bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1019: EGFR signal induces T cell non-inflamed tumor microenvironment (TME) through suppression of chemokine production from human EGFRmt lung adenocarcinoma
Authors: Sumimoto Hidetoshi , Takano Atsushi , Teramoto Koji , Daigo Yataro 
Published: September 2020

Abstract
EGFR mutation-positive (EGFRmt) lung adenocarcinoma (LA) is refractory to immune checkpoint inhibitors, such as anti-PD-1/anti-PD-L1 mAbs. However, the refractory mechanism remains to be elucidated. We found CD8A mRNA level was significantly lower in EGFRmt LA than in EGFRwt LA in TCGA data, which was validated at protein expression levels by immunohistochemistry of surgically obtained LA tissues (p&lt;0.0001). We identified several chemokines showing positive correlations to the CD8A mRNA level on the TCGA data set, some of which were significantly lower in EGFRmt LA than in EGFRwt LA, suggesting that oncogenic EGFR signal might be related to the suppression of chemokine expression in the TME, leading to the less recruitment of CD8 T cells to the tumor. We conducted multiplex chemokine assays of several EGFRmt LA cell lines, and found EGFR-TKI of osimertinib treatment significantly increased several chemokine expressions in the culture supernatant compared to control DMSO (p&lt;0.005), indicating EGFR signal may inhibit tumor intrinsic chemokine production, which may explain the T cell non-inflamed TME. Among the upregulated chemokines, IFN-responsive chemokines, CXCL9, 10, and 11, showed prominent increase (by 30 to 167-fold) under osimertinib treatment and IFN-γ stimulation. A T cell migration assay revealed CXCL10 was a major chemokine contributing to the chemotaxis. We further examined the suppressive mechanisms of CXCL10 expression via EGFR signal. siRNA experiments against EGFR confirmed the specific inhibition of CXCL10 expression by EGFR signal. Inhibitor experiments for the downstream of EGFR signal revealed that MAPK, but neither PI3K nor STAT3 signal, partially contributed to CXCL10 suppression. The increase of CXCL10 expression by osimertinb treatment occurred at an mRNA level. But an mRNA stability test revealed that EGFR signal did not decrease, but increased the mRNA stability of CXCL10, suggesting that EGFR signal might suppress the promoter activity of CXCL10. We conducted the promoter analysis of proximal 2kb of CXCL10 gene, however, the regulatory elements within the region, such as NFκB or IRF-1, were not accounted for the CXCL10 up-regulation upon EGFR-TKI treatment, suggesting the transcriptional control with EGFR signal at more remote cis-element(s). The data indicate that EGFR signal might work as a T cell excluding signal in human EGFRmt LA by suppressing several chemokine productions from the cells.
Citation Format: Hidetoshi Sumimoto, Atsushi Takano, Koji Teramoto, Yataro Daigo. EGFR signal induces T cell non-inflamed tumor microenvironment (TME) through suppression of chemokine production from human EGFRmt lung adenocarcinoma [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 1019.
Abstract 1077: Macrophage PI3Kγ controls T cell activation and T cell memory generation through the production of IL-12
Authors: Takahashi Hideyuki , Shepard Ryan M. , Paradise Marc A. , Lee Sang Min , Shih Ann , Flores-Arenas Cristina , Kim William , Varner Judith A. 
Published: September 2020

