bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4519: The reciprocal interaction between neutrophil extracellular traps and cancer cells impacts on their malignant potentials
Authors: Kajioka Hiroki , Kagawa Shunsuke , Ito Atene , Kuwada Kazuya , Kikuchi Satoru , Kuroda Shinji , Yoshida Ryuichi , Tazawa Hiroshi , Fujiwara Toshiyoshi 
Published: August 2019

Abstract
Although the neutrophil extracellular traps (NETs) are first recognized to function to trap invading microorganisms and eliminate them as a defense mechanism, the involvement of NETs in cancer metastasis is being elucidated. The mechanism of interaction between NET and cancer cells, however, remains to be fully understood. Here, we investigated the direct and indirect interaction between NETs and cancer. NETs were detected in surgically resected metastatic liver cancer tissue specimens. In direct co-culture, NETs actually attracted cancer cells with their web-like structure. Of note, indirect transwell co-culture of neutrophils and pancreatic cancer cells provoked NETs without the other stimuli. In addition, conditioned media derived from cancer cells also induced NETs. The co-culture of NETs and cancer cells dramatically accelerated their migration and invasion abilities. Further investigation revealed that NETs induced mesenchymal markers in cancer cells which was associated with upregulated epithelial to mesenchymal transition (EMT)-related transcriptional factors. Finally, the accelerated cancer migration and overexpression of mesenchymal markers induced via NETs were inhibited by pharmacological blockade of NETs including NADPH oxidase inhibitor, peptidylarginine deiminase inhibitor, and neutrophil elastase inhibitor. These results suggested that cancer cells and neutrophils reciprocally interact when they coexist and NETs drive malignant potentials via EMT, implicating NETs as a candidate therapeutic target.
Citation Format: Hiroki Kajioka, Shunsuke Kagawa, Atene Ito, Kazuya Kuwada, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara. The reciprocal interaction between neutrophil extracellular traps and cancer cells impacts on their malignant potentials [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 4519.
Abstract 4540: Discover cell signaling pathways using antibody arrays
Authors: Tang Hao , Fang Jianmin , Kuang Zhizhou , Huang Ruo-Pan 
Published: August 2019

Abstract
Cell Signaling pathways are complex networks that are normally regulated and connected by multiple components. Analyzing signaling pathways is essential for understanding the molecular mechanism of human disease and drug development. However, it remains a great challenge to study pathways using traditional methods. Thus, a high-content and high-throughput method for simultaneous detection of multiple targets is necessary. Using a sandwich-based ELISA format, we have developed an antibody array technology which can simultaneously identify relative expression levels or phosphorylation levels of major signaling pathway proteins. This array-based system features a nitrocellulose membrane or glass slide solid support, each spotted with up to 71 different antibodies against a selected panel of classical signaling pathway proteins, including RTK, EGFR, MAPK, AKT, Apoptosis, TGFb, JAK/STAT, NFkB and Insulin Receptor pathways, spanning 182 total proteins. To test our system, we investigated the molecular mechanism of Camptothecin’s anti-cancer effect using several pathway arrays. Our array data suggest that Camptothecin-treatment induced DNA double-strand breaks in Jurkat cell activates the DNA damage pathways ATM and Chk2, and then further induces apoptosis through Caspase 3 and BAD. We also studied phorbol 12-myristate 13-acetate (PMA)’s effect on HeLa cells, and found that PMA induces the MAPK pathway through activation of Erk, MSK2, and RSK1. These array results are consistent with previous studies using traditional methods and were further confirmed by western blot analysis. Our studies demonstrate that pathway antibody arrays provide a rapid and efficient approach to study the mechanism of cell events, human diseases and drug effects. With this technology, researchers can quickly screen activation of multiple target proteins in one or multiple pathways in their experimental system.
Citation Format: Hao Tang, Jianmin Fang, Zhizhou Kuang, Ruo-Pan Huang. Discover cell signaling pathways using antibody arrays [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 4540.
Abstract 4544: PTP4A3 expression associated with increased invasion in esophageal adenocarcinoma
Authors: Wang Zhuwen 
Published: August 2019

