bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4679: NRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma
Authors: Leung Hoi Wing , Lau Eunice Yuen Ting , Lee Kin Wah 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. The long-term prognosis of HCC remains unsatisfactory due to high recurrence rates and chemoresistance. Solid evidence shows that tumor-initiating cells (T-ICs) are the root of tumor relapse and drug resistance, which led to poor prognosis of patients with hepatocellular carcinoma (HCC). Therefore, identification of crucial transcriptional regulator in liver T-IC may improve the prognosis of these patients. Through in vitro liver T-IC enrichment approach, we identified Nuclear Factor (Erythroid-Derived 2)-Like 2 (NRF2) as transcriptions regulator be significantly upregulated in enriched liver T-IC populations. NRF2 regulated liver T-IC properties including self-renewal, tumorigenicity, and liver T-IC marker expression and significantly affected patients’ clinical outcome. Furthermore, NRF2 repression led to sensitization to doxorubicin and 5-FU treatment. Furthermore, we found that ROS-induced NRF2 activation regulates sorafenib resistance of HCC cells. Mechanistically, NRF2 was found to physically bind to promoter SHH, which triggers activation of sonic hedgehog pathway. NRF2 was significantly correlated with SHH expression, which was associated with poor patient’s survival. The effect of NRF2 knockdown was eliminated upon administration of recombinant SHH, demonstrating that NRF2 mediated the TIC function via upregulation of SHH expression. Our study suggested a novel regulatory mechanism for the canonical sonic hedgehog pathway that may function through NRF2/SHH/GLI signaling axis, thus mediating T-IC phenotypes. Targeting NRF2 mediated signaling cascade alone or in combination with other treatment modalities may be a new a potential therapeutic approach for treatment of HCC.
Citation Format: Hoi Wing Leung, Eunice Yuen Ting Lau, Kin Wah Lee. NRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma [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 4679.
Abstract 4706: Temperature-dependent transcription artifacts and cell population biases in scRNAseq data are minimized by tissue dissociation at low temperatures
Authors: O'Flanagan Ciara H. , Campbell Kieran R. , Kabeer Farhia , Zhang Allen , Lim Jamie , Shah Sohrab P. , Aparicio Samuel 
Published: August 2019

Abstract
Single cell RNA sequencing (scRNAseq) is a powerful tool, particularly for studying complex biological systems, such as tumor heterogeneity and the tumor microenvironment, which may not be resolved by sequencing of bulk material. Nonetheless, it is not without limitations, which include the technical challenges of generating a high quality single cell suspension. Dissociation of tissue to single cell suspension requires mechanical and enzymatic disruption, and the effect of these methods on gene expression or cellular population bias has not been established. In this study, we examined the effects of enzymatic dissociation on cell population capture and transcriptional changes at single cell resolution in breast and ovarian cancer patient samples, patient-derived breast cancer xenografts and cultured cell lines. scRNAseq data showed that enzymatic dissociation of tissues at 37oC with collagenase resulted in significant induction of heat shock, stress and immediate response genes, which was conserved across all tissues. This gene expression induction was not observed when tissues were dissociated at 6oC with a protease derived from a Himalayan glacier soil bacterium. Moreover, dissociation of patient tumors at low temperature enhanced the abundance of rare cell populations, including B-cells, T-Cells and cytotoxic T-cells, which were significantly depleted following dissociation at 37oC. These biases resulting from standard sample preparation methods could significantly affect biological interpretation of scRNAseq data, and can be minimized by dissociation of tissues at low temperature.
Note: This abstract was not presented at the meeting.
Citation Format: Ciara H. O'Flanagan, Kieran R. Campbell, Farhia Kabeer, Allen Zhang, Jamie Lim, Sohrab P. Shah, Samuel Aparicio. Temperature-dependent transcription artifacts and cell population biases in scRNAseq data are minimized by tissue dissociation at low temperatures [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 4706.
Abstract 4711: PRMT5 selective inhibitor enhances therapeutic efficacy of cisplatin in lung adenocarcinoma cells
Authors: Bajbouj Khuloud , Ramakrishnan Rakhee , M.H.Ihmaid Ahmed , Ali Suhaib Al Haj , Alalool Abdulla , Abdullah Reem , Saber-Ayad Maha , Hamid Qutayba 
Published: August 2019

