bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3255: A novel small molecule inhibitor of AhR suppresses the polarization and activity of M2 macrophages
Authors: Garcia Candy , Lemar Hadia , Galang Christina , Joseph James , Gonzalez-Lopez Marcos , Hager Jeffrey , Dillon Michael P. , Aswad Fred J. 
Published: August 2019

Abstract
Tumor associated macrophages, mainly represented by the M2-like phenotype, are a highly immunosuppressive macrophage subset that exert a pro-tumorigenic role in a variety of cancer types. Understanding the factors that promote M2 macrophage differentiation and activity is of critical importance to unlocking the potential of anti-tumor immune therapy. Thus, we investigated the role of the AhR pathway in M2 macrophages. We found the Aryl Hydrocarbon Receptor (AhR) highly expressed in in vitro polarized human M2 macrophages derived from peripheral blood mononuclear cells. Stimulation of AhR with small molecule agonists TCDD or kynurenine resulted in a significant enhancement of the suppressive activity of M2 macrophages on anti-CD3/CD28 stimulated CD4 T cell proliferation and IFNγ production. Inhibition of AhR using a novel, highly potent and selective AhR inhibitor (IDE-AhRi-1) fully inhibited the suppressive activity of M2 macrophages on T cells. Surprisingly, stimulated CD4 T cells co-cultured with IDE-AhRi-1 exposed M2 macrophages had an enhanced ability to proliferate and produce IFNγ compared with stimulated T cells in the absence of M2 macrophages. This suggests that IDE-AhRi-1 not only inhibits the suppressive mechanisms of M2 macrophages, but also boosts their ability to generate pro-inflammatory responses that enhance T-cell activity. Further studies to elucidate the AhR-driven molecular mechanisms responsible for this activity are underway. To find out whether AhR driven M2 polarization and activity is evident in human cancer, we analyzed TCGA-derived RNA sequencing data from an array of solid tumor indications. In a subset of cancer indications, high AhR activity correlated with key M2 macrophage and immuno-regulatory signature genes. Surprisingly, expression of CYP1B1 also correlated with expression of TDO2 mRNA, but not IDO1 mRNA. These finding establish AhR as a key modulator of M2 macrophages and demonstrate a correlation between AhR activity and tumor associated macrophages in human tumor samples. Furthermore, we demonstrate that IDE-AhRi-1 can potently suppress M2 macrophages and propose IDE-AhRi-1 as a novel approach for potentiating anti-tumor immunity.
Citation Format: Candy Garcia, Hadia Lemar, Christina Galang, James Joseph, Marcos Gonzalez-Lopez, Jeffrey Hager, Michael P. Dillon, Fred J. Aswad. A novel small molecule inhibitor of AhR suppresses the polarization and activity of M2 macrophages [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 3255.
Abstract 3267: Cancer immunotherapy by use of FANA ASO therapy to silence Foxp3, impair Treg function and promote anti-tumor immunity
Authors: Hancock Wayne W. , Wang Liqing , Aishwarya Veenu 
Published: August 2019

