bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2473: NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation
Authors: Guo Hongshan , Golczer Gabriel , Maheswaran Shyamala , Lawrence Michael S. , Haber Daniel A. 
Published: July 2021

Abstract
Deregulation of oncogenic proliferative signals triggers replication stress in cancer cells to which they must adapt. Immediate early genes (IEGs), identified by their rapid stress-induced transient bursts of expression, are critical to integrating downstream signaling pathways. In studying tumor initiation by patient-derived breast cancer cells, we observed acquisition of open chromatin domains at the genebody and 3'-UTR of IEGs, uniquely across the genome. Through in vivo and in vitro modeling, we show that the IEG and orphan nuclear receptor NR4A1 localizes across multiple IEG genebodies, where it binds to RNA Pol II, arresting transcriptional elongation and generating extensive R-loops and accessible chromatin. Acute stress promptly removes NR4A1 from IEG genebodies, triggering immediate release of their poised transcripts. In breast cancer cells, NR4A1 overexpression increases tumorigenesis; conversely, its deletion leads to uncompensated replication stress, chromosomal instability and mitotic catastrophe, driven by deregulation of its IEG target FOS. A large fraction of primary breast and other cancers exhibit open genebody chromatin at IEGs, consistent with preserved NR4A1 function. Thus, NR4A1 mediates a novel transcriptional elongation checkpoint, unique to stress-induced genes and required for their rapid bursts of expression. Cancers that have retained this mechanism in adapting to chronic replication stress may be dependent on NR4A1 for proliferation.
Citation Format: Hongshan Guo, Gabriel Golczer, Shyamala Maheswaran, Michael S. Lawrence, Daniel A. Haber. NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2473.
Abstract 2505: Fibrinogen suppresses tumor growth and metastasis in lung cancer
Authors: Wang Xinran , Swartz Mary Katherine , Liu Runhua 
Published: July 2021

Abstract
About 80% to 85% of lung cancers are non-small cell lung cancers (NSCLC), including lung adenocarcinoma (LUAD, 40% of lung cancers) and lung squamous cell carcinoma (LUSC, 25% to 30% of lung cancers). Fibrinogen is an extracellular matrix protein composed of three polypeptide chains with fibrinogen alpha (FGA), beta (FGB), and gamma (FGG). A recent genome-scale screening reveals that loss of FGA affects the acceleration of tumor growth and metastasis of lung cancer, but the mechanism remains elusive. Based on our bioinformatics analysis, genetic alterations of FGA are unlikely to be a frequent event in human lung cancers. However, our expression analysis showed a low expression of FGA in human lung cancer tissues, including LUAD and LUSC. DNA hypermethylation in the promoter region of FGA is correlated with low expression of FGA in human LUAD tissues. Furthermore, FGA knockout promotes but the administration of FGA inhibits LUAD cell growth, migration, and invasion, as well as tumor colonization in the lung. Our functional analysis revealed the FGA-mediated regulation of tumor growth and metastasis through apoptosis and EMT is also involved in the integrin-AKT signaling pathway in LUAD cells in vitro and xenograft tumor model in vivo. These data suggest that FGA may play a suppressive role in LUAD cells to inhibit tumor growth and metastasis through induction of apoptosis and inhibition of EMT. In LUAD cells, FGA can bind integrin α5 and reduce phosphorylation of AKT, leading to an inhibition of mTOR signaling. The administration of FGA may provide a new therapeutic approach to inhibit LUAD cell growth and metastasis. However, FGA may also affect TME cells in vivo, such as endothelial cells, leading to the various roles of FGA in tumor growth and metastasis.
Citation Format: Xinran Wang, Mary Katherine Swartz, Runhua Liu. Fibrinogen suppresses tumor growth and metastasis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2505.
