bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3214: BART: An integrative bioinformatics toolkit and web server for functional transcription factor prediction
Authors: Wang Zhenjia , Ma Wenjing , Zhang Yifan , Magee Neal E. , Chen Yang , Zang Chongzhi 
Published: September 2020

Abstract
The goal of this bioinformatics tool is to predict functional transcription factors (TFs) from various queries of target genomic features. TFs play a key role in regulating gene expression in a dynamic chromatin structure. From a target gene set or a genomic region set, it is challenging to identify functional TFs that regulate these genes or bind in these regions, because of complexity of enhancer distributions and insufficient specificity of DNA sequence motifs. Here, we present BART (Binding Analysis for Regulation of Transcription), an interactive bioinformatics toolkit and web server to predict functional TFs that regulate a set of co-regulated genes or associate with a genomic profile. From a gene set, BART first uses a machine learning approach to generate a genome-wide cis-regulatory profile by leveraging hundreds of publicly available ChIP-seq profiles for active enhancer histone mark H3K27ac and DNase-seq profiles for genome-wide cis-regulatory elements. Then it identifies a list of TFs whose binding profiles most correlate with the cis-regulatory profile by comparing with tens of thousands of ChIP-seq datasets. BART can also identify TFs associated with differential chromatin interaction from a pair of three-dimensional (3D) genomic datasets, such as Hi-C. BART integrates over 12,000 ChIP-seq datasets for over 900 TFs for human and over 500 TFs for mouse to make accurate predictions. We demonstrate that BART outperforms existing methods in identifying the true TF from target gene sets. BART can be useful for any researcher in studying cancer gene regulation and cancer epigenetics, and demonstrates the power of utilizing public data for computational biology research. BART web server is freely available at: http://bartweb.org.
Citation Format: Zhenjia Wang, Wenjing Ma, Yifan Zhang, Neal E. Magee, Yang Chen, Chongzhi Zang. BART: An integrative bioinformatics toolkit and web server for functional transcription factor prediction [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3214.
Abstract 3241: Targeting the tumor stroma using CAR T-cells
Authors: Ash Sarah , Turrell Frances , Isacke Clare , Lee Steven 
Published: September 2020

Abstract
The majority of breast cancer deaths are due to metastatic disease, thus developing new strategies to target the metastatic cascade is clinically relevant and of scientific importance. Breast cancer metastasis is a multi-step process influenced by many factors, including the tumor microenvironment (TME). Key interactions between the TME and tumor cells have been identified as promoting metastasis, thus presenting novel clinical targets. One such target is endosialin (CD248), a transmembrane glycoprotein which has limited expression in the healthy adult but is strongly upregulated on tumor-associated pericytes and fibroblasts in most solid cancers, including breast cancer. Using endosialin knockout mice, our laboratory has demonstrated that expression of endosialin in the tumor stroma promotes tumor cell intravasation, thereby promoting metastatic dissemination. Endosialin-expressing cells present an interesting target for CAR T-cell therapy, an emerging approach within cancer immunotherapy. Thus far, targeting tumor cells with CAR T-cells has proven challenging in solid neoplasms owing to the harsh, immunosuppressive environment that CAR T-cells encounter. Here, we describe an alternative approach of targeting cells of the microenvironment, which are more accessible to the infiltrating CAR T-cells, to limit breast cancer metastasis. Experiments comparing the effects of endosialin-directed CAR T-cells (Endo3 CARs) and mock- transduced T-cells (mock T-cells) in a spontaneously metastatic BALB/c breast cancer model reveal that Endo3 CAR treatment significantly reduces the number of metastatic deposits in the lungs. Endo3 CARs expand by at least 2-fold in tumor-bearing mice and endosialin staining confirms that Endo3 CAR treatment results in the depletion of endosialin-positive cells in the tumor stroma, without affecting normal tissue. Strikingly, Endo3 CAR treatment also results in significant growth inhibition and necrosis of the primary tumor. However, some evidence of Endo3 CAR T-cell associated toxicity is observed in treated mice, and we are currently testing therapeutic options to minimize these side effects. No off- target activity is observed in parallel experiments with tumor-bearing endosialin knockout mice. In conclusion, these promising results demonstrate that Endo3 CAR T-cell therapy presents a novel approach to limiting breast cancer metastasis via the targeting of activated stromal cells in the tumor microenvironment.
Citation Format: Sarah Ash, Frances Turrell, Clare Isacke, Steven Lee. Targeting the tumor stroma using CAR T-cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3241.
Abstract 3254: MOTO-CARs™: A novel macrophage-based chimeric antigen receptor technology
Authors: Townsend Michelle Hannah , Ewell Zachary D. , Bennion Kelsey A. , Wang Guoying , Skidmore Jonathan , Lum David , Boyer Michael , O'Neill Kim L. 
Published: September 2020

