bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2260: Non-alcoholic fatty liver disease polygenic risk score and risk of hepatocellular carcinoma in an East Asian population
Authors: Thomas Claire E. , Diergaarde Brenda , Kuipers Allison L. , Adibi Jennifer J. , Luu Hung N. , Chang Xuling , Dorajoo Rajkumar , Heng Chew-Kiat , Khor Chiea-Chuen , Wang Renwei , Jin Aizhen , Koh Woon-Puay , Yuan Jian-Min 
Published: June 2022

Abstract
Purpose: It is difficult to identify people with non-alcoholic fatty liver disease (NAFLD) who are at high risk for the development of hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat derived from non-Asians has been reported to be associated with HCC risk in European populations. However, population level data of this risk in non-European populations are lacking.
Methods: Utilizing resources from the Singapore Chinese Health Study (SCHS), we examined the relationship between the previously published hepatic fat PRS (HFC-PRS) and HCC risk. We also constructed and evaluated a NAFLD-related PRS (NAFLD-PRS); the final version included SNPs in similar gene regions as the HFC-PRS but weighted by effect estimates for NAFLD among those with East Asian ancestry. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of HCC incidence with both HFC-PRS and NAFLD-PRS.
Results: The HFC-PRS and NAFLD-PRS were highly correlated (Spearman r = 0.79, P &lt; 0.001). The highest quartiles of both the HFC-PRS and the NAFLD-PRS were associated with significantly increased risk of HCC with HR of 2.39 (95% CI 1.51, 3.78) and 1.77 (95% CI 1.15, 2.73), respectively, compared to their respective lowest quartile.
Conclusion: The HFC-PRS and the NAFLD-PRS may both be useful in stratifying Asian populations according to their risk of HCC. In addition, the association between the NAFLD-PRS, derived from East Asians, and HCC risk suggests a potential causal role for NAFLD in the development of HCC in this population.
Citation Format: Claire E. Thomas, Brenda Diergaarde, Allison L. Kuipers, Jennifer J. Adibi, Hung N. Luu, Xuling Chang, Rajkumar Dorajoo, Chew-Kiat Heng, Chiea-Chuen Khor, Renwei Wang, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan. Non-alcoholic fatty liver disease polygenic risk score and risk of hepatocellular carcinoma in an East Asian population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2260.
Abstract 2263: The role of E-Cadherin mediated cell division in promoting collective colon cancer cell migration
Authors: Li Yu-Lin , Weng Yu-Cheng , Winarso Viriya Adhiguna , Lu Yi-Wen , Koo Hui Min , Hou Xiang-Ling , Tseng Kai-Yu , Chao Wei-Ting 
Published: June 2022

Abstract
Collective cell migration is the cell cohort migrates toward the direction. Other than single cell migration, collective cell migration requires cell-cell connection with E-cadherin, however, E-cadherin is the epithelial marker in epithelial mesenchymal transition and acts as tumor suppressor function. Therefore, the role of E-cadherin in collective cell migration is still under investigated. In the collected cells, cell migration and cell division are coordinated for the cohort motility, the mechanism is still not clear. This study is to investigate the role of E-cadherin orientation in cell division dependent collective cell migration. Colorectal cancer cell line HT29 with epithelial morphology were used and treated with Cetuximab and Dasatinib to inhibit EGFR and Src activity. Cells were also incubated on fibronectin to monitor the matrix dependent environment. The polarity of E-cadherin distribution and cell contact inhibition were defined and detected by Immunofluorescence. The molecular expression of p-FAK, CDK4, and cell proliferation marker, Ki67 were revealed by Immunofluorescence confocal microscopy and Western blot. The collective cell migration is analyzed and compared by wound healing and transwell assay. In the results, the polarized distribution of E-cadherin in leading cells which revealed pFAK expression on the cell membrane was associated with Ki67 and CDK4 positive proliferated cells. When cells were grown on fibronectin, the proliferated cells in the leading were decreased. When cells were treated with cetuximab, the E-cadherin distribution were not changed and had fewer effect on cell migration. However, dasatinib treatment can modulate E-cadherin orientation and suppress cell proliferation and cell migration. These results suggested modulate E-cadherin orientation such as Src inhibition can be the potential treatment strategy in colon cancer
Citation Format: Yu-Lin Li, Yu-Cheng Weng, Viriya Adhiguna Winarso, Yi-Wen Lu, Hui Min Koo, Xiang-Ling Hou, Kai-Yu Tseng, Wei-Ting Chao. The role of E-Cadherin mediated cell division in promoting collective colon cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2263.
Abstract 2271: Patient-specific visualization of cancer pathways
Authors: Swaminathan Padmapriya , Williams Casey B. , Meissner Tobias 
Published: June 2022