Abstract 2523: Novel genomic characterization in late stage colorectal cancer
Authors: Li Jianxia , Wu Qianchao , Zhang Jianwei , Hu Huabin , Cai Yue , Lin Jiayu , Liu Jun , Deng Yanhong 
Published: July 2021

Abstract
Introduction: Colorectal cancer patients with high-level microsatellite instability benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all colorectal cancer patients. The remaining patients are still lack of effective therapeutic biomarkers. For patients in late stage without optimal treatment, it is essential to find novel biomarkers which can be used to select appropriate therapies and therefore improve patients' overall survival.
Methods: We used whole-exome sequencing to analyze 114 colorectal cancer samples. The samples included 86 primary late stage tumors and 28 metastatic tumors from liver, lung and other organs. The primary samples were further divided into different groups based on their tumor location (sideness) and microsatellite status (MS) since these indications are of great significance in clinical presentation and treatment. We then assessed somatic genomic lesions, copy number variations, germline gene alterations and mutational signatures in the above three pairs of comparisons respectively (primary vs. metastatic, right- vs. left-sided, MS instable vs. stable).
Results: There were significant differences between the analyzed pairs. For the primary and metastatic samples, the most prominent difference was the copy number variation which happened in 25 genes in the metastatic samples and only one gene in the primary samples (gain of IL12) (p = 0.036). For the right- and left-sided comparison, SNP/Indel mutations were the most prominent. They happened more frequently in the right-sided than the left-sided tumors and those are rare genes in colorectal cancer, including BCL11A (p = 0.018), DICER1 (p = 0.038), NR4A3 (p = 0.004), NIN (p = 0.008) and FBXW7 (p = 0.019). For the MSI-MSS comparison, tumor mutation burden (TMB) stands out high in the MSI group compared to the MSS group (p &lt; 0.0001). In addition, dozens of significantly mutated genes were observed in the MSI samples (p &lt; 0.0001), such as KMT2B, ACVR2A, KMT2D, ASXL1, TCF7L2 and etc. However, TP53 occurred mainly in the MSS patients (p = 0.0007).
Conclusion: Our study enables a deeper understanding of the genomic characterization of colorectal cancer from an integrated view. Copy number variations, gene mutations, and TMB were found to be the most significant differences between the comparison groups of primary vs. metastatic samples, left vs. right sided samples, and MSI vs. MSS samples respectively. Genomic differences between metastatic and primary samples may be potential therapeutic targets for metastatic colorectal cancer.
Citation Format: Jianxia Li, Qianchao Wu, Jianwei Zhang, Huabin Hu, Yue Cai, Jiayu Lin, Jun Liu, Yanhong Deng. Novel genomic characterization in late stage colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2523.
Abstract 2529: Specific racial CYP2R1 correlation with circadian rhythm genes in prostate adenocarcinoma
Authors: Adelani Isaacson Bababode , Rotimi Solomon Oladapo , Yates Clayton , Campbell Moray 
Published: July 2021

Abstract
Introduction: Vitamin D in its hormonal form, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) binds to the vitamin D receptor (VDR) to regulate genes, for example, in skeletal mineralization. However, it also has other potent biological functions in regulating apoptosis, proliferation, and inflammation. In carcinogenesis, 1,25(OH)2D3 may be exploited to regulate these crucial pathways. It is also clear that a frequent cancer disparity exists amongst African American (AA) men with prostate cancer compared to European Americans (EA). AA men show a higher incidence rate and two to three times increased risk of mortality than EA counterparts. Various groups have suggested that 1,25(OH)2D3 levels and/or VDR functions are risk factors linked with increased prostate cancer incidence in AA men. Incidentally, reports showed that VD plays a crucial role in regulating circadian rhythm (CR). There is, therefore, a need to understand and evaluate 1,25(OH)2D3-dependent CR regulation and the association with racial disparity in prostate cancer. This study aimed to determine if there are differentially expressed VD metabolic enzymes in AA and EA and evaluate if the differential expression correlates with CR genes.
