bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3196: Analysis of taxane drug target engagement of microtubules in circulating tumor cells from metastatic castration resistant prostate cancer patients treated with CRLX301, a nanoparticle of docetaxel
Authors: Mukhtar Eiman , Worroll Daniel , Galletti Giuseppe , Schuster Shelly , Piha-Paul Sarina A. , Giannakakou Paraskevi 
Published: September 2020

Abstract
We reviewed the radiographic response of three patients with metastatic castration-resistant prostate cancer (mCRPC) treated with CRLX301, a docetaxel nanoparticle. For these three patients, we isolated and analyzed circulating tumor cells (CTC) to explore microtubule (MT) drug-target engagement (MT-DTE) as a biomarker of response to treatment. We quantitatively assessed the MT cytoskeleton in CTCs from pre- and post-treatment patient samples as a potential read-out of CRLX301 activity. We isolated CTCs using negative CD45+ depletion and subjected them to multiplex confocal microscopy using our established protocol. CTCs were identified as CD45-/CK+/DAPI+ cells and MT-DTE was determined using our developed, semi-high-throughput, high-content imaging algorithm to quantify MT bundling in CTCs across multiple time points, from baseline to on-treatment to disease progression. We collected CTCs at seven time points from three mCRPC patients. Clinical response was evaluated by RECIST v.1.1 criteria in those patients with measurable disease. Of the three patients who received CRLX301, one experienced partial response and two patients were unevaluable per RECIST given bone only disease, however showed stable disease clinically per bone scans. MT-DTE across all time points revealed that, early time points within four and 24 hours of drug administration exhibited the highest levels of drug engagement as compared to baseline but did not discriminate the responding patient from the patients with stable disease. However, the limited sample size makes this an observation that warrants validation in a larger cohort of patients. We observed that the CTCs collected one week after the first or second dose of CRLX301 treatment in the responding patient had numerically higher levels of MT-DTE as compared to the other two patients. MT-DTE can be detected and analyzed quantitatively in CTCs by tubulin immunofluorescence. The clinical utility of the 1-week CTC DTE should be tested and validated in future clinical trials involving nanoparticle formulations of taxanes or taxanes in general.
Citation Format: Eiman Mukhtar, Daniel Worroll, Giuseppe Galletti, Shelly Schuster, Sarina A. Piha-Paul, Paraskevi Giannakakou. Analysis of taxane drug target engagement of microtubules in circulating tumor cells from metastatic castration resistant prostate cancer patients treated with CRLX301, a nanoparticle of docetaxel [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 3196.
Abstract 3213: DIAS, the COSMIC data integration and annotation system
Authors: Boutselakis Charalampos , Kok Chai , Harsha Bhavana , Bindal Nidhi , Wang Shicai , Yong Siew-Yit , Cole Charlotte , Sondka Zbyslaw , Forbes Simon 
Published: September 2020

Abstract
COSMIC, the catalog of somatic mutations in cancer (https://cancer.sanger.ac.uk/) is the leading and most comprehensive global genetic resource for the exploration of somatic variation across all forms of human cancer. Since the initial inception of COSMIC 15 years ago, cancer genetics have seen substantial changes. Maintaining interoperability between COSMIC and various bioinformatics resources across the globe is a non-trivial task. Resources update at different intervals and as information is interdependent is difficult to keep synchronized. Standardization and adherence to FAIR principles have fueled the development of COSMIC DIAS (Data Integration and Annotation System).For all variants where the genomic location is known, DIAS using the ensembl VEP (Variant Effect Predictor) has ensured the re-annotation of all COSMIC variants, for all available genes and transcripts to a specific ensembl version, independently and for both the GRCh37 and GRCh38 assemblies. From release v90 we have created new stable cosmic genomic identifiers (COSV) for all simple nucleotide variants which point to the corresponding locations on the reference genome. A flip mechanism has been developed that maps the same COSV identifier to both GRCh37 and GRCh38 assemblies, easily searchable from the COSMIC website. The legacy COSM and COSN identifiers have been mapped to the COSV genomic identifiers for backwards compatibility. Additionally, where redundant variants have been identified, these were merged and website redirection has been implemented. Standardized variant annotations have been utilized that adhere to the most recent HGVS recommendations on genomic, transcriptomic and proteomic syntaxes.The cross-references between COSMIC genes and other widely-used databases, such as HGNC, RefSeq, UniProt and CCDS, have been updated and kept up-to-date.Curated cross references between COSMIC phenotypes, NCI terminologies and EFO codes are also available.All the information stored in COSMIC is easily accessible by the website where users are able to explore cancer genomics in high resolution, with the various views available in downloadable formats with a simple click (https://cancer.sanger.ac.uk/cosmic/download).The DIAS system, minimized redundancy of variants, and enhanced the interoperability of COSMIC with other variation resources enabling more precise analysis and easier integration with in-house systems for our users.