Abstract
Esophageal adenocarcinoma (EAC) is the most rapidly growing solid malignancy with an overall 5-year survival rate of only 19%. The majority of EACs are diagnosed with advanced locoregional disease requiring neoadjuvant chemoradiation followed by esophagectomy. Understanding the molecular mechanisms associated with locoregional invasion are crucial for improving the treatment outcome.
Protein tyrosine phosphatase (PTP) type IVA member 3 (PTP4A3/PRL-3) is part of the PTP subfamily, which are phosphatases with dual-specificity. PTP4A3 has been shown to be overexpressed in a number of cancer types and often correlates with cell proliferation, migration, invasion, tumor growth, and metastasis. Here, we examine PTP4A3’s potential role in the invasive properties of EAC.
Methods: We analyzed PTP4A3 mRNA levels of 122 chemo-naïve EAC samples using Human Gene 2.1 ST Arrays and compared these to available histological features. We also used RNA-seq analysis to examine the expression of PTP4A3 in 68 samples that consisted of Barrett’s Esophagus, low-grade dysplasia, high-grade dysplasia, and EAC. PTP4A3 knockdown was achieved by using small interfering RNA and a rhodamine derivative (BR-1) inhibitor and was confirmed by both RT-PCR and Western blot. WST and clonogenic assays were performed to assess cell proliferation in cell lines derived from EAC tumors. Cell invasion and migration were measured by matrigel invasion and cell migration assays.
Results: PTP4A3 was significantly overexpressed in EAC samples compared to a cohort of normal esophageal samples (p&lt;0.001). In addition, the expression of PTP4A3 increased with progression from Barrett’s to EAC. PTP4A3 was overexpressed in 15 EACs relative to 26 Barrett’s samples on U133A Array, which was confirmed in the 68-sample RNAseq progression cohort (p&lt;0.01). Analysis of 122 EAC samples indicated that overexpression of PTP4A3 was significantly associated with decreased survival (p&lt;0.05) and correlated with poor differentiation, high immune cell infiltration, and a high desmoplastic response (p&lt;0.05). Inhibition of PTP4A3 in EAC cell lines led to a decrease in cell invasion and migration (p&lt;0.01). However, there was no significant change in cell proliferation following knockdown.
Conclusion: PTP4A3 is frequently overexpressed in EAC and is associated with decreased survival. Inhibition of PTP4A3 decreased matrigel invasion and cancer cell migration, suggesting that PTP4A3 may play a role in the invasion and metastases of EAC cells and could serve as a biomarker of more aggressive disease.
Note: This abstract was not presented at the meeting.
Citation Format: Zhuwen Wang. PTP4A3 expression associated with increased invasion in esophageal adenocarcinoma [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 4544.
Abstract 4611: Identifying drivers of mammary tumorigenesis & elucidating the mechanisms of cancer initiation in DNA replication defective Chaos3 mice
Authors: Winters Marquita , Schimenti John 
Published: August 2019

Abstract
Distinguishing commonly deleted genes as drivers or passengers of human cancers are key to delineating mechanisms of tumor initiation. The “Chaos3” mouse model of spontaneous breast cancer carries a missense mutation in a gene called Mcm4 (minichromosome maintenance 4), causing destabilization of the MCM2-7 replicative helicase, which in turn causes elevated genomic instability. Approximately 80% of female mice homozygous for this mutation in the C3HeB/FeJ strain background develop mammary tumors with an average latency of 12 months. Genomic analysis of these tumors revealed a recurrent subset of genes with copy number alterations such as Arid1a and Nf1. This project aims to: 1) test whether the genes Arid1a and Nf1 act as mammary tumor drivers in the Chaos3 breast cancer model; 2) understand the genome-wide effects of Arid1a loss in mammary tumorigenesis; 3) identifying potential therapeutic targets for Arid1a-deficient mammary tumors; and 4) unravel the mechanism by which destabilization of MCM2-7 replicative helicase leads to cancer onset. To achieve these aims, several experiments such as conditional mutagenesis, CUTandRUN, RNA-seq, and replication timing profiling were conducted to address my aims. Preliminary data indicates that heterozygous loss of Arid1ain Chaos3 mammary tumors produces a distinct transcriptional profile compared to mammary tumors without Arid1a deletion. Additionally, Chaos3 primary cells have markedly altered replication timing patterns in certain regions of the genome that might explain increased susceptibility to mutations. My experiments can validate new candidates like Arid1a as a driver of sporadic breast cancer in humans. In addition, these studies will not only lend insight into how key tumor suppressors are deleted in the Chaos3 model, but also potentially reveal features of genomic regions that are particularly susceptible to genetic or environmental perturbations to DNA replication. The Chaos3 sporadic breast cancer mouse model mimics sporadic human luminal breast cancer and can be used as a tool to better understand the biology and genetics of a common disease that plagues women worldwide.
Citation Format: Marquita Winters, John Schimenti. Identifying drivers of mammary tumorigenesis & elucidating the mechanisms of cancer initiation in DNA replication defective Chaos3 mice [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 4611.
Abstract 4648: Cellular senescence and transformation induced by an oncogenic EML4-ALK fusion gene in normal and immortalized human cells
Authors: Miyanaga Akihiko , Horikawa Izumi , Matsumoto Masaru , Oike Takahiro , Beck Jessica , Tanaka Hiromi , Robles Ana I. , Seike Masahiro , Gemma Akihiko , Harris Curtis C. 
Published: August 2019