Methods: The Cancer Genome Atlas Research Network (TCGA), 2015 database was queried for expression of VD metabolizing enzymes and CR genes. The search was carried out on prostate adenocarcinoma expressions of AA and EA. VD metabolizing enzymes queried are CYP2R1, CYP24A1, CYP27B1, CYP27A1, while CR genes queried include ARNTL, CLOCK, CRY1, CRY2, CSNK1E, NPAS2, PER1, PER2, PER3, and TIMELESS. Prostate adenocarcinoma racial differential expressions of AA and EA were evaluated, and a correlation study was done using the Pearson correlation.
Results: VD metabolic enzyme, CYP2R1, and CR gene, ARNTL were significantly upregulated in AA compared to EA counterparts. Although CYPR1 correlates negatively with CLOCK, CRY2, and PER3 in both races, CYPR1 specifically showed a positive correlation with CR gene CRY1 in EA and negative correlations with CR genes NPAS2 and CSNK1E in AA. However, a significant correlation between CYP2R1 and ARNTL in EA and AA was not observed.
Conclusion: The data suggest a relationship between racial influence and prostate cancer associated with VD metabolism and CR regulation. Hence, it is crucial to elucidate CYP2R1 regulation in prostate cancer related to VD levels and CR regulation, especially with a focus on racial disparities.
Citation Format: Isaacson Bababode Adelani, Solomon Oladapo Rotimi, Clayton Yates, Moray Campbell. Specific racial CYP2R1 correlation with circadian rhythm genes in prostate adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2529.
Abstract 2543: Venue-based recruitment to increase colorectal screening rates using fecal immunochemical test in Essex County, New Jersey
Authors: Alzate-Duque Luis , Valera Pamela , Cueto Vivian , Shome Ashna , Natale-Pereira Ana 
Published: July 2021

Abstract
Background: Overall, Essex County, New Jersey's age-adjusted prevalence for completion of colorectal cancer screening is 71.5%; however, Black and Latinx residents have a lower colorectal cancer screening rate of 65%. To increase urban residents' colorectal screening rates, we used venue-based recruitment to educate the community about fecal immunochemical testing.
Methods: Education about fecal immunochemical testing was implemented at community-based events following a colorectal cancer education session. These sessions were carried out in English, Spanish, and Portuguese. Eligibility criteria included the following: (1) between the ages of 45-85 and (2) not current with U.S. Preventive Services Task Force recommended colorectal cancer screening. Eligible participants who agreed to participate were provided a fecal immunochemical testing kit and instructed to complete these kits to be returned within two weeks. Patient navigators followed up with study participants to explore barriers to completion and facilitate the fecal immunochemical testing kit's timely return.
Results: Approximately 132 participants received the fecal immunochemical testing kit, and 55% were returned. On average, participants who received the fecal immunochemical testing kit were at least 60 years of age, 11% were men, 71% indicated no primary care provider, 72% reported no health insurance, and 81% reported no prior colorectal cancer screening. Of the 55% of the fecal immunochemical testing kit that was returned, 9 (12%) were positive for occult blood, and two diagnostic colonoscopies were completed. Participants noted several barriers to completing and returning the fecal immunochemical testing kit. They noted the following barriers: misplaced or loss of fecal immunochemical testing kit, limited time, and perceived comfortability of handling a stool sample.
Discussion: Targeting study participants at community-based events may increase access to colorectal screening for underserved populations. Barriers to colorectal cancer screening could be mitigated by co-locating colorectal cancer screening education in the community.
Citation Format: Luis Alzate-Duque, Pamela Valera, Vivian Cueto, Ashna Shome, Ana Natale-Pereira. Venue-based recruitment to increase colorectal screening rates using fecal immunochemical test in Essex County, New Jersey [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2543.
Abstract 2582: Gnetin C inhibits reactivated AR signaling in advanced prostate cancer
Authors: Deabel Rabab M. Al , Zhang Joyce , Puaar Anand , Kumar Avinash , Levenson Anait S. 