Citation Format: Charalampos Boutselakis, Chai Kok, Bhavana Harsha, Nidhi Bindal, Shicai Wang, Siew-Yit Yong, Charlotte Cole, Zbyslaw Sondka, Simon Forbes. DIAS, the COSMIC data integration and annotation system [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 3213.
Abstract 3217: An integrated web server for multi-omics data deconvolution
Authors: Lu Xiaoyu , Dang Pengtao , Tu Szu-Wei , Chang Wennan , Wan Changlin , Zhang Chi , Cao Sha 
Published: September 2020

Abstract
Tissue data deconvolution has been broadly utilized to characterize the variation of cell components and their relative abundance in cancer tumor microenvironment. Numerous deconvolution methods have been developed with different mathematical and biological considerations. Our previous studies have derived a rigorous mathematical condition for a less biased deconvolution. We have demonstrated a cell type can be reliably inferred from an omics data only of the cell type is with distinct signature genes, i.e., the cell type specific expression signature of the selected marker genes of all cell types are orthogonal or at least non-positively associated with each other, which is named as strong or weak “identifiable” conditions. Our analysis suggests the identifiability of a certain cell type is mostly determined by the significance of its gene markers, which is data set and tissue microenvironment dependent. However, such data set specificity has been commonly ignored in existing methods.
In this study, we developed a comprehensive web server, namely ISMD (an Integrated web Server for Multi-omics data Deconvolution), to recommend a best deconvolution method and optimize the gene markers and cell types in analyzing a specific data set. The server solved to two fundamental challenges in the practical application of deconvolution methods, namely (1) method selection and (2) parameter optimization. Specifically, ISMD utilized a semi-supervised approach for method recommendation and parameter optimization, which first evaluate the species, sample size, and tissue type of a given data set and test the low rank structure of commonly used cell type specific markers for cell type and signature gene selection. ISMD can handle the blood, normal, inflammatory, and cancer tissue, and central nervous and hematopoietic systems of human and mouse. The semi-supervised knowledge transfer encoded in ISMD enables its application to multi-omics data including general transcriptomics, ATAC-seq and DNA-methylation data. The method has been validated by using a large collection of tissue samples. A user friend web-server has been released through https://github.com/xiaoyulu95/ISMD. We anticipate ISMD can help to increase the specificity and rigorousness in the application of tissue deconvolution methods, to bring more insights of the role of different cell types and their interactions and stimulate the discovery of new therapeutic targets in a tumor micro-environment.
Citation Format: Xiaoyu Lu, Pengtao Dang, Szu-Wei Tu, Wennan Chang, Changlin Wan, Chi Zhang, Sha Cao. An integrated web server for multi-omics data deconvolution [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 3217.
Abstract 3272: Is PD-L1 expression a decision-making biomarker for immunotherapy: a meta-analysis and cross-sectional study
Authors: Wang Zhijie , Duan Jianchun , Cui Longgang , Cai Shangli , Wang Jie 
Published: September 2020

Abstract
Background: PD-L1 expression has been approved by FDA as a diagnosis for anti-PD-(L)1 therapy in several types of cancer, however, there were still discrepancies of the predictive value of PD-L1 expression. Here we aimed to systematically assess the value of PD-L1 expression in determining cancer patients who should be offered anti-PD-(L)1 therapy and to characterize PD-L1 expression in Chinese cancer population.