Abstract
Background: Chromosomal inversions involving Anaplastic lymphoma kinase (ALK) and Echinoderm Microtubule Associated Protein Like 4 (EML4) generate a fusion protein EML4-ALK with the constitutive ALK kinase activity in non-small cell lung carcinoma (NSCLC). The basic understanding of EML4-ALK remains insufficient due to the lack of functional studies using normal human cells.
Material and Method: We investigate the activities of EML4-ALK in mortal and immortalized normal human cells.
Results: The expression of EML4-ALK in normal, mortal human fibroblasts caused, through its ALK kinase activity, the early induction of cellular senescence with senescence-associated β-galactosidase activity, upregulation of p16INK4A and p21WAF1, telomere shortening and fusions, and accumulated DNA damage. In contrast, when EML4-ALK was expressed in telomerase reverse transcriptase (hTERT)-immortalized normal human fibroblasts, the cells showed accelerated proliferation and anchorage-independent growth, revealing its transformation activity. No chromosome aberration, no mutation or loss of p53, nor impairment of the p16INK4A response was associated with this transformation, likely reflecting clinical features of EML4-ALK-positive NSCLC. In both mortal and immortalized cells, EML4-ALK induced the phosphorylation of STAT3, which is involved in both cellular senescence and transformation. EML4-ALK was also able to transform hTERT-immortalized human bronchial epithelial cells, a cell type relevant to NSCLC.
Conclusions: Our data not only validate that EML4-ALK functions as an oncogene in human cells, but also suggest that telomerase-mediated immortalization manifests the oncogenic activity of EML4-ALK, switching from its senescence-inducing activity. This study also provides the isogenic pairs of human cell lines with and without EML4-ALK as an in vitro model for screening and testing candidate drugs.
Citation Format: Akihiko Miyanaga, Izumi Horikawa, Masaru Matsumoto, Takahiro Oike, Jessica Beck, Hiromi Tanaka, Ana I. Robles, Masahiro Seike, Akihiko Gemma, Curtis C. Harris. Cellular senescence and transformation induced by an oncogenic EML4-ALK fusion gene in normal and immortalized human cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4648.
Abstract 4714: Preclinical evaluation of a novel LSD1 inhibitor SYHA1807 for the treatment of small cell lung cancer
Authors: Wu Lingyun , Yang Hanyu , Zhao Lele , Sun Jianjun , Liu Jian , Xia Yuanfeng , Chan Chichung , Chen Shuhui 
Published: August 2019

