bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 599: Smoking-associated AHRR demethylation in cord blood DNA: Impact of CD235a+ nucleated red blood cells
Authors: Bergens Matthew A. , Pittman Gary S. , Thompson Isabel J. , Campbell Michelle R. , Wang Xuting , Wan Ma , Hoyo Cathrine , Bell Douglas A. 
Published: August 2019

Abstract
Prenatal tobacco smoke exposure is associated with numerous adverse health outcomes at birth and in later life. Numerous studies have demonstrated that Aryl Hydrocarbon Receptor Repressor gene (AHRR) hypomethylation in umbilical cord blood is significantly associated with prenatal tobacco smoke exposure and is suitable as a fetal exposure biomarker. The mechanism driving this demethylation and whether all cord blood cell types are impacted is unclear. Nucleated red blood cells (nucleated CD235a+ cells, nRBCs) are developmentally immature RBCs that display genome-wide demethylation and are observed at increased frequency in the cord blood of smoking mothers. We assessed if nRBC counts or methylation level affected smoking-associated DNA methylation in the AHRR gene as measured in whole cord blood. We analyzed methylation in DNA from whole cord blood, CD14+ monocytes, and nRBCs across four AHRR CpGs using pyrosequencing and also with Illumina 850K arrays (cg05575921) from smoking (n=34) and nonsmoking (n=19) mothers. nRBCs present in cord blood were determined by conventional CBCs and also estimated with a Houseman deconvolution model. AHRR methylation levels were significantly lower in nRBCs relative to whole blood and CD14+ monocytes. Methylation values at each AHRR CpG averaged 14.6% lower in nRBCs (range 0.4% to 24%, p=3.9E-13) relative to CD14+ monocytes with nonsmokers displaying significantly greater hypomethylation in nRBCs than smokers. Methylation levels at each CpG across the AHRR DMR were strongly associated with either self-reported smoking or cord blood cotinine levels in both CD14+ monocytes (r2=0.45, p=4.6E-08) and nRBCs (r2=0.26, p=1.2E-04). The most significant prenatal smoking effect on methylation occurred in CD14+ monocytes at the CpG located at chr5:373490 (-16.7%, p=6.7E-09), 112nt downstream of cg05575921. For subjects with 850K data, adjusting a regression analysis model with estimated cell-type composition, including nRBC counts or estimates, marginally increased the magnitude and significance of the prenatal smoke exposure effect on AHRR cg05575921 methylation. Prenatal tobacco smoke exposure strongly affects DNA methylation in the AHRR gene and this prenatal smoke exposure biomarker is largely unaffected by cord blood cell type composition.
Citation Format: Matthew A. Bergens, Gary S. Pittman, Isabel J. Thompson, Michelle R. Campbell, Xuting Wang, Ma Wan, Cathrine Hoyo, Douglas A. Bell. Smoking-associated AHRR demethylation in cord blood DNA: Impact of CD235a+ nucleated red blood cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 599.
Abstract 6: Computationally assisted target screening of STING agonist for immunologic therapy
Authors: Binder Grace A. , Gambino Christine S. , Kharitonova Anna , Metcalf Rainer S. , Daniel Kenyon G. , Guida Wayne C. 
Published: August 2019

Abstract
Stimulator of interferon genes (STING) is a receptor protein involved in the propagation of innate immune sensing of cytosolic DNA through the production of IFN-β. Mechanistic studies have shown IFN-β production within the tumor microenvironment can result in activation of tumor antigen-specific CD8+ T-cell immunity that can lead to tumor regression [1, 2]. STING activation by STING agonists should result in innate T-cell mediated anti-tumor immunity in the tumor microenvironment and have significant potential as a cancer therapeutic. Conversely, inhibition of STING would lead to a decreased production of IFN-β which could have implications in the treatment of autoimmune disease such as lupus erythematosus.
MD equilibrated crystal structures for human HAQ, REF, and WT alleles were clustered to find optimal conformations for diverse chemical library screening. Novel consensus docking protocols utilizing rigid receptor, induced fit, and quantum polarized ligand docking were applied for quantifying and refining proposed binding mechanisms of STING isoforms. Models for STING agonists and antagonists were developed.
From directed virtual screening, a novel low-molecular-weight organic molecule (GF3-002) that is not based on a cyclic dinucleotide was found as a potential STING activator and is currently under investigation.
GF3-002 and analogs were synthesized and structures were confirmed with LCMS and proton NMR. Both the HAQ and WT alleles, representing 78.3% of the human population were tested against compounds and controls. 2,3-cGAMP and DMSO were used as positive and negative controls, respectively. Microscale thermophoresis and SPR confirmed binding of GF3-002 to WT STING CTD with a kD of 3.2 ± 1.7 μM. IFN-dependent luciferase expression was measured by luminescence in THP-1 monocytic leukemia cells and found an EC50 of 29 ± 1.6 μM, compared to the native ligand 2,3-cGAMP EC50 of 42 ± 4.1 μM. Finally, qPCR was used quantify production of IFN-β via treatment of dendritic cells with GF3-002.
1. Sali, Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. 2017.
2. Corrales, L., et al., Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell reports, 2015. 11(7): p. 1018-1030.
Citation Format: Grace A. Binder, Christine S. Gambino, Anna Kharitonova, Rainer S. Metcalf, Kenyon G. Daniel, Wayne C. Guida. Computationally assisted target screening of STING agonist for immunologic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 6.
Abstract 633: Association between saturated fat intakes and lung cancer risk among low-income populations in the Southeastern United States
Authors: Yoon Hyung-Suk , Cai Hui , Yang Jae Jeong , Yu Danxia , Murff Harvey J. , Shu Xiao Ou , Zheng Wei , Blot William J. , Cai Qiuyin 
Published: August 2019