Published: July 2021

Abstract
The activation of androgen receptor (AR) is a key process in the development and progression of prostate cancer (PCa). After significant clinical response to androgen-deprivation therapy, patients with advanced PCa regularly relapse with more aggressive castrate-resistant PCa, in which AR and its oncogenic variants are reactivated. Therefore, there is an urgent necessity to develop therapeutic strategies that effectively suppress the tumor promoting signals associated with AR action in castrate-resistant PCa. Dietary stilbenes found in grapes and various berries are promising anticancer agents with multiple cellular targets, including AR. Particularly, we previously demonstrated that resveratrol (Res) and its naturally occurring analogs, pterostilbene and piceatannol, can decrease expression of AR in LNCaP and 22Rv1 cells, therefore presenting an attractive potential for stilbenes as promising pharmacologically safe agents in managing PCa. Gnetin C, a Res-dimer found abundantly in melinjo (Gnetum gnemon) plant, which possesses potent biological properties compared to Res and analogs due to its improved pharmacokinetics, is shown to be safe in healthy volunteers. Here, for the first time, we examine the efficacy of Gnetin C in targeting both full-length and ligand-independent AR splice variant (AR-V7) expressed in the castrate-resistant 22Rv1 cells. First, we found that Gnetin C shows significantly more potent cytotoxic effect in 22Rv1 cells compared to Res and Pter. Immunoblot analysis demonstrated that Gnetin C inhibited expression of both full-length (100 kDA) and truncated (80 kDA) AR-V7 in a dose-dependent manner and, importantly, with significantly higher efficacy than Res and Pter when treated with the same dose (50 μM). In addition, Gnetin C used in twice lesser dose (25 μM), showed substantially more inhibitory effect compared to flutamide and enzalutamide (50 μM), two known AR antagonists used in clinic. Moreover, since neuroendocrine trans-differentiation (NED) is associated with AR-dependent mechanisms and enzalutamide resistance in PCa, we evaluated the effects of Gnetin C on SYP and CHGA. Ongoing in vivo studies using transgenic mice with activated AR signaling treated with Gnetin C are in progress. Taken together, we propose that Gnetin C is a lead compound among stilbenes for effectively blocking AR reactivation in PCa and may potentially have noteworthy therapeutic implications against advanced PCa.
Citation Format: Rabab M. Al Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, Anait S. Levenson. Gnetin C inhibits reactivated AR signaling in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2582.
Abstract 2595: Cancer cachexia is mediated by the suppression of PGC1-alpha expression in the skeletal muscle vasculature
Authors: Kim Young-Mee , Mancinelli Georgina , Grippo Paul , Rehman Jalees 
Published: July 2021

Abstract
Background: Cancer patients experience cachexia which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. However, there are no approved treatments that can effectively counteract cancer cachexia. Prior research has focused on the changes within the muscle tissue but little is known about the role of the muscle vasculature in mediating cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply and preventing inappropriate transmigration of immune cells into the tissue. We therefore hypothesized that endothelial dysfunction in the skeletal muscle results in the development of cachexia in cancer. The transcriptional co-activator PGC1α (peroxisome proliferation activator receptor-γ coactivator1-α) regulates endothelial health.
