bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2604: The Georgetown Database of Cancer (G-DOC): A web-based data sharing platform for precision medicine
Authors: Bhuvaneshwar Krithika , Belouali Anas , Rao Shruti , Alaoui Adil , Gusev Yuriy , Clarke Robert , Weiner Louis M. , Madhavan Subha 
Published: July 2017

Abstract
Introduction An overarching goal of biomedical research is to improve the use and dissemination of rapidly growing biomedical datasets to support precision medicine. Individualized molecular profiling and the identification of predictive biomarkers can powerfully inform the choice of therapies for cancer patients. However, both require integration of extensive molecular, clinical, and pharmacological data, often from disparate and diverse sources. The Georgetown Database of Cancer (G-DOC) was designed and engineered to be a unique multi-omics data analysis platform to enable translational research and precision medicine.
Methods G-DOC is home to 61 datasets that contain data from over 10,000 patients across 14 diseases (10 cancers and 4 non-cancers). 1700+ researchers from over 48 different countries worldwide currently use the platform. The data and tools in the G-DOC system have enabled over 40 research publications. G-DOC has the largest public collection of brain cancer patients from NCI Rembrandt dataset (671 patients).G-DOC integrates clinical, transcriptomic, metabolomic, microRNA, next generation sequencing (NGS) data, and MRI medical images with systems-level analysis tools into a single, user-friendly platform. The “Variant Search” feature in G-DOC currently enables exploratory analysis of mutations based on genes, chromosomes, and functional location. A researcher can use this feature to 1) identify clinically actionable mutations in their dataset 2) identify pathways that may be affected by these mutations, and 3) identify novel mutations in their dataset and explore their potential impact on protein function.
Results and Conclusion We are currently working on developing features to support the import, integration, search, and retrieval of CLIA/CAP-certified cancer molecular diagnostic (molDx) data. This will enhance G-DOC’s interoperability with clinical and patient molecular profiling data that may be already stored in other databases. Our vision is to continuously improve and expand G-DOC with the long-term vision of supporting integration of informatics techniques into everyday research and practice.
Citation Format: Krithika Bhuvaneshwar, Anas Belouali, Shruti Rao, Adil Alaoui, Yuriy Gusev, Robert Clarke, Louis M. Weiner, Subha Madhavan. The Georgetown Database of Cancer (G-DOC): A web-based data sharing platform for precision medicine [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 2604. doi:10.1158/1538-7445.AM2017-2604
Abstract 2610: A database for evaluating methylation biomarkers in bladder cancer
Authors: Kennedy Meaghan M. , Dancik Garrett M. 
Published: July 2017

Abstract
Bladder cancer is the fourth-most common cancer in men, one of the most expensive types of cancer to treat, and recurs frequently. While the genomic pathways associated with high-grade, muscle invasive (MI) tumors and low-grade, non-muscle invasive (NMI) tumors are well-established, recent studies have also found that MI and NMI tumors have unique methylation patterns, and that methylation may play a role in the development of early-stage bladder cancer. Interestingly, bladder cancer patients have frequent mutations in chromatin remodeling genes that alter known histone markers of DNA methylation. Since methylation marks are pharmacologically reversible, the identification of methylation biomarkers is a promising avenue for therapeutic treatment. Indeed, several candidate prognostic methylation biomarkers have been identified, but await prospective evaluation.
The Bladder Cancer Biomarker Evaluation Tool (BC-BET) is a web-based resource for rapidly evaluating biomarkers in publicly available genomic datasets. Initially developed for gene expression biomarkers, BC-BET includes 1451 patients across 13 cohorts, and 40 bladder cancer cell lines, with gene expression profiles. In this work, we describe the addition of methylation data to BC-BET, so that candidate methylation biomarkers can be rapidly evaluated across multiple patient cohorts.