Abstract
Background: Lung cancer is the leading cause of cancer death in the United States. Previous studies have indicated that a higher intake of dietary saturated fat was associated with lung cancer risk. However, little is known about the association of specific classes of saturated fat with the risk of lung cancer. We conducted a nested case-control study to investigate the association of different classes of saturated fat with lung cancer risk among low-income African Americans (AAs) and European Americans (EAs) in the Southeastern United States.
Methods: A total of 1,528 incident lung cancer cases and 5,699 matched controls from the Southern Community Cohort Study were included in this study. The controls were matched to the cases on age, sex, race, and recruitment site. Using validated food frequency questionnaires, saturated fat was estimated and classed to short-chain (SCSF, 2-4 carbon atoms), medium-chain (MCSF, 6-12 carbon atoms), and long-chain (LCSF, 14-18 carbon atoms). Multivariate logistic regression models were used to estimate odds ratios (ORs) and corresponding confidence intervals (95% CIs) for lung cancer risk associated with saturated fat after adjusting for age, smoking status, pack-years, alcohol consumption, total energy intake, education, household income, body mass index (BMI), and history of chronic obstructive pulmonary disease (COPD).
Results: Total saturated fat intakes were associated with an increased lung cancer risk among EAs with an OR of 1.66 (95% CI: 1.06-2.60) for the highest vs. lowest quartiles (p-trend=0.03). The positive association was only observed for LCSF (highest vs. lowest quartile: OR=1.68, 95% CI: 1.07-2.64 for palmitic acid; OR=1.60, 95% CI 1.02-2.53 for stearic acid; and OR=1.63, 95% CI 1.04-2.56 for total LCSF; all p-trends&lt;0.05). The association was more evident among heavy smokers, which was defined as smoke ≥ 30 pack-years, and for adenocarcinoma subtype. No association between saturated fat intakes with lung cancer risk were observed among AAs. In addition, no association between lung cancer risk and SCSF or MCSF was observed in our study.
Conclusion: Our findings indicate that a high intake of LCSF was associated with an increased risk of lung cancer among low-income EAs. Further studies are needed to confirm our findings.
Citation Format: Hyung-Suk Yoon, Hui Cai, Jae Jeong Yang, Danxia Yu, Harvey J. Murff, Xiao Ou Shu, Wei Zheng, William J. Blot, Qiuyin Cai. Association between saturated fat intakes and lung cancer risk among low-income populations in the Southeastern United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 633.
Abstract 648: Effects of bazedoxifene and lapatinib in the prevention of estrogen receptor positive (ER+) and negative (ER-) mammary cancers
Authors: Grubbs Clinton J. , Mohammed Altaf , Sei Shizuko , Shoemaker Robert H. 
Published: August 2019

