bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4690: ARD1-mediated NRF2 acetylation promotes human colon cancer cell proliferation
Authors: Fang Xizhu , Lee Yeon-Hwa , Zheng Jie , Kim Seong Hoon , Jang Jeong-Hoon , Kim Do-Hee , Surh Young-Joon 
Published: September 2020

Abstract
The transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2) is regarded as one of the main orchestrators of the cellular antioxidant and carcinogen-detoxifying response. NRF2 plays a pivotal role in protecting normal cells from carcinogenic insults, but it may also accelerate the proliferation and progression of cancer cells. Abnormally elevated expression or activation of NRF2 has been attributed to mutation, especially in the sequences involved in interaction with its negative regulator KEAP1. However, other mechanisms responsible for NRF2 overactivation/overexpression are less well understood. Arrest defective (ARD1), an N-terminal acetyltransferase that catalyzes N-terminal acetylation of target proteins, has lysine acetyltransferase activity and is involved in mediating various (patho)physiological processes, such as proliferation, apoptosis, autophagy, and differentiation. Aberrant overexpression of ARD1 is correlated with metastasis and poor prognosis in several types of cancer, suggesting that it may act as a tumor promoter. In the present study, we found that NRF2, acteyl-NRF2, and ARD1 were highly expressed in some human colon cancer cell lines (HCT-116, HCT-15, DLD1) and tissues obtained from colorectal cancer patients. Furthermore, overexpression of NRF2 and ARD1 was also verified by quantitative immunofluorescence analysis of colorectal tissue microarray. We noticed that silencing of NRF2 and ARD1 individually in human colon cancer cells (HCT-116) led to the decreases in viability, anchorage-independent growth, and migration capacity of HCT-116 cells. While there was no change in the protein level of ARD1 when NRF2 expression was knock down by siRNA, protein expression of Nrf2 and acteyl-NRF2 was markedly reduced by silencing of the ARD1 gene. This prompted us to explore the association between ARD1 and NRF2 in the human colon cancer cell proliferation and progression. Co-immunoprecipitation and immunocytochemical analyses showed that two proteins colocalized in the cytosol, and ARD1 directly bound to NRF2. Taken together, ARD1 may potentiate the oncogenic function of NRF2 in human colon cancer cells by acetylating and stabilizing this transcription factor. This study was supported by the Global Core Research Center (GCRC) Grant (No. 2011-003-0001) from the National Research Foundation (NRF) of Republic of Korea.
Citation Format: Xizhu Fang, Yeon-Hwa Lee, Jie Zheng, Seong Hoon Kim, Jeong-Hoon Jang, Do-Hee Kim, Young-Joon Surh. ARD1-mediated NRF2 acetylation promotes human colon cancer cell proliferation [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 4690.
Abstract 4709: Loss of GPSM2 promotes the metastasis of non-small cell lung cancer by inducing the expression of Snail
Authors: Liu Bofang , Deng Mingming , Zhang Jingdong , Li Feifei , Han Weidong , Pan Hongming 
Published: September 2020

Abstract
Background/Aims: Non-small cell lung cancer (NSCLC) is the leading global cause of cancer-related death. Due to the lack of reliable diagnostic or prognostic biomarkers, the prognosis of NSCLC remains poor. Consequently, there is an urgent need to explore the mechanisms underlying this condition in order to identify effective biomarkers. G protein signaling modulator 2 (GPSM2) is widely recognized as a determinant of mitotic spindle orientation. However, its role in cancer, especially NSCLC, remains uncertain.
Methods: Tissue microarray (TMA) were used to compare differences in GPSM2 expression, and its relationship with clinical characteristics and prognosis. Wound healing assay, transwell assay and lung metastatic mice model were used to explore the biological function of GPSM2 on NSCLC cells in vitro and in vivo. Western blot and immunohistochemistry were conducted to investigate the potential pathways of GPSM2.
Results: In this study, we found that GPSM2 was downregulated in NSCLC tissues and was correlated with a poor prognosis,and the expression status of GPSM2 was a favorable independent prognostic factor(HR = 0.222; 95% CI = 0.052 - 0.959; P = 0.044). Furthermore, the knockdown of GPSM2 promoted NSCLC cell metastasis in vitro and in vivo and accelerated the process of epithelial-to-mesenchymal transition (EMT). Mechanistically, we demonstrated that silencing GPSM2 induced cell metastasis and EMT via the ERK/GSK-3β/Snail pathway.
Conclusion: These results confirm that GPSM2 plays an important role in NSCLC. Moreover, GPSM2, as an independent prognostic factor, may be a potential prognostic biomarker and drug target for NSCLC.
Citation Format: Bofang Liu, Mingming Deng, Jingdong Zhang, Feifei Li, Weidong Han, Hongming Pan. Loss of GPSM2 promotes the metastasis of non-small cell lung cancer by inducing the expression of Snail [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 4709.
Abstract 4849: YPN-005, an oral CDK7 inhibitor, shows a significant antitumor activity in Myc amplified solid tumors and MCL-1 overexpressed blood cancer
Authors: Yoo Jakyung , Lee Jun Hee , Lee Mi Jung , Lee Kang Woo , Min Ji Eun , Kim Jinhwan , Min Ki-Nam , Jeon Da-Hye , Lim Dae Seong , Lee Kwang-Ok 
Published: September 2020

