bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2972: Urolithin A decreases cell proliferation of three genetically diverse glioblastoma multiforme cell lines
Authors: Hearne Alexandra Lynn , Brockway Dakota , Wu Shiyong , Li Yunsheng 
Published: September 2020

Abstract
Glioblastoma multiforme is one of the most common and malignant tumors of the central nervous system, remaining incurable with a median survival time of only 15 months. Over the past 50 years there has been little change in this overall survival rate, due to the many challenges in treating glioblastoma, including molecular complexity, tumor location, and resistance towards standard therapies. Therefore, an improved method for treating glioblastoma is urgently needed. Urolithin A is a natural biometabolite from ellagitannins and ellagic acid, which can be found in pomegranates, berries, and nuts. Urolithin A exhibits anti-cancer activities in several cancer cell lines, including prostate, colon, and bladder cancer cells. However, the anti-cancer activities of urolithin A have yet to be characterized in glioblastoma multiforme. In this project, we investigated whether urolithin A could reduce human glioblastoma cell proliferation by conducting clonogenic assays and cell cycle analysis in three genetically diverse human glioblastoma cell lines: U87MG, T98G, and LN229. Clonogenic assay results showed that urolithin A significantly decreased cell proliferation in a dose-dependent manner in all three glioblastoma cell lines. Depending on the different cell lines, the cell proliferation was inhibited at concentrations of 10 to 60 µM urolithin A. In addition, cell cycle analysis via flow cytometry found that urolithin A was capable of arresting cell cycle progression in either the G2/M or S phase of the cell cycle in U87 and LN229 or T98G cells, respectively.
In conclusion, we have found that urolithin A can reduce cell proliferation and alter cell cycle progression of three genetically diverse glioblastoma cell lines. Importantly, urolithin A can pass the blood-brain barrier and has previously shown to be non-toxic in humans, a prerequisite for a drug to treat glioblastoma. Therefore, urolithin A has the potential to be used as a novel drug which can be combined with current standard methods to improve the efficacy of glioblastoma treatment. In the future, we plan to investigate specific signaling pathways involved in apoptosis, cellular proliferation, and cell cycle arrest. Once we elucidate the specific mechanisms we will investigate the efficacy of urolithin A in vivo, using an animal model. If successful, urolithin A will have the potential to be used alongside radiation and chemotherapy to further reduce glioblastoma cell proliferation.
Citation Format: Alexandra Lynn Hearne, Dakota Brockway, Shiyong Wu, Yunsheng Li. Urolithin A decreases cell proliferation of three genetically diverse glioblastoma multiforme cell lines [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 2972.
Abstract 2978: Cyclic GMP-independent inhibition of colon cancer cell growth by phosphodiesterase inhibitors
Authors: Islam Bianca N. , Hou Yali , Mylarapu Namratha , Browning Kaylin A. , Vega Kenneth J. , Browning Darren D. 
Published: September 2020

Abstract
There is growing interest in the potential use of phosphodiesterase (PDE) inhibitors for colon cancer chemoprevention, but the tumor suppressive mechanism is not understood. The present study has tested the idea that PDE inhibitors can suppress growth and promote apoptosis of colon cancer cell lines by increasing cGMP and activating cGMP-dependent protein kinase (PKG). Treatment of LS174T, Caco2, and HCT116 colon cancer cells with membrane permeable 8Br-cGMP had no effect on cell proliferation or viability. Endogenous PKG was undetectable in any of these cells using phosphorylation of the PKG substrate vasodilator-stimulated phosphoprotein (VASP) as a readout. Ectopic expression of PKG2 conferred modest inhibition of proliferation by cGMP treatment (15-25% over 3 days), but did not affect cell viability. The lack of effect of cGMP on colon cancer proliferation is incongruous with many reported effects of PDE inhibitors. To understand the reason for the discrepant observations, colon cancer cells were treated with sildenafil, PF-0447943, and TAK-063 that are specific inhibitors of the cGMP-targeting PDE5, 9, 10a (respectively). At clinically unachievable concentrations exceeding 10μM, all of these drugs reduced proliferation to various degrees in the different cell lines. TAK-063 was the most effective, and the only one that reduced cell viability. Notably, growth-inhibition by the PDE inhibitors was independent of PKG expression, and surprisingly, none of them increased cGMP levels. The inability of the PDE inhibitors to increase cGMP was due to the lack of endogenous cGMP generation, because treatment with the guanylyl-cyclase C agonist linaclotide conferred a robust cGMP response to a physiological dose of sildenafil (1µM). The growth inhibitor effects of high, non-physiological levels of PDE inhibitors is likely due to off-target effects, but apart from a transient inhibition of the ERK pathway, no common mechanism was identified. Taken together, these results refute the idea that cGMP elevating agents prevent colon carcinogenesis by inhibiting cancer cell growth, and support the inhibition of tumor initiation as a more likely mechanism.
Citation Format: Bianca N. Islam, Yali Hou, Namratha Mylarapu, Kaylin A. Browning, Kenneth J. Vega, Darren D. Browning. Cyclic GMP-independent inhibition of colon cancer cell growth by phosphodiesterase inhibitors [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 2978.
Abstract 2980: Effects of cetuximab and CD-3379 on cytokine/chemokine balance in the tumor micro-environment (TME) of squamous cell carcinoma of the head and neck (SCCHN)
Authors: Wang Dongsheng , Nannapaneni Sreenivas , Lesinski Gregory B. , Shin Dong M. , Saba Nabil F. , Chen Georgia Z. 
Published: September 2020