Abstract
​Introduction: Analysis of whole transcriptomics datasets to quantify gene expression and determine differentially expressed genes has provided valuable information for precision medicine. Evaluating enrichment of specific gene groups and pathways, and visualizing these results is an important step to obtain inferences about patient treatment outcomes, overall survival, drug resistance and therapeutic targets.
However, pathway analysis of cancer patient samples in a N-of-1 setting without their respective control (normal) samples remains to be challenging. There is a crucial need for methods and tools to conduct and visualize pathway analysis results in this setting.
Methods and Results: Our method focuses on a visualization technique showing patient-specific pathway activation relative to reference populations from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEX). Patient-specific pathway activity scores are displayed within the respective percentiles and averages of the TCGA and GTEX cohorts to visualize a patient's individual pathway activation profile within the TCGA tumor and GTEX normal reference population. Patient-specific pathway scores are derived from an individual patient's transcriptomic profile and transformed into activity scores for each of 14 cancer pathways. This allows for the comparison of an individual patient’s pathway activation profile with reference samples from TCGA and GTEX. We used PROGENy (Pathway RespOnsive GENes for activity inference) to calculate activity scores for the 14 cancer related pathways.
The pathway activity scores of each new tumor sample are scaled using the parameters of scaled pathway activity scores obtained from TCGA and GTEX gene expression data of all cancer tissue types. Finally we visualized the pathway activity scores of each patient sample.
Conclusion: Our visualization method is expected to unravel the activation patterns of each of the 14 cancer pathways in our patient samples. Specific pathway genes can then be evaluated in the patient samples to identify causal mutations and their associations with the pathway activity scores hence aid in treatment selection and in the further development of precision medicine therapeutic solutions.
Citation Format: Padmapriya Swaminathan, Casey B. Williams, Tobias Meissner. Patient-specific visualization of cancer pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2271.
Abstract 2319: Niclosamide enhances the antitumor effect by inducing ubiquitination of β-catenin in pancreatic cancer
Authors: Kang HyeonWoong , Park JoonSeong , Lee YunSun , Lee Daeun , Kim HyoJung 
Published: June 2022

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is known as one of the critical cancers that have a high morbidity and mortality worldwide. Due to lack of therapeutic agents, patients’ overall survival rate has been decreased. Gemcitabine is the only well-known drug to treat pancreatic cancer patients but less effective. Therefore, it is significantly required to discover and develop novel therapeutic agents for PDAC therapy. The present study represents the first study evaluating the anticancer efficacy of niclosamide in PDAC. Here, we found that niclosamide co-treatment with gemcitabine inhibited pancreatic cancer cells compared with gemcitabine alone by suppressing the Wnt/β-catenin signaling pathway. In addition, niclosamide co-treatment with gemcitabine inhibited cell proliferation as determined by MTS assay and induced cell apoptosis as determined by Annexin V and PI staining. Further, niclosamide induced G1 arrest of the cell cycle as evidenced by down-regulated CDK4/6 and Cyclin D1 expression. Our findings proved that combining niclosamide and Gemcitabine effectively down-regulates the tumor size and growth in pancreatic cancer. Altogether, our results indicate that niclosamide synergistically enhances the antitumor effect with treating gemcitabine by inducing the ubiquitination and degradation of β-catenin in pancreatic cancer and could be a novel potential candidate for PDAC therapy.Key words: PDAC, Niclosamide, Gemcitabine, β-catenin ubiquitination, Apoptosis, Cell cycle
Citation Format: HyeonWoong Kang, JoonSeong Park, YunSun Lee, Daeun Lee, HyoJung Kim. Niclosamide enhances the antitumor effect by inducing ubiquitination of β-catenin in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2319.
Abstract 2320: Ivermectin suppresses pancreatic cancer via mitochondria dysfunction
Authors: lee daeun , park joon seong , lee yun sun , kang hyeon woong , kim hyo jung 
Published: June 2022

