bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-024: Development of a non-invasive clinically applicable real time cell tracking platform for evaluating cell-based cancer therapy using magnetic resonance imaging (MRI)
Authors: Akers Johnny C. , Wei Zhao , Jang Hyungseok , Chang Eric , Du Jiang , Thu Mya S. 
Published: September 2020

Abstract
While advancement in chimeric antigen receptors (CARs) has greatly improved the anti-tumor activity of immune cell-based therapies utilizing modified T lymphocytes (CAR-T) and natural killer cells (CAR-NK), there remains a critical unmet need for diagnostic technologies to help evaluate their biological performance effectively and efficiently after injecting into the body.The ability to better understand the biodistribution of injected cells and devise dosing strategies are key determinants to the success or failure of cell therapy. However, clinicians are limited by the available technology for real time in-vivo tracking of cell therapy products in clinical settings. Here we present a clinically applicable novel magnetic agent that can effectively label a variety of cell types used in cancer cell therapy development including T cells, NK cells, and neural stem cells (NSCs), and when combined with the 3D ultrashort echo time Cones (3D UTE-Cones) sequence, can enable quantitative assessment of cell therapy products using MRI. In this study, we optimized loading of our tracking agent into T cells, NK cells, and NSCs, evaluated the morphology and viability of the labeled cells, and confirmed internalization of the labeling agent by Prussian blue staining and TEM. The in vitro MRI properties of the labeled cells were quantitated by the 3D UTE-Cones sequence. Ex vivo MRI analysis was performed by injecting labeled cells into harvested mouse livers and brains to ascertain their MRI visibility in tissues using a clinical MRI scanner. We confirmed that our magnetic labeling agent efficiently labeled each cell line tested, and the morphology or viability of the labeled cells were unaffected. The MRI detectability of labeled cells were confirmed by in vitro MRI phantoms. Further, using quantitative susceptibility mapping (QSM), T1, and T2* mapping based on 3D UTE-Cones sequences, we found near perfect correlations between cell density and MRI properties. By applying the parameters established in the MRI phantoms, we were able to detect and quantity the number of labeled cells injected into mouse livers and brains ex vivo. In summary, we have developed a clinically applicable imaging-based platform that empowers cell therapy researchers to better understand the results of their biodistribution and dosing studies through real-time cell tracking and quantitative assessments using MRI.
Citation Format: Johnny C. Akers, Zhao Wei, Hyungseok Jang, Eric Chang, Jiang Du, Mya S. Thu. Development of a non-invasive clinically applicable real time cell tracking platform for evaluating cell-based cancer therapy using magnetic resonance imaging (MRI) [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 LB-024.
Abstract LB-031: The significant role of 14-3-3 sigma including signal transduction, cell cycle regulation, and malignant transformation in human gastric cancer
Authors: Jung Jiyoon , Lee Kyunghee , Koh sungae , Kim sangwoon 
Published: September 2020

Abstract
Background: 14-3-3 protein family have many diverse functions in cellular responses including cell cycle regulation, apoptosis and malignant transformation in a broad range of organisms. 14-3-3 sigma induces G2 arrest enabling the repair of damaged DNA. Especially 14-3-3 sigma is frequently lost in tumor cells and surrounding tissues, indicate that becomes lost at an early stage in invasive cancer. The purpose of this study is to identify the role of HGF upregulated 14-3-3 sigma associated with cancer cell proliferation and invasion in gastric cancer and to identify the role of 14-3-3 sigma level in vivo by analysis 14-3-3 serum level in gastric cancer patients who underwent gastrectomy.
Methods: In our study we used cell culture, Northern blotting, cDNA microarray analysis, western blotting, RT-PCR, Zymography, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 14-3-3 sigma knock-down with short hairpin RNA (shRNA), electrophoresis mobility-shift assay, chromatin immunoprecipitation assay, Standard two chamber invasion assay. And we conducted the 14-3-3 sigma ELISA (enzyme-linked immunosorbent assay) of 37 blood samples of patients, who underwent gastrectomy for gastric cancer.
