bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6917: Ba/F3 AKT engineering cell lines, a useful platform for novel drug discovery
Authors: Wang Guoqian , Tang Yao , Xu Jingxiao , Peng Yao , Wang Yu , Ning Jingying , Hao Feng 
Published: March 2024

Abstract
AKT, also known as phosphoinositide 3-kinase (PI3K), plays a key role in various signaling cascades involved in cell growth and division, apoptosis inhibition, and angiogenesis. For AKT, which is at the central node of the PI3K/AKT/mTOR signaling pathway, the loss of PTEN, mutation, or amplification of AKT/PIK3CA can lead to the overactivation of the AKT signaling pathway, resulting in the occurrence and development of tumors. Recent studies have also found that AKT activation is associated with drug resistance in tumor therapy. Therefore, AKT has become a hot target for tumor therapy. The AKT family consists of three highly homologous isoforms, AKT1 (PKBα), AKT2 (PKBβ), and AKT3 (PKBγ), with more than 85% homology in their kinase regions. E17K is the most common and well-characterized activating mutation, accounting for approximately 15% of all AKT mutations. Rare mutations mainly include L52R, Q79K, and D323H. The failures of AKT inhibitors LY2780301 and Bayer's BAY1125976 demonstrate the significant challenges and complexities in developing inhibitors of the AKT pathway. Currently, the most advanced AKT inhibitor globally is AstraZeneca's capivasertib, which is primarily indicated for HR+ breast cancer and triple-negative breast cancer. Our group has generated 21 Ba/F3-AKT engineering cell lines, as useful models for novel drug discovery in vitro and in vivo, almost all clinically significant mutations were included, such as common mutations AKT1/2-E17K as well as rare mutations L52R, Q79K, D323H, and others. The Ba/F3-AKT engineering cell lines can be useful for developing and evaluating next-generation AKT inhibitors and exploring newly acquired resistance mutations in AKT.
Citation Format: Guoqian Wang, Yao Tang, Jingxiao Xu, Yao Peng, Yu Wang, Jingying Ning, Feng Hao. Ba/F3 AKT engineering cell lines, a useful platform for novel drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6917.
Abstract 6947: Exploring the single-cell dynamics of FOXM1 under cell cycle perturbations
Authors: Jawwad Tooba , Kamkaew Maliwan , Phongkitkarun Kriengkrai , Chusorn Porncheera , Sampattavanich Somponnat 
Published: March 2024

Abstract
The cell cycle plays a critical role in maintaining normal cellular functions and preventing abnormal cell growth. The transcription factor FOXM1 has emerged as a crucial regulator of cell cycle progression and has been implicated in various physiological and pathological processes. Notably, FOXM1 overexpression has been observed in numerous cancer types, including liver, prostate, breast, lung, and colon cancer. Despite its significance, our understanding of how FOXM1 dynamic behaves at the single-cell level under different cell cycle perturbations and its link to cell behavior heterogeneity remains limited. Here, we investigated the dynamic behavior of FOXM1 in individual cells exposed to various cell cycle perturbations, focusing on understanding heterogeneity in cell behavior and improving disease treatment. At the single-cell level, our investigation reveals six distinct dynamic features of FOXM1 in response to various therapeutic interventions, each of which corresponds to a unique cell phenotype. Our result further demonstrates that for cells exhibiting a high FOXM1 pattern, targeting aurora kinase and PLK1 may hold promise as a therapeutic approach for cancer suggesting that FOXM1 is a strong biomarker, and its pattern can be predictive of drug response, especially in cases with G1 checkpoint defects like Rb1 loss or p53 deficiency.
Citation Format: Tooba Jawwad, Maliwan Kamkaew, Kriengkrai Phongkitkarun, Porncheera Chusorn, Somponnat Sampattavanich. Exploring the single-cell dynamics of FOXM1 under cell cycle perturbations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6947.
Abstract 7: Ginsenoside Rb1 delays the senescence of CD8+ T cells to expand T cells with superior antitumor immunity
Authors: Ma Chunhong , Sheng Xue , Li Chunyang 
Published: March 2024