Abstract
Background: The Anti-EGFR agent cetuximab has shown promising outcomes and remains to be the only FDA-approved non-immunotherapeutic targeted agent for the treatment of squamous cell carcinoma of the head and neck (SCCHN). There is evidence that immune modulation represents a mechanism by which cetuximab elicits its clinical activity in SCCHN. As resistance inevitably occurs to cetuximab, there is a need to further elucidate the biological mechanisms by which cetuximab affects immune effectors in the tumor microenvironment (TME). We aimed to explore the effect of EGFR inhibition on the cytokine/chemokine balance in the TME.
Methods: Three SCCHN cancer cell lines UM-SCC47 (HPV positive), JHU022 (HPV negative), and SCC-1C (HPV negative and resistant to cetuximab) were treated with cetuximab, CD-3379 (a HER3 inhibitor), and their combination. After 48 and/or 72 hours, the supernatants of the treated and untreated cells were collected and subjected to multiplexed immunoassay [Meso Scale Discovery (MSD) U-PLEX Assays] to study the cytokine/chemokine alteration. Changes in immune suppressive chemokines were confirmed by ELISA. A potential effect of a chemokine neutralizing antibody on apoptosis was further evaluated using patient-derived organotypic cancer spheroids (PDOCSs).
Results: Our results identified 10 down regulated cytokines/chemokines, including IL6, IL-8, IL-2, IL-12, IL-27, IL-4, IL-5, TGF-β, GM-CSF, and IFN-γ in at least one SCCHN cell line. Three cytokines/chemokines were up regulated, including IL-15, MCP-3, and MCP-1. MCP-1 (CCL2) is a modulator of myeloid-derived suppressor cells (MDSCs). Enhancing MCP-1 by cetuximab and/or CD-3379 in the SCCHN cell lines was confirmed by ELISA. Treating multiple PDOCSs with the same combination along with MCP-1 neutralizing antibody enhanced apoptosis in comparison to cetuximab, CD-3379, or the cetuximab/CD-3379 combination.
Conclusions: Our findings suggest that cetuximab in combination with HER3 inhibition affects secretion of cytokines/chemokines which are both immune stimulatory and suppressive in the TME of SCCHN. Alteration of the selected cytokines/chemokines may enhance the clinical activity of EGFR targeting in SCCHN.
Citation Format: Dongsheng Wang, Sreenivas Nannapaneni, Gregory B. Lesinski, Dong M. Shin, Nabil F. Saba, Georgia Z. Chen. Effects of cetuximab and CD-3379 on cytokine/chemokine balance in the tumor micro-environment (TME) of squamous cell carcinoma of the head and neck (SCCHN) [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 2980.
Abstract 2983: A synthetic derivative of 1,2,3-triazole-pyrimidine hybrid reverses multidrug resistance mediated by MRP7
Authors: Wang Jing-Quan , Lei Zi-Ning , Teng Qiu-Xu , Wang Bo , Ma Li-Ying , Liu Hong-Min , Chen Zhe-Sheng 
Published: September 2020

