bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1497: A PRC2 independent role of EZH2 in androgen receptor signaling in prostate cancer
Authors: Lee Yongik , Kim Jung a , Changsheng Zhao , Lu Xiadong , Fong Ka Wing , Yu Jindan 
Published: August 2018

Abstract
Prostate cancer is the most frequently diagnosed cancer and third most frequent cause of cancer deaths in US males. Prostate cancer patients have benefitted from androgen deprivation therapy and small molecular inhibitors targeting androgen receptor (AR). However, 30% of patients have primary resistance to both forms of treatment with a majority of patients eventually developing resistance to these therapies and progressing from androgen dependent prostate cancer (ADPC) to castration resistant prostate cancer (CRPC). Unfortunately, there are no effective therapeutic options available for CRPC patients, so novel and more effective therapeutic strategies for CRPC are urgently needed. Enhancer of Zeste 2 (EZH2) is a well-characterized oncogene that is one of the most highly upregulated genes in aggressive PCa and suggested as a prognostic biomarker. EZH2 is a part of polycomb repressive complex2 (PRC2) with embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12) to function as a repressor through the SET domain, especially Histidine 689 to methylate H3K27. Recently, some studies suggest a context-dependent or PRC2 independent function of EZH2, but new functional role of EZH2 in cancer that are yet to be delineated. In the present study, we demonstrated EZH2 enhances AR signaling through direct AR promoter occupancy at exon1, independent of histone methyltransferase activity. EZH2 has a dual role as a transcriptional activator mediated by AR and an epigenetic silencer mediated by H3K27me3. Therefore, simultaneously targeting EZH2 and AR by drug inhibitors, EPZ and enzalutamide (Enz), respectively, leads to synergistic cell growth inhibition. Taken together, our data reveal a dual function of EZH2 in PCa as a transcriptional activator and an epigenetic silencer. We believe that this study provide not only a novel function of EZH2 in the regulating AR signaling pathway but also provide novel therapeutic strategies for advanced prostate cancer which currently has no therapeutic options available.
Citation Format: Yongik Lee, Jung a Kim, Zhao Changsheng, Xiadong Lu, Ka Wing Fong, Jindan Yu. A PRC2 independent role of EZH2 in androgen receptor signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1497.
Abstract 1503: Arsenic trioxide inhibits proliferation of acute leukemia cells through reduced expression of E2F1, cyclin E, and activation of retinoblastoma protein
Authors: Kumar Sanjay , Tchounwou Paul 
Published: August 2018

Abstract
Arsenic trioxide (ATO) is has been used successfully in the treatment of all age group of acute promyelocytic leukemia (APL) patients in both induction and consolidation therapy. It inhibits growth APL cells through various mechanism including oxidative stress, cell cycle regulation, and apoptosis. However, detail molecular mechanism ATO-induced APL cell proliferation inhibition mostly poorly known. E2F1, a transcriptional factor widely involved proliferation and differention of many types of cancer cells through providing signal to accumulation p53, cell cycle regulation, and apoptosis. We hypothesized that ATO inhibits proliferation and differentiation of APL cells through reduced expression of E2 F1, cyclin E and stimulation of retinoblastoma and AMPKα2 expressions in APL cells. To test hypothesis, we used APL cell lines and after treatment with different concentration (2,4,6, and 8μg/ml) ATO, checked expression level of E2F1, cyclin A, cyclin E, Akt, retinoblastoma (Rb D20 & H1) and AMPKα2 by western blotting, immunocytochemistry, and confocal imaging. We found that it reduced expression significantly of E2F1, cyclin E by modulating expression profile of retinoblastoma (Rb D20 & H1), Akt and AMPKα2 proteins in APL cells concentration dependent manner. Our data showed that E2F1 associated with p53 and its association may involve ATO -induced cell cycle regulation and apoptosis. On the basis of these findings, we conclude that ATO inhibits APL cells proliferation by reducing E2F1, cyclin E expression through stimulation of retinoblastoma (Rb D20 & H1), Akt , and AMPKα2 proteins. It is novel mode of action of ATO in APL cells and may help in the designing of new anti-leukemic drugs for treatment of APL patients more efficiently and quickly.
Keywords: Arsenic trioxide, E2F1, cyclin E, Rb proteins, AMPKα2, and APL cells.
Acknowledgements: This research was financially supported by National Institutes of Health NCRR Grant No. 5G12RR013459 and MIMHD Grant No. 8G12MD007581, through the RCMI-Center for Environmental Health at Jackson State University.
Citation Format: Sanjay Kumar, Paul Tchounwou. Arsenic trioxide inhibits proliferation of acute leukemia cells through reduced expression of E2F1, cyclin E, and activation of retinoblastoma protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1503.
Abstract 1505: GATA3 expression is associated with poor differentiation of osteosarcoma cells
Authors: Hiraoka Koji 
Published: August 2018