Abstract
Bazedoxifene is a third-generation selective estrogen receptor modulator (SERM) that has been clinically approved in Europe for the prevention and treatment of postmenopausal osteoporosis. Our research previously showed that this agent (at a dose of 5 mg/kg diet) would decrease ER+ mammary cancers in rats by 73%. Lapatinib, an epidermal growth factor receptor (EGFR) inhibitor, is commonly used to treat patients with HER2+ breast cancer. We have also shown that the compound inhibits the development of ER+ mammary cancers in rats and ER- mammary cancers in mice at a dose of 75 mg/kg BW/day. The present studies were done to determine if lower doses and different treatment regimens designed to reduce possible toxicity would also be effective in preventing mammary cancers. Bazeodxifene was added directly to the diet (Teklad, 4% fat), while lapatinib was given by oral gavage. When evaluated in rats receiving methylnitrosourea (MNU), lapatinib given daily at doses of 75, 50 and 25 mg/kg BW/day reduced mammary cancer multiplicity by 93, 84 and 67%, respectively. Equivalent doses given 1x/week caused reductions of 87, 56, and 40%. When lapatinib was given to dimethylbenzanthracene (DMBA) treated MMTV/Neu mice at dose levels of 250, 125, and 63 mg/kg BW, 5x/week, mammary cancer multiplicity was reduced by 89, 60 and 80%, respectively. When equivalent doses were given 1x/week, the number of cancers were reduced by 82, 61, and 70%. Bazedoxifene given at 5.0 and 2.5 mg/kg diet to female MMTV/Neu mice also receiving DMBA caused reduction of mammary cancers by 73 and 51%. In a biomarker study lasting two weeks, bazedoxifene at the 5.0 mg/kg BW/day dose decreased the proliferation rate of normal mammary epithelial cells in MMTV/Neu mice by 60%. Additional studies to determine why this SERM is having a preventive effect against ER- mammary cancers are warranted. Studies to evaluate the efficacy of the combination of low doses of bazedoxifene and lapatinib in prevention of ER+ and ER- mammary cancers are in progress and will be presented.
Supported by the NCI contract number HHSN261201500036I, Task Order HHSN26100005.
Citation Format: Clinton J. Grubbs, Altaf Mohammed, Shizuko Sei, Robert H. Shoemaker. Effects of bazedoxifene and lapatinib in the prevention of estrogen receptor positive (ER+) and negative (ER-) mammary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 648.
Abstract 667: A mouse model of APOE to define effects of doxorubicin on cognition
Authors: Demby Tamar C. , Lee Yichien , Rodriguez Olga , Albanese Christopher , Mandelblatt Jeanne , Rebeck G. William 
Published: August 2019

Abstract
The purpose of this study was to establish the effects of Apolipoprotein E (APOE) genotype on cognitive function following doxorubicin treatment in a mouse model. Chemotherapy treatment can lead to cognitive impairment in cancer survivors, and, in older breast cancer survivors, APOE4 carriers have been shown to have higher risk for these impairments. Though APOE4 genotype is known as the strongest genetic risk factor for late-onset Alzheimer’s Disease compared to the APOE2 and APOE3 alleles, its effects on cognitive outcomes following treatment with common breast cancer chemotherapeutics are not yet well characterized. One year old female mice with targeted replacement of human APOE3 or APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or saline. Five weeks following treatment, spatial learning and memory was tested using the Barnes Maze. In APOE3 mice, doxorubicin treatment left spatial learning and memory intact. In APOE4 mice, doxorubicin treatment lead to impairment in spatial learning over the four days of training. This represents a promising model for studying the mechanisms behind cognitive impairment following doxorubicin treatment in a genetically vulnerable population.
Citation Format: Tamar C. Demby, Yichien Lee, Olga Rodriguez, Christopher Albanese, Jeanne Mandelblatt, G. William Rebeck. A mouse model of APOE to define effects of doxorubicin on cognition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 667.
Abstract 674: Predicting cellular response to therapy in breast cancer using mathematical modeling
Authors: He Wei , Demas Diane M. , Conde Isabel , Fallah Yassi , Baumann William T. , Shajahan-Haq Ayesha N. 
Published: August 2019

Abstract
About 70% of all breast cancer tumors are estrogen receptor positive (ER+) and are treated with antiestrogen therapies. While the inevitability of developing resistance to these therapies remains uncontested, little is known about the mechanism and prevention of resistance. Our ultimate goal is to use mathematical modeling to optimize dynamic therapies that decrease proliferation and stave off resistance. In this initial study, we used MCF7 cells as a model of ER+ breast cancer and estrogen deprivation as a surrogate for aromatase inhibitors. We developed long-term estrogen deprived MCF7s (LTEDs) that proliferate similarly to untreated MCF7s but are resistant to antiestrogens. We collected time-course data for simultaneous gene expression and protein levels (NanoString Pan Cancer panel, a non-amplification based digital method) over 6 weeks to capture early molecular adaptations of deprived MCF7s and compare them to those present in LTEDs. PCA analysis of the mRNA and protein data shows a dramatic change in the first component due to estrogen deprivation, and a dramatic change in the second component associated with long-term resistance. Correlation analysis shows a large number of cell cycle genes that are similarly regulated, decreasing with estrogen deprivation and increasing with the onset of resistance. There is also a highly-correlated group of genes associated with resistance. This knowledge allowed us to hypothesize a molecular mechanism for resistance that can be tested experimentally. To begin building a dynamic model, we measured a 7-day time course of estrogen related proteins. The model is built around ER signaling and the cell cycle, and simulates protein and proliferation changes in response to deprivation and antiestrogen (ICI182,780; ICI) treatment. To determine which treatments to model in addition to estrogen deprivation and ICI, we looked for a promising sequential therapy to limit proliferation and, hopefully, stave off resistance compared to a single non-stop therapy. We found that alternating the targeting of CDK4/6 using Palbociclib (clinical anti-cancer therapy) with targeting of RUNX1 (gene that is increased at the onset of resistance in our model), could be a plausible strategy to inhibit endocrine resistance. Future work will involve extending the model to longer time scales and using it for treatment optimization.
Citation Format: Wei He, Diane M. Demas, Isabel Conde, Yassi Fallah, William T. Baumann, Ayesha N. Shajahan-Haq. Predicting cellular response to therapy in breast cancer using mathematical modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 674.
Abstract 685: Development of a multiscale QSP model to characterize the tumor suppressive effects of a cytokine mRNA immunotherapy in a preclinical melanoma mouse model
Authors: Pierre Kamau , Lin Lin , Gruenbaum Lore , Young Carissa , Apgar Joshua , Hotz Christian , Wagenaar Timothy , Stamatelos Spyros K. 
Published: August 2019

