bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2601: COSMIC-3D: exploring cancer mutations in three dimensions for drug design and discovery
Authors: Jubb Harry C. , Saini Harpreet , Verdonk Marcel , Forbes Simon 
Published: July 2017

Abstract
Explosions in the availability of cancer genomic data and protein structure data give us the potential to explore cancer molecular biology at an unprecedented scale, and in atomic detail. We present COSMIC-3D, which combines COSMIC, the most comprehensive cancer mutation database available (http://cancer.sanger.ac.uk), with the wealth of publicly available 3D protein structure data, to create a resource with which the protein-structural nature of cancer can be probed.
COSMIC-3D will help us understand which cancer mutations drive the progression of cancers, by identifying which are in functional sites that have an effect on driving cell growth and proliferation, and where they are clustered in protein structures across the proteome, for specific cancer types. Through understanding the effects of cancer mutations on known and predicted drug binding sites, we aim to predict potential new drug targets in cancers, and improve the specificity and efficacy of new or existing drugs, by using protein structure with cancer mutation data to guide mutation-specific drug design.
COSMIC-3D is available as a web interface at http://cancer.sanger.ac.uk/cosmic3d, and enables interactive exploration of the cancer mutome in a 3D peptide environment, showing all forms of exonic point mutation. Individual mutant locations can be highlighted as molecular surfaces, while recurrence across nonsynonymous substitutions is visualized as 3D heat-maps. Cancer mutations can also be visualised in combination with precalculated small-molecule “druggable” binding sites, providing a powerful visual approach for development of hypotheses across structural, functional, and drug-resistance impacts of cancer variants. COSMIC-3D shows, for example, the steric occlusion of the binding site of ATP-competitive small-molecule inhibitors in the EGFR kinase domain by the mutation of L858 to arginine; these kinds of insights can be applied to novel cancer targets for any protein-structural mutation of interest.
The human cancer structural proteome comprising COSMIC-3D extends to nearly 8,500 human genes; 1/3rd of genes in COSMIC. Over 30,000 human protein structures are available across these genes, to which over 345,000 cancer mutations are mapped. From structure based druggability prediction, over 6,500 proteins in COSMIC are predicted to have small-molecule druggable binding sites, making COSMIC-3D a powerful and exciting resource for the exploration and guidance of drug design and discovery in oncology.
Citation Format: Harry C. Jubb, Harpreet Saini, Marcel Verdonk, Simon Forbes. COSMIC-3D: exploring cancer mutations in three dimensions for drug design and discovery [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 2601. doi:10.1158/1538-7445.AM2017-2601
Abstract 2611: A crowdsourcing-based clinical trial information curation and searching system
Authors: Yu Pengfei , Song Qingxuan , Han Yang , Hu Guanghui 
Published: July 2017

Abstract
Targeted cancer therapies based on actionable mutations identified are the future of cancer treatment. Besides those approved by the Food and Drug Administration (FDA) for different types of cancers, many other target therapy drugs are in development under different phases of clinical trials. Access to information about these clinical trials is important to health care professionals and patients. Public clinical trials database (www.clinicaltrials.gov) provides a very comprehensive resource for clinicians and researches to search for relevant clinical trials based on different kinds of searching criteria. However, due to the complexity of wording and phasing upon submission, some of the searching results returned by native search engine did not perfectly match the search criteria. Many undesired results are presented with false positives and false negatives when users are searching for clinical trials targeting specific actionable mutations. To tackle this problem, we developed a crowd-sourcing based clinical trial curation and searching system on top of the information extracted from public database. We divide the information extracted from clinicaltrials.gov into three different levels: standard, easy-to-clean and unstructured. With the crowdsourcing approach, our online system can harness the brainpower of biological scientists to translate the most unstructured information such as cancer types, gene mutations into standard format that is easy to be queried. In the searching phase, we combine the aspects of actionable mutation, cancer type, location, and clinical trial phase to select the best matches between patient conditions and clinical trials in our curated database. With the same searching criteria, our system can provide more relevant clinical trials compared with those provided by clinicaltrials.gov. The curation system is currently open to reviewers with eligibility check. And the search engine is publicly available at: https://agis.admerahealth.com/AGIS/ClinTrials/.
Citation Format: Pengfei Yu, Qingxuan Song, Yang Han, Guanghui Hu. A crowdsourcing-based clinical trial information curation and searching system [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 2611. doi:10.1158/1538-7445.AM2017-2611
Abstract 2633: Identification of novel T cell co-inhibitory and co-stimulatory receptors from screening a comprehensive library of extracellular proteins
Authors: Brace Arthur , Sallee Nathan , Chou Justin , Garrenton Lindsay , Chen Diana , Liang Ryan , Kemper Greg , Yang David , Jaquez Marina , Powers Janine , Mkrtichyan Mikayel , Brennan Thomas , Borges Luis 
Published: July 2017