Abstract
Objective: GATA3, a transcriptional factor promoting differentiation of Th2 cells, was expressed in breast cancer cells or bladder cancer cells. We reported that Gata3 expression in soft tissue sarcoma is an independent factor for poor prognosis. However, the role of GATA3 in osteosarcoma is unknown. We investigated whether GATA3 expression is associated with cell differentiation or clinical prognosis of osteosarcoma. Methods: We examined whether decreased GATA3 expression in MG63 osteosarcoma cells by induction of siRNA GATA3 using electroporation affects cell differentiation. We also evaluated GATA3 expression in biopsy samples of 31 osteosarcoma cases using immunohistochemical analysis, and statistically compared clinicopathological characteristics of GATA3-positive and GATA3-negative cases. In particular, the correlation between osteoid formation and GATA3 expression was examined. Result: GATA3 expression was observed in MG63 cells by Western blotting and real-time PCR. Decreased GATA3 expression caused by induction of siRNA promoted the expression of the osteoblast differentiation markers; osteopontin, osteocalcin and RUNX2; in MG63 cells, while ALP and DMP-1, pre-osteocyte markers, had not increased. The expression of p21, one of the differentiation markers of osteosarcoma, is also elevated by decreased GATA3 expression. GATA3 significantly expressed in osteosarcoma cases with less osteoid formation (P&lt;0.001), although no significant correlation between GATA3 expression and clinical prognosis was observed. Conclusion: These data indicated that GATA3 expression might be associated with poor differentiation of osteosarcoma cells. GATA3 may be a target to treat for osteosarcoma through promotion of cell differentiation.
Citation Format: Koji Hiraoka. GATA3 expression is associated with poor differentiation of osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1505.
Abstract 1521: Role of Trim28 in prostate cancer
Authors: Fong Ka-Wing , Zhao Jonathan , Zheng Bin , Yu Jindan 
Published: August 2018

Abstract
TRIM28 is an essential gene during embryonic development, which is involved in a wide range of biologic processes. From the pathologic viewpoint, TRIM28 overexpression was proved to broadly exist in pancreatic, liver, breast, glioma and lung cancer, and often expression of TRIM28 is correlated with clinical stage. Functional assays have demonstrated that TRIM28 promotes cancer cell growth and metastasis, further supporting TRIM28 as a promising target for therapeutic intervention. For past decade, TRIM28 is considered to be a transcriptional co-repressor due to TRIM28-dependent recruitment of histone modifiers such as CHD1/NuRD complex and SETDB1 for histone methylation and heterochromatin formation to achieve gene silencing. Surprisingly, transcriptome study revealed that TRIM28 can activate the expression of its target genes as much as it represses, hypothesizing the main role of TRIM28 may not lie in transcriptional repression. In addition, recent findings demonstrated that TRIM28 interacts with 7SK snRNP complex, which facilitates P-TEFb kinase module recruitment and productive transcription elongation at inducible genes. This evidence implicated that TRIM28 may form distinct complexes to induce or repress gene expression in context-dependent manner. On top of that, it remains unclear about the role of TRIM28 in prostate cancer. Our preliminary study revealed that TRIM28 is upregulated in castration-resistant prostate cancer (CRPC). TRIM28 knockdown markedly decreased prostate cancer cell proliferation, clonogenicity as well as CRPC-xenograft tumor growth. Moreover, proteomic analysis in LNCaP prostate cancer cells revealed that TRIM28 associates with a number of transcription co-activators. Gene expression profiling showed that androgen signaling is positively regulated by TRIM28. We proposed that TRIM28 forms the transcription activation complexes that modulate gene expression of various oncogenic pathway and promote PCa progression.
Citation Format: Ka-Wing Fong, Jonathan Zhao, Bin Zheng, Jindan Yu. Role of Trim28 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1521.
Abstract 1535: T Cells engineered to express the IL-13Rα2 specific CAR and a PD-L1 specific switch receptor show increased anti-tumor activity in the Glioblastoma tumor microenvironment
Authors: Castro Abel De , Keys Megan E. , Arroyo Jonathan , Prosser Megan E. 
Published: August 2018