Abstract
Background: Lung cancer is the most common cancer globally, with an estimate of more than 2 million new cases every year. Protein arginine methyltransferase 5 (PRMT5) is an enzyme that is identified to be involved in multiple cellular events, including gene expression regulation transcriptional regulation and cell division. It has been shown that PRMT5 is highly expressed in cancers including lung adenocarcinoma, hepatocellular carcinoma, and melanoma, raising evidence that PRMT5 might be involved in tumorigenesis. The aim of this study is to examine the potential selective anti-neoplastic activity of AMI-1 and cisplatin on lung adenocarcinoma.
Experimental methods: The effect of AMI-1 and subsequent PRMT5 activity inhibition on lung adenocarcinoma (A549 cell line) behavior with the standard chemotherapeutic agent, cisplatin was assessed, by measuring cell viability using MTT assay, PMRT5/β-catenin protein levels via Western Blotting, the extent of cell migration through wound healing assay, and survival of cancer cells by performing cell cycle progression and Annexin-V staining assays along with both drugs combination potential toxicity that was evaluated in human bronchial epithelial cells (HBEC).
Results and Discussions: Combination treatment with 10 µM AMI-1 and IC50 of Cisplatin (23.4 µM) significantly reduced viable cell percentages at 24 and 48 hours. Treatment with both drugs at 48 hours led to a decreased cells migration rate. G2/M arrest in A549 cells was evident at 24 hours of AMI-1 addition, which was reinforced after drugs combined treatment. Furthermore, 48 hours of both drug administration hindered the ability of A549 cells to recycle again as they G1 occupying cells percentage was increased after 48 hours of combination treatment. There was a minor cell death induction after 48 hours of treatment with both drugs. Western blot analysis showed that there was no evidence change in total PRMT5 and β-catenin protein levels. Nevertheless, there was a reduction in demethylation Histone 4, a PRMT5- downstream target, after 48 hours treatment with AMI-1 alone or in combination with Cisplatin. Interestingly, as combination approach increased anti-survival effect on lung cancer cells, it exhibited cyto-protective abilities on normal epithelial cells.
Conclusion: This study shows a novel selective antitumor activity of AMI-1 and cisplatin in adenocarcinoma cells.
Citation Format: Khuloud Bajbouj, Rakhee Ramakrishnan, Ahmed M.H.Ihmaid, Suhaib Al Haj Ali, Abdulla Alalool, Reem Abdullah, Maha Saber-Ayad, Qutayba Hamid. PRMT5 selective inhibitor enhances therapeutic efficacy of cisplatin in lung adenocarcinoma 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 4711.
Abstract 4713: Extraction, purification and evaluation of prmt5-inhibitory phytochemical compounds for the treatment of prostate adenocarcinoma
Authors: Richmond Oliver H. , Wang Zhengxin 
Published: August 2019

Abstract
The development and advancement of prostate cancer is supported by a plethora of genetic and proteomic abnormalities, including events of post-translational modifications. The protein arginine methyltransferase 5 (PRMT5) enzyme regulates epigenetic events of histone modifications and of post-translational modifications within protein signaling pathways. Under abnormal conditions of overexpression and/or upregulation, PRMT5 functions by constitutively driving the growth and/or proliferation of dysregulated cells. Overexpression and/or upregulation of PRMT5 correlates with disease progression as observed among numerous cancer types, including breast, colorectal, leukemia, lung, melanoma and prostate cancers. We demonstrated previously that PRMT5 localized to the cytoplasm, functions to drive both growth and proliferation of prostatic tumors. Plants naturally produce chemical toxins as mechanisms of defense against microbial and other biological threats. Human exploitation, consumption and/or application of agents isolated from plants for therapeutic intervention dates back throughout the millennia. In this study, we extracted, purified and evaluated natural, small, chemical compounds from plant products that antagonize PRMT5 activity in prostate cancer cells. We found that crude and purified extracts of Dendrobium, Fennel Seed and Magnolia plants attenuated prostate tumor growth and proliferation by selective inhibition of PRMT5 methyltransferase activity. These findings establish the first set of natural PRMT5-specific inhibitors reported.
Citation Format: Oliver H. Richmond, Zhengxin Wang. Extraction, purification and evaluation of prmt5-inhibitory phytochemical compounds for the treatment of prostate 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 4713.
Abstract 4725: Efficacy of a new small-molecule inhibitor of histone deacetylase 6 (HDAC6) in preclinical models of B-cell lymphoma and acute myeloid leukemia
Authors: Villanueva Lorea , Perez-Salvia Montserrat , Aldaba Eneko , Vara Yosu , Fabre Myriam , Ferrer Cristina , Masdeu Carme , Zubia Aizpea , Sebastian Eider San , Otaegui Dorleta , Llinàs-Arias Pere , Rosselló-Tortella Margalida , Berdasco María , Setien Fernando , Moutinho Catia , Villanueva Alberto , González-Barca Eva , Muncunill Josep , Navarro José Tomás , Piris Miguel Ángel , Cossio Fernando , Esteller Manel 
Published: August 2019

