a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 function could be a viable approach to overcome treatment failure.
Citation Format: Ratnakar Singh, Zeeshan Fazal, Emmanuel Bikorimana, Andrea Corbet, Jennifer Rodriguez, Alyssa Steege, Sarah J. Freemantle, Michael J. Spinella. Epigenetic changes mediated by polycomb repressive complex 2 are associated with cisplatin acquired resistance in testicular germ cell tumor [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 5188.
Abstract 5194: Epigenomic and transcriptional profiling of CRC cell lines with distinct response patterns to the BET inhibitor BI 894999
Authors: Savarese Fabio , Gerlach Daniel , Koller Larissa , Straubinger Susy , Träxler Paula Elena , Kaya Onur , Schweifer Norbert , Tontsch-Grunt Ulrike , Kraut Norbert 
Published: August 2019

Abstract
The bromodomain and extra-terminal (BET) protein BRD4 is a “reader” of epigenetic information and binds to acetylated chromatin. BRD4 acts as key regulator of transcriptional elongation by activating P-TEFb at distinct genes. It is via this specific activation of potentially oncogenic transcripts, e.g. MYC, that BRD4 is thought to contribute to tumorigenesis. Inhibition, via so-called BET inhibitors, has indeed proven to be a novel and attractive treatment option tested in ongoing clinical trials for both hematological as well as solid cancers. While BET inhibition shows good efficacy in pre-clinical models of hematological indications, solid tumors show much more heterogeneous responses to monotherapy. Consequently, biomarkers predicting response to treatment with BET inhibitors are of high interest. Colorectal cancer (CRC) is a heterogeneous disease in which novel treatment options are urgently needed. Our pre-clinical studies show that the BET inhibitor BI 894999 is highly active in a fraction of cell lines tested. H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) and transcriptional profiling of sensitive and resistant cell lines identified a small set of H3K27ac peaks associated with sensitivity to BET inhibition. Much of the transcriptional response in CRC cell lines however was cell line specific, leading to only few commonly regulated genes within sensitive versus resistant cell lines. Regarding pharmacodynamic biomarkers in CRC, we could confirm modulation of HEXIM1 after treatment in both sensitive and resistant cell lines. In agreement with previous results (Cohen et al, Nature Comm. 2017), we identified AP1 binding sites in BRD4-bound regulatory regions, which indicates that BRD4 may regulate expression of these genes cooperatively with the transcription factor AP1. Furthermore, the transcription factor TCF4 showed enrichment, suggesting possible interactions between BRD4 and the WNT pathway in a subset of CRC cell lines. The AXIN1, a core WNT pathway component, e.g. is down-regulated in 5/9 cell lines, which however does not track with overall BI 894999 sensitivity. These results, further supporting heterogeneous responses to single-agent BETi treatment, will be discussed. These studies support the further evaluation of BI 894999 as a therapeutic option for colorectal cancer therapy.
Citation Format: Fabio Savarese, Daniel Gerlach, Larissa Koller, Susy Straubinger, Paula Elena Träxler, Onur Kaya, Norbert Schweifer, Ulrike Tontsch-Grunt, Norbert Kraut. Epigenomic and transcriptional profiling of CRC cell lines with distinct response patterns to the BET inhibitor BI 894999 [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 5194.
Abstract 5196: Vorinostat exhibits anticancer effects through modulation of nuclear receptors and tumor suppressor genes in sub-types of triple negative breast cancer cells
Authors: NouriEmamzadeh Fatemeh , Word Beverly , Cotton Ebony , Littlejohn Kai , Miranda-Carboni Gustavo , Lyn-Cook Beverly 
Published: August 2019

Abstract
Aberrantly expression of histone deacetylases (HDAC) play a critical role in tumorigenesis. The expression of individual HDACs has been shown to correlate to decreases in both, disease-free and overall survival, thus targeting HDACs is emerging as a new therapy for cancer. Histone acetylation is associated with elevated transcription, while deacetylation is associated with gene repression. Emerging evidence suggests their role in triple negative breast cancer (TNBC) progression. TNBC is an aggressive type of cancer that has poor prognosis and molecular studies have shown several subtypes within TNBC. These cancers lack targeted treatments and several options used such as, PARP inhibitors, angiogenesis inhibitors, androgen receptor inhibitors and others have shown limited efficacy, however histone deacetylase inhibitors are showing promising results in clinical trials. Vorinostat, a histone deacetylase inhibitor, also known as suberanilohydroxane acid (SAHA) was approved by the FDA for treatment of cutaneous T cell lymphoma. In this study, vorinostat was investigated in subtypes of TNBC cell lines, MB231(MSL) and two basal-like 2 TNBC cell lines, HCC70 and HCC1806. Cells were treated with vorinostat for 24 hrs. Vorinostat significantly up-regulated the tumor suppressor gene NR4A1 by 20 fold, NR4A3 by 10 fold and AR5A by 5 fold. RORα gene had the highest up-regulation, 60 fold, whereas PPARγ 4.5 fold. Estrogen related receptor A, ESRRA was also up-regulated in HCC70 cells. A decrease in expression was noted in DDX5, which is known to be elevated in basal-like tumors. A different profile was noted in the MB231 TNBC cells. Vorinostat also decreased growth and cell invasion, which shows its functional effects on these aggressive TNBC cell lines These changes suggest that vorinostat, which is currently in clinical trials for TNBC may be exerting its effect through modulation of orphan nuclear receptors and reactivation of tumor suppressor genes through epigenetic mechanisms. Further studies are needed to determine other signaling pathways modulated by this HDAC inhibitor.
Citation Format: Fatemeh NouriEmamzadeh, Beverly Word, Ebony Cotton, Kai Littlejohn, Gustavo Miranda-Carboni, Beverly Lyn-Cook. Vorinostat exhibits anticancer effects through modulation of nuclear receptors and tumor suppressor genes in sub-types of triple negative breast cancer cells [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 5196.
Abstract 5205: EWS-FLI1 activates HOXD13 expression through enhancer reprogramming
Authors: Apfelbaum April Ann , Svoboda Laurie , Magnuson Brian , Ljungman Mats , Lawlor Elizabeth 
Published: August 2019