Abstract
Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor prognosis with traditional treatments such as chemotherapy and radiotherapy, which often leave lasting and pervasive damage to the individual. GBM cells upregulate the surface protein interleukin 13 receptor subunit alpha-2 (IL13Rα2), which can be targeted as a novel immunotherapeutic marker for the immune response to be initiated. In this study, IL13Rα2 is targeted using a first generation chimeric antigen receptor (CAR) that contains an intracellular zeta chain domain. However, a limitation to this approach is that the tumor microenvironment exhausts the T cells that interact with the tumor through a receptor-mediated response. Programmed Death Ligand 1 (PD-L1) is a molecule that is expressed on cancerous cells that binds to Programmed Death 1 (PD-1) on T cells. When the ligand binds to PD-1 on T cells, there is decreased T cell proliferation, cytokine production, and anti-tumor activity. This problem can be avoided via creation of a switch receptor with a PD-1 extracellular domain fused to transmembrane and intracellular costimulatory CD28, which converts tumor mediated inhibition into stimulation upon ligation of PD-L1. It is hypothesized that the incorporation of additional costimulatory domains will enhance the stimulatory effects of the switch receptor. Engineered T cells expressing varied switch receptors in conjunction with the IL13Rα2-specific CAR have been created and have been assessed in vitro as a basis for glioblastoma treatment. Tests performed include cytokine secretion and T-cell proliferation assays. Results of these preliminary studies suggest that the the inclusion of additional costimulatory domains in the switch receptor design may be advantageous in enhancing anti-tumor responses in the GBM microenvironment.
Citation Format: Abel De Castro, Megan E. Keys, Jonathan Arroyo, Megan E. Prosser. T Cells engineered to express the IL-13Rα2 specific CAR and a PD-L1 specific switch receptor show increased anti-tumor activity in the Glioblastoma tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1535.
Abstract 1539: In vivo study of natural killer cell cytotoxicity against cholangiocarcinoma in a nude mouse model
Authors: Jung Inhye , Kim DoHee , Chung Yong Yoon , Park Seung Woo , Yoo Da Kyung 
Published: August 2018

Abstract
NK cell is one of the lymphocytes clinically used for various cancer types. Cytotoxicity of NK cell to cholangiocarcinoma (CC), however, has not been studied yet, nor has NK cell therapy against CC been clinically applied. In this study, relevance of NK cell therapy for antitumor efficacy against CC was preclinically investigated. Human HuCCT-1 cells, an intrahepatic CC cell line, were xenografted into nude mice. The HuCCT-1 tumor-bearing nude mice then received multiple infusions of ex vivo expanded human NK cell (SMT01) and were evaluated for in vivo cytotoxic activity of the NK cells. Dosage-dependent safety and toxicity of SMT01 was evaluated at three different dose levels. The mice well tolerated the maximum dose of SMT01. All of the three dosage groups did not show any significant adverse event. To evaluate in vivo activity of SMT01 against CC, we administered 5 infusions of SMT01 into the HuCCT-1 tumor-bearing nude mice. A standard chemotherapy as a positive control was also included. The result showed that SMT01 infusions resulted in significant inhibition of the CC tumor growth compared to the negative control (normal saline infusion), suggesting that NK cell contains in vivo cytolytic activity against cholangiocarcinoma. When body weights of the nude mice were measured, however, the body weight of the nude mice administered with chemotherapy was found to be maintained as lowest among all treatment groups while all the NK cell infusion groups well maintained the body weight during the treatment, suggesting beneficial effect of NK cell therapy in relevance of quality of life. IHC experiments and TUNEL assay using the tumor tissue sections clearly supported the cytotoxicity results of SMT01 against CC. We found that a robust infiltration of the infused NK cells was located along the loose tissue where feeding vessels entered. TUNEL-positive tumor cells were mainly localized at the vicinity of populated NK cells. In conclusion, our in vivo study demonstrates that NK cell also contains cytolytic activity against cholangiocarcinoma. Further investigation of the NK cell-based immunotherapy can be useful to determine cancer therapeutics for the specific tumor.
Citation Format: Inhye Jung, DoHee Kim, Yong Yoon Chung, Seung Woo Park, Da Kyung Yoo. In vivo study of natural killer cell cytotoxicity against cholangiocarcinoma in a nude mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1539.
Abstract 1541: Directed, unbiased mapping of lentiviral integrations with next generation sequencing in CAR-T cells
Authors: Johnstone Timothy G. , Chari Rajagopal , Koppstein David , Hause Ronald J. , Ponce Rafael , Briggs Adrian W. , Vigneault Francois 
Published: August 2018