Abstract
Antibody blockade of immune checkpoint regulators such as PD-1 and CTLA-4 has been shown to be an effective cancer treatment strategy; however, a large percentage of patients still do not respond to existing therapies. Discovery of additional immune checkpoints and co-stimulatory receptors and development of antibody therapeutics against them are likely critical to address this unmet patient need. We generated a comprehensive library of essentially all human extracellular proteins and have used this library to screen for new agents that modulate the function of various immune cell subsets both in vitro and in vivo. Using primary T effector and regulatory T cells, we have identified new targets that modulate the activities of these T cell populations in vitro and are currently evaluating these proteins as possible targets for cancer immunotherapy. In addition, we have expressed a subset of the library in three different models of tumor-bearing mice and have identified several proteins that modulate anti-tumor immunity in vivo. Several of the proteins identified in these screens have activity across multiple primary cell and in vivo tumor model screens and we are rapidly evaluating them as possible targets for novel immuno-oncology therapeutics. Taken together, we believe that we have developed robust in vitro and in vivo platforms that will allow us to discover novel cancer immuno-therapeutics that will help address the needs of cancer patients that fail to respond to current immunomodulatory therapies.
Citation Format: Arthur Brace, Nathan Sallee, Justin Chou, Lindsay Garrenton, Diana Chen, Ryan Liang, Greg Kemper, David Yang, Marina Jaquez, Janine Powers, Mikayel Mkrtichyan, Thomas Brennan, Luis Borges. Identification of novel T cell co-inhibitory and co-stimulatory receptors from screening a comprehensive library of extracellular proteins [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 2633. doi:10.1158/1538-7445.AM2017-2633
Abstract 265: Global transition in cardia and non-cardia gastric cancer incidence, 1998-2007
Authors: Shin Aesun , Kim Dalis Seungeun , Woo Hyungtaek 
Published: July 2017

Abstract
Gastric cardia and non-cardia cancer differs in their descriptive patterns and risk factors. The objective of this study was to determine the global trends in incidence of cardiac and non-cardiac gastric cancer. Ninety two high quality registries with the proportion of Not Otherwise Specified (NOS) gastric cancer (ICD-10 code C16.8-9) below 50% and the total number of gastric cancer cases above 300 were selected from 225 registries in Cancer Incidence of Five Continent (CI5) volume 9 and 262 registries from CI5 volume 10. The NOS cases were re-distributed to cardia and non-cardia according to the registry-specific proportion. Age-standardized incidence rates (ASRs) per 100,000 population and incidence rate ratios (IRR) from 1998-2002 to 2003-2007 were calculated. Non-cardia cancer incidence was significantly decreased in 5 out of 10 Asian registries, 17 out of 18 European registries, 27 out of 56 North American registries, and all 5 Oceanian registries in men. Only two registries in Asia showed a significant increase in non-cardia cancer incidence. In contrast, cardia cancer significantly increased in one Asian registry, two European registries, and two North American registries. Significant decrease in cardia cancer was observed in 3 Asian registries, 6 European registries, 11 North American registries, and 3 Oceanian registries in men. In women, six registries (1 Asian, 2 European, and 3 North American) showed significant increase in non-cardia cancer, whereas registries 25 (3 Asian, 13 European, 8 North American, and 1 Oceanian) showed significant decrease in non-cardia cancer incidence. Cardia cancer in women increased in 16 registries (2 Asian and 14 North American) and decreased in 9 registries (1 Asian, 5 European, and 3 North American). In conclusion, non-cardia cancer incidence decreased in most registries, whereas decrease in cardia cancer is more prominent in men but not in women.
Citation Format: Aesun Shin, Dalis Seungeun Kim, Hyungtaek Woo. Global transition in cardia and non-cardia gastric cancer incidence, 1998-2007 [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 265. doi:10.1158/1538-7445.AM2017-265
Abstract 2657: PD-L1 blockade enhances T cell cytotoxicity against primary mediastinal B cell lymphoma
Authors: Shah Tishi , Luo Wen , Awasthi Aradhana , Ayello Janet , Hochberg Jessica , Cairo Mitchell 
Published: July 2017