Abstract
We report the development of a novel macrophage-mediated immunotherapy targeting mesothelin-expressing solid tumors. Although the advent of immunotherapy heralded a new era in cancer treatment, it has been accompanied by severe limitations, including antigen escape, cytokine release syndrome (CRS), and the inability to penetrate solid tumors. We sought to ameliorate these issues by developing a macrophage toll-like chimeric antigen receptor (MOTO-CAR™) designed to target and activate upon cancer antigen recognition. Here we show evidence supporting this proof-of-concept MOTO-CAR™ technology in a murine macrophage cell line (RAW 264.7) targeting a mesothelin-expressing, triple-negative, mammary gland squamous carcinoma cell line (HCC-1806). The MOTO-CAR™ construct was transfected into macrophage cells with an average efficiency above 50%. The presence of the chimeric construct was confirmed via mesothelin scFv amplification of isolated mRNA, and the engineered macrophages stably expressed the chimeric receptor for over 7 days, with the highest level of expression approximately 24 hours post transfection. We found that upon exposure to HCC-1806 cells, MOTO-CARs™ are not only effective at eliminating the cancer cells, but also secrete significant levels of TNF-α when compared to mock controls (p= 0.009), indicating activation and polarization to an M1 phenotype upon target recognition. In vitro cytotoxicity assays confirmed that macrophages containing the MOTO-CAR™ construct increasingly targeted and killed HCC-1806 cells when compared to the mock control (p &lt; 0.0001) in three different effector to target ratios. Furthermore, in NSG mice containing HCC-1806-derived xenografts, tumor burdens were significantly lower in mice treated with MOTO-CARs™ when compared to the mock control (p = 0.006). In these models, the MOTO-CARs were administered through the tail vein, which indicates the MOTO-CARs™ can traffic effectively to the tumor site in vivo. Both TLR4 and TLR2 based toll-like receptor signaling domains were evaluated with TLR4 vectors showing higher killing and better efficacy against target cancer cells. Following initial testing in RAW 264.7 macrophages, similar results were observed when MOTO-CARs™ derived from primary human monocytes were co-incubated with the same target cells. These data illustrate the potential for MOTO-CARs™ to be a powerful alternative to current immunotherapies targeting solid tumors.
Citation Format: Michelle Hannah Townsend, Zachary D. Ewell, Kelsey A. Bennion, Guoying Wang, Jonathan Skidmore, David Lum, Michael Boyer, Kim L. O'Neill. MOTO-CARs™: A novel macrophage-based chimeric antigen receptor technology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3254.
Abstract 3321: Immunogenic clearance sensitizes cold tumor to PD-1 blockade by enhancing quantity and quality of CD8+ T cells
Authors: Nam Gi-Hoon , Choi Yoonjeong , Kim In-San 
Published: September 2020