Abstract
We previously reported that macrophage PI3kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ inhibition polarizes tumor-associated macrophages (TAMs) into pro-inflammatory macrophages, leading to the recruitment and activation of intratumoral CD8+ T cells, tumor growth inhibition and anti-tumor memory (Kaneda et al 2016). In the present study, we elucidated the role of PI3Kγ in the control of T cell immune responses, including activation, memory generation and exhaustion, in mouse models of head and neck squamous cell carcinomas (HNSCC). High-dimensional single-cell analysis including single-cell RNA sequencing and mass cytometry of HPV+ HNSCC tumors revealed significant differences in intratumoral immune cell clusters in HPV+ HNSCC tumors from WT and Pik3cg−/− mice. Primary tumors from Pik3cg−/− mice exhibited more pro-inflammatory TAMs, more activated CD8+ T cells and fewer exhausted T cells than in tumors from WT mice. Both tumor- and spleen-derived T cells from Pik3cg−/− mice exhibited more IFNγ expression than those from WT mice; this increase could be reversed by the neutralization of IL-12 and MHCII. We observed significantly more effector memory T cells in spleens of Pik3cg−/− mice than WT mice; accordingly, adoptive transfer of Pik3cg−/− but not WT splenic T cells conferred tumor resistance onto naive WT mice, indicating that PI3Kγ inhibition promotes T cell mediated immunological memory. In summary, Pik3cg−/− mice exhibited more activated T cells, T cell mediated immune responses and T cell memory than WT mice, resulting significant and sustained suppression of tumor growth. These results indicate that PI3Kγ-targeted therapy may activate durable T cell immune responses in patients with HNSCC.
Citation Format: Hideyuki Takahashi, Ryan M. Shepard, Marc A. Paradise, Sang Min Lee, Ann Shih, Cristina Flores-Arenas, William Kim, Judith A. Varner. Macrophage PI3Kγ controls T cell activation and T cell memory generation through the production of IL-12 [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 1077.
Abstract 1083: Heterozygous knockout of the histone modifier MLL4 promotes Ptch+/−-driven medulloblastoma
Authors: Dhar Shilpa S. , Zhao Dongyu , Lin Tao , Sillitoe Roy V. , Chen Kaifu , Lee Min Gyu 
Published: September 2020

Abstract
Medulloblastoma (MB) is the most common primary childhood brain tumor. MB development frequently results from the dysregulation of sonic hedgehog and wingless pathways. In contrast to our understanding of these pathways, the pathogenic roles of aberrant epigenetic modifiers in MB remain little known. MLL4 is one of the most commonly mutated genes in MB. In our recent study, we showed that brain-specific knockout of the gene encoding the histone H3 lysine 4 methyltransferase MLL4 (also called COMPASS-like methyltransferase, KMT2D, MLL2, and ALR) induced spontaneous MBs. Mll4 loss highly upregulated several oncogenic signaling programs, including expression of several oncogenic Ras activators (e.g., Rasgrp1, Rasgrf1, and Rasgef1a). In contrast, Mll4 loss downregulated expression of tumor-suppressive genes, such as Dnmt3a. In this study, we sought to determine whether Mll4 loss cooperates with other oncogenic event in MB genesis. Particularly, PTCH (also known as PTCH1) is one of the most frequently mutated genes in MB, and its loss induces MB in mouse models. Thus, we examined the effect of Mll4 loss on of Ptch+/−-driven MB genesis. A heterozygous loss of Mll4 increased the incidence and progression of Ptch+/−-driven MB genesis. MBs were confirmed by H & E staining, and immunohistochemical staining using anti-Ki-67 showed that cell proliferation was markedly increased. Calbindin signals were undetectable in Nestin-Cre Mll4f/+ Ptch+/−, and NeuN levels were decreased in Nestin-Cre Mll4f/+ Ptch+/− cerebellum compared to Ptch+/− cerebellum, suggesting the impairment of Purkinje and granule cells. Mll4 loss reduced cerebellar granule cell differentiation. These findings indicate that a haploinsufficiency of MLL4 promotes Ptch+/−-driven MB genesis. This mouse model may be useful for future preclinical therapeutic experiments for the treatment of MB patients with MLL4 mutations.
Citation Format: Shilpa S. Dhar, Dongyu Zhao, Tao Lin, Roy V. Sillitoe, Kaifu Chen, Min Gyu Lee. Heterozygous knockout of the histone modifier MLL4 promotes Ptch+/−-driven medulloblastoma [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 1083.
Abstract 1085: Interrogating the RAS interactome identifies EFR3A as a novel enhancer of RAS oncogenesis
Authors: Adhikari Hema , Kattan Walaa , Hancock John F. , Counter Christopher M. 
Published: September 2020