Abstract
Despite the success of checkpoint blockade immunotherapy, most patients do not respond adequately to treatment and tumors effectively evade T lymphocyte and Natural Killer (NK) cell immune surveillance. Within the tumor microenvironment, the activities of immune cells are regulated by a multitude of signals including the local cytokine milieu. Intratumoral administration of our cytokine mRNA cocktail therapy, consisting of transcripts encoding for IL-12sc, IFNα2b, IL-15sushi and GM-CSF, has induced regression in tumor-bearing mice. Leveraging in vitro, in vivo and in silico data, we have developed a QSP platform that captures the observed preclinical tumor responses and allows for systemic predictions under a variety of conditions. A 5-compartment model was employed to account for the pharmacokinetics, cellular interactions and signaling within the tumor, lymph node, peritoneum, blood and periphery. We model the intratumoral (i.t.) injection of the mRNA mixture and its subsequent uptake, translation and secretion of activated cytokines that induce an immune response. Specifically, when released into the tumor, these cytokines promote tumor killing and trigger the activation and proliferation of CD4+/CD8+ T lymphocytes and NK cells. The model’s simulation results are well aligned with our preclinical data; indicating increased tumor regression with escalating doses of the mRNA monotherapy. The wealth of data and the intertwined information derived from the interaction of receptors and ligands defining the T cell phenotype necessitate a systems approach in order to identify suitable targets and mechanisms of drug action. Our murine immuno-oncology QSP model could be translated across species and be used as part of a computational platform to test various assets with similar MoA.
Citation Format: Kamau Pierre, Lin Lin, Lore Gruenbaum, Carissa Young, Joshua Apgar, Christian Hotz, Timothy Wagenaar, Spyros K. Stamatelos. Development of a multiscale QSP model to characterize the tumor suppressive effects of a cytokine mRNA immunotherapy in a preclinical melanoma mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 685.
Abstract 686: Quantitative analysis of the role of homologous recombination in response to radiotherapy for prostate cancer
Authors: Qian Mengdi , Almasan Alexandru , Gürkan-Çavusoglu Evren 
Published: August 2019

Abstract
The purpose of this study is to computationally analyze how the interaction between androgen receptor (AR) and homologous recombination (HR) affects the treatment outcome for ionizing radiation (IR) combined with androgen deprivation therapy (ADT) for prostate cancer (PCa). Combination treatment with radiation and ADT is currently a standard treatment for PCa. The effectiveness of radiation treatment alone depends on the cells’ capacity to repair the damage that is mostly in the form of double-strand breaks (DSBs). Two major pathways that repair DSBs are non-homologous end joining (NHEJ) and HR. The experimental data in the literature show that AR promotes both NHEJ and HR following IR, and inhibition of AR by ADT impairs both of these pathways in PCa cells leading to either increased radiosensitivity or sensitization to PARP inhibitors. In our previous work, we developed mathematical models of the NHEJ pathway and in this current work we have developed such models for HR to comprehensively analyze the response of PCa cells to IR combined with ADT. We have modeled HR using a series of ordinary differential equations. The parameters that needed to be estimated are the kinetic rate constants, and we have used least square estimation to obtain these model parameters. The data sets used in the parameter estimation were obtained from the literature and they were from both in vitro experiments as well as clinical data from PCa patients. The experimental data show that AR influences the DNA end resection that is required for proficient HR and we have computationally included this effect in the kinetics of the models. We have developed models for IR treatment alone or in combination with ADT. We have carried out sensitivity analysis and identifiability tests on all the parameters from both models in order to determine the parameters that are reliably estimated. The outputs from both NHEJ and HR models show that the suppression of AR activity through ADT has the potential to enhance the IR treatment outcomes for PCa patients. The impairment of HR by ADT also opens up an avenue for achieving synthetic lethality using PARP inhibitors as shown in the literature; in the future we are planning to extend our modeling efforts to include the effect of PARP inhibitors on the treatment outcome.
Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu. Quantitative analysis of the role of homologous recombination in response to radiotherapy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 686.