Abstract
Multidrug resistance protein 7 (MRP7) is an important member of ABC transporter superfamily and has been revealed to transport a wide range of chemotherapeutic agents including taxanes, epothilone B, vinca alkaloids, daunorubicin and etoposide. In our previous study, a 1,2,3-triazole-pyrimidine hybrid 25 was synthesized and found significantly reversing multidrug resistance (MDR) mediated by ABCB1. In this study, we evaluated the efficacy of compound 25 in reversing MDR mediated by MRP7 in vitro. The results showed that 25 significantly sensitized cells overexpressing MRP7 to anticancer drugs that are MRP7 substrates at 3 μ;;M. Mechanism study showed that 25 reversed MRP7-mediated MDR by increasing the intracellular accumulation of anticancer drugs and decreasing drug efflux, without altering protein expression level or intracellular localization. Ligand-protein interactions were also modeled by docking with homology MRP7 model. Since limited researches on synthetic MRP7 modulators have been published, our findings provide a valuable prototype for structures which have the potential to be used in combination with conventional anticancer drugs to overcome MDR-mediated by MRP7.
Citation Format: Jing-Quan Wang, Zi-Ning Lei, Qiu-Xu Teng, Bo Wang, Li-Ying Ma, Hong-Min Liu, Zhe-Sheng Chen. A synthetic derivative of 1,2,3-triazole-pyrimidine hybrid reverses multidrug resistance mediated by MRP7 [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 2983.
Abstract 3006: Anticancer and multidrug resistance-reversing activities of novel antimicrobial peptides
Authors: Teng Qiu-Xu , Lei Zi-Ning , Luo Xiaofang , Wang Jing-Quan , Qin Zuodong , Wurpel John N. , Chen Zhe-Sheng 
Published: September 2020

Abstract
Cancer is a growing concern in public health problems worldwide. Although the development of advanced chemotherapies has already partly reduced the cancer death rate and improved patients' prognosis, the phenomenon of multidrug resistance (MDR), which impairs the efficacy of a serial structure-unrelated anticancer agent, casts a large shadow over the bright future of chemotherapies. MDR has various mechanisms to induce acquired drug resistance of cancer cells after a relatively long period of chemotherapy. One of the most common causes of MDR is the expression of ATP-binding cassette (ABC) transporters, which act as efflux pumps on cancer cell membranes and transport anticancer drugs out of cancer cells thereby reducing the intracellular drug concentration. The growing resistance of cancer cells to current anticancer drugs leads to the urgent need to develop anticancer drugs with a new mechanism of action. Over the past decade, antimicrobial peptides have entered the view of scientists as a new generation of anticancer drugs. In this study, the anticancer effects and the reversal activities against ABC transporter mediated MDR of four novel antimicrobial peptides were investigated. The results showed that, at non-toxic concentrations in vitro, peptides #7, #14, #22, and #24 significantly sensitized ABCB1- and ABCC1-overexpressing cell lines, including both drug-selected MDR cancer cell lines and ABCB1 or ABCC1 gene transfected HEK293 cell lines, to the substrate anticancer drugs paclitaxel and vincristine. Among the antimicrobial peptide compounds, #14 and #24 with the most potent reversal ability were selected for further investigation. These peptides increased the intracellular accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells and that of [3H]-vincristine in ABCC1 overexpressing cells by suppressing the efflux function of ABCB1 and ABCC1 transporters, without causing alteration in the expression levels and localization patterns of ABCB1 and ABCC1 in overexpressing cells. Furthermore, the results of the ATPase assay showed that both two peptides stimulated ABCB1 ATPase activity. Taken together, these results demonstrated that peptide #14 and #24 reverse ABCB1- and ABCC1-mediated MDR through blocking the function of ABCB1 and ABCC1 without affecting the transporters' expression and cellular localization, which suggests that antimicrobial peptides may be used as a novel prospective cancer therapeutic strategy in the combination with traditional anticancer agents.
Citation Format: Qiu-Xu Teng, Zi-Ning Lei, Xiaofang Luo, Jing-Quan Wang, Zuodong Qin, John N. Wurpel, Zhe-Sheng Chen. Anticancer and multidrug resistance-reversing activities of novel antimicrobial peptides [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 3006.
Abstract 3020: Tumor pharmacokinetics of the metastatic cancer inhibitor MBQ-167 in mice
Authors: Del Mar Maldonado Maria , Cruz-Collazo Ailed M. , Borrero-García Luis D. , Rosado-González Gabriela T. , Ruiz-Calderon Jean F. , Duconge Jorge , Dharmawardhane Suranganie 
Published: September 2020