Abstract
Pancreatic cancer is an aggressive cancer characterized by high mortality and poor prognosis with survival of less than 5 years when advanced. Several studies showed that the ivermectin has antitumor effects on a variety of cancer cells. The present study represents the first study evaluating the anticancer efficacy of ivermectin in pancreatic cancer. We found that the anticancer effect of ivermectin in combination with gemcitabine on pancreatic cancer is more effective than gemcitabine alone. Ivermectin-gemcitabine combination inhibited cell proliferation via G1 arrest of the cell cycle, as evidenced by down-regulated cyclin D1 expression through mTOR/STAT3 signaling pathway. In addition, ivermectin-gemcitabine induced apoptosis by ROS generation and reduction of mitochondrial membrane potential (MMP), and blocked mitophagy. In vivo experiments also confirmed that ivermectin-gemcitabine groups significantly suppressed the tumor growth of pancreatic cancer compared with gemcitabine alone groups. These results indicate that ivermectin has a synergistic effect with gemcitabine in preventing cancer progression and could be a potential antitumor drug for the treatment of pancreatic cancer. Key words: Pancreatic cancer, Gemcitabine, Ivermectin, apoptosis, ROS, mitochondria dysfunction
Citation Format: daeun lee, joon seong park, yun sun lee, hyeon woong kang, hyo jung kim. Ivermectin suppresses pancreatic cancer via mitochondria dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2320.
Abstract 2338: Bioluminescent assays for measuringthemetabolic state of cancer and immune cells
Authors: Bach Maggie , Leippe Donna , Karassina Natasha , Valley Michael , Cali James , Vidugiriene Jolanta 
Published: June 2022

Abstract
In the tumor microenvironment, cancer and immune cells compete for limited nutrients and both must undergo complex metabolic changes to support their function. To better understand the underlying mechanisms of tumor growth, metastasis and adaptation, a comprehensive analysis of metabolic pathways is needed. Success of such studies requires rapid and reliable approaches for monitoring key metabolic pathways, including glycolysis, the pentose phosphate pathway, fatty acid metabolism, amino acid metabolism and TCA cycle. Due to its inherent robustness, sensitivity and broad dynamic range, bioluminescence detection provides an attractive opportunity for developing such assays. Here, we implement a panel of bioluminescent metabolite assays (glucose, lactate, glutamine/glutamate, triglyceride/glycerol, cholesterol esters/cholesterol) to investigate the metabolic state of immune and cancer cells. We demonstrate flexibility of the assays in various volumes (96-, 384- well plates), sample types (2D, 3D cultures), automation platforms, and workflows, including detecting multiple metabolites in the same sample and monitoring metabolite changes over time by assaying multiple samples. We validate the performance of the assays by using metabolic pathway-specific inhibitors and demonstrating the utility of the assays as early indicators of cytotoxic T-cell activation. Finally, since metabolism is a dynamic process guided by fuel availability, we show the importance of medium composition when designing studies and suggest guidance for future work. In conclusion, understanding the crosstalk between tumor cells and their microenvironment is required for next-generation drug development. Bioluminescent metabolite assays provide the sensitivity, throughput and robustness required for rapid evaluation of changes in major metabolic pathways and are well suited for novel inhibitor screening and drug development.
Citation Format: Maggie Bach, Donna Leippe, Natasha Karassina, Michael Valley, James Cali, Jolanta Vidugiriene. Bioluminescent assays for measuringthemetabolic state of cancer and immune cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2338.
Abstract 236: Nuclear receptor 4A1 ligands target T-cell exhaustion in colorectal cancer
Authors: Mohankumar Kumaravel , Wright Gus , Kumaravel Subhashree , Shrestha Rupesh , Zhang Lei , Abdelrahim Maen , Chapkin Robert S. , Safe Stephen 
Published: June 2022

Abstract
Colorectal cancer (CRC) is a highly complex disease with multiple risk factors. The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in several cancers and is a negative prognostic factor for cancer patient survival. Previous reports indicate a potential role for overexpression of NR4A1 in T-cell exhaustion and in this study, we aim to investigate the antitumorigenic activity of two bis-indole derived ligands (DIMs) that act as receptor antagonists. Immune competent C57BL/6 mice and mouse MC-38 colon cancer cells were used and tumor Infiltrating Lymphocytes (TILs) were isolated from mice either untreated or treated with CDIM/NR4A1 antagonists. FACS analysis and Real -Time PCR were performed to determine expression of exhaustion markers in these tumor T-cell population. 1,1-Bis(3΄-indolyl)-1-(3-bromo-5-trifluoromethoxyphenyl)methane (DIM-3-Br-5-OCF3) and the 3,5-dichlorophenyl analog (DIM-3,5-Cl2) at doses of 2.5 and 7.5 mg/kg/d inhibited tumor growth and downregulated expression of PD-L1, an NR4A1-regulated gene in MC-38 - derived tumors and cells. The mouse MC-38 colon cancer cell line was used in a syngeneic mouse model of colon cancer and tumor infiltrating lymphocytes (TILs) from MC-38 cell-derived colon tumors exhibited multiple markers of T-cell exhaustion in both CD8+ and CD4+ T-cells. Lymphocytes from an enlarged spleen in these tumor-bearing animals also exhibited markers of CD8+ and CD4+ T-cell exhaustion. Analysis of CD8+ cells from TILs showed that treatment with the NR4A1 antagonists modulated expression of several genes associated with T-cell exhaustion namely a decrease in TOX, TOX2 and NFAT mRNAs, activation of T-Bet. The percentage of CD8+ and CD4+ T-cells from tumors and spleen expressing PD-1, 2B4 and TIGIT was decreased in the treated vs control mice and TIM3 expression was also decreased in CD8+ (tumors and spleen) and CD4+ (tumors) T-cells. These findings suggest that NR4A1 antagonists are highly effective as anticancer agents in this mouse syngeneic colon tumor model by inactivating the pro-oncogenic activities of NR4A1 in tumors and by remediating NR4A1-regulated T-cell exhaustion in tumor and splenic lymphocytes.
Citation Format: Kumaravel Mohankumar, Gus Wright, Subhashree Kumaravel, Rupesh Shrestha, Lei Zhang, Maen Abdelrahim, Robert S. Chapkin, Stephen Safe. Nuclear receptor 4A1 ligands target T-cell exhaustion in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 236.
Abstract 2393: Chemerin signaling presents a novel metabolic weakness in clear cell renal cell carcinoma (ccRCC)
Authors: Wang Dazhi 
Published: June 2022