Abstract
Histone post translational modification is an important epigenetic regulation to activate or suppress specific gene expressions. Methylation which is dynamically regulated by methyltransferase and demethylase (e.g. lysine specific demethylase) is one of the mechanisms and is critical for cell cycle and differentiation. Lysine specific demethylase 1 (LSD1) is the first identified histone modifying enzyme that removes methyl from histone lysine and arginine residues. Its overexpression has been found in many human cancers, like blood, lung and breast cancers. Small cell lung cancer is a neuroendocrine cancer characterized as low differentiation, rapid metastatic spread and resistance to regular chemotherapy. Aberration of epigenetic regulation is a common feature in small cell lung cancer, like down regulation of tumor suppression gene and up regulation of oncogenes. LSD1 expression of small cell lung cancer patients is up regulated in tumor tissue but not in normal tissues. Dysregulated histone methylation may contribute to the tumor malignance and treatment resistance. Taken together, LSD1 activity inhibition may provide a promising treatment option for small cell lung cancer. A challenge in LSD1 drug development is how to maintain optimal therapeutic effects while reducing mechanism related hematological toxicity. Through scaffold hopping and thoroughly SAR exploration, a novel LSD1 inhibitor SYHA1807 has been identified. The exposure level of this candidate at lung tissue is about four times higher than in bone marrow. The ideal drug tissue distribution characteristics may provide further safety assurance in clinical application. Detailed ADME/PK, in vitro, in vivo properties and preliminary safety evaluation results will be presented.
Note: This abstract was not presented at the meeting.
Citation Format: Lingyun Wu, Hanyu Yang, Lele Zhao, Jianjun Sun, Jian Liu, Yuanfeng Xia, Chichung Chan, Shuhui Chen. Preclinical evaluation of a novel LSD1 inhibitor SYHA1807 for the treatment of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4714.
Abstract 4718: SR-4370, a potent and selective inhibitor of class I HDACs, suppresses AR signaling and in vivo prostate tumor growth
Authors: Mahmud Iqbal , Tian Guimei , Wang Jia , Stowe Ryan , Huo Zhiguang , Zhang Yushan , Purayil Hamsa Thayek , Helm Eric , Drashansky Theodore , Avram Dorina , Daaka Yehia , Roush William R. , Liao Daiqing 
Published: August 2019

Abstract
Androgen receptor (AR) is an androgen-activated transcription factor and drives prostate cancer (PCa) progression. Class I HDACs 1-3 are critical for activating AR-mediated transcription. Thus, targeting these HDACs is a promising strategy for treating PCa. Notably, along with significant adverse effects, several FDA-approved HDAC inhibitors broadly inhibiting different HDACs were ineffective for treating castration-resistant prostate cancer in clinical trials. Significantly, entinostat, an aminobenzamide analog specific to HDACs 1-3, extended overall survival for patients with breast cancer resistant to endocrine therapy. These observations suggest that HDACi selective to HDACs 1-3 may be effective for treating solid tumors including PCa. We have recently discovered the novel benzoylhydrazide class of HDAC inhibitors highly specific to HDACs 1-3. An optimized analog, SR-4370, exhibited low µM to nM potency against HDACs 1-3. SR-4370 markedly suppressed AR signaling, PCa cell proliferation in vitro, and prostate tumor growth in vivo. Gene expression profiling experiments revealed that SR-4370 downregulated AR, AR-Vs and AR target genes as well as the MYC oncogenic network. Chromatin accessibility assay using ATAC-seq showed that SR-4370 altered chromatin states in PCa cells. The chromatins with AR-binding sites became inaccessible on SR-4730 treatment, indicating that altered chromatin accessibility may contribute to the inhibition of AR signaling. Interestingly, SR-4370 sensitized C4-2 cells to enzalutamide. In PCa xenograft models, SR-4370 was effective to suppress tumor growth in vivo. Importantly, SR-4370 was well tolerated and did not cause observable adverse effects as judged by body weight and blood chemistry tests of treated mice. Our data suggest that SR-4370 may be a safe and clinically applicable treatment for advanced PCa refractory to current frontline treatments. (Supported by UFHealth Cancer Center, Florida Breast Cancer Foundation, James and Esther King Biomedical Research Program, and Bankhead-Coley Cancer Research Program, Florida Department of Health)
Citation Format: Iqbal Mahmud, Guimei Tian, Jia Wang, Ryan Stowe, Zhiguang Huo, Yushan Zhang, Hamsa Thayek Purayil, Eric Helm, Theodore Drashansky, Dorina Avram, Yehia Daaka, William R. Roush, Daiqing Liao. SR-4370, a potent and selective inhibitor of class I HDACs, suppresses AR signaling and in vivo prostate tumor growth [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 4718.
Abstract 4728: IFNγ signaling drives EZH2 degradation to induce MHC-II expression in melanoma
Authors: James Jamaal L. , Opalenik Susan R. , Toren Abigail , Cook Rebecca S. , Balko Justin M. 
Published: August 2019