Results: First, we confirmed that the expression level of 14-3-3 sigma was up-regulated by HGF(hepatocyte growth factor) in gastric cancer cell. To identify associated pathway of HGF-induced 14-3-3 sigma about MMP-1 (matrix metalloproteinase-1) expression, the cells were treated with MEK (Mitogen-activated protein kinase kinase) inhibitor(PD098059) and then analyzed by Western blotting. The HGF-mediated MMP-1 protein level was decreased with PD098059. The role for 14-3-3 sigma associated with MMP-1 was determined by knock down cell of 14-3-3 sigma. 14-3-3 sigma-sh RNA cells showed a decreased level of MMP-1, pERK and pp38. HGF-mediated cell proliferation and in vitro invasion was decreased in 14-3-3 sigma knock down cell. We also identified that 14-3-3 sigma serum level was statistically significant decreased after gastrectomy in gastric cancer patients with stage 2 or 3. (p value &lt; 0.05)
Conclusions: Our results support the hypothesis that 14-3-3 sigma plays an important role in the cell proliferation in gastric cancer, and knock down this domain, it can be preventing to gastric cancer progression. And 14-3-3 sigma serum level is associated with status of treatment locally advanced gastric cancer.
Citation Format: Jiyoon Jung, Kyunghee Lee, sungae Koh, sangwoon Kim. The significant role of 14-3-3 sigma including signal transduction, cell cycle regulation, and malignant transformation in human gastric 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 LB-031.
Abstract LB-107: TET2/DNMT3A mutations and exceptional response to novel epigenetic agent in human malignancies
Authors: Yang Sherry X. , Rubinstein Larry , Nguyen Dat , Larenjeira Angelo B. , Kinders Robert , Difilippantonio Michael , Doroshow James H. 
Published: September 2020

Abstract
Background: Challenges remain on the selection of patients who potentially respond to a class of drugs that target the epigenetics for cancer treatment. This study aims to investigate TET2/DNMT3A mutations, their role on prognosis, and relation between the mutations and antitumor activity of a novel epigenetic agent in multiple human cancer cell lines and animal models. Methods: TET2/DNMT3A mutation data in human malignancies were obtained from cBioPortal. Eighteen cancer cell lines and multiple mouse models bearing representative human solid tumors were subjected to 4'-thio-2'-deoxycytidine (T-dCyd) or saline treatment. Gene mutations were examined by whole exome and/or Sanger sequencing in these cell lines. Pharmacodynamic modulation of specific gene expression was analyzed in xenograft tumor samples by immunohistochemistry. Results: TET2 and DNMT3A were frequently mutated in angioimmunoblastic/peripheral T-cell lymphomas, several types of leukemias and cutaneous squamous cell carcinoma, and mutated in lung, breast, skin, and kidney cancers. T-dCyd significantly reduced cell survival in lung NCI-H23, breast BT549, melanoma SKMEL5 and renal ACHN cancer cells that harbor deleterious TET2 and nonsynonymous DNMT3A mutations compared to 14 lines without such pattern of alterations (P = 0.006; 2-sided T-test). Anti-tumor effect was validated in vivo; T-dCyd significantly inhibited tumor growth in mice with TET2/DNMT3A mutation-positive tumors. Histological evaluation revealed a near eradication of tumor cells by T-dCyd in NCI-H23 xenografts. T-dCyd administrations led to a remarkable and persistent p21Waf1/Cip1 increase during treatment (P &lt; 0.0001). In contrast, little activity was observed in xenograft models without this pattern of gene mutations. Conclusions: Cancer cells and animal models examined with TET2 and DNMT3A-mutant genotype are sensitive to T-dCyd treatment.
Citation Format: Sherry X. Yang, Larry Rubinstein, Dat Nguyen, Angelo B. Larenjeira, Robert Kinders, Michael Difilippantonio, James H. Doroshow. TET2/DNMT3A mutations and exceptional response to novel epigenetic agent in human malignancies [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 LB-107.