Abstract
The effective immune response against cancer requires stepwise events from the release of tumor antigens to T cells' exhibiting cytotoxic effects in the tumor microenvironment (TME). Immunogenic clearance reveals intrinsic tumor antigenicity with immunogenic cell death of the tumor cells and increases priming of T cells with increased phagocytosis activity of professional antigen-presenting cells (pAPCs), therefore, overcome the failure in immune surveillance of cancer caused by immunological ignorance. Here, we investigated the potential strategy to induce immunogenic clearance with immunogenic cell death (ICD) inducers and phagocytosis enhancer. Using anthracyclines, one of the renowned ICD inducers and fasudil, rho-kinase (ROCK) inhibitors that increases phagocytosis activity, reinforced cross-presentation of dendritic cells and cross-priming of CD8+ T cells in secondary lymphoid organ contributes to consecutive infiltration of CD8+ T cells in TME. Inducing the CD8+ T cell immune response, this strategy could surmount the resistance to immune checkpoint blockade of the immunologically cold tumor where little infiltrated T cells exist in the tumor site, which leads not just increased tumor-specific CD8+ T cells, but prolonged survival accompanied with the formation of sustainable CD8+ T cell memory.
Citation Format: Gi-Hoon Nam, Yoonjeong Choi, In-San Kim. Immunogenic clearance sensitizes cold tumor to PD-1 blockade by enhancing quantity and quality of CD8+ T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3321.
Abstract 3346: Changes of gut microbiota in FAP and UC that might harbor colorectal cancer carcinogenesis
Authors: Bisgin Atil , Hanta Abdullah , Rencuzogullari Ahmet , Boga Ibrahim 
Published: September 2020

Abstract
Inflammatory bowel diseases, Familial adenomatous polyposis(FAP) and colorectal cancer(CRC) are associated with alterations of the intestinal microbiota. However, few data are available on the perpetuation of FAP and Ulcerative Colitis(UC) in relation to microbial dysbiosis. This study evaluated the UC and genetically confirmed FAP patients' gut microbial balance in concordance to clinical outcome. Fecal materials (average mass of 0.54 g) were collected from three FAP and five UC patients to compare with healthy individuals as control group. Genomic materials of microbiota were isolated via QIAamp PowerFecal DNA kit according to manufacturer instructions. Next generation sequencing of 16S rRNA was performed by using QIAseq 16S/ITS panel in Illumina Miseq Platform. Data processing and bioinformatics analysis were performed via CLC Genomic Workbench bioinformatics tool. The comparison between FAP subjects, UC patients and control group revealed an alteration in the intestinal microbial composition. More in details, relative abundance of class levels showing statistical significance differences among FAP, UC and control group was given in Table 1, in which the sample groups are reported in column while class levels are in row. Our preliminary data focused on the explanation of how dysbiosis can lead to inflammation and drive processes together with host genetic profile that leads to colorectal carcinogenesis.
Abundance table of class levels compared between FAP, UC and control groupClass (Aggregated)Cont AbundanceUlc. Col. AbundanceFAP AbundanceActinobacteria65847688013162Alphaproteobacteria899923560Bacilli4806197740237684Bacteroidia13247361374676321973Campylobacteria0730Clostridia748894613039897452Coriobacteriia5684586513543Deltaproteobacteria493780Erysipelotrichia6787833346228289Fusobacteriia18374510Gammaproteobacteria328501859739269883Halanaerobiia27000Kiritimatiellae700Lentisphaeria75400Melainabacteria201100Methanobacteria65600Mollicutes29069949Negativicutes578632230683666Oligosphaeria1700Oxyphotobacteria21150Saccharimonadia048360Stramenopiles200Verrucomicrobiae32065733252
Citation Format: Atil Bisgin, Abdullah Hanta, Ahmet Rencuzogullari, Ibrahim Boga. Changes of gut microbiota in FAP and UC that might harbor colorectal cancer carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3346.
Abstract 3381: Identifying tumor antigen-specific CD4+ T cell dysfunctional states by single cell transcriptomics in immunotherapy-treated cancer patients
Authors: Kozlova Edgar , Eikawa Shingo , Gnjatic Sacha , Losic Bojan 
Published: September 2020