Abstract
The Rho GTPases Rac and Cdc42 are potential targets against metastatic disease. Our group characterized the small molecule MBQ-167 as an effective dual Rac/Cdc42 inhibitor that reduces HER2 positive and triple negative tumor growth and metastasis in mice by ~90%. To continue validating this drug for FDA approval, we recently elucidated the plasma pharmacokinetics and the tissue distribution of MBQ-167 in mice (Maldonado et al., 2019). However, further studies are needed to characterize the tumor pharmacokinetics of MBQ-167 to determine drug exposure, time-to-peak, and the length of time that MBQ-167 remains in tumors after administration. The purpose of this study was to determine the tumor pharmacokinetics of MBQ-167 in a single dose input scheme (10 mg/kg BW) following intraperitoneal (IP) administration. Thirty-five female BALB/c mice (5 mice/group) were injected with 2.5 × 105 4T1 murine metastatic breast cancer cells at the mammary fat pad. After tumor establishment, a single dose of MBQ-167 (10 mg/kg BW) was administered via IP. Tumors were collected at 0.5, 1, 3, 6, 9,12, and 24 hours following drug administration. We used a validated bioanalytical method using supercritical fluid chromatography coupled with tandem mass spectrometry (SFC-MS/MS) to quantify MBQ-167 in tumors. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNolin® software. Pharmacokinetic analysis revealed that MBQ-167 has an elimination half-life (t1/2) of 8.64 hours in tumors, which is much longer than its half-life in plasma (2.17 hours), indicating preferential absorption and retention of this lipophilic small molecule in tumor tissues. The area under the curve (AUC0-t) was 4.39 %ID⋅hr/g with a maximum concentration (Cmax) of 1268.9 ng/g in tumors. Moreover, the time-to-peak concentration in tumors was 0.5 hours. Hence, this study supports the continued development of MBQ-167 as a potential anti-cancer therapeutic.
Citation Format: Maria Del Mar Maldonado, Ailed M. Cruz-Collazo, Luis D. Borrero-García, Gabriela T. Rosado-González, Jean F. Ruiz-Calderon, Jorge Duconge, Suranganie Dharmawardhane. Tumor pharmacokinetics of the metastatic cancer inhibitor MBQ-167 in mice [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 3020.
Abstract 3101: Utility of a new targeted next generation sequencing test for liquid biopsy samples from patients with NSCLC
Authors: Reese Jordan , Maxwell Victoria , Jackson Leisa , Pestano Gary , Mellert Hestia S. 
Published: September 2020

Abstract
Blood-based methods for profiling tumor-sourced nucleic acids have become increasingly important in the diagnostic workup for cancer patients, particularly in non-small cell lung cancer (NSCLC). Blood-based assays address several limitations of tissue-based testing approaches such as inaccessible lesions, limited tissue, extended time to results, and invasive specimen collection procedures. Broad-profiling next-generation sequencing (NGS) methods are used to detect rare variants in blood samples. Here we describe the utility of a newly developed 52 gene NGS test, which uses the GeneStudio S5 Prime platform. We report on performance verification of the assay using contrived specimens as well as studies which evaluated clinical specimens at diagnosis and during monitoring. Thirty-eight cell-free nucleic acid (cfNA) specimens were evaluated from donors previously diagnosed with NSCLC. Specimens were collected in blood collection tubes containing preservatives (Streck cfDNA BCT) and shipped at ambient temperature to our central testing Laboratory. cfNA was isolated from plasma and reverse transcribed. The sequencing metrics for these studies included an average of 15 million mapped reads, 94.4% of on target reads, and a mean sequencing depth of 52,000. Additionally, the average molecular coverage was 2400 reads per amplicon with 99.9% uniformity at 500x coverage. Detected variants and their allelic frequencies were compared with reference results from a validated ddPCR method. Eleven variants (6 EGFR and 5 KRAS) were detected in the cohort with allele frequencies ranging from 0.90 - 96.16%. Results were highly concordant between the two methods (R2=0.992) with 90.3% sensitivity and 100% specificity. In addition, we present a case study to further demonstrate clinical utility of NGS for longitudinal monitoring over 540 days for clearance followed by re-emergence of EGFR positive cfNA harboring the EGFR C797S resistance mutation. These studies add to the growing body of knowledge supporting the utility of molecular detection for actionable and emerging biomarkers in liquid biopsy.
Citation Format: Jordan Reese, Victoria Maxwell, Leisa Jackson, Gary Pestano, Hestia S. Mellert. Utility of a new targeted next generation sequencing test for liquid biopsy samples from patients with NSCLC [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 3101.
Abstract 3106: Accurate estimation of circulating tumor DNA fraction from ultra low-pass whole-genome sequencing
Authors: Finkle Justin , Lo Christine , Boulos Hala , Driessen Terri , Zhu Wei , Tell Robert 
Published: September 2020