Abstract
Background: Cyclin dependent kinase 7 (CDK7) has been recognized as one of potential therapeutic targets in Myc-driven cancers. Previously, we synthesized selective irreversible CDK7 inhibitor and we demonstrated a significant inhibition of the proliferation of TNBC and HCC cells by down-regulation of c-Myc and MCL-1. We further report YPN-005 of the preclinical data with biological characterization.
Methods: Antiproliferative activity of YPN-005 was measured in solid tumor cell lines with Myc amplification and in hematologic cancer cells with MCL-1overexpression. To investigate the mechanism of action of YPN-005, the expression levels of phospho-RNA polymerase II, phospho-CDK2 and -CDK4, BClXL, cleaved-PARP, c-Myc and MCL-1 were analyzed by Western Blot analyses. CDK7 occupancy was determined by using a biotinylated small molecule probe following incubating of TNBC, HCC, AML cells and hPBMC with YPN-005. The therapeutic efficacy of YPN005 was evaluated in TNBC and HCC xenograft mouse model.
Results: YPN-005 treatment induced apoptosis and cell cycle arrest. Selectivity of YPN-005 on CDK7 was confirmed in the 468 kinases panel assay. YPN-005 significantly inhibited the proliferation of TNBC, ER+ breast cancer, HCC, ovarian cancer, small cell lung cancer (SCLC), pancreas, prostate and various types of blood cancer cells and IC50's were determined in 1-20 nM range. Inhibition of cell proliferation was accompanied by down-regulation of RNA PolII phosphorylation, c-Myc and MCL-1 expression. Washout assay by Western Blot demonstrated that YPN-005 irreversibly blocked RNA PolII phosphorylation. In addition, YPN-005 downregulated the adaptive immune checkpoint PD-L1 by the depletion of c-Myc in TNBCs. CDK7 occupancy over 90% was observed in TNBC, HCC, and AML cells with 100nM of YPN-005. In vivo xenograft models of TNBC and HCC showed that daily oral administration of YPN-005 for 21 days (once, and 10~20mg/kg) efficiently inhibited the growth of tumor. All the mice survived and there was no significant changes in their hematologic profiles.
Conclusion: Our findings suggest that YPN-005 is an orally available, potent, and selective CDK7 inhibitor which can be used for the treatment of Myc and MCL-1 overexpressing cancer patients. These data support the rationale for advancing YPN-005 towards IND-enabling studies.
Citation Format: Jakyung Yoo, Jun Hee Lee, Mi Jung Lee, Kang Woo Lee, Ji Eun Min, Jinhwan Kim, Ki-Nam Min, Da-Hye Jeon, Dae Seong Lim, Kwang-Ok Lee. YPN-005, an oral CDK7 inhibitor, shows a significant antitumor activity in Myc amplified solid tumors and MCL-1 overexpressed blood cancer [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 4849.
Abstract 4855: Development of highly selective CDK7 inhibitor Q901 for solid tumors
Authors: Yu Donghoon , Jeon Yeejin , Park Dongsik , Seo Mooyoung , Ahn Wongyun , Kim Jaeseung , Park Choa , Jeong Euna , Yoon Sukjoon , Nam Kiyean 
Published: September 2020