Abstract
Dysfunctional T cell states resulting from continuous exposure to self shared tumor antigens or neoantigens are key to understanding immune mechanisms that prevent proper antitumor immunity. We previously showed that repeated administration of recombinant tumor antigen vaccines without immunological adjuvant emulates a tolerized-like immune response that cannot be rescued even after in vivo re-challenge with adjuvant. We used bulk and single-cell RNA-seq of purified antigen-specific CD4+ T-cells (i.e., the orchestrator of immunity) from 12 ovarian and non-small cell lung cancer patients receiving NY-ESO-1 or MAGE-A3 vaccines with or without adjuvant, over a period of 13 weeks.
First, using bulk RNA-seq data, we derived novel temporal, tolerization CD4+ T cell expression and clonotype evolution signatures using differential expression and VDJ-deconvolution analyses, highlighting significant association with cell cycle and immune activation. Then, we projected these signatures onto several recently published single-cell RNA-seq data profiling exhausted tumor-infiltrating and peripheral blood lymphocytes, finding reasonable predictive power (AUC~0.8) to classify dysfunctional T-cell states that could distinguish exhaustion from tolerance. Next, we characterized in depth the transcriptional profiles and heterogeneity of our antigen-specific CD4+ T-cells pre- and post-treatment at the single-cell level using combined scRNAseq and scTCRseq. Finally, we computationally inferred the regulatory axis of tolerized T-cells by deriving transcription factor signaling networks upstream of gene expression.
In conclusion, we characterized transcriptional signatures of tumor antigen-specific CD4+ T-cells and derived a specific tolerization profile, distinguishable from exhaustion, and conserved across datasets. Through comprehensive identification of genes and pathways in a human experimental setting for induction of tolerization and exhaustion, these findings provide relevant and promising avenues to reverse dysfunctional CD4+ T cell states.
Citation Format: Edgar Kozlova, Shingo Eikawa, Sacha Gnjatic, Bojan Losic. Identifying tumor antigen-specific CD4+ T cell dysfunctional states by single cell transcriptomics in immunotherapy-treated cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3381.
Abstract 3402: BCAT1 as a druggable target in immuno-oncology
Authors: Papathanassiu Adonia E. , Lodi Francesca , Elkafrawy Hagar , Certo Michelangelo , Vu Hong , Ko Jeong Hun , Behmoaras Jacques , Mauro Claudio , Lambrechts Diether 
Published: September 2020

Abstract
BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, has recently been implicated in the development and growth of various types of cancer. The limited expression of BCAT1 in adult tissues under physiological conditions suggests that the enzyme is a sensible target for drug development. To better understand the role of BCAT1 in cancer, we examined its gene expression at the single cell level (scRNAseq) in specimens obtained from lung, colorectal, breast, and ovarian cancer patients (n=36; &gt;200,000 single cells). In those samples, Bcat1 gene expression was primarily associated with myeloid cells and fibroblasts with the exception of ovarian cancer in which robust Bcat1 presence was also seen in cancer cells. In tumor infiltrating lymphocytes (TILs), enrichment in Bcat1 gene expression was observed in exhausted CD4+ and CD8+ T cells compared to other T cell subtypes; this was independent of the cancer type examined. We speculated that inhibition of BCAT1 in TILs reverses exhaustion and has a therapeutic impact in cancer. In the syngeneic CT26 colon cancer model, combination treatment of a BCAT1 inhibitor (ERG245; ip administration of 5 mg/kg, given at days 7, 8 and 9 after tumor cell inoculation) and an anti-PD1 antibody (ab) (clone RMP1-14; ip administration given at days 7, 11, 14, and 18) led to eradication of established tumors. In the same model, limited treatment of large tumors (average size of ~600 mm3) with ERG245+anti-PD1 ab suppressed tumor growth and increased the frequency of CD8+ T cells expressing Granzyme B and IFNγ by ~50% compared to anti-PD1 monotherapy. Mechanistically, in vitro treatment of newly activated hCD8+ T cells with ERG245 impaired translocation of the lactate transporter MCT1 to the cell surface and increased the levels of intracellular lactate within 30 min of activation leading to upregulation of transcription factor ATF3. ERG245-driven metabolic reprogramming of CD8+ T cells towards an oxidative phenotype (increased OXPHOS) was also observed at 24h of treatment. Withdrawal of ERG245 restored intracellular lactate levels without reversing the metabolic reprogramming of the cells. We propose that these are elements of a mechanism that links temporal inhibition of BCAT1 to the rise of highly energetic CD8+ T cells with increased cytotoxicity and proliferative capacity in vitro and in vivo.
Citation Format: Adonia E. Papathanassiu, Francesca Lodi, Hagar Elkafrawy, Michelangelo Certo, Hong Vu, Jeong Hun Ko, Jacques Behmoaras, Claudio Mauro, Diether Lambrechts. BCAT1 as a druggable target in immuno-oncology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3402.
Abstract 3426: A synthetic lethality approach to eradicate AML via synergistic activation of pro-apoptotic p53 by MDM2 and BET inhibitors
Authors: Li Sha , Latif Anne , Newcombe Ashley , Gilroy Kathryn , Robertson Neil , Lei Xue , Finlay Darren , Stewart Helen , Barbosa Karina , Higgins Brian , Chevassut Tim , Huang Xu , Copland Mhairi , Keeshan Karen , Deshpande Ani , Adams Peter 
Published: September 2020