Abstract
Ewing sarcomas (ES) are bone tumors of mesenchymal stem cell (MSC) origin. ES is defined by EWS-FLI1 fusions, which initiate tumorigenesis via enhancer reprogramming. Posterior homeobox D (HOXD) genes, in particular HOXD13, are over-expressed by ES, where they function as obligate, cooperative oncogenes. These genes play crucial roles in limb development and spatiotemporal control of HOXD13 expression depends on long-range enhancers that flank the HOXD locus. We hypothesize that HOXD13 is aberrantly activated in the ES cell of origin as a result of EWS-FLI1-dependent hijacking of developmental enhancers.
We interrogated ChIP-seq and RNA-seq data to identify EWS-FLI1 binding sites and HOXD13 activation states in ES cells. These analyses revealed an EWS-FLI1 binding site within the developmentally conserved posterior HOXD enhancer region, which we will refer to as Desert Enhancer 268 (DE268). These sites were also marked with the active enhancer marks, H3K27Ac and H3K4me1. EWS-FLI1 knockdown was associated with loss of EWS-FLI1 binding, loss of H3K27Ac and H3K4me1, and loss of HOXD13 expression. Findings were independently validated by ChIP-qPCR and RT-qPCR. Through BruUV-seq we also identified that DE268 has eRNA expression that is lost upon EWS-FLI1 knockdown. Thus, HOXD13 expression in ES cells is maintained by EWS-FLI1-mediated enhancer activation. To address whether hijacking of HOXD13 enhancers is an initiating event in tumorigenesis, we evaluated enhancer profiles in MSCs ± EWS-FLI1. Whereas DE268 was not active in parent MSC, EWS-FLI1 binding and enhancer activation were evident in EWS-FLI1+ MSC. However, although EWS-FLI1 reproducibly binds and activates DE268, expression of HOXD13 is limited to discrete conditions. Together, these results suggest that EWS-FLI1 is necessary for enhancer activation, but that the fusion is alone is insufficient for induction of HOXD13 expression. Ongoing studies will utilize CRISPRi technologies to determine the contribution of DE268 on HOXD13 gene expression.
Citation Format: April Ann Apfelbaum, Laurie Svoboda, Brian Magnuson, Mats Ljungman, Elizabeth Lawlor. EWS-FLI1 activates HOXD13 expression through enhancer reprogramming [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 5205.
Abstract 5206: Role of super-enhancers in HPV+ head and neck squamous cell carcinoma
Authors: Zamuner Fernando T. , Vorontsov Ilya , Flam Emily , Mukhina Vera , Danilova Ludmila , Ou Tingting , Stavrovskaya Elena , Guo Theresa , Windsor Eric , Kelley Dylan Z. , Parfenov Michael , Considine Michael , Fertig Elana J. , Favorov Alexander , Gaykalova Daria A. 
Published: August 2019

Abstract
Head and neck squamous cell carcinomas (HNSCC) are the sixth leading cause of cancer worldwide with different incidences, mortalities, and prognosis for different subsites. Infection by Human Papilloma Viral (HPV) can cause the development of HPV+ HNSCC, the most rapidly growing population of cancer patients. The molecular biology of HPV+ HNSCC is related to abnormal transcriptional regulation. Super-enhancers (SEs) were recently identified as critical regulators of gene expression during cell differentiation and disease development. SEs are long clusters of enhancers that recruit master transcription factors (TFs) and coactivators to regulate the expression of target genes. We have recently developed a new whole-genome analytical pipeline to optimize ChIP-Seq procedures on primary surgical samples, and this protocol helped us to define the whole-genome distribution of H3K27ac, the hallmark of SEs, in HPV+ HNSCC samples. To detect SEs, we used a novel LILY algorithm that corrects the ChIP-Seq signal for copy number variation and CpG density. The analysis revealed that HPV+ HNSCC-specific SEs regulate genes critical for head and neck cancer development, such as EGFR, TP63, JAG1, IRF6, SMAD3, MAP4K2, SNAI1, TNFAIP3, ANO2, and TNFRSF1A. These genes are located in the vicinity of HNSCC-specific SEs, and the expression of those genes was altered by JQ1, the inhibitor of BRD4, the main component of SE machinery, supporting the role of SE in their regulation. The following Cistrome analysis allowed us to elucidate the TF composition of the SE machinery. Thus, we have found out that P63, P53, SOX2, FOSL1, SMAD3, and SNAI2 are TFs that are the most overrepresented in the HPV+ HNSCC-specific SEs. These comprehensive analyses have revealed novel insight into the HPV+ HNSCC biology and paved the basis for the implications for epigenetic therapeutics for this tumor types, and potentially other virus-related malignancies.
Citation Format: Fernando T. Zamuner, Ilya Vorontsov, Emily Flam, Vera Mukhina, Ludmila Danilova, Tingting Ou, Elena Stavrovskaya, Theresa Guo, Eric Windsor, Dylan Z. Kelley, Michael Parfenov, Michael Considine, Elana J. Fertig, Alexander Favorov, Daria A. Gaykalova. Role of super-enhancers in HPV+ head and neck squamous 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 5206.