Abstract
There is an inverse correlation between tumor and draining lymph node infiltration by Foxp3+CD4+CD25+ Treg cells and clinical outcomes in carcinomas of the breast, liver, stomach, ovary, pancreas, and lung, as well as melanomas and glioblastomas. Tregs suppress tumor responses by host CD8 and CD4 T cells, B cells, NK cells, macrophages and dendritic cells. There are currently no effective ways to target Tregs, since toxins (e.g. IL-2-diptheria toxin) and cyclophosphamide have only transient effects with rebound and may also affect conventional T cells, use of CD25 monoclonal antibodies have confounding effects given IL-2 receptor (CD25) expression by activated T cells, and given the phenomenon of “peripheral” conversion (iTreg development) at the tumor site that can allow Tregs to evade therapy. These problems led us explore use of FANA antisense oligonucleotides (ASO) to suppress expression of Foxp3 mRNA. FANA ASO are highly specific and are taken up by cells without use of any delivery agents, conjugates or formulations, making them attractive compounds for cancer drug development. Various Foxp3 sequence-specific or scrambled FANAs were designed, and fluorescently-labeled FANA tested by addition to Foxp3+ Tregs in vitro; these studies showed successful uptake and both cytoplasmic and nuclear localization. FANAs were further screened by assessing effects on Treg suppressive function, and those resulting in 40-50% reductions were assessed for effects on expression of Foxp3 mRNA (qPCR) and protein (Western blots). We next tested the in vivo efficacy of Foxp3 FANA by intravenous or intraperitoneal injection, either daily or twice/week, of Foxp3 FANA, followed by isolation of Tregs from lymphoid tissues. Selected fluorescently-labeled FANA showed Treg uptake, and unlabeled FANA led to &gt;75% reduction in Foxp3 protein expression (flow cytometry, Western blots), and marked reductions in Treg suppressive function. Lastly, we compared the effects of scrambled vs. specific Foxp3 FANA ASO on TC1 lung tumor growth in syngeneic C57BL/6 mice. Compared with mice receiving scrambled FANA ASO, mice receiving specific Foxp3 FANA ASO showed impaired tumor growth, with 50% showing complete tumor elimination (p&lt;0.0001), and markedly reduced Foxp3+CD4+ Treg infiltration (p&lt;0.01). Our data indicate that FANA oligos can modulate Foxp3 expression and Treg function in vitro and in vivo, such that their use may provide an important new approach to cancer immunotherapy.
Citation Format: Wayne W. Hancock, Liqing Wang, Veenu Aishwarya. Cancer immunotherapy by use of FANA ASO therapy to silence Foxp3, impair Treg function and promote anti-tumor immunity [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 3267.
Abstract 3292: Prevalence and socio-behavioral determinants of psychological distress among cancer patients and survivors in the United States, 2010-2015
Authors: Singh Gopal K. , Liu Lihua , Chai Audrey L. , Ung Alexander , Allender Michelle 
Published: August 2019

Abstract
Background: Cancer patients face many unique physical and mental health challenges that directly affect their cancer outcome and quality of life. As cancer treatment improves, the prevalence of long-term cancer survivors increases. However, the psychological well-being of cancer survivors has been largely understudied, which may lead to missed opportunities to improve cancer survivorship.
Methods: Using 2010-2015 National Health Interview Surveys (N=194,757), we examined the prevalence of psychological distress among 17,657 adult cancer patients and survivors and identified the socio-demographic and behavioral correlates in the United States. Differentials in serious psychological distress (SPD, defined by a 6-item scale) and factor-based psychological distress scores (a composite index with a mean of 100 to measure levels of psychological distress) were analyzed by multivariate linear and logistic regression models.
Results: The prevalence of SPD among cancer patients was 4.7% (95% CI: 4.2, 5.1), compared with 3.3% (95% CI: 3.1, 3.4) for the general population without a cancer history or diagnosis. The SPD prevalence was significantly higher among patients diagnosed with stomach, ovarian, cervical, and uterine cancers than the non-cancer population (age-adjusted odds ratio: 3.2, 3.1, 2.9, 2.7, respectively). Patients diagnosed with lung, colorectal, and thyroid cancer also reported significantly higher levels of psychological distress. SPD prevalence and distress index scores were substantially higher among American Indian/Alaska Native, Hispanic, and non-Hispanic (NH) Black cancer patients, compared with NH whites with cancer. Prevalence and levels of psychological distress were significantly greater among cancer patients with low education and income levels, non-professional occupations, unmarried status, functional limitation, and among smokers and physically inactive patients.
Conclusions: Our findings underscore the importance of addressing the psychological well-being of cancer patients and survivors, particularly among the high-risk groups, in order to achieve the best treatment outcome and quality of life among the increasing number of cancer survivors.
Citation Format: Gopal K. Singh, Lihua Liu, Audrey L. Chai, Alexander Ung, Michelle Allender. Prevalence and socio-behavioral determinants of psychological distress among cancer patients and survivors in the United States, 2010-2015 [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 3292.
Abstract 3346: The role of insurance on mammogram adherence among Latina ethnicity and citizenship status
Authors: Johnson Roman B. , Bae Sejong 
Published: August 2019