Abstract
Cyclin-dependent kinase 7 (CDK7) a member of the cyclin-dependent kinase family, forms a functional CDK-activating kinase (CAK) with cyclin H and MAT1, which regulates the cell cycle by phosphorylating other CDKs. CDK7 is also a component of transcription factor II H (TFIIH) that regulates transcriptional initiation and elongation through the phosphorylation of the RNA polymerase II C-terminal domain (CTD). Inhibition of CDK7 has been reported as a potential cancer therapeutic by addressing aberrant cell cycle regulation and transcription, as these abnormalities are considered main factors for tumor progression in specific types of cancer. Q901 is a novel highly selective CDK7 inhibitor in IND enabling development stage. Q901 shows extreme selectivity by singular inhibition of CDK7 among tested kinome panel. Q901 triggers G1 cell cycle arrest in specific cancer models in vitro and in vivo. Good correlation has been demonstrated between Q901 tumor growth inhibition and target engagement of a pharmacodynamics marker in treated models, suggesting CDK7 is a main driver of tumor progression in the selected models. The Q901 data supports the continued preclinical evaluation and potential of the compound as investigational treatment for patients with multiple solid tumors.
Citation Format: Donghoon Yu, Yeejin Jeon, Dongsik Park, Mooyoung Seo, Wongyun Ahn, Jaeseung Kim, Choa Park, Euna Jeong, Sukjoon Yoon, Kiyean Nam. Development of highly selective CDK7 inhibitor Q901 for solid tumors [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 4855.
Abstract 4887: Direct mutational consequences of CRISPR-cas9 gene-edited DNA repair genes
Authors: Zou Xueqing , Koh Gene , Nanda Scott , Degasperi Andrea , Urgo Katie , Bushell Wendy , Agu Chukwuma , Perez-Alonso Vanesa , Rueda Daniel , Foreman Julia , Harris Rebecca , Jiricny Josef , Skarnes Bill , Nik-Zainal Serena 
Published: September 2020

Abstract
Cancer whole-genome sequencing has revealed characteristic mutational signatures associated with defective DNA repair that underpin human genetic diseases. To define the direct mutagenic effects of DNA repair deficiency at the genome-wide level, we investigate mutational signatures generated by CRISPR-Cas9-based knockouts of 42 genes involved in DNA repair/replication using a human-induced pluripotent stem cell line. Knockouts (Δ) of nine DNA repair genes reveal substitution/indel mutational signatures. Notably, dissection of signatures of defective mismatch repair (MMR) uncovers gene-specific characteristics including distinguishing features of ΔMLH1, ΔMSH2, and ΔMSH6 from ΔPMS2. This gene-specificity is also exhibited by hIPSCs derived from patients with autosomal recessive Constitutional Mismatch Repair Deficiency (CMMRD) that carry biallelic germline mutations of MMR genes. Furthermore, gene-specificity manifests in whole genome sequenced primary human cancers. Additionally, detailed analyses reveal putative sources of endogenous DNA damage that contribute to MMR signatures, including guanine oxidation, errors of DNA polymerases and reversed template slippage or double slippage. Finally, we find that using all mutational signatures of MMR-deficiency as identified in this study results in improved sensitivity and specificity in classifying MMR-deficient tumors, critical for accurate patient stratification for therapeutic intervention.
Citation Format: Xueqing Zou, Gene Koh, Scott Nanda, Andrea Degasperi, Katie Urgo, Wendy Bushell, Chukwuma Agu, Vanesa Perez-Alonso, Daniel Rueda, Julia Foreman, Rebecca Harris, Josef Jiricny, Bill Skarnes, Serena Nik-Zainal. Direct mutational consequences of CRISPR-cas9 gene-edited DNA repair genes [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 4887.
Abstract 491: Encapsulation of the stem cell inhibitor Salinomycin in novel QUATRAMER sustained injectable suspension (HSB-1216) for the treatment of small cell lung cancer
Authors: Kharbanda Surender M. , Mohammad Anees , Appajosyula Sireesh , Rosenberg Mark , Hill James , Laumas Sandeep , Kufe Donald W. , Singh Harpal 
Published: September 2020