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer,accounting for 70-80% of the cases. While surgical resection of early-stage tumors remains the standard carefor patients, advanced ccRCC, metastatic or recurrent, portends a 5-year survival rate of only 12%, primarilydue to insensitivity toward conventional chemotherapy. ccRCC is identifiable histologically by its dramaticlipid storage phenotype, similar to adipocytes; yet the role of lipid metabolism in ccRCC is poorly understood.One of the well-established risk factors for ccRCC is obesity, and given that adipose tissue is known to producea variety of pro-adipogenic signaling molecules (called adipokines), we hypothesized that adipokine signalingmight be involved in the etiology of ccRCC. Our lab has recently identified a pro-tumorigenic adipokineprotein, chemerin (RARRES2), that is positively correlated with tumor aggressiveness. Suppression of chemerinvia either monoclonal antibody or siRNA led to reduction in lipid storage and significant tumor growthimpairment in both in vitro and in vivo models, suggesting the feasibility of targeting lipid metabolism as atreatment option in ccRCC patients. In this study, we investigate the signaling mechanisms of chemerin andhave found that chemerin drives downstream cellular activities and lipid deposition. We utilized CRISPR toknockout two candidate receptors of chemerin, GPR1 and CMLKR1, to gain insight into the signal transduction.CMLKR1 is a G-protein coupled receptor widely expressed on a variety of immune cells whereas GPR1expression is reported primarily in adipose tissues. While unknown on their detailed signaling cascadez, bothreceptors affect lipid metabolism related gene profiles in our ccRCC cell lines. Furthermore, both GPR1 andCMKLR1 knockout lead to growth suppression and decreased intracellular lipid deposition, highlighting theinvolvement of both receptors in regulating lipid metabolism and conferring growth advantage in ccRCC. Ourdata so far have shown the feasibility of identifying metabolic weaknesses in ccRCC, raising that possibility thattargeting lipid metabolism could be beneficial in ccRCC. Further investigation will be conducted to assess thetargetability of this ligand/receptor axis and various in vivo models including PDX and transgenic will be usedto assess the translational potential of our findings.
Citation Format: Dazhi Wang. Chemerin signaling presents a novel metabolic weakness in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2393.
Abstract 2395: Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine
Authors: Barekatain Yasaman , Ackroyd Jeffrey , Yan Victoria , Khadka Sunada , Chen Ko-Chien , Kalluri Raghu , de Groot John , Huse Jason , muller Florian 
Published: June 2022

Abstract
Homozygous deletion of the CDK2NA locus frequently results in the co-deletion of methylthioadenosine phosphorylase (MTAP) in many fatal cancers such as glioblastoma multiform (GBM). In cell culture, cell lines with MTAP-deletions show elevations of its substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit PRMT5, which sensitizes MTAP-deleted cell lines to PRMT5 and MAT2A inhibition. While extensively corroborated in vitro, the clinical efficacy of these strategies ultimately relies on equally significant accumulations of MTA in human tumors. In this work, using comprehensive metabolomic profiling, we show that MTA is primarily secreted, resulting in exceedingly high levels of extracellular MTA in vitro. We further show that primary human glioblastoma tumors minimally accumulate MTA in vivo, which is likely explained by the metabolism of MTA by MTAP-competent stromal cells. Together, these findings highlight the metabolic discrepancies between in vitro models and primary human tumors and should thus be carefully considered in the development of the precision therapies targeting MTAPhomozygous deleted GBM.
Citation Format: Yasaman Barekatain, Jeffrey Ackroyd, Victoria Yan, Sunada Khadka, Ko-Chien Chen, Raghu Kalluri, John de Groot, Jason Huse, Florian muller. Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2395.