Abstract
Introduction: Cancer screening researchers have long observed that Latinas are less likely to be mammogram adherent, but little is understood how this varies by citizenship status.
Methods: Logistic regression analysis. The sample size was weighed according to CDC specifications. There were 1002 latina women in the sample. The 2016 National Health Interview Survey was utilized.
Results: Compared to naturalized Latina women, both U.S. citizen and non-citizen Latina women are less likely to be mammogram adherent (p&lt;0.05). Insurance status attenuated the relationship between Latina ethnicity and mammogram adherence. For those who have a private insurance and other insurance, they were significantly more likely to be mammogram adherence (p&lt;0.05).
Findings: Cancer screening researchers benefit from disaggregating Latina ethnicity by citizenship status to develop more tailored interventions regarding mammogram adherence in this population. This study points to the need for policy makers to advocate for Latina populations impacted by insurance coverage disparities.
Citation Format: Roman B. Johnson, Sejong Bae. The role of insurance on mammogram adherence among Latina ethnicity and citizenship status [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 3346.
Abstract 3378: Systematic pharmacogenomic analysis of large patient derived xenografts data
Authors: Mer Arvind Singh , Ba-alawi Wail , Smirnov Petr , Wang Yi Xiao , Brew Ben , Tsao Ming-Sound , Cescon David , Goldenberg Anna , Haibe-Kains Benjamin 
Published: August 2019

Abstract
One of the key challenges in cancer precision medicine is finding robust biomarkers of drug response. Patient-derived tumor xenografts (PDXs) have emerged as reliable preclinical models since they better recapitulate tumor response to chemo- and targeted therapies. However, the lack of standard tools poses a challenge in the analysis of PDXs with molecular and pharmacological profiles. Efficient storage, access and analysis is key to the realization of the full potential of PDX pharmacogenomic data. To address this, we have developed Xeva (XEnograft Visualization & Analysis), an open-source software package for processing, visualization and integrative analysis of a compendium of in vivo pharmacogenomic datasets. The Xeva package follows the PDX minimum information (PDX-MI) standards and can handle both replicate-based and 1x1x1 experimental designs. We used Xeva to characterize the variability of gene expression and pathway activity across passages. We found that only a few genes and pathways have passage specific alterations (median intraclass correlation of 0.53 for genes and positive enrichment score for 92.5% pathways). For example, activity of the mRNA 3'-end processing and elongation arrest and recovery pathways were strongly affected by model passaging (gene set enrichment analysis false discovery rate [FDR] &lt;5%). We then leveraged our platform to link the drug response and the pathways whose activity is consistent across passages by mining the Novartis PDX Encyclopedia (PDXE) data containing 1,075 PDXs spanning 5 tissue types and 62 anticancer drugs. We identified 87 pathways significantly associated with response to 51 drugs (FDR &lt; 5%), including associations such as erlotinib response and signaling by EGFR in cancer pathways and MAP kinase activation in TLR cascade and binimetinib response. Among the significant pathway-drug associations, we found novel biomarkers based on gene expressions, Copy Number Aberrations (CNAs) and mutations predictive of drug response (concordance index &gt; 0.60; FDR &lt; 0.05). Xeva provides a flexible platform for integrative analysis of preclinical in vivo pharmacogenomics data to identify biomarkers predictive of drug response, a major step toward precision oncology.
Citation Format: Arvind Singh Mer, Wail Ba-alawi, Petr Smirnov, Yi Xiao Wang, Ben Brew, Ming-Sound Tsao, David Cescon, Anna Goldenberg, Benjamin Haibe-Kains. Systematic pharmacogenomic analysis of large patient derived xenografts data [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 3378.
Abstract 3394: Diagnosis of intrahepatic metastasis (IM) and multi-entric (MC) carcinogenesis by novel mutational signature in patients with multiple and recurrent hepatocellular carcinomas
Authors: Yang Pinghua , Bai Shilei , Zhang Yanpeng , Xie Zhihao , Cheng Zhangjun , Yang Jie , Li Jun , Wang Jiaqian , Lei Zhengqing , Xia Yong , Wang Kui , Li Zheng , Zhang Baohua , Wan Xuying , Wu Mengchao , Shen Feng 
Published: August 2019