BC-BET now contains methylation profiles from four patient cohorts (250 patients) and includes the available bladder cancer data from the Gene Expression Omnibus and The Cancer Genome Atlas. In "evaluation" mode, a user selects a gene of interest, and BC-BET evaluates whether the selected gene is differentially methylated between tumor vs. normal samples, NMI vs. MI tumors, and low- vs. high-grade tumors. Alternatively, the “biomarker discovery” mode allows a user to identify all differentially methylated genes at a desired false discovery rate (FDR). In both cases, graphical summaries of the results are displayed and statistical results can be downloaded to an Excel spreadsheet. The methylation module of BC-BET is implemented using shiny, a web application framework for R for developing interactive web pages.
The addition of methylation data to BC-BET makes it a valuable resource for evaluating methylation biomarkers in bladder cancer. BC-BET is available from the following link: https://gdancik.github.io/bioinformatics/BCBET
Citation Format: Meaghan M. Kennedy, Garrett M. Dancik. A database for evaluating methylation biomarkers in bladder 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 2610. doi:10.1158/1538-7445.AM2017-2610
Abstract 2634: EVT801: Standalone cancer immunotherapy in VEGFR3+ tumors and combination with immune checkpoint therapies in VEGFR3- tumors
Authors: Esquerré Michael , Fons Pierre , Badet Gaëlle , Barron Pauline , Kagan Jérémy , Alam Antoine , Meneyrol Jérôme , Blanc Isabelle , Broussy Roselyne , Gaujarengues Florence , Lisztwan Joanna , Paillasse Michael , Whittaker Mark , Bono Françoise 
Published: July 2017

Abstract
In collaboration with Sanofi, we previously showed that inhibition of the VEGFR3 pathway by SAR131675 leads to reduction of tumor growth by acting on the tumor microenvironment. We have identified a new drug candidate, EVT801, and evaluated its activity on tumor models expressing VEGFR3. For proof-of-concept, we transfected the mouse BNL hepatoma cell line with VEGFR3. EVT801 displayed a strong therapeutic activity by acting on both VEGFR3+ tumor cells and on the Tumor Microenvironment (TME). By deciphering the mechanism of action of the compounds we showed that EVT801 strongly decreased tumor-associated immunosuppression by decreasing MDSCs (Myeloid Derived Suppressor cells) and CD4+ regulatory T cells and by increasing macrophages with a M1 phenotype inside the tumor. As a consequence the T-cell:MDSC ratios were increased in the TME and also in peripheral blood. In addition to its immunomodulatory properties, EVT801 decreased angiogenesis without increasing hypoxia. We have evaluated EVT801 therapeutic activity in syngeneic tumor mouse models which are not expressing VEGFR3 such as 4T1 mammary carcinoma and CT26 colon carcinoma models. As expected, we observed an intermediate therapeutic activity of the compound on both tumor models. Positive modulation of the TME was equivalent to what we observed with the VEGFR3+ tumor model. With this unique mechanism of action of EVT801 on the TME, we evaluated its ability to increase therapeutic activity of standard Immune Checkpoint Therapies (ICT) such as anti-CTLA-4 and anti-PD-1 mAbs. Strong additive therapeutic activities were observed with EVT801 in combination with these ICT as illustrated by the development of long-term tumor-specific memory CD8+ T cell responses.
Toxicological data show that EVT801 has a favorable pharmacological profile consistent with its entry into pre-clinical development. Taken together, these results indicate that EVT801 represents an innovative drug for cancer Immunotherapy which provide a favorable microenvironment to promote tumor regression. In addition, EVT801 may improve the frequency of response to ICT.