Abstract
During manufacturing of an exemplary CD19-directed CAR-T cell product, patient T cells were transduced with a viral vector encoding the CD19-directed, 41BBζ endodomain-containing chimeric antigen receptor (CAR) construct, enabling permanent genetic modification of the target T cells. Lentiviral transduction with a self-inactivating (SIN) vector can offer certain advantages in safety and consistency over other DNA delivery methods. Although the integration patterns of wildtype HIV-1 have been well-characterized and shown to have a low risk of insertional transformation, the addition of an artificial construct may have the potential to affect integration patterns. Existing techniques for viral integration mapping, such as ligation-mediated polymerase chain reaction (LM-PCR), have limitations precluding comprehensive, unbiased, high-throughput insertion site mapping. To characterize insertional events in engineered CAR-T cells, we developed an unbiased NGS assay and computational pipeline capable of characterizing viral integration events genome-wide. The method leverages Tn5 transposase, coupled with a long terminal repeat-specific PCR, to map integration events down to nulceotide resolution. This assay identified over 150,000 high-confidence integration events across 23 patient-derived CAR-T cell products. Analysis of these sites revealed a similar integration preference to lentiviruses described in the literature: driven by GC content, local nucleotide content, chromatin status, and transcriptional activity, with no indication of preferential integration at oncogenic loci. In conclusion, in this assay a CD19-directed, CAR-containing lentivirus exhibited a low risk integration profile with no significant evidence of construct-specific risk factors. Furthermore, the findings suggest that the NGS assay may be useful for more efficient, cost-effective, and sensitive measurement of CAR-T integration events for a range of constructs.
Citation Format: Timothy G. Johnstone, Rajagopal Chari, David Koppstein, Ronald J. Hause, Rafael Ponce, Adrian W. Briggs, Francois Vigneault. Directed, unbiased mapping of lentiviral integrations with next generation sequencing in CAR-T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1541.
Abstract 1563: Characterization of two new recombinant rabbit anti-PDL1 IHC staining in bladder cancer, NSCLC, and melanoma with immune cell markers
Authors: Gonzalez Rachel M. , Fu Wei , Logis Evelin , Ding Emma , Chen Casey , Li Xiaojie , Merritt Sonia , Liu Mingjuan , Zhang Amy , Wang Yiran , Wang Guangli , Ma Donghui 
Published: August 2018