Abstract
Activating mutations in one of the three RAS genes (HRAS, NRAS, and KRAS) are detected in as much as a third of all human cancers. As oncogenic RAS mediates it tumorigenic signaling through protein-protein interactions primarily at the plasma membrane, we sought to document the protein networks engaged by each RAS isoform to identify new vulnerabilities for future therapeutic development. To this end, we determined interactomes of oncogenic HRAS, NRAS, and KRAS by BirA-mediated proximity labeling. This analysis identified roughly ** proteins shared among multiple interactomes, as well as a smaller subset unique to a single RAS oncoprotein. To identify those interactome components promoting RAS oncogenesis, we created and screened sgRNA library targeting the interactomes for genes modifying oncogenic HRAS-, NRAS-, or KRAS-mediated transformation. This analysis identified the protein EFR3A as not only a common component of all three RAS interactomes, but when inactivated, uniformly reduced the growth of cells transformed by any of the three RAS isoforms. EFR3A recruits a complex containing the druggable phosphatidylinositol (Ptdlns) 4 kinase alpha (PI4KA) to the plasma membrane to generate the Ptdlns species PI4P. We show that EFR3A sgRNA reduced multiple RAS effector signaling pathways, suggesting that EFR3A acts at the level of the oncoprotein itself. As lipids play a critical role in the membrane localization of RAS, we tested and found that EFR3A sgRNA reduced not only the occupancy of RAS at the plasma membrane, but also the nanoclustering necessary for signaling. Furthermore, the loss of oncogenic RAS signaling induced by EFR3A sgRNA was rescued by targeting PI4K to the plasma membrane. Taken together, these data support a model whereby EFR3A recruits PI4K to oncogenic RAS to promote plasma membrane localization and nonclustering, and in turn, signaling and transformation. To investigate the therapeutic potential of this new RAS enhancer, we show that EFR3A sgRNA reduced oncogenic KRAS signaling and transformed growth in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines. Encouraged by these results we are exploring whether genetically inactivating the kinase activity of PI4KA inhibits oncogenic signaling and transformation in PDAC cell lines. If true, pharmacologically targeting PI4K may hold promise as a way to enhance the anti-neoplastic activity of drugs targeting oncogenic RAS or its effectors.
Citation Format: Hema Adhikari, Walaa Kattan, John F. Hancock, Christopher M. Counter. Interrogating the RAS interactome identifies EFR3A as a novel enhancer of RAS oncogenesis [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 1085.
Abstract 1088: Elucidating the regulation of delayed-early gene targets of sustained MAPK signaling
Authors: Dale Kali J. , McMahon Martin 
Published: September 2020

Abstract
RAS and its downstream effector, BRAF, are commonly mutated proto-oncogenes in many types of human cancer. Mutationally activated RAS or BRAF signal through the MEK→ERK MAP kinase (MAPK) pathway to regulate key cancer cell hallmarks such as cell division cycle progression, reduced programmed cell death, and enhanced cell motility. Amongst the list of RAS/RAF-regulated genes are those encoding integrins, alpha-beta heterodimeric transmembrane proteins that regulate cell adhesion to the extracellular matrix. Altered integrin expression has been linked to the acquisition of more aggressive behavior by melanoma, lung, and breast cancer cells leading to diminished survival of cancer patients. We have previously documented the ability of the RAS-activated MAPK pathway to induce the expression of ITGB3 encoding integrin β3 in several different cell types. RAS/RAF-mediated induction of ITGB3 mRNA requires sustained, high-level activation of RAF→MEK→ERK signaling mediated by oncogene activation and is classified as “delayed-early”, in that it is sensitive to the protein synthesis inhibitor cycloheximide. However, to date, the regulatory mechanisms that allow for induced ITGB3 downstream of sustained, high-level activation of MAPK signaling remains obscure. We have identified over 300 DEGs, including those expressing additional cell surface proteins, that display similar regulatory characteristics as ITGB3. We use integrin β3 as a model to test our hypothesis that there is a different mechanism of regulation for delayed-early genes (DEG) compared to the canonical regulation of Immediate-Early genes. There are three regions in the chromatin upstream of the ITGB3 that become more accessible during RAF activation. We are relating the chromatin changes seen during RAF activation to active enhancer histone marks. To elucidate the essential genes of this regulation process, we are employing the use of a genome-wide CRISPR knockout screen. The work presented from this abstract will help elucidate the regulatory properties of oncogenic progression in BRAF mutated cancers that could lead to the identification of biomarkers.
Citation Format: Kali J. Dale, Martin McMahon. Elucidating the regulation of delayed-early gene targets of sustained MAPK signaling [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 1088.
Abstract 1104: Folate intake and colorectal cancer risk during 36 years of follow-up in US women: A prospective cohort study
Authors: Wang Fenglei , Wu Kana , Li Yanping , Smith-Warner Stephanie , Giovannucci Edward , Willett Walter 
Published: September 2020