Methods: Cochrane library, PubMed and Embase databases were systematically searched to include relevant studies published between January 2000 and June 2019. We also reviewed the reports from all major conference proceedings. All randomized controlled trials investigating anti-PD-(L)1 efficacy in solid tumors were initially included if overall survival (OS) data were stratified by PD-L1 expression. Differences in OS benefits between PD-L1-positive and PD-L1-negative patients were analyzed. Effect size derived from each study was pooled using a random-effects model. Data regarding PD-L1 expression in Chinese patients were obtained from a CAP-accredited and CLIA-certified laboratory.
Results: Twenty-five RCTs involving 14,471 patients were included. OS benefit was observed in patients with either positive (HR=0.68 [0.63-0.73], P&lt;0.00001) or negative (HR=0.86 [0.78-0.95], P=0.003) PD-L1 expression, though significant longer OS was achieved in patients that are PD-L1 positive (P interaction=0.0001). Superior PFS were observed in patients with positive PD-L1 expression (HR=0.69 [0.57-0.82]) while not with negative PD-L1 expression (HR=1.00 [0.85-1.19]). PD-L1-positive patients exhibited significantly improved ORR than those who tested negative for PD-L1 when treated with immunotherapy (OR=0.50 [0.39-0.65], P&lt;0.00001), while no differences were observed among patients given SOC (OR=1.02 [0.86-1.21], P=0.81). Analysis of Chinese patients PD-L1 status revealed that thymoma and small cell lung cancer expressed the highest and the lowest levels of PD-L1, respectively.
Conclusion: PD-L1 expression alone is not determinative in patient selection for anti-PD-(L)1 treatment. Multiple modality biomarkers should be considered for cancer patients especially for those with PD-L1-negative tumors.
Citation Format: Zhijie Wang, Jianchun Duan, Longgang Cui, Shangli Cai, Jie Wang. Is PD-L1 expression a decision-making biomarker for immunotherapy: a meta-analysis and cross-sectional study [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 3272.
Abstract 3313: iPSC-derived natural killer cells expressing EGFR-CAR against glioblastoma
Authors: Yu Melissa , Mansour Anthony G. , Teng Kun-Yu , Sun Guoqiang , Shi Yanhong , Caligiuri Michael A. 
Published: September 2020

Abstract
Background: Natural Killer (NK) cells are a type of immune cells that belong to the innate immune system and executes a rapid immune reaction against cancer cells and viruses without prior activation. The huge success of chimeric antigen receptor (CAR)-T cells has motivated scientists to genetically modify human NK cells with CARs to further improve their tumor killing capacity. To engineer NK cells with a CAR, NK cells can be isolated from peripheral blood and umbilical cord blood. NK cells can also be derived from induced pluripotent stem cells (iPSCs) to produce a homogenous and standardized group of NK cells for the treatment of cancer. Here, we test the feasibility to engineer our EGFR-CAR construct into iPSC-derived hematopoietic stem cells (iPSC-HSC) to generate EGFR-CAR NK cells that will eradicate glioblastoma (GBM).
Material and Methods: iPSCs-derived HSCs were differentiated into NK cells using co-culture with a feeder stroma of OP9-DL1 cells in the presence of human cytokines and NK cells were assessed by flow cytometry. Expanded NK cells (with K562 feeder cells expressing mb-IL-21 and 4-1BB) and HSCs from peripheral blood were efficiently transduced with a retroviral vector, carrying a CAR targeting EGFR. CAR expression was assessed by flow cytometry. After transduction, the CAR-NK cells were collected for cytotoxicity assay to test their efficacy. CAR-HSCs were differentiated into CAR-NK cells utilizing OP9-DL1 stroma cells.
Results: Our results demonstrated that iPSCs can be fully differentiated into NK cells expressing typical NK cell surface markers including CD56, NKp46, CD16 and NKG2A, etc. In addition, HSCs can be engineered with EGFR-CAR without affecting their differentiation into CAR-NK cells. Our engineered EGFR-CAR NK cells showed an enhanced antitumor activity against GBM compared to NK cells without the EGFR-CAR.
Conclusion: Collectively, our study suggests the feasibility of engineering CAR-EGFR NK cells from iPSCs for effective “off the shelf” immunotherapy. Our approach can be utilized to generate an unlimited number of CAR-NK cells to treat patients with cancer such as GBM in the clinical setting.