Citation Format: Michael Esquerré, Pierre Fons, Gaëlle Badet, Pauline Barron, Jérémy Kagan, Antoine Alam, Jérôme Meneyrol, Isabelle Blanc, Roselyne Broussy, Florence Gaujarengues, Joanna Lisztwan, Michael Paillasse, Mark Whittaker, Françoise Bono. EVT801: Standalone cancer immunotherapy in VEGFR3+ tumors and combination with immune checkpoint therapies in VEGFR3- tumors [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 2634. doi:10.1158/1538-7445.AM2017-2634
Abstract 2639: Development of small molecule selective inhibitors of GCN2 as an immunotherapy aimed at preventing immune escape of tumor cells
Authors: Gałęzowski Michał , Sitarz Kamil , Majewska Eliza , Chmielewski Stefan , Michalik Kinga , Masiejczyk Magdalena , Adamus Agnieszka , Białas Arkadiusz , Fogt Joanna , Bień Marcin , Świrski Mateusz , Mikulski Maciej , Zachmann Julian , Brzózka Krzysztof 
Published: July 2017

Abstract
GCN2 is a protein kinase capable of sensing amino acid (AA) shortage. It gets activated by binding of unloaded tRNAs and subsequently phosphorylates translation initiation factor 2 alpha (eIF2α) eventually leading to induction of ATF4-mediated integrated stress response (ISR). Elevated catabolism of one of the essential amino acids - tryptophan (Trp), driven by overexpression of critical enzymes in Trp metabolism - IDO and TDO, leads to immunosuppressive microenvironment in many types of cancer. GCN2 is a key effector signaling component for IDO/TDO and is considered as a metabolic checkpoint of highly Trp-dependent T-cells. GCN2 activation through accumulation of unloaded tRNAs leads to inhibition of CD8+ effector T-cells and increase in generation and activation of regulatory T-cells. According to these findings, selective inhibition of GCN2 may be an effective strategy for targeting Trp-dependent immunosurveillance of tumor cells. In this study, we report the results for a series of novel small molecule GCN2 kinase inhibitors that have been developed at Selvita and, to our best knowledge, are the most potent GCN2 inhibitors reported so far. Newly synthesized compounds exert low nanomolar potency for GCN2, good selectivity as well as ADME profiles. Profound assessment of the compounds potency and efficacy using a selection of in vitro activity/binding assays will be presented.
Citation Format: Michał Gałęzowski, Kamil Sitarz, Eliza Majewska, Stefan Chmielewski, Kinga Michalik, Magdalena Masiejczyk, Agnieszka Adamus, Arkadiusz Białas, Joanna Fogt, Marcin Bień, Mateusz Świrski, Maciej Mikulski, Julian Zachmann, Krzysztof Brzózka. Development of small molecule selective inhibitors of GCN2 as an immunotherapy aimed at preventing immune escape of tumor 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 2639. doi:10.1158/1538-7445.AM2017-2639
Abstract 2648: CD47 antibody-induced engulfment of human T-cell leukemia cells by bone marrow-derived macrophages
Authors: Lovell Gillian , Szybut Clare , Patel Kalpana , Campwala Hinnah , Bevan Nicola , Appledorn Dan , Dale Tim James , Trezise Derek John 
Published: July 2017

Abstract
CD47 is a trans-membrane “don’t-eat-me” signaling protein that enables tumor cells to evade clearance by neighboring phagocytes. Blocking CD47 allows phagocytes to identify and clear tumor cells and is a promising new approach for cancer immunotherapy. In this study, we characterized anti-CD47 antibody-mediated engulfment of living tumor cells (CCRF-CEM) by mouse bone-marrow derived macrophages (BMDMs) or immortalized mouse macrophages (J774A.1). Phagocytosis was quantified using a pH-sensitive cell-labeling fluorescent probe, pHrodo, and automated kinetic live-cell analysis (IncuCyte). CCRF-CEM cells were first labeled using pHrodo (250ng ml-1 for 1h), washed and then treated with antibody for 1 h. Target cells were then added to BMDMs or J774A.1 that had been seeded overnight on 96-well plates. Phase- and fluorescence images were captured and quantified every 15min. Anti-CD47 antibody (B6H12.2, 0.04-5μg ml-1), but not IgG-control, produced time- and concentration-dependent engulfment of CCRF-CEMs by BMDMs (30’-4h), as evidenced by an increase in intracellular fluorescence as the label accumulates in the acidic phagosome. After 4h the red fluorescence area was increased by 25-fold (1975 ± 391 μm2 vs 80 ± 41 μm2). From close inspection of the time-lapse images cellular engulfment could be clearly observed, coincident with the appearance of the fluorescent signal. Similar observations were made with J774A.1 as the effector cell. Interestingly, the rate and degree of engulfment appeared effector cell-dependent. The mechanism of engulfment was not via induction of target cell apoptosis since anti-CD47 did not induce PS externalization (Annexin V) or activate caspase 3/7. Anti-CD47 had no direct effect on CCRF-CEM proliferation for the first 4 h but upon longer exposures (&gt;8 h) cell growth was attenuated. Our experimental findings substantiate the known pro-phagocytic effects of anti-CD47 antibodies, and provide a model system and method for quantitative functional analysis and mechanistic insight of CD47 modulators as cancer therapeutics.