Abstract
Background: Folate intake has been reported to be associated with a lower colorectal cancer (CRC) risk in several epidemiological studies. However, there are concerns about the potential for cancer promotion with an overly-abundant folate intake, especially after the mandatory folate fortification in the United States in 1998.
Method: We investigated the association between folate intake and CRC risk among 83,165 women in the Nurses' Health Study, including 18 years of post-fortification follow-up; 2268 incident CRC cases were ascertained from 1980 to 2016. Folate intake from foods and supplements was assessed at baseline and updated every 4 years using a validated food-frequency questionnaire. Multivariate hazards ratios (HR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards regression.
Results: Over the entire follow-up period (1980-2016), higher total folate intake was associated with a decreased risk of CRC (HRQ5vsQ1=0.80; 95% CI: 0.64-0.99). This association was stronger when total folate was assessed 12-24 years before CRC diagnosis. Multivitamin use for &gt;15 years, but not a shorter duration of use, was associated with lower CRC risk. In the post-fortification period (1998-2016, n= 1169 CRC cases), high total folate intake (HRQ5vsQ1=0.80; 95% CI: 0.64-1.00) and current multivitamin uses, regardless of duration, were each associated with lower CRC risk.
Conclusions: There was no evidence that high folate intake in the post-fortification period was related to increased CRC risk. Rather, high total folate intake was inversely associated with risk of CRC.
Citation Format: Fenglei Wang, Kana Wu, Yanping Li, Stephanie Smith-Warner, Edward Giovannucci, Walter Willett. Folate intake and colorectal cancer risk during 36 years of follow-up in US women: A prospective cohort 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 1104.
Abstract 1127: Adarza's ZIVA multiplex protein detection platform utilizes a label-free technology to simultaneously monitor murine and human inflammation cytokines in a CAR-T model system
Authors: Schmuke Jon J. , Carter Alun , Zhou You , Mueller Ernest , Cooper Matt 
Published: September 2020

Abstract
We have used Arrayed Imaging Reflectometry (AIR™), a label-free protein microarray technology that relies on the target binding-induced perturbation of an antireflective coating on the surface of a silicon biosensor, to create a multiplex antibody array for the detection of human and murine serum cytokines and inflammatory markers. The biosensor is capable of providing quantitative protein concentrations, with limits of detection in the low picograms per mL. Provided in a standard 96-well microplate format, the label-free nature of the array enables flexible creation of standard or custom panels for development of model systems. Here, we demonstrate a custom 22 plex panel developed in collaboration with WUGEN Inc. to provide multi-species cytokine analysis in humanized CAR-T cell models for the evaluation of biologic product efficacy and safety. Samples from in vitro and in vivo models developed for the evaluation of CAR-T activity were analyzed and demonstrated a novel platform for concurrent cross-species cytokine analysis on a single array. Results are evaluated for sensitivity, precision, and accuracy with ZIVA assays comparable to traditional ELISAs. With array capabilities from low to hundreds of plex combined with a hands-free, automation-friendly workflow enabled by the ZIVA instrument, the technology has been designed for the ultimate user-experience.
Citation Format: Jon J. Schmuke, Alun Carter, You Zhou, Ernest Mueller, Matt Cooper. Adarza's ZIVA multiplex protein detection platform utilizes a label-free technology to simultaneously monitor murine and human inflammation cytokines in a CAR-T model 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 1127.
Abstract 1140: Declining awareness of HPV and HPV vaccination within the general US population
Authors: Chido-Amajuoyi Onyema G. , Jackson Inimfon , Yu Robert , Shete Sanjay 
Published: September 2020