Abstract LB-145: Immunomodulatory activity of selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC)
Authors: Tarapore Rohinton S. , Prabhu Varun V. , Mok Samuel C. , Yeung Chilam Au , Rodriguez Lorna , Girda Eugenia , Mantia-Smaldone Gina , Bae-Jump Victoria , Lu Guangrong , Oster Wolfgang , Allen Joshua E. 
Published: September 2020

Abstract
ONC201 is a small molecule DRD2 antagonist and ClpP agonist that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The enhanced immune modulatory nature of ONC201 was observed in a Phase I study that revealed increased infiltration of granzyme B+ and CD56+ cells, corroborating preclinical reports of NK cell intratumoral infiltration in response to ONC201. A broad induction of immune cytokines and effector molecules was observed in patients treated with ONC201, in particular among patients who experienced at least stable disease by RECIST for 12 or more weeks. Patients who had a &gt; 50% induction in serum perforin, a cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and NK cells, upon ONC201 administration had better outcomes. Regressions in individual metastatic lesions were noted in a small number of EC patients. A multi-center Phase 2 study to explore the efficacy of weekly ONC201 in recurrent or metastatic Type II EC enrolled 5 patients with recurrent EC who underwent paired tumor biopsies before and 9 days after ONC201 initiation. Four of the 5 patients exhibited a 2-5-fold increase in CD4+ Thelper cells in their tumors and the majority of these patients also had CD4+FoxP3+ cells, indicating a significant population of Tregulatory cells (Treg). One patient exhibited an 80% increase in CD8+ T-cells in their tumor 8 days after initiating ONC201. Two of the patients had &gt;2 fold induction of intratumoral granzyme B expression that was surprisingly not accompanied by NK cell infiltration, as assessed by CD56 staining. These results may be consistent with innate immune system activation by ONC201 that results in T-cell modulation. The multi-fold increase in Treg expression could be suppressing tumor cell death. As such, ONC201 dose intensification or combination with immunotherapy are being evaluated for ONC201 in the context of endometrial cancer.
Citation Format: Rohinton S. Tarapore, Varun V. Prabhu, Samuel C. Mok, Chilam Au Yeung, Lorna Rodriguez, Eugenia Girda, Gina Mantia-Smaldone, Victoria Bae-Jump, Guangrong Lu, Wolfgang Oster, Joshua E. Allen. Immunomodulatory activity of selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC) [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 LB-145.
Abstract LB-146: The impact of pancreatic cancer resection on long-term survival in the era of effective systemic treatment
Authors: Lawrence Yaacov R. , Shtern Alina , Margalit Ofer , Golan Talia , Symon Zvi 
Published: September 2020

Abstract
Background: Surgical resection is the only curative modality in pancreatic cancer, yet the vast majority of patients undergoing surgery succumb of their disease. No large randomized studies have been performed to assess the survival impact of the procedure. We hypothesized that in the era of effective systemic treatments the survival advantage of surgical resection would be lessened.
Methods: A meta-analysis of published phase II and phase III clinical trials in pancreatic cancer in both the post resection adjuvant setting and the locally advanced / metastatic setting. Trials were included based upon a systemic literature search. Eligibility criteria included: at least 50 patients per arm, detailed overall survival rates reported. Exclusion criteria: patients from trial arms for which there were not complementary data sets with / without surgical resection, trials testing non-pharmacological modalities or neoadjuvant approaches. Data was stratified based upon the systemic agents used, and analysed using an indirect aggregate approach. Primary endpoint was 3 year overall survival (OS_3yr), comparing patients treated with systemic treatment alone vs. surgery followed by adjuvant systemic treatment.