Citation Format: Gillian Lovell, Clare Szybut, Kalpana Patel, Hinnah Campwala, Nicola Bevan, Dan Appledorn, Tim James Dale, Derek John Trezise. CD47 antibody-induced engulfment of human T-cell leukemia cells by bone marrow-derived macrophages [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 2648. doi:10.1158/1538-7445.AM2017-2648
Abstract 2738: A commutable circulating tumor DNA (ctDNA) reference material
Authors: Konigshofer Yves , Tomson Farol L. , Ryder Matthew , Garlick Russell , Anekella Bharathi 
Published: July 2017

Abstract
We developed and assessed a novel ctDNA reference material that was designed with an emphasis on commutability. Possessing qualities that are well-matched with clinical specimens is critical for a reference material, however many existing methods of preparing ctDNA analogues result in material that is not commutable for certain assays. For example, sonication of genomic DNA yields fragments across a broad range of sizes that must be used at greater input amounts relative to native cell-free DNA (cfDNA) - even after enzymatic end-repair to reduce damage. This can affect the utility of the reference material for assays that depend on the ligation of adapters to double-stranded DNA, such as many hybrid/capture-based Next Generation Sequencing (NGS) assays. If higher input amounts are not used, then the LOD and precision of such an assay may appear substantially poorer than expected. At the same time, sonicated DNA has been shown to be acceptable for amplicon-based ctDNA assays.
We created commutable ctDNA reference material by starting with genomic DNA from GM24385 cells and mixing with synthetic variant-containing DNA sequences at defined ratios. The use of GM24385 cells allows for the comparison of detected variants against the NIST RM 8391 high confidence variants. The use of synthetic DNA permits addition of large numbers of different cancer-associated variants at defined allele frequencies. Fragmentation was followed by size-selection in order to obtain ctDNA-like sizes. Additional steps were performed to increase the amount of output material from the size-selection step. The general method of preparing the reference material is also compatible with native cfDNA, such as that isolated from cancer patients.
The reference material was submitted to several testing laboratories along with similar sonicated material. When tested using hybrid/capture-based assays, variant detection was superior in the novel reference material compared to sonicated DNA when similar amounts of material were used as the input. We therefore conclude that our new reference material has greatly improved commutability compared to existing materials composed only of sonicated DNA.
Citation Format: Yves Konigshofer, Farol L. Tomson, Matthew Ryder, Russell Garlick, Bharathi Anekella. A commutable circulating tumor DNA (ctDNA) reference material [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 2738. doi:10.1158/1538-7445.AM2017-2738
Abstract 2773: A prospective observational study evaluating c-MET expression and EGFR gene mutation correlation with erlotinib response in second line treatment for advanced/metastatic non-small cell lung cancer patients
Authors: Park Cheol-Kyu , Choi Yoo-Duk , Oh In-Jae , Lee Jung-Eun , Lee Shin Yup , Jang Tae-Won , Ryu Jeong-Seon , Kim Young-Chul 
Published: July 2017

Abstract
Background: The c-MET is associated with tumor progression and acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The aim of this study was to evaluate the prevalence and predictive role of c-MET and EGFR mutation in non-small cell lung cancer (NSCLC).
Methods: This was a multicenter prospective observational study for patients with stage IV or recurrent NSCLC who had progressive disease after 1st line chemotherapy and was followed by erlotinib for 2nd line treatment from September 2011 to September 2014. The primary outcome was to measure the rates of c-MET expression/amplification and EGFR mutation in tumor tissue. MET expression was evaluated by immunohistochemistry (IHC) and gene copy number was assessed by silver in situ hybridization (SISH). EGFR mutations were analyzed by Cobas™ version 1.