Abstract
Acute Myeloid Leukemia (AML) is a typically-lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, over 90% of AML patients retain wild type TP53, encoding pro-apoptotic tumor suppressor p53. However, wild-type p53 functions are frequently suppressed by MDM2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation. MDM2 inhibitors (MDM2i), which activate wild-type p53, show encouraging pre-clinical activity, but limited clinical activity. In an effort to find targets that synergize with p53 activation and minimize toxicity via MDM2i, we performed a cell-based synthetic lethal drug screen and a CRISPR viability screen. By integrating the results of these two screens, we found inhibition of BRD4 activates p53 and its target genes. BRD4 (Bromodomain-containing protein 4) is a member of the bromodomain and extraterminal (BET) family proteins, which has typically been reported to activate genes, such as c-MYC, BCL2 and CDK4/6. However, we unexpectedly reveal that BRD4 acts as a transcriptional repressor of p53 target genes. Our combined therapy of MDM2i and BETi is synergistically lethal to human AML cell lines harboring wild type p53 in vitro, against two mouse models of AML in vivo, and against several primary human patient blasts in vitro. Synergistic cell killing was associated with synergistic activation of p53 target genes, and cell killing and p53 target gene expression. Taken together, our data show BRD4 represses p53-mediated transcription activation and apoptosis in AML. Therefore, targetable wild-type p53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.
Citation Format: Sha Li, Anne Latif, Ashley Newcombe, Kathryn Gilroy, Neil Robertson, Xue Lei, Darren Finlay, Helen Stewart, Karina Barbosa, Brian Higgins, Tim Chevassut, Xu Huang, Mhairi Copland, Karen Keeshan, Ani Deshpande, Peter Adams. A synthetic lethality approach to eradicate AML via synergistic activation of pro-apoptotic p53 by MDM2 and BET inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3426.
Abstract 3450: Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
Authors: Tao Ting , Shi Hui , Durbin Adam D. , Wang Meng , Perez-Atayde Antonio R. , London Wendy B. , Gutierrez Alejandro , Lemos Bernardo , Look A. Thomas 
Published: September 2020

Abstract
Peripheral sympathetic nervous system tumors are the most common extra-cranial pediatric tumors in children and include neuroblastoma, ganglioneuroblastoma (intermixed and nodular) and ganglioneuroma. The etiology and molecular pathogenesis of ganglioneuromas remains largely unknown. Surgery is the only effective therapy for ganglioneuroma, which can be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is need for well tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma, and therefore limit surgical morbidity. Here we found high levels of phosphorylated AKT expressed in 10 of 11 patients with ganglioneuroma, but only in 1 of 15 who had poorly differentiated neuroblastoma (p&lt;0.0001, Fisher's exact test). Consistent with these results, zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Histopathological analysis and whole-transcriptome sequencing revealed that zebrafish ganglioneuroma highly resembles human ganglioneuroma. Inhibition of the downstream AKT target, mTOR, using sirolimus in zebrafish with ganglioneuroma effectively reduced the tumor burden, providing preclinical evidence for efficacy with this well tolerated drug. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of sirolimus as a means to shrink large ganglioneuromas prior to resection in order to reduce surgical morbidity.
Citation Format: Ting Tao, Hui Shi, Adam D. Durbin, Meng Wang, Antonio R. Perez-Atayde, Wendy B. London, Alejandro Gutierrez, Bernardo Lemos, A. Thomas Look. Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3450.