Abstract
Published studies show tumor cells overexpress PD-L1 to escape the host immune defense by binding to PD-1 on surveilling T-cells causing the T-cells to shut down. Immunotherapies disrupting PD-1/PD-L1 signaling interactions have great success in treating PD-L1 positive tumors. Immunohistochemistry (IHC) is an important diagnostic tool currently used to determine the expression level of PD-L1 in tumor and immune cells. The FDA approved PD-L1 clones (SP142 and 28-8) for IHC present different staining patterns when evaluated on the same tumor tissue. In this study, we assessed both the immune cells and tumor cells IHC positive stain of PD-L1. To do this we evaluated multiple immune cell markers with multiple PD-L1 antibodies. IHC screens were done with 5 PD-L1 antibodies, 2 recombinant rabbit monoclonal antibodies (clone OR-5E3 and OR-5H8), the mouse monoclonal antibody (clone UMAB229), and the FDA approved clones (SP142 and 28-8). The immune cell markers used were CD3, CD8A, CD20, CD68, and FOXP3. NSCLC, Bladder Cancer, and Melanoma immune cells, as indicated by the CD3, CD8A, CD20, CD68 and FOXP3 staining, generated different distribution pattern in the three tumor types. The five PD-L1 antibodies did show variation in detection of both the immune and tumor cells. For example, PD-L1 clones OR-5E3 and OR-5H8 stained tumor cells stronger and picked up weak expression of PD-L1 better than clone SP142, suggesting the two antibodies have higher affinity. The mouse monoclonal anti-PDL1 clone UMAB229 picked up strong and weak staining similar or better than clones OR-5H8 and picked up the immune cells similar to SP-142. The five PD-L1 antibodies were made from different antigens which may contribute to their sensitivity and specificity to detect PD-L1 in tumor cells. This study suggests the new generation of PD-L1 antibodies may make a better tool for diagnostic screens.
Citation Format: Rachel M. Gonzalez, Wei Fu, Evelin Logis, Emma Ding, Casey Chen, Xiaojie Li, Sonia Merritt, Mingjuan Liu, Amy Zhang, Yiran Wang, Guangli Wang, Donghui Ma. Characterization of two new recombinant rabbit anti-PDL1 IHC staining in bladder cancer, NSCLC, and melanoma with immune cell markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1563.
Abstract 1591: Cell-free DNA quantification reflects survival in non-small cell lung cancer patients with low metabolic tumor burden
Authors: Hyun Myung Han , Lee Eun Sung , Eo Jae Seon , Sung Jae Sook , Kang Eun Joo , Choi Yoon Jee , Park Kyong Hwa , Shin Sang Won , Lee Sung Yong , Kim Yeul Hong 
Published: August 2018

Abstract
We aimed to assess the role of tumor biological behavior/aggressiveness measured by cell-free DNA (cfDNA) quantification according to metabolic tumor burden measured by FDG-PET/CT scan to predict survival of advanced non-small cell lung cancer (NSCLC). Newly-diagnosed eighty-two NSCLC patients with baseline cfDNA quantification and positron emission tomography/computed tomography (PET/CT) scan were prospectively enrolled. The cfDNA level was quantified by Agilent High Sensitivity DNA kit. Metabolic tumor burden was measured by metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from PET/CT scan. The optimal cut-off value for cfDNA quantification, MTV, and TLG were found using X-tile analysis. The high-cfDNA quantification is associated with poor overall survival (OS) (hazard ratio=2.71, 95% confidential interval=1.33-5.52; p=0.006) than that of low. After categorized by metabolic tumor burden, however, the patients with high-MTV showed poor prognosis regardless of cfDNA quantification (low-cfDNA quantification vs high-cfDNA quantification, median OS = 3.9 months vs 7.0 months; p value &gt; 0.05). On the other hands, the patients with high-cfDNA quantification showed poor prognosis in patients with low-MTV (low-cfDNA quantification vs high-cfDNA quantification, median OS = 52.8 months vs 22.9 months; p values &lt; 0.001). According to baseline TLG level, the role of cfDNA quantification to predict survival was similar to MTV. Although cfDNA quantification independent prognostic factors for OS, the significance was disappeared when adjusted by MTV or TLG. This finding provides novel insights that the cfDNA quantification reflect survival for selected patients with low metabolic tumor burden in NSCLC.
Citation Format: Myung Han Hyun, Eun Sung Lee, Jae Seon Eo, Jae Sook Sung, Eun Joo Kang, Yoon Jee Choi, Kyong Hwa Park, Sang Won Shin, Sung Yong Lee, Yeul Hong Kim. Cell-free DNA quantification reflects survival in non-small cell lung cancer patients with low metabolic tumor burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1591.