Abstract
Background: Programs aimed at boosting awareness on Human Papillomavirus (HPV) and HPV vaccination are considered one of the most effective strategies for increasing vaccination uptake and eliminating HPV-associated cancers. Several US states have demonstrated a strong commitment to this effort through legislation and dedicated funds, however the impact of this intervention over time remains poorly studied.
Methods: Using a nationally representative population of US adults from the Health Information National Trends Survey (HINTS), we examined for awareness of HPV and HPV vaccination between 2009 and 2018. Prevalence estimates and confidence intervals were calculated for HPV and HPV vaccination awareness. Further, we assessed awareness status after stratifying by key sociodemographic characteristics.
Results: Overall, the awareness of HPV and HPV vaccination declined over time. This finding was consistent across gender and socioeconomic strata. The lowest rates of awareness were found among those with educational level at or below high school completion, those who earned less than $35,000 per annum, rural residents, and male adults, aged 60 years and older. Declines in awareness of HPV or HPV vaccination between 2014 and 2018 were more than 10% among male adults, those with educational level at or below high school completion and those who earned less than $35,000 per annum. Only 36.1% of adults with high school education or lower had ever heard of HPV vaccine in 2018, a 15.6% reduction from 2009. In 2018 awareness of HPV and HPV vaccine was highest among non-Hispanic whites (65.8% and 66.5%) and female adults (70.5% and 71.4%), however these figures represented declines of at least 5% from rates observed in 2009.
Discussion: Amid a background of sub-optimal HPV vaccination uptake and a growing incidence of HPV-associated cancers in the US, the awareness of HPV and HPV vaccination within the general population has declined over time. This calls for stricter enforcement of legislature aimed at boosting HPV awareness, as well as frequent evaluations of government-funded HPV awareness programs.
Citation Format: Onyema G. Chido-Amajuoyi, Inimfon Jackson, Robert Yu, Sanjay Shete. Declining awareness of HPV and HPV vaccination within the general US population [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 1140.
Abstract 1154: AFPep mitigates the risk of breast cancer
Authors: Fordyce Samuel B. , Andersen Thomas T. , Bennett James A. 
Published: September 2020

Abstract
Women whose risk of breast cancer is elevated (based on Gail or Tyrer-Cuzik models) have only limited options to intervene in attempt to alter disease progression, and most options are of limited efficacy or have unwanted side effects. Options include increased surveillance, lifestyle changes, drugs such as tamoxifen or aromatase inhibitors, or removal of target tissue. Options that are more efficacious, better tolerated, and more empowering are needed for women in high-risk cohorts. For this purpose, we have developed AFPep, a homobiotic, selective anti-estrogenic/anti-breast cancer active site-analog of alpha-fetoprotein (AFP). AFPep stops growth of human breast cancers growing in xenograft models and prevents development of either estrogen-induced or MNU-induced mammary cancers in rats. In all models, AFPep is effective against tamoxifen-resistant breast cancer, is additive with tamoxifen (allowing dose reduction of tamoxifen), and reduces the uterine hyperplasia induced by tamoxifen. AFPep does not disrupt the estrous cycle of rats, nor does it alter fertility or fecundity and does not induce teratogenicity. The mechanism of action of AFPep differs from that of tamoxifen in that AFPep inhibits phosphorylation of the estrogen receptor leading to a downstream biomarker profile consistent with inhibition of tumor growth. AFPep is orally bioavailable and well tolerated in mice, rats, dogs and primates. The therapeutic index of AFPep in rats shows a substantially broader safety margin than that of currently used agents. AFPep may offer an effective, well tolerated option for women in high risk cohorts who wish to mitigate their risk of breast cancer.
Citation Format: Samuel B. Fordyce, Thomas T. Andersen, James A. Bennett. AFPep mitigates the risk of breast 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 1154.