Abstract
Small cell lung cancer (SCLC) represents approximately 15% of all cases of lung cancer. SCLC patients have a poor prognosis and limited treatment options. Conventional chemotherapy can reduce the bulk of SCLC lesions, but cancer stem cells (CSCs) survive, reconstitute the tumor and contribute to metastases. Thus, targeting CSCs, which are resistant to many current treatments, may significantly improve outcomes of SCLC patients. Salinomycin (SAL), a potassium ionophore, preferentially targets CSCs. However, SAL is extensively metabolized in animal models and is associated with substantial toxicity at higher doses, limiting its potential for anti-cancer activity in patients In this study, we report a novel QUATRAMER polymeric nanoparticle (NP)-based formulation, that potentially overcomes toxicity of SAL. SAL was encapsulated in polymeric NPs comprised of a polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG-modified PLA-tetra-block copolymer (SAL-NPs; HSB-1216). SAL release from the NPs was controlled by both PEG/PEG-PPG-PEG chain length and the PLA molecular weight, permitting time-dependent release over sustained periods. Treatment of the human SCLC cell line NCI-H69 with HSB-1216 demonstrated an IC50 of 0.5 uM. Once weekly treatment of BALB/c nu/nu mice harboring NCI-H69 xenografts with HSB-1216 at a dose of 5 mg/kg resulted in substantial tumor growth inhibition The tumor growth inhibition was without any effect on the body weights of the mice. These results demonstrate that a novel formulation for sustained delivery of SAL in a sustained injectable suspension represents an approach for targeting CSCs in SCLCs and potentially other cancer types.
Citation Format: Surender M. Kharbanda, Anees Mohammad, Sireesh Appajosyula, Mark Rosenberg, James Hill, Sandeep Laumas, Donald W. Kufe, Harpal Singh. Encapsulation of the stem cell inhibitor Salinomycin in novel QUATRAMER sustained injectable suspension (HSB-1216) for the treatment of small cell lung cancer [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 491.
Abstract 4931: Yap1 regulates the transcription of cofilin to facilitate the metastatic movement of colorectal cancer cells
Authors: Islam S M Anisul , Acevedo-Duncan Mildred 
Published: September 2020

Abstract
Colorectal cancer (CRC) is one of the most leading death-causing cancers in the United States which accounts for 23,380 estimated death cases in 2019 as per American Cancer Society. Surgical removal of cancerous tissue coupled with chemotherapeutic intervention is the primary treatment of metastatic CRC and the only hope of enhanced survival. Dysregulation of kinases is pivotal in the various pathological process, including cancer. In addition, the metastatic events in a cancer cell are usually brought by the alteration of different key molecules. One such key molecule is called cofilin that acts on the actin cytoskeleton to induce metastatic phenotype in cancerous cells. In this study, we used two atypical Protein Kinase C (PKC) inhibitors, namely ICA-I (a PKC-ι inhibitor) and ζ-Stat (a PKC-ζ inhibitor), to investigate the role of atypical PKCs in regulating the expression of cofilin in metastatic colorectal cells. Our findings suggested that the atypical PKC inhibitors reduced the expression and translocation of Yap1 from cytosol to nucleus which ultimately leads to the reduced expression of cofilin in CRC cells. This mechanistic study provides an important insight into the metastatic behavior of the cancerous colorectal cells that can be used to target metastasis regulating molecules to improve the survival rate in patients with CRC.
Citation Format: S M Anisul Islam, Mildred Acevedo-Duncan. Yap1 regulates the transcription of cofilin to facilitate the metastatic movement of colorectal cancer cells [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 4931.
Abstract 4988: Multiplex immunofluorescence detection of resident memory T cells in solid tumors
Authors: Baranova Elena , Finan-Marchi Amanda , Motte Manon , Tliba Maroua , Iglesias Sabine , Belda Carole , Mace Alexandra , Hunt Sylvie , Lazzaro Domenico , Coton Jean-Philippe , Burrer Renaud 
Published: September 2020