Abstract
Background and Objective: Immunosenescence represents a distinct state of T cell dysfunction in the TME, and plays crucial role in many age-related diseases including tumor. Senescent cell removal by senolytic agents or therapies that inhibit the SASP have demonstrated benefit in both preclinical and clinical models of geriatric decline and chronic diseases. Here, we aimed to screen anti-aging compounds to delay T-cell senescence in TME, and explore novel strategies of reversing tumor induced T-cell senescence to restore antitumor immunity.
Methods and Results: Using in vitro senescence inducing system, we screened ginsenoside Rb1 from 22 anti-aging compounds as the compound that had the most effective activity to reduce CD8+ T cell senescence, displayed as decreased β-gal, p16, and p21. Further analysis showed that ginsenoside Rb1 promoted anti-CD3/CD28-induced TCR signaling and the secretion of effector cytokines IFN-γ, TNF-α and IL -2 in OTI T cells. Intriguingly, ginsenoside Rb1 treatment significantly increased TCF-1 in CD8+ T cells, and ginsenoside Rb1 treated OT-I T cells significantly inhibited tumor growth. Moreover, ginsenoside Rb1 greatly enhanced the efficiency of CD19-CART cells to kill Namalwa tumor cells.
Conclusion: Ginsenoside Rb1 delays T cell senescence and enhances T cell antitumor activity. This data provides a new insight into T cell based antitumor therapy.
Citation Format: Chunhong Ma, Xue Sheng, Chunyang Li. Ginsenoside Rb1 delays the senescence of CD8+ T cells to expand T cells with superior antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7.
Abstract 7012: Studying mosaic epimutations at scale
Authors: Nikolaienko Oleksii , Lønning Per E. , Knappskog Stian 
Published: March 2024

Abstract
Mosaic epimutations (i.e., epigenetic gene inactivation) within the BRCA1 gene promoter occur in 5-8% of healthy individuals and are associated with a significantly elevated risk of breast and ovarian cancer. These epimutations arise prenatally and then serve as an underlying cause of cancer in adulthood, likely accounting for about 20% of triple-negative breast cancers. Similar mosaic epimutations have been detected in some other tumor suppressor genes as well, but the intraindividual and population frequencies of this phenomenon remain unknown. To address this gap, we have developed novel methodology for detection of mosaic epimutations. The experimental technique is a multiplexed, hybridization capture-based, targeted methylation sequencing assay covering gene regulatory areas. It allows cost-effective assessment of epimutations in established and emerging tumor suppressor genes. An accompanying tailored data analysis pipeline is designed to quantify epimutations. The pipeline is sensitive and robust to variance in methylation, sequencing errors and batch effects. We applied this method to a set of samples from healthy young males. Analysis uncovered significant interindividual epimutational heterogeneity and confirmed high sensitivity of the assay and its superiority compared to methylation profiling using microarrays. Here, we present details on the highly sensitive, scalable and robust methodology for analysis of mosaic epimutations together with the results on initial assessment of the prevalence of epimutations in healthy individuals. We anticipate that this method will become widely used for studies of epigenetic gene regulation and related cancer risk.
Citation Format: Oleksii Nikolaienko, Per E. Lønning, Stian Knappskog. Studying mosaic epimutations at scale [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7012.
Abstract 7020: Prognostic implications of microRNA 181a 2 3p expression in association with tumor budding in patients with stage III lung squamous cell carcinoma
Authors: Lee Eunhyo , Kim Seoree , Kim Jeana , Lee Minho , Ko Yoonho , Chun Sang Hoon 
Published: March 2024