Results: A total of 196 patients were enrolled and major histologic types were adenocarcinoma (67%). c-MET was overexpressed (MET IHC-positive) in 44.4% of the patients and dominant in female and non-squamous histology. c-MET amplification and high polysomy (MET SISH-positive) were observed in 1.5% and 8.7%, but there was no specific clinical characteristics. The detection rate of EGFR mutation was 10.2% (19 deletion: 11, L858R: 7, exon 20 insertion: 2 cases). The response rate of erlotinib was significantly higher in EGFR sensitive mutant group (55% vs. 4%, p&lt;0.001) and the median progression-free survival (PFS) was significantly longer than wild type (173 vs 58 days, p&lt;0.001). c-MET positivity (IHC- or SISH-positive) did not show significant correlation with response or PFS. Patients with SISH-positive for c-MET tended to have shorter overall survival (OS) than patients with SISH-negative (127 vs 303 days, p=0.051).
Conclusion: In this observational study with 2nd line erlotinib treatment, we reconfirmed EGFR mutation is strong predictive marker, and EGFR-TKI use in EGFR wild-type patients should be considered carefully and may be harmful. c-MET overexpression was related to some clinical characteristics such as female and non-squamous histology. Although c-MET positivity was not associated with response or PFS, c-MET SISH may be predictive marker for OS.
Citation Format: Cheol-Kyu Park, Yoo-Duk Choi, In-Jae Oh, Jung-Eun Lee, Shin Yup Lee, Tae-Won Jang, Jeong-Seon Ryu, Young-Chul Kim. A prospective observational study evaluating c-MET expression and EGFR gene mutation correlation with erlotinib response in second line treatment for advanced/metastatic non-small cell lung cancer patients [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 2773. doi:10.1158/1538-7445.AM2017-2773
Abstract 2791: CDC25A overexpression is correlated with tumor response to radiotherapy in locally advanced rectal cancer
Authors: Huang Ming-Yii 
Published: July 2017

Abstract
Background. Radiotherapy is increasingly used in preoperative approaches for locally advanced rectal cancer to reduce local recurrence. However, the principal limitation is large variability in response among different individuals due to tumor heterogeneity. In current study, we compared gene expression profiles between radiation responder and non-responder in cancerous tissues to identify radiation-related molecules that can be used to evaluate the tumor response of radiation.
Methods. We investigated five genes (CDC25A, VAV1, TP73, BRCA1 and ZAP70) which were significantly related to prognostic factors (tumor size, advanced stage, invasive depth, lymph node metastasis and differentiation) from 110 colorectal cancer tissues confirmed by membrane array and RT-PCR methods in our previous study. Therefore, we further investigate those protein overexpressions by immunohistochemical stain in pretherapeutic rectal cancerous tissues. The expression profiles were evaluated according to the frequency of positive staining in the cytoplasm and/or nucleus of cancer cells. Its expression was classified as positive in cases with more than 50% positive-stained cells, with other samples being classified as negative. Cancer tissues that expressed scores of + were regarded as the overexpression group, whereas those with scores of negative staining were regarded as the non-overexpression group.
Results. We focused on these 5 genes and validated data with pretherapeutic biopsies from 36 locally advanced rectal cancer patients, and found that overexpression of CDC25A, VAV1 and ZAP70 were correlated with tumor response (P=0.001, 0.033, and 0.016, respectively). The multivariate logistic regressions with adjustment of age, sex and stage, CDC25A overexpression more than 2-fold were significantly correlated with tumor response (OR = 2.667, 95%CI = 1.591-4.470, P=0.03). Positive findings of CDC25A immunohistochemistry stain were also present in the tumor specimens of responders.
Conclusion. We identified radiation-related genes in rectal cancer and demonstrated that CDC25A may play an important role in response to radiotherapy. These findings suggest that CDC25A may be a novel marker for predicting the effectiveness of radiotherapy in clinical patients.
Note: This abstract was not presented at the meeting.
Citation Format: Ming-Yii Huang. CDC25A overexpression is correlated with tumor response to radiotherapy in locally advanced rectal 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 2791. doi:10.1158/1538-7445.AM2017-2791