Abstract
Hepatocellular carcinoma is a common solid tumor worldwide and represents the third leading cause of cancer death. Patients with hepatocellular carcinoma (HCC) have poor prognosis because of frequent multi-centric (MC) and intrahepatic metastasis (IM). The discrimination between MC and IM is profoundly important for interpreting tumorigenesis and treatment decision making. However, it is difficult to correctly estimate by histological. Previous studies suggest that HBV integration sites, mitochondrial D-loop mutations, microsatellite loss of heterozygosity (MSI LOH) may provide more accurate information. Paired two tumor lesions and adjacent non-tumor tissues from 10 HBV-position patients were collected for whole genome sequencing. The proportion of shared somatic SNV among the tumor lesions was used to separate MC and IM groups. 4 of 10 patients with shared mutation rate higher than 10% (15.89-49.48%) were identified as IMs. 6 patients with shared mutation rate lower than 10% (0.33-1.97%) were identified as MCs. We also used shared HBV integration rate, mitochondrial D-loop, MSI LOH, diameter ratio to identify IM and MC. The coincidence rates between shared mutation rate and shared HBV integration rate, mitochondrial D-loop, MSI LOH, diameter ratio is 88.89%, 77.78%, 88.89%, and 90%, respectively. It suggests that the diameter ratio of multiple HCCs provide a no-invasion method in clonality analysis. Finally, we developed a panel covering 1M regions to replace whole-genome sequencing to identify IM and MC. We validated the shared mutation rate of target panel region in another 19 whole-genome sequencing HCC patients with multiple tumor lesions from ICGC. A
consistent rate of 94.74% in shared mutation rate between target panel region and whole genome region, indicated that for patients with resectable multiple HCCs, sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques. And a smaller size of target panel contains adequate information is more cost-effective approach for clinical decision making.
Citation Format: Pinghua Yang, Shilei Bai, Yanpeng Zhang, Zhihao Xie, Zhangjun Cheng, Jie Yang, Jun Li, Jiaqian Wang, Zhengqing Lei, Yong Xia, Kui Wang, Zheng Li, Baohua Zhang, Xuying Wan, Mengchao Wu, Feng Shen. Diagnosis of intrahepatic metastasis (IM) and multi-entric (MC) carcinogenesis by novel mutational signature in patients with multiple and recurrent hepatocellular carcinomas [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 3394.
Abstract 3415: Tumor fitness and immune exhaustion: Checkpoint vs endogenous settings
Authors: Bubie Adrian , Akers Nicholas , Villanueva Augusto , Losic Bojan 
Published: August 2019

Abstract
Recently proposed tumor fitness measures based on neoepitope profiling and viral epitope similarity have led to treatment efficacy and immune response prediction models in the checkpoint setting for melanoma (SKCM) and small-cell lung cancer (NSCLC). In this work we test if these checkpoint based fitness measures are associated with either tumor-infiltrating T-cell activity or abundance, and also overall patient survival, in the endogenous setting for the SKCM (n=337) and NSCLC (n = 307) TCGA cohorts. We also investigated if epitopes arising from tumor viral co-factors in Hepatitis B liver cancer (HBV+ HCC) drove T cell activity or response compared to neo-epitope burden.
We find no statistically significant correlation between immune activity and response (as measured by tumor RNA-seq profiling) and the proposed neo-epitope checkpoint-based fitness measures, and similarly no significant survival effect. Further, we found firm evidence that tumor neoepitopes dominate HBV viral epitopes in putative immunogenicity and drive immune response in TCGA HCC (n = 178), and confirmed this trend in multi-regional data (12 patients, 72 samples). These results suggest that tumor-immune response and recruitment in SKCM and NSCLC, and their interplay with viral-cofactor HBV in HCC, are fundamentally driven by different factors in the endogenous setting.
Finally, we propose that tumor fitness may be partially encoded by a simple T-cell exhaustion expression signature, which we demonstrate is a significant predictor of patient survival for SKCM and NSCLC and may translate more widely into other tumor types in the endogenous setting.
Citation Format: Adrian Bubie, Nicholas Akers, Augusto Villanueva, Bojan Losic. Tumor fitness and immune exhaustion: Checkpoint vs endogenous settings [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 3415.
Abstract 3435: Targeting AKT activity inhibits MYCN and sensitizes neuroblastoma to chemotherapeutic agents
Authors: Grand Marion Le , Kimpton Kathleen , Gana Christine , Valli Emanuele , Mayoh Chelsea , Kavallaris Maria 
Published: August 2019