Results: 74 treatment arms from 56 prospective trials published between 1990 and 2018 were included in the analysis. Overall a total of 11,898 patients were included, of whom 3,600 underwent resection. Median follow-up was 29.8 months for studies were stated. OS_3yr was for systemic treatment alone was 0%, 0%, 0.5%, 2.5%, 0.16%, 1.2%, 3.8% for No chemo, 5FU, Gemcitabine, S-1, Gemcitabine + xeloda, Gemcitabine + S-1, and Folfirinox respectively, and 19.9%, 24.9%, 32.9%, 58.8%, 42.5%, 52%, and 62.5% for the same agents delivered in the adjuvant setting; the advantage in OS_3yr provided by resection was 19.9%, 24.9%, 32.4%, 56.3%, 42.3%, 50.8%, and 58.8% for these agents, respectively. The advantage in OS_3yr provided by resection correlated closely with reported response rates for each systemic agent, r=0.96 p&lt;0.001.
Conclusions: Within the limitations of this analysis, it appears that our hypothesis was incorrect, and that the opposite is true. The introduction of effective systemic therapies has greatly increased the impact of pancreatic surgery on long-term survival in pancreatic cancer. Furthermore, it appears that for pancreatic cancer, systemic agents are more active in the adjuvant than the metastatic setting. Consequently, every effort should be made to bring patients to curative resection.
Citation Format: Yaacov R. Lawrence, Alina Shtern, Ofer Margalit, Talia Golan, Zvi Symon. The impact of pancreatic cancer resection on long-term survival in the era of effective systemic treatment [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 LB-146.
Abstract LB-157: Obesity at early adulthood increases subsequent risk of gastric cancer in high incidence nation: Results from the Health Examinees-Gem (HEXA-G) study
Authors: Lee Hwi-Won , Shin Woo-Kyoung , Yang Jae Jeong , Song Minkyo , Shin Aesun , Lee Jong-koo , Kang Daehee 
Published: September 2020

Abstract
Background: The global trend of obesity, or the “obesity epidemic,” is not confined to adults. The increasing rates of obesity at young age signifies potential burden to our society as a whole, and requires prompt attention. Although emerging evidence has indicated a possible link of obesity in early life to subsequent cancer risks, the association with gastric cancer remains largely unknown, especially among the populations with high incidence rates of gastric cancer. Objective: Using data from the Health Examinees (HEXA) study of Korea, this study aimed to investigate the association of obesity at younger age (ages 18-20 and 35) with the later risk of gastric cancer in a population with high incidence rate of gastric cancer. Method: Included were 114,155 cancer-free subjects who participated in the large-scale prospective cohort study of the Health Examinees-Gem (HEXA-G) study during 2004-2013. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for gastric cancer risk associated with body mass index (BMI) at age 18-20 and 35. To consider substantial differences in incidence rates between men and women, the overall associations were further evaluated, separately by sex. Results: During a median follow-up period of 6.2 years, 851 gastric cancer cases (476 men and 375 women) were identified. When compared to normal BMI (18.5 - 23.0kg/m2), obesity (BMI ≥30kg/m2) at age 35 was significantly associated with increased risk of gastric cancer later in life: HR (95% CI) = 2.60 (1.57-4.33) for total participants, 2.11 (1.03-4.34) for men, and 3.82 (1.86-7.86) for women. No significant associations were found for obesity at late adolescence in both men and women. Conclusion: Our findings suggest that obesity in early adulthood may be associated with increased risk of gastric cancer. Preventing obesity in early life may help reduce the health burden of gastric cancer in later life.
Citation Format: Hwi-Won Lee, Woo-Kyoung Shin, Jae Jeong Yang, Minkyo Song, Aesun Shin, Jong-koo Lee, Daehee Kang. Obesity at early adulthood increases subsequent risk of gastric cancer in high incidence nation: Results from the Health Examinees-Gem (HEXA-G) study [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 LB-157.