Abstract
Background: The molecular mechanisms governing anti-PD-1 resistance in melanoma are not fully understood. Suboptimal transcriptional and molecular response to interferon-gamma (IFNγ) is commonly identified in tumors with intrinsic or acquired resistance to anti-PD-1. Epigenetic regulators have been shown to reprogram IFNγ responses in some cases, though the mechanism is not clear. The ability of melanoma cells to express MHC-II is a positive clinical predictor to anti-PD-1 therapy, and MHC-II is induced only on cells with robust IFNγ responses. Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator with both methyltransferase-dependent and -independent function, can suppress IFNγ target genes and is frequently overexpressed in melanoma. However, the mechanisms whereby EZH2 interacts with the IFNγ pathway and its role in melanoma-specific MHC-II expression is not known.
Methods: HLA-DR (MHC-II)-proficient (A375, SKMEL28 and SKMEL5) and -deficient (CHL-1 and MEWO) melanoma cell lines were stimulated with IFNγ for up to 48h, and the modulation of EZH2 protein and function were studied temporally. To test the role of EZH2 in MHC-II (HLA-DR) expression in IFNγ responses, genetic (siRNA) and chemical (GSK343) EZH2 inhibition was utilized.
Results: EZH2 was highly expressed in all cell lines tested, regardless of HLA-DR-proficiency. In 2 out of 3 HLA-DR-inducible melanoma cell lines, EZH2 protein expression was downregulated (4-24 hrs) in response to IFNγ stimulation, without effects on EZH2 mRNA expression or downstream tri-methylated H3K27 expression. Blocking proteosomal degradation with MG-132 reversed the IFNγ-induced decrease in EZH2 expression in HLA-DR-proficient cell lines. After siRNA knockdown of EZH2, SKMEL28 cells increased constitutive HLA-DR expression, while A375 cells became more sensitive to IFNγ-induced HLA-DR upregulation. In addition, IFNγ-induced HLA-DR was increased in A375 cells with EZH2 inhibition using GSK343.
Conclusion: This work demonstrates a potential role for EZH2 in suppressing IFNγ responses, including the induction of MHC-II, in melanoma cells. EZH2 is subject to proteosomal degradation in MHC-II-inducible cell lines, which, in part, contributes to the expression of MHC-II.
Citation Format: Jamaal L. James, Susan R. Opalenik, Abigail Toren, Rebecca S. Cook, Justin M. Balko. IFNγ signaling drives EZH2 degradation to induce MHC-II expression in melanoma [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 4728.
Abstract 4729: Targeting c-MYCdegradation as a novel therapeutic strategy for osteosarcoma: Studies in canine and human osteosarcoma cells
Authors: Yang Ya-Ting , Yuzbasiyan-Gurkan Vilma , Tepe Jetze J. 
Published: August 2019

Abstract
Osteosarcoma (OS) is the most common bone tumor in both humans and dogs, and has a nearly ten-fold higher incidence in dogs than humans. For the past twenty years, despite advances in treatment of other cancers, the overall survival rates for OS have stagnated. Thus, there is a great need for novel therapeutic strategies. In osteosarcoma, MYC activation is critical for both initiation and maintenance of tumorigenesis and tissue invasion. While targeting c-MYC is a rational strategy to treat OS, c-MYC has evaded therapeutic manipulation to date. In this study, we evaluated using a novel proteasome modulator, TCH-165, which induces c-MYC degradation, and compared it with convention treatments in in vitro studies. We demonstrated dose dependent decrease of c-MYC protein expression with TCH-165 treatment. Utilizing seven canine OS cell lines and three human OS cell line, we determined that the IC50 values for TCH-165 range from 2.2 to 11.6 μM in canine OS, 3.1 to 4.5 μM in human OS cell lines, while IC50 of several primary canine ranged from 22.3 μM to &gt;200μM, suggesting a wide margin of safety. In cell cycle studies, we showed that TCH-165 resulted in G1 arrest after 12 hours of incubation. In addition, we examined the potential of combing TCH-165 with convention therapeutic agents. We selected carboplatin, one of the standard anti-tumor drugs for OS. Combination index calculations using TCH-165 and carboplatin in the canine D17 cell line support synergistic effects of this combination. The data point to potential novel avenues for treatment of OS which can be further examined in proof of concept studies in dogs with OS, serving as a relevant translational model, and accelerate drug development for human OS patients.
Citation Format: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan, Jetze J. Tepe. Targeting c-MYCdegradation as a novel therapeutic strategy for osteosarcoma: Studies in canine and human osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4729.