Abstract
MYCN-amplified neuroblastoma is one of the deadliest forms of childhood cancer and remains a significant clinical problem. Direct pharmacological inhibition of MYCN protein is challenging and one possible strategy to treat MYCN-amplified neuroblastoma patients is antagonizing proteins involved in its regulation. The AKT/GSK3β pathway directly regulates stabilization of MYCN, providing a therapeutic rational in MYCN-amplified neuroblastoma. In this study, we addressed the question of how AKT can play a pivotal role in MYCN-amplified neuroblastoma and whether small molecule AKT inhibitors can be promising anti-cancer compounds in children diagnosed from this cancer.
Bioinformatics analysis revealed that high gene expression of AKT1 and AKT2, but not AKT3 was correlated with MYCN amplification and was significantly associated with poor outcome in neuroblastoma patients. Using RNAi-mediated depletion of AKT isoforms or pharmacological inhibition, we then demonstrated that the total AKT activity inhibition rather than the expression of particular isoforms was necessary to cause a significant decrease in neuroblastoma cell proliferation. Our results showed that AKT activity inhibition led to a significant downregulation of MYCN expression through GSK3β regulation. These results demonstrated the potential of targeting AKT activity in MYCN-amplified neuroblastoma patients. Our in vitro and in vivo data revealed promising efficacy for the pan-AKT inhibitor perifosine combined with conventional cytotoxic drugs in MYCN-amplified neuroblastoma cell. Importantly, by genetically modulating MYCN expression (siRNA or plasmid vector), our results demonstrated that MYCN expression is required for perifosine chemosensitisation. This effect was linked to the combined actions of apoptosis activation and the downregulation of ABC transporter expressions.
Collectively, our data strongly support that combining the pan-AKT inhibitor perifosine, which is currently in clinical trial, with clinically-approved drugs for neuroblastoma patients could be a novel therapeutic strategy to indirectly target MYCN in neuroblastoma.
Citation Format: Marion Le Grand, Kathleen Kimpton, Christine Gana, Emanuele Valli, Chelsea Mayoh, Maria Kavallaris. Targeting AKT activity inhibits MYCN and sensitizes neuroblastoma to chemotherapeutic agents [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 3435.
Abstract 3455: TNFAIP8 increases drug resistance and steatosis in liver cancer by inducing autophagy
Authors: Niture Suresh , Gyamfi Maxwell A. , Kumar Deepak 
Published: August 2019

Abstract
Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) is a TNF-α inducible anti-apoptotic protein which facilitates tumor growth and progression in several cancers. The molecular mechanisms how TNFAIP8 modulates the progression of liver cancer remain elusive. The present study investigated the role of TNFAIP8 in the liver cancer cell growth, drug resistance/survival and cell steatosis. Tissue microarray data from patients demonstrated an increased expression of TNFAIP8 protein during development of different stages of liver cancer compared with normal liver tissues. To test the correlation between TNFAIP8 expression and liver cancer progression, we transiently/stably expressed TNFAIP8 protein in liver cancer cell lines. Expression of TNFAIP8 in liver cancer cells HepG2 and SK-Hep1 increased both cell growth/survival and drug resistance against anti-liver cancer drugs sorafenib and regorafenib by inhibition of apoptosis. In addition, TNFAIP8 knockdown sensitized tumor cell lines to sorafenib and regorafenib. Expression of TNFAIP8 modulates AKT/mTOR pathway and induced autophagy and thus increased drug resistance. Moreover, TNFAIP8 induced liver cancer cell steatosis by increasing the expression of L-FABP1, SCD1, ACC, and PPARγ proteins which involved in lipid synthesis. We also demonstrate that chronic EtOH induced steatosis in mice liver was associated with increased TNFAIP8 expression and autophagy suggesting that TNFAIP8 mediate EtOH induced steatosis. In addition, increased expression of TNFAIP8 and hepatic steatosis was observed in patients with a history of alcohol use compared with no history of alcohol use. Taken together our data suggested that TNFAIP8 increases drug resistance/survival, EtOH-induced cell steatosis and early liver cancer development by the induction of autophagy.
Citation Format: Suresh Niture, Maxwell A. Gyamfi, Deepak Kumar. TNFAIP8 increases drug resistance and steatosis in liver cancer by inducing autophagy [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 3455.