Abstract LB-177: BET and CDK9 protein inhibitors: Novel epigenetic therapy to synergistically kill human melanoma cells
Authors: Emran Abdullah Al , Tseng Hsin-Yi , Gunatilake Dilini , Cook Stuart , Tiffen Jessamy , Gallagher Stuart , Hersey Peter 
Published: September 2020

Abstract
Background: Dysregulation of epigenetic modifiers is a frequent event in melanoma and underlies many aspects of melanoma biology including resistance to targeted and immunotherapies. Here we report that dual targeting of BET and CDK9 proteins have synergistic effect in melanoma cells in vitro and in vivo. Methods: Cell viability was measured by Cell titre glow and colony forming assays. Annexin V/PI staining was performed to assess apoptosis. Apoptotic, anti-apoptotic, pro-survival signalling proteins were probed by immunoblotting. Genome wide expression analysis were performed by RNA-seq analysis of sensitive cell lines. Live-dead staining and apoptosis were performed in 3D spheroid models. In vivo studies were carried out on the YUMM1.1 mouse model in C57BL/6 syngeneic mice. Results: We report that BET and CDK9 inhibitor iBET151 and CDKI73 synergistically killed melanoma cells independent of their genetic background compared to single inhibitors. Combination index (CI) was calculated by calcusyn software also showed strong synergism (&lt;0.3). However, these drugs did not kill human dermal fibroblast suggestive of a cancer cell specific effect. There was a time dependent increase in cell death that was associated with downregulation of anti-apoptotic proteins BCL2 and MCL1 and the oncogene c-MYC. These findings in 2D models were corroborated in 3D spheroid models. Gene Set Enrichment Analysis (GSEA) revealed that HALLMARK G2M CHECKPOINT, HALLMARK E2F TARGETS, HALLMARK MYC TARGETS were negatively enriched in the combination treatment (Normalized enrichment score =&lt;-2.5). The in-vivo studies on the anti-PD1 resistant mouse melanoma cell line YUMM 1.1. showed that iBET151 and CDKI73 combination had marked effects on tumour growth compared to vehicle control and the individual drugs (p&lt;0.05). Conclusion: Our findings have revealed that this novel combination of two epigenetic inhibitors targets multiple downstream genes associated with cell cycle, oncogenesis and, apoptotic pathways which augments cell death compared to effects of the single drugs. Overall, the findings warrant further investigation of key targets involved in the responses and the extent to which effects of CDK9 inhibition is due to effects on chromatin modelling. The combination would appear promising to consider for future clinical trial in melanoma patients not responding to current therapies.
Citation Format: Abdullah Al Emran, Hsin-Yi Tseng, Dilini Gunatilake, Stuart Cook, Jessamy Tiffen, Stuart Gallagher, Peter Hersey. BET and CDK9 protein inhibitors: Novel epigenetic therapy to synergistically kill human melanoma 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 LB-177.
Abstract LB-178: Identification of DNA 5hmC decision signature biomarkers for azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk AML
Authors: HAN Dali , Zhang Wei 
Published: September 2020

Abstract
DNA 5hmC biomarkers to predict the outcomes to the of azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy for patients with high-risk AML. Azacitidine (AZA), a DNA methyltransferase inhibitor and epigenetic modulator, has been combined with chemotherapy to treat high-risk AML patients for better clinical outcomes. However, the complete remission (CR) rate and prognosis remains unsatisfactory. Here, we proposed that the use of AZA for high-risk AML patients helped to sensitize leukemia cells to chemotherapy. We analyzed 45 high-risk AML patients who had received AZA treatment followed by High-dose cytarabine and mitoxantrone (AZA-HiDAC-Mito) therapy. We performed RNA-Seq and DNA 5hmC-Seq on available RNA/DNA samples. By comparing differential expressed genes between patients responded to therapy (CR or CRi, responder) and those did not (non-responder), we found that patients with better response had lower expression on ephrin receptor gene and AR pathway related genes. Using XGBoost machine learning model, we developed an 11-gene-5hmC signature to predict treatment outcomes, and it achieved 87.76% sensitivity and 87.10% specificity (AUC=0.911). The signature was also capable of distinguishing which patients would have better response to HiDAC-Mito only treatment, indicating that the signature had a potential to serve as a general predictor for intensive chemotherapy. Our findings show that DNA 5hmC patterns could be used as the prognostic biomarker for AZA-HiDAC-Mito therapy, which could guide further biomarker-based clinical trials.
Citation Format: Dali HAN, Wei Zhang. Identification of DNA 5hmC decision signature biomarkers for azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk AML [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 LB-178.