Abstract
Background:
Primary Mediastinal B cell Lymphoma (PMBL) represents 2-4% of Non-Hodgkin Lymphomas (NHL) in adolescents and young adults (AYA) (Gerrard/Cairo et al., Blood, 2013). Disease progression, relapse and long-term toxicity remain a concern for patients treated on current chemo-immunotherapy and mediastinal radiotherapy. Alternative therapeutic regimens are urgently needed, especially in patients without an early response to therapy. Programmed Death 1 (PD-1) is a negative co-stimulatory receptor critical for suppression of T-cell activation, with binding of PD-1 and Programmed Death Ligand 1 (PD-L1) resulting in T cell exhaustion (Postow/Wolchok et al., J Clin Oncol, 2015). Gain in 9p associated with amplification of PD-L1 has been reported in up to 60% of PMBL specimens, leading to overexpression of PD-L1 and potential immune cell evasion of PMBL (Rosenwald/Staudt et al., J Exp Med, 2003; Twa/Steidl et al., Blood, 2014). Blockade of PD-1/PD-L1 interaction, therefore, constitute a potentially promising alternative for treatment of resistant PMBL.
Objective:
In the current study, we sought to investigate whether PD-L1 blockade enhances T cell responses in PD-L1 expressing PMBL.
Methods:
PD-L1 expression on Karpas 1106p PMBL treated with or without IFN γ was investigated by western blotting and flow cytometry analyses. T cells were isolated from human PBMC followed by activation and expansion using anti-CD2, anti-CD3 and anti-CD28 Biotinylated MACSiBead particles. T cell activation was confirmed by CD25 and CD69 expression using flow cytometry. Activated T cells were incubated with or without anti-PD-L1 (Clone 6E11, Genentech) at a dose of 10 ug/ml together with Karpas 1106p cells treated with or without IFN γ. Cell proliferation was assessed with MTS assays after incubation for 24 hours.
Results:
We demonstrated that Karpas 1106p cells express a low level of PD-L1. However, following IFN γ treatment (48 hours) there was a significant increase in PD-L1 expression. Anti-PD-L1 had no significant effect on T cell mediated inhibition of cell proliferation in Karpas 1106p cells with low PD-L1 expression. However, anti-PD-L1 and T cell treatment significantly inhibited cell proliferation in IFN γ treated Karpas 1106p cells when compared to T cell treatment alone (32±18% vs. 3±3% at E:T=5:1, p=0.048).
Conclusion:
PD-L1 blockade enhances T cell cytotoxicity against PMBL, which is dependent on PD-L1 expression level on PMBL cells. Future in-vivo NSG xenograft studies are ongoing.
Citation Format: Tishi Shah, Wen Luo, Aradhana Awasthi, Janet Ayello, Jessica Hochberg, Mitchell Cairo. PD-L1 blockade enhances T cell cytotoxicity against primary mediastinal B cell lymphoma [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 2657. doi:10.1158/1538-7445.AM2017-2657
Abstract 2660: PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model
Authors: Li Yuan , Du Yang , Sun Ting , Xue Huadan , Tian Jie , Jin Zhengyu 
Published: July 2017