Citation Format: Melissa Yu, Anthony G. Mansour, Kun-Yu Teng, Guoqiang Sun, Yanhong Shi, Michael A. Caligiuri. iPSC-derived natural killer cells expressing EGFR-CAR against glioblastoma [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 3313.
Abstract 3364: Preclinical evaluation of BiTE®immune therapy targeting MUC17 or CLDN18.2 for gastric cancer
Authors: Bailis Julie M. , Lutterbuese Petra , Thomas Oliver , Locher Kathrin , Harrold John , Boyle Michael , Wahl Joachim , Li Shyun , Sternjak Alexander , Henn Anja , Dahlhoff Christoph , Naegele Virginie , Rattel Benno , Raum Tobias , Coxon Angela 
Published: September 2020

Abstract
Advanced gastric cancer remains a disease of high unmet medical need. In the United States, most patients present with symptomatic, incurable disease and prognosis is poor, with a 5-year survival rate of less than 10%. BiTE® (bispecific T cell engager) immune therapy activates a patient's own T cells to kill tumor cells and has the potential to overcome common mechanisms of therapy resistance. We generated fully human, half-life extended (HLE) BiTE® molecules against the tumor antigens MUC17 and CLDN18.2 for the treatment of gastric cancer. The mucin MUC17 is a protein normally found in the mucosal layer of intestinal epithelial cells that is delocalized and expressed in 45% of gastric tumors. The claudin CLDN18.2 is a protein normally found in the cellular tight junctions of gastric mucosa and intestinal epithelium that is delocalized and expressed in &gt;60% of gastric tumors. AMG 199 (MUC17 HLE BiTE®) and AMG 910 (CLDN18.2 HLE BiTE®) show potent cytotoxic activity against gastric cancer cell lines that express MUC17 or CLDN18.2, respectively, in vitro, and promote significant tumor growth inhibition against established gastric tumor xenograft models in vivo. In preclinical non-human primate (NHP) toxicology studies, both molecules show evidence for BiTE® target engagement, including T cell activation and proliferation, but demonstrate different effects on target-expressing tissue. Weekly administration of AMG 199 is well tolerated in NHP with minimal findings in MUC17-expressing normal tissues. In contrast, treatment with AMG 910 led to direct cell killing of CLDN18.2-expressing gastric mucosal cells in NHP, a finding which was fully reversible once treatment was stopped. AMG 199 and AMG 910 may offer the potential to improve outcomes in advanced gastric patients worldwide.
Citation Format: Julie M. Bailis, Petra Lutterbuese, Oliver Thomas, Kathrin Locher, John Harrold, Michael Boyle, Joachim Wahl, Shyun Li, Alexander Sternjak, Anja Henn, Christoph Dahlhoff, Virginie Naegele, Benno Rattel, Tobias Raum, Angela Coxon. Preclinical evaluation of BiTE®immune therapy targeting MUC17 or CLDN18.2 for gastric cancer [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 3364.
Abstract 3415: Mutant BRAF small molecule inhibition enhances oncolytic herpes virus immunotherapy through increased immune cell recruitment and activation in melanoma
Authors: Bozhanova Galabina , Jennings Victoria , Pedersen Malin , Kyula Joan , Patin Emmanuel , Hassan Jehanne , Ono Masahiro , Harrington Kevin , Melcher Alan 
Published: September 2020

Abstract
Small molecule inhibitors of the MAPK pathway have demonstrated rapid responses in melanoma patients, but their use is hindered by the frequent development of acquired resistance. Oncolytic viruses are a novel class of immunotherapeutics which selectively replicate inside cancer cells, causing lysis and subsequent activation of anti-tumor immunity. BRAF and MEK inhibitors have previously been shown to synergise with oncolytic viruses to kill melanoma cells, but the consequences of these interactions on immune responses have not been assessed. Here, we show that the combination of PLX4720 (BRAFV600E inhibitor) and intratumoral oncolytic herpes virus HSV1716 led to a significant tumor reduction and improved survival over single-agent treatment in a murine BRAFV600E melanoma model. The combination led to a significant increase of PD-L1+ neutrophils and monocytes at an early time point following therapy administration, suggesting an inflammatory switch in the tumor microenvironment. Importantly, the combination led to a significant increase in cytotoxic CD8+ cells at a later time point, which was accompanied by an increase in CD25+ Foxp3+ T-regulatory (Treg) cells. Addition of an anti-CD25 antibody to the PLX4720/HSV1716 doublet led to complete eradication of melanoma tumors in vivo. Current efforts are focused on deciphering T-cell dynamics during this therapy using a novel technology, Timer of cell kinetics and activity (Tocky). Tocky uses a fluorescent Timer protein which spontaneously changes its emission spectrum from blue to red, reporting real-time activation of the T-cell receptor and subsequent activation of immune cells in vivo. Using Tocky, we are identifying specific immune subsets that are stimulated following therapy and the real-time dynamics of antigen recognition and subsequent cell activation. These findings form the basis of future testing of drug-virus combinations in an effort to identify potent cytotoxic, as well as immuno-modulatory, strategies and their detailed mechanism of action.