Abstract
Tissue-resident memory T cells (TRM) represent a lineage of T cells localized in peripheral tissues that do not reenter the circulation. Their establishment in the tissue makes them the initial T cell response in local infections and inflammatory conditions. TRM are characterized by the expression of CD103, CD69, and CD49a. TRM play a role in the efficacy of cancer vaccines and have been correlated with improved prognosis and/or survival in a number of cancers. Comparisons of TRM and cytotoxic CD8 T cells in the tumor microenvironment are limited. Due to this, we have developed a Histoprofile TRM multiplex immunohistochemistry panel, validated by in-depth image analysis, for TRM and CD8 T cell profiling. Here we present our in depth multiplex immunofluorescence validation assay including tests of repeatability and reproducibility. Human tissue microarrays of tumors in a range of tissues were investigated with the TRM multiplex panel. After multi-spectral acquisition, the TRM and CD8 T cells could be differentiated in all of the tissue types examined. After delineation by a pathologist, we demonstrate the capability to quantify TRM and CD8 cells within the tumor and stroma compartments. The presented approach has the power to expand the clinical implications of TRM in cancer vaccine and immunotherapy.
Citation Format: Elena Baranova, Amanda Finan-Marchi, Manon Motte, Maroua Tliba, Sabine Iglesias, Carole Belda, Alexandra Mace, Sylvie Hunt, Domenico Lazzaro, Jean-Philippe Coton, Renaud Burrer. Multiplex immunofluorescence detection of resident memory T cells in solid tumors [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 4988.
Abstract 5049: Development of huPBMC-NCG mice to study xenogenic graft versus host disease (GVHD)
Authors: Ju Cunxiang , Sun Hongyan , Wang Dingyu , Guo Shiying , Zhang Mingkun , Wu Hainan , Li Shuai , Ju Chao , Zhao Jing , Gao Xiang 
Published: September 2020

Abstract
Graft versus host disease (GVHD) is a severe complication of allogeneic stem cell transplantation for leukemia treatment. NCG mice lacking functional murine T, B, NK cells as well as decreasing functional macrophage and dendritic cells could be used as recipients of human peripheral blood mononuclear cells (huPBMC) for the studies of human GVHD. In this study, huPBMC-NCG mice were developed by the engraftment of huPBMC into unconditioned or irradiated NCG mice. The engraftment kinetics, irradiation effect, and preclinical treatment were explored in these mice. After huPBMC engraftment, NCG mice developed GVHD symptoms, including body weight loss, fur loss, reduced activity, hunched posture and severe ruffling, and eventually led to mortality. We also observed human T cell trafficking to target organs including gut, heart, liver, skin, and lung by flow cytometry and immunohistochemistry. Interestingly, irradiation could significantly accelerate the onset of GVHD following huPBMC engraftment. Meanwhile, irradiated huPBMC-NCG mice presented less variability in the kinetics of GVHD and the frequency of this disease in comparison with unconditioned counterparts, thus providing a more stable model for human GVHD studies. For preclinical studies, we found immunomodulatory drugs including Abatacept (CTLA4-Ig) targeting APC cells or anti-Ly6G antibody targeting neutrophils could alleviate GVHD-associated symptoms along with improving overall survival of huPBMC-NCG mice. Taken together, this study established stable huPBMC-NCG mice to mimic the onset and development of human GVHD, which was helpful for the development of therapeutic intervention.
Citation Format: Cunxiang Ju, Hongyan Sun, Dingyu Wang, Shiying Guo, Mingkun Zhang, Hainan Wu, Shuai Li, Chao Ju, Jing Zhao, Xiang Gao. Development of huPBMC-NCG mice to study xenogenic graft versus host disease (GVHD) [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 5049.
Abstract 5080: Prognostic immune subtypes in glioblastoma
Authors: Joy Anna , Dong Xishuang , Kim Seungchan 
Published: September 2020

Abstract
Variations in the tumor immune microenvironment between Glioblastoma (GBM) patients complicates development and testing of immunotherapies. We used publicly available single cell RNA sequencing data of GBM patients to extract pan immune-specific genes in GBM. Interrogating bulk GBM sequencing or microarray data with pan immune-specific genes should allow examination of the immune component. We used these genes to investigate subtypes of GBM immune microenvironments. Consensus clustering using these genes on GBM TCGA RNAseq data gave 4 distinct subtypes while 12% of tumors were not assigned to any of those subtypes. Immune subtypes had distinct clinical outcomes. Differences in median survival (16.6 vs 5.8 months; longest vs. shortest survival; p &lt; 1e-05 Logrank, Wald and Likelihood ratio tests) suggests the immune microenvironment significantly impacts clinical course. Cox univariate analysis indicates age had no contribution to risk (HR = 1.034; 95% confidence interval 1.017-1.052). We propose that immune-subtyping of GBM with pan immune-specific genes will lead to biomarkers that predict immunotherapeutic response. It will also help to identify molecular pathways and targets that suppress the immune anti-tumor response.
Citation Format: Anna Joy, Xishuang Dong, Seungchan Kim. Prognostic immune subtypes in glioblastoma [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 5080.