Abstract
Early detection of recurrence is critical to improve the survival of cancer patients. Blood-based “liquid biopsies” provide a minimally invasive method to detect variants, and ultra low-pass whole-genome sequencing (LPWGS) can accurately and sensitively detect low fractions of circulating tumor DNA in blood plasma. We previously conducted LPWGS on approximately 400 samples (primarily from lung, breast, prostate, and pancreatic cancers) residual to samples previously analyzed with our xF liquid biopsy assay. In this analysis, we demonstrate that circulating tumor fraction estimates from LPWGS correlate with the maximum detectable pathogenic variant allele fraction, and where there are discrepancies the LPWGS estimates are more reasonable. We also show differences in tumor fractions and ploidy between cancer cohorts and stages. Our results suggest LPWGS provides an accurate measure of the fraction of circulating DNA derived from tumors across cancer cohorts and stages.
Citation Format: Justin Finkle, Christine Lo, Hala Boulos, Terri Driessen, Wei Zhu, Robert Tell. Accurate estimation of circulating tumor DNA fraction from ultra low-pass whole-genome sequencing [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 3106.
Abstract 310A: Transcription factors FOXP3 regulate ATF3 expression
Authors: Yang Wei-Hsiung , Wang Chiung-Min , Yang William 
Published: September 2020

Abstract
Activating transcription factor 3 (ATF3), a stress sensor, is rapidly induced by a variety of physiological and pathological signals, including those from cancer cells, and is essential in the complex processes of stress response. Several lines of evidence have demonstrated that ATF3 is involved in host defense and cancer development. Several studies also provide the relationship between ATF3 and p53 indicating that ATF3 binds to and stabilizes p53 while ATF3 is a negative regulator of TP53 gene expression. FOXP3, a well-known breast and prostate tumor suppressor, is a novel transcriptional repressor for several oncogenes including SKP2. However, whether ATF3 is the target protein of FOXP3 remains unknown. Herein, we demonstrate that ATF3 expression is regulated by FOXP3. First, we observed that overexpression of FOXP3 reduced ATF3 protein level in several cancer cell lines (H1299, HepG2, and Ishikawa cells). Secondly, FOXP3 dose-dependently reduced ATF3 promoter activity in gene reporter assay in several cell lines (MCF7, H1299, MDAMB231, and Saos2 cells). Since FOXP3 is regulated by post-translational modifications (PTMs), we next investigated whether PTMs affect FOXP3-mediated ATF3 expression. Interestingly, we observed that phosphorylation mutation on FOXP3 (Y342F) abolished FOXP3-mediated ATF3 expression. However, other PTM mutations on FOXP3, including S418 phosphorylation, K263 acetylation and ubiquitination, and K268 acetylation and ubiquitination, did not alter FOXP3-mediated ATF3 expression. Finally, FOXP3 binding site was found on ATF3 promoter region, around -870 bp region. Taken together, our results suggest that FOXP3 functions as a novel regulator of ATF3 and this novel event may be involved in tumor development and progression.
Citation Format: Wei-Hsiung Yang, Chiung-Min Wang, William Yang. Transcription factors FOXP3 regulate ATF3 expression [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 310A.