Abstract
Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes. In this regard, the compound ACY-1215 (Rocilinostat), the described selective HDAC6 inhibitor, is undergoing clinical trials for the treatment of multiple myeloma. Taking into account the previous information about HDAC6 inhibitor structures, the structural differences between HDAC6 and other HDAC isoforms and also the structural information of other developed HDAC inhibitors, we have previously designed and synthesized a new potential HDAC6 selective inhibitor, QTX125 with growth inhibitory effects in mantle cell lymphoma (MCL) cell lines, mouse models and ex vivo treatment of primary samples obtained from patients with MCL. Herein, we have extended these findings to show that the newly identified HDAC6 inhibitor QTX125 is also able to inhibit the growth of preclinical models of other B-cell lymphomas such as follicular lymphoma and Burkitt’s cell lymphoma, but also of acute acute myeloid leukemia. In addition beyond a-tubulin, a well known HDAC6 target, we have developed a pharmacological and proteomic screening to identify other proteins modified by HDAC6 that can contribute to the described lymphoma and leukemia phenotypes.
Citation Format: Lorea Villanueva, Montserrat Perez-Salvia, Eneko Aldaba, Yosu Vara, Myriam Fabre, Cristina Ferrer, Carme Masdeu, Aizpea Zubia, Eider San Sebastian, Dorleta Otaegui, Pere Llinàs-Arias, Margalida Rosselló-Tortella, María Berdasco, Fernando Setien, Catia Moutinho, Alberto Villanueva, Eva González-Barca, Josep Muncunill, José Tomás Navarro, Miguel Ángel Piris, Fernando Cossio, Manel Esteller. Efficacy of a new small-molecule inhibitor of histone deacetylase 6 (HDAC6) in preclinical models of B-cell lymphoma and acute myeloid leukemia [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 4725.
Abstract 4745: Reversal by inhibiting XBP1 activation of glucose deprivation-induced tolerance to multiple anticancer therapies
Authors: Jeong Mini , Jo Serin , Park Serkin , Sohn Jeongwon , Park Yun Gyu 
Published: August 2019

Abstract
Tumor microenvironment is harsh condition including low pH, hypoxia and nutrient deprivation. Cancer cells can switch their phenotypes and characteristics dependent on the microenvironment. Most previous researches have focused mainly on the effect of hypoxia on cancer cells plasticity and resistance to anticancer therapies. Despite the accumulation of emerging evidences, the effect of nutrient deficiency to multiple anticancer therapies is still unclear.In this study, human lung adenocarcinoma cells (A549), triple-negative breast cancer (MDA-MB-231), hepatocellular carcinoma cells (HepG2), pancreas adenocarcinoma cells (AsPC-1) were cultured in the medium containing low concentrations of glucose. Low sensitivity to cisplatin or taxol was observed in the cancer cells maintained for 28 weeks or so under the glucose-deprived condition. In addition, the multidrug tolerant cells were also insensitive to cytotoxic T cell (CTL)-based immunotherapy and had increased migration ability compared with control group under normal glucose condition. Reversion to normal glucose condition only for short term period (at least 4 days) made the multidrug tolerant cells susceptible to cisplatin-induced apoptotic cell death. In the unfolded protein response, BiP-XBP1 signaling was increased but PERK signaling was decreased in response to long-term glucose deprivation. Sensitivity to cisplatin treatment and CTL-based immunotherapy was restored by inhibiting XBP1 splicing in glucose deprivation-induced multidrug tolerant cells in various types of cancer.This study demonstrated that glucose deprivation-induced tolerance to multiple anti-cancer therapies is transient and reversible, and requires activation of IRE1-XBP1 pathway.This research was supported by the National Research Foundation of Korea (2018R1D1A1B07045297, 2016R1D1A1A02936945 and 2017R1D1A1B03036008).
Citation Format: Mini Jeong, Serin Jo, Serkin Park, Jeongwon Sohn, Yun Gyu Park. Reversal by inhibiting XBP1 activation of glucose deprivation-induced tolerance to multiple anticancer therapies [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 4745.
Abstract 4746: Identifying states of collateral sensitivity during the evolution of therapy resistance in Ewing’s sarcoma
Authors: McClure Erin , Hitomi Masahiro , Scarborough Jessica , Scott Jacob 
Published: August 2019