Abstract
Purpose: Blockade of PD-1 receptor may provide proof of concepts for the activity of an immune-modulation approach for the treatment of a breast cancer (BC). Zoledronic acid (ZA) has been proven to inhibit angiogenesis, invasion, and adhesion of tumor cells. The aim of this study was to investigate the potential of antibody treatment towards the T-cell checkpoint inhibitor PD-1 alone or in combination with ZA in BC mouse model.
Experimental Design: The 4T1-Luc mouse mammary tumor model was used in this study. The anti-tumor efficacy of anti-PD-1 antibody alone or in combination with ZA was monitored by measuring tumor volume and bioluminescence imaging (BLI). At the end of study, the tumor immunohistochemistry was performed to confirm the in vivo observation and flow cytometry was used to determine the immune cell population in tumors. The survival rate was also calculated to evaluate the treatment efficacy.
Results: The results showed that mice treated with the combination therapy exhibited the best antitumor response compared to untreated controls or single therapy. Furthermore, Combination therapy inhibited tumor regrowth as determined by BLI imaging, and thus significantly improved the median overall survival compared to other groups.
Conclusions: Our study provides evidence for enhanced clinical BC treatment benefit from targeting co-signal molecules by combining PD-1 blockade with ZA treatment.
Citation Format: Yuan Li, Yang Du, Ting Sun, Huadan Xue, Jie Tian, Zhengyu Jin. PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse 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 2660. doi:10.1158/1538-7445.AM2017-2660
Abstract 2665: Green tea catechin, EGCG, enhances antitumor immunity by down-regulation of PD-L1 expression in non-small human lung cancer cell lines
Authors: Rawangkan Anchalee , Iida Keisuke , Sakai Ryo , Fujiki Hirota , Suganuma Masami 
Published: July 2017

Abstract
(-)-Epigallocatechin gallate (EGCG) is now widely accepted as a non-toxic, effective cancer preventive compound. EGCG also acts as a synergist with anti-cancer drugs for cancer treatment. Considering the wide beneficial effects of EGCG, we think EGCG might have antitumor immunity. Programmed death-ligand 1 (PD-L1) expression on tumor cells is involved in PD-L1/PD-1 pathway. PD-L1 protein levels varied among 6 non-small human lung cancer cell lines (NSCLCs): LC-AI and Lu99 cell lines showed the highest PD-L1 expression, A549 and H322 cell lines were medium, and H1703 and H1299 were very low, independent on cancer cell lines. Since PD-L1 expression is induced by various cytokines and growth factors, we studied the effects of IFN-γ and EGF on cell-surface PD-L1 level using flow cytometry, and its gene expression using RT-PCR. Treatment with IFN-γ dose-dependently stimulated PD-L1 expression in both A549 and H1299 cells, and not effective on Lu99 cells, whereas treatment with EGF stimulated PD-L1 in Lu99 cells only.
Pretreatment with EGCG for 3 h, dose-dependently inhibited INF-γ-induced PD-L1 gene expression and protein level on cell-surface in both A549 and H1299. It is important to note that EGCG also inhibited phosphorylation of STAT1. In addition, EGCG inhibited EGF-induced PD-L1 gene expression and protein level in Lu99 cells via inhibition of phosphorylation of Akt. In order to study the effects of EGCG in between rodent carcinogenesis experiment and antitumor immunity, green tea extract (GTE) was given to NNK-induced lung tumors in A/J mice, which showed significant reduction of PD-L1 protein level, determined by immunohistochemical analysis using anti-PD-L1 antibody. Furthermore, the group treated with NNK + GTE significantly showed reduced number of tumors per mouse from 3.2 to 2.2, and decreased tumor size. Treatment with Wortmannin, a PI3K inhibitor, as a control, did not inhibit PD-L1 expression in A549 and H1299 cells. The results strongly suggest that EGCG enhances antitumor immunity via inhibition of PD-L1 expression in cancer cells, resulting in significant cancer preventive activity.
Citation Format: Anchalee Rawangkan, Keisuke Iida, Ryo Sakai, Hirota Fujiki, Masami Suganuma. Green tea catechin, EGCG, enhances antitumor immunity by down-regulation of PD-L1 expression in non-small human lung cancer cell lines [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 2665. doi:10.1158/1538-7445.AM2017-2665
Abstract 267: GeoSurveillance of invasive cervical cancer incidence by counties in the state of Maryland
Authors: Peprah Sally , Curriero Frank , D'Souza Amber 
Published: July 2017