Methods and Results: To evaluate whether skeletal muscle EC-PGC1α is modulated in the setting of malignancy, we isolated muscle ECs from control and melanoma bearing mice at 1, 2, and 3 weeks after melanoma implantation. PGC1α expression was significantly decreased in mECs of melanoma bearing mice from early stage (1 week) compared with control mice. Thus, we generated an EC-specific inducible PGC1α deletion mouse model (ECΔPGC1α) to investigate the mechanistic role of EC-PGC1α in cancer cachexia in vivo. Interestingly, vascular density and muscle area were significantly decreased in the gastrocnemius (GC) of ECΔPGC1α mice compared with ECWT mice using an innovative tissue clearing and high-resolution 3D-tissue imaging system. Tumor bearing ECWT mice had decreased GC mass and weight compared with no tumor mice by enhancing cachexia marker genes, MuRF1 and Atrogin1. The tumor bearing ECΔPGC1α mice had further decreased muscle mass and weight, and grip strength than tumor bearing ECWT mice. We assessed the role of EC-PGC1α in the regulation of capillary function in vivo, and observed that ECΔPGC1α mice demonstrated significantly greater vascular leak than ECWT mice.
Conclusion: These data suggest that the presence of melanoma suppresses PGC1α expression in the skeletal muscle endothelium. Endothelial PGC1α, in turn, is essential for maintaining the integrity of the skeletal muscle vascular barrier. Our study suggests that restoring muscle endothelial dysfunction could be a novel therapeutic approach to prevent or reverse cancer cachexia.
Citation Format: Young-Mee Kim, Georgina Mancinelli, Paul Grippo, Jalees Rehman. Cancer cachexia is mediated by the suppression of PGC1-alpha expression in the skeletal muscle vasculature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2595.
Abstract 2597: Non-clinical studies of systemic delivery of oncolytic virus arms with IL-12 and anti-PD-1 antibody
Authors: Zheng Yanxin , Yan Runbin , Tang Yuxin , Zhan Borui , Huang Yue , Ni Dongyao , Chen Xiaoqing , Zhou Grace 
Published: July 2021

Abstract
Background: Limited success has been reported with intravenous delivery of oncolytic viruses because of dilution of viruses in the blood volume, rapid clearance of viral particles and sequestration in non-target organs. We have reported construction of MVR-T3011, a recombinant oncolytic herpes virus embodies immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody. Intratumoral Injection of MVR-T3011 has entered into clinical stage for the study of its safety and preliminary efficacy. Here we propose systemic delivery of MVR-T3011 by intravenous (IV) injection to treat tumor types that are not easily accessible by local injection.
Methods: The pharmacological activity, safety and biodistribution of MVR-T3011 by intravenous injection have been studied in immune deficient and competent mouse model.
Results: (i) In immune deficient mice, MVR-T3011 is enriched in tumor following tail vein injection. MVR-T3011 inhibits tumor growth of A549 xenograft. (ii) In immune competent mice, MVR-T1013L, the virus backbone carries a reporter gene encodes luciferase was enriched in upper abdomen and thorax 24hr following IV injection. (iii) IV administration of mouse surrogate oncolytic virus MVR-T3855 extended survival of mice in B16-F10 mouse melanoma lung metastasis model, LLC mouse orthotopic lung cancer model and H22 mouse orthotopic hepatocarcinoma model significantly. (iv) IV administration of MVR-T3855 delayed the onset of peritoneal effusion in H22 mouse hepatocarcinoma model significantly. (v) The biodistribution studies showed: following IV injection, tumor viral DNA reached peak level at 24hr, and dropped to baseline at 48hr; Subsequent injection showed similar patterns with lower peak levels. Consistent virus DNA level in the blood was detected without spike of viral DNA in other tissues probably due to non-complete virus genome circulating following virus clearance. Both IL-12 and anti-PD-1 antibody were detected in tissue and/or blood with low level 24hr following injection.
Conclusions: MVR-T3011 is a suitable herpes oncolytic virus agent for intravenous injection through studies of pharmacological activity, safety and biodistribution. The significant finding reported in this article is clinical potential of herpes oncolytic virus for extensive metastatic tumors.
Citation Format: Yanxin Zheng, Runbin Yan, Yuxin Tang, Borui Zhan, Yue Huang, Dongyao Ni, Xiaoqing Chen, Grace Zhou. Non-clinical studies of systemic delivery of oncolytic virus arms with IL-12 and anti-PD-1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2597.