Citation Format: Galabina Bozhanova, Victoria Jennings, Malin Pedersen, Joan Kyula, Emmanuel Patin, Jehanne Hassan, Masahiro Ono, Kevin Harrington, Alan Melcher. Mutant BRAF small molecule inhibition enhances oncolytic herpes virus immunotherapy through increased immune cell recruitment and activation in melanoma [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 3415.
Abstract 3460: Effects of feeding soy protein isolate diet on hepatic methylation and oxidative stress in DMBA-induced mammary tumor in obese rat model
Authors: Hakkak Reza , Melnyk Stepan , Korourian Soheila 
Published: September 2020

Abstract
The obesity epidemic is in the United States and world for past two decades. There is a link between obesity and chronic diseases development such as diabetes, cardiovascular disease and certain types of cancers including breast cancer. Obesity has a significant impact on the metabolic profiles for a variety of cellular-tissue-organ levels in animals and humans. The objective of this study was to determine the effects of obesity and a soy protein isolate (SPI) diet on liver methylation and oxidative stress using 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor model. We hypothesize that SPI diet is capable to reduce the liver damage by reducing oxidative stress and modifying methylation status. After one week of acclimation, five weeks old female lean and obese Zucker rats were randomly fed AIN-93-G diet with either casein (CAS as control) or SPI as source of protein. All rats were orally gavaged at age 50 days with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly and sacrificed 22 weeks post-DMBA treatment. Liver sample metabolites concentrations were measured using HPLC with Electrochemical Detection and LC-MS. Our results shows that: 1) Obesity increased significantly (P&lt;0.001) body weight for both CAS and SPI diets; 2) 69% of the Lean casein rats developed mammary tumors compared to 50% in lean soy group (p= 0.176) and in the obese group, 76% of the soy-fed rats developed mammary tumors compared to 15% (P&lt;0.001) of obese casein- fed rats; 4) Obesity in both diets significantly modify liver methylation and oxidative stress status; 5) lean SPI-fed rats significantly (P&lt;0.025) increased SAM/SAH “methylation ratio” compare to lean CAS-fed rats; 6) obese SPI-fed rats significantly (P&lt;0.001) decrease level of Homocysteine in liver and increase significantly (P&lt;0.001) Methionine/Homocysteine ratio compared CAS obese rats; 7) obesity caused a significant increase in oxidative stress (GSH/GSSG ratio decrease) in liver for both CAS (P&lt;0.004) and SPI (P&lt;0.01) diets and 8) obese SPI fed rats significantly (P&lt;0.02) decreased oxidative in liver (GSH/GSSG ratio increase) compared to obese CAS fed rats. In summary, we found that SPI diet capable make significant impact on methylation status by increasing a “methylation ratio”, decrease level of toxic intracellular compound homocysteine, and improving redox environment in liver triggered by obesity in mammary tumor model.
Citation Format: Reza Hakkak, Stepan Melnyk, Soheila Korourian. Effects of feeding soy protein isolate diet on hepatic methylation and oxidative stress in DMBA-induced mammary tumor in obese rat model [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 3460.