Abstract
Background: Invasive cervical cancer (ICC) is a highly preventable cancer whose rates have dramatically declined over the past few decades. In spite of the progress made, new ICC cases are recorded annually in Maryland and in other parts of the United Sates. We assessed if ICC incidence varied significantly 2005-2012 and across counties within the state of Maryland.
Methods: Using a discrete Poisson model we evaluated significant space-time clusters of both high and low ICC incidence rates over a retrospective 10-year period. All analyses were conducted at the county level, using 2-year aggregates of time. We adjusted for age, percent minority, cervical cancer screening rates, median income, obesity as well as smoking rates within each county in our final cluster detection
analysis.
Results: ICC was 13.1 per 100,000 female population and did vary by county and over the 10-year period assessed. We identified five significant space-time clusters of ICC incidence, three of which were clusters of higher than expected rates. The most likely cluster identified was a cluster of low ICC incidence [aRR=0.08, p-value&lt;0.01] observed for the period 2009-2012 and comprised six high-income suburban counties. The other cluster of low rate [aRR=0.41, p-value&lt;0.01], which was a secondary cluster, was observed for the same time period, 2009-2012 in three high to moderate-income suburban counties. There were two clusters of high ICC incidence, observed for recent time periods. One cluster [aRR=1.74, p-value&lt;0.01], which was made up of a single moderate to low-income urban county was identified for the period 2009-2012. The other cluster of elevated rates [aRR=2.47, p-value&lt;0.01] was identified in a suburban moderate-income county for the period 2011-2012. Additionally, for the period 2005-2008 we identified a historical cluster of elevated incidence [aRR=2.53, p-value&lt;0.01].
Conclusion: Overtime some counties in Maryland have experienced significantly lower rates of disease than expected. However there are more recent clusters of higher than expected rates of disease, which are not explained by the county level variables adjusted for. These clusters of high rates need to be further examined and addressed.
Citation Format: Sally Peprah, Frank Curriero, Amber D'Souza. GeoSurveillance of invasive cervical cancer incidence by counties in the state of Maryland [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 267. doi:10.1158/1538-7445.AM2017-267
Abstract 2688: Multiplex IHC detection of immune checkpoint receptors in the tumor microenvironment
Authors: Ziello Jennifer E. , Klein Sarah R. , Alonzo Emily , Haack Herbert 
Published: July 2017

Abstract
As immune checkpoint blockade has been shown to partially reverse the exhausted T cell phenotype and consequently lead to a decrease in tumor burden, there is a need for an understanding of this T cell type. Using recently developed, highly validated antibodies, we have developed a fluorescent multiplex, TSA-based assay in order to examine the interaction of PD-L1 with PD-1-expressing exhausted T cells in various tumor types. Here, we construct a seven-color multiplex panel in order to simultaneously visualize cytokeratin (the tumor mask), DAPI (nuclear counterstain), CD8 (cytotoxic T cell marker), the exhausted T cell markers PD-1, Tim-3 and Lag-3, and the ligand for PD-1, PD-L1. This technique not only enabled the concurrent detection of these markers, but also provided high-resolution visualization of interactions between PD-1-expressing CD8+ T cells and PD-L1-expressing CD68+ macrophages in the tumor microenvironment. The seven-plex panel was applied to FFPE tumor microarrays (TMAs) consisting of breast, lung and ovarian tumor tissue and each core was subsequently analyzed for the distribution, co-localization, frequency and proximity of these targets in relation to one another. While we often visualized co-expression of Lag-3 and PD-1 on T cells, Tim-3 was frequently observed on PD-L1+ macrophages in several tumor types. This data provides valuable insight into the co-expression profiles of these markers in multiple tumor types and has implications for the use of combination therapies that aim to target both the innate and adaptive immune systems.
Citation Format: Jennifer E. Ziello, Sarah R. Klein, Emily Alonzo, Herbert Haack. Multiplex IHC detection of immune checkpoint receptors in the tumor microenvironment [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 2688. doi:10.1158/1538-7445.AM2017-2688