Abstract
During the evolution of therapeutic resistance many cancers exhibit a phenomenon termed collateral sensitivity, where resistance to one drug aligns with sensitivity to another drug. It has further been shown, in leukemia and non-small cell lung cancer, that this state of collateral sensitivity can vary over time. We hypothesized that this process will also occur in Ewing’s sarcoma (EWS), and that these phenotypic states can be identified with molecular signatures based on gene expression. The standard chemotherapy for EWS is repeated cycles of two alternating drug cassettes, one is a combination of vincristine, doxorubicin, and cyclophosphamide (VDC), and a second is a combination of ifosfamide and etoposide (IE). This treatment is highly effective, though advanced stage disease often relapses, and then drug resistance invariably develops, a process following the laws of Darwinian evolution. Finding predictable patterns, or signatures, of collateral sensitivity would provide a useful decision support tool in the clinic to help guide chemotherapy choices. Recent studies in other cancers, bacteria, and in silico simulations have explored and identified optimal timing of switching among the drugs of collateral sensitivity to achieving maximal efficacy. To analyze temporal changes in collateral sensitivity in EWS, we exposed two EWS cell lines, A673 and TTC-466, to half maximal inhibitory concentrations of VDC/IE combinations in vitro. As the cultures recovered from drug exposures, we determined their sensitivities against a panel of drugs including the ones used for the treatment and a new generation of drugs that show efficacy against EWS. The new drugs consist of SP2509, pazopanib, olaparib, dactinomycin, temozolomide, vorinostat, and SN-38. We also collected RNA samples to analyze the transcriptomic alterations which correlate with changes in their collateral sensitivity. Significant findings for the A673 cell line include increased resistance to dactinomycin, doxorubicin, etoposide and vincristine for all treatment replicates, and maximal sensitivity to temozolomide halfway through the treatment schedule for all treatment replicates. Notably, every tumor is different and may develop collateral sensitivity at unique time points. Even in this experiment we observe variation between evolutionary replicates that were originally genetically identical. Future work should include investigating a quick and cost-effective method for testing temporal collateral sensitivity of individual tumors so our findings can be implemented clinically.
Citation Format: Erin McClure, Masahiro Hitomi, Jessica Scarborough, Jacob Scott. Identifying states of collateral sensitivity during the evolution of therapy resistance in Ewing’s sarcoma [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 4746.
Abstract 477: Targeted deep sequencing contributes to guiding personalized targeted therapy in advanced biliary tract cancer
Authors: Feng Feiling , Cheng Qingbao , Zhang Dadong , Li Bin , Qin Hao , Xu Chang , Han Miao , Yu Yong , Li Zhizhen , Li Jing-Yu , Qiu Zhiquan , Xiong Lei , Liu Chen , Li Fugen , Yi Bin , Jiang Xiaoqing 
Published: August 2019

Abstract
Purpose: Biliary tract cancer (BTC) is a devastating disease of the digestive system with poor prognosis. Targeted therapy based on specific genetic alterations has been proven to be an effective treatment for some cancer subtypes. However, the effect of this targeted therapy is unclear in BTC. In this study, we aimed to explore the clinical efficacy and safety of personalized targeted therapy guided by targeted deep sequencing for advanced biliary tract cancer (BTC) patients.
Materials and Methods: In this retrospective study, targeted deep sequencing was employed for 49 patients with BTC and the recommendation of biologic agent was offered. Among 32 patients with stage IV and R2 resection, 21 patients underwent conventional chemotherapy (mGEMOX) (chemotherapy group), while the remaining 11 patients received a personalized targeted agent (targeted therapy group). The progression-free survival (PFS), overall survival (OS), disease control rate (DCR) were used to assess the efficacy of treatments, while the grade of treatment-related toxicities was evaluated for safety.
Results: The genomic landscape of 49 patients with BTC was depicted by targeted deep sequencing. Further analysis of all alterations demonstrated that these altered genes were highly enriched in the ERBB family or cell cycle pathway. After a median follow-up of 12 months, the targeted therapy group had a significant prolonged PFS (4.5 months vs. 1.5 months, P = 0.014) and a trend of prolonged OS (12.9 months vs. 4.1 months, P = 0.104) in comparison to the chemotherapy group. The DCR in the targeted therapy group was marginally higher but without statistical significance (63.6% vs. 33.3%, P = 0.142). In addition, there was no statistically significant difference in the percentage of patients that experienced Grade &gt;2 treatment-related toxicities in either treatment group (36.4% vs 19.0%, P = 0.397).
Conclusions: This real-world clinical study suggests that targeted deep sequencing contributes to guiding personalized targeted therapy based on individual actionable mutations, which may benefit advanced BTC patients. Large umbrella trials of personalized precision therapy are needed to further confirm the clinical efficacy and safety of this therapeutic strategy in BTC.
Note: This abstract was not presented at the meeting.
Citation Format: Feiling Feng, Qingbao Cheng, Dadong Zhang, Bin Li, Hao Qin, Chang Xu, Miao Han, Yong Yu, Zhizhen Li, Jing-Yu Li, Zhiquan Qiu, Lei Xiong, Chen Liu, Fugen Li, Bin Yi, Xiaoqing Jiang. Targeted deep sequencing contributes to guiding personalized targeted therapy in advanced biliary tract 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 477.