Abstract
Introduction: Tumor budding (Bd) has been known as an independent prognostic factor in various malignancies. MicroRNA (miRNA) are known to play an important role in regulating Bd. However, understanding the relationship between Bd and miRNA in Lung Squamous cell carcinoma (LUSC) remains limited.
Methods: 115 LUSC patients who underwent curative resection were included in the discovery cohort. Bd was verified through immunohistochemical (IHC) stain. Bd was classified according to a three tier system: Bd1 with 0-4 buds, Bd2 with 5-9 buds, and Bd3 with 10 or more buds. MiRNA expression profiles were analyzed through RNA sequencing. Differences in survival outcomes for miRNA, as identified in the discovery cohort, were confirmed using LUSC data of The Cancer Genome Atlas (TCGA) as a validation cohort.
Results: The relationship between Bd2 and the prolongation of recurrence-free survival (RFS) was statistically significant (p=0.0113), whereas Bd1 was correlated with Overall Survival (OS) (p=0.0468). Multivariate analysis indicated that both a high T stage (HR: 5.211, 95% CI: 1.168-23.250, p = 0.031; and HR: 5.107, 95% CI: 1.447-18.030, p &lt; 0.011) and Bd3 (HR: 3.683, 95% CI: 1.370-9.900, p = 0.010; and HR: 1.600, 95% CI: 0.800-3.201, p = 0.018) are independently significant poor prognostic factors for both RFS and OS. MiRNA-181a-2-3p was identified through Differentially Expressed miRNA (DER) analysis. A higher expression of miRNA-181a-2-3p in stage III LUSC of the TCGA dataset was associated with OS (p=0.0463).
Conclusions: Our study demonstrates that the miRNA 181a 2 3p expression is associated with improved OS. This association may be attributed to its inhibitory effect on Bd in advanced stages of LUSC.
Citation Format: Eunhyo Lee, Seoree Kim, Jeana Kim, Minho Lee, Yoonho Ko, Sang Hoon Chun. Prognostic implications of microRNA 181a 2 3p expression in association with tumor budding in patients with stage III lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7020.
Abstract 7035: Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics
Authors: Park Mi-So , Cho Hyunbin , Kim Hyeree , Park Woong-Yang , Paik Yong-Han , Yoon Yeup , Kang Wonseok , Won Hong-Hee 
Published: March 2024

Abstract
As the fifth leading cause of cancer-related mortality, liver cancer imposes a global burden. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with a five-year overall survival rate of less than 20% for advanced-stage cases. Even the most advanced immunotherapy for HCC has disparate response rates in each patient with HCC, which has led to efforts to unravel the underlying factors in the progression of HCC using bioinformatic approaches. In recent decades, numerous studies have explored T-cell subtypes with tissue-specific residency, suggesting their early protective functions and therapeutic potential within tumor microenvironment (TME). This study aimed to understand inter-individual and intercellular TME through single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) in five recurrent/non-recurrent HCC patients. We identified tumor-associated tissue-resident memory T (TA-TRM) cells and investigated the heterogeneous characteristics of two TRM clusters (CD69+ and CD103+). Whereas CD69+ TA-TRM showed high expression of genes associated with immunological activation, CD103+ TA-TRM exhibited upregulation of genes related to proliferation capacity. To validate the unique molecular patterns, we analyzed an independent HCC dataset (GSE140228) and observed high concordance of significant core marker genes for TA-TRM clusters between the two datasets. Moreover, we assessed the association of gene expression in TA-TRM cells with overall and recurrence-free survival by conducting survival analysis in two independent large-scale cohorts. The cross-validation approach was applied to estimate risk scores for patients with primary HCC tumors in The Cancer Genome Atlas (TCGA), and the trained model was evaluated using the International Cancer Genome Consortium (ICGC) data. The result of calculating the risk scores clearly indicates that TA-TRM cells are associated with survival in HCC. Therefore, our study characterized two distinct subtypes of TA-TRM cells in HCC, delineated their unique molecular signatures, and established their relevance to survival outcomes. The findings can potentially enhance the understanding of the roles of TA-TRM cells in the context of HCC.
Citation Format: Mi-So Park, Hyunbin Cho, Hyeree Kim, Woong-Yang Park, Yong-Han Paik, Yeup Yoon, Wonseok Kang, Hong-Hee Won. Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7035.
Abstract 7039: Leveraging single cell RNA-seq for uncovering immune landscape of hepatocellular carcinoma
Authors: He Jian 
Published: March 2024

Abstract
The immune cell types as well as tumor microenvironment (TME) status may influence prognosis, metastasis, tumor progression, and clinical response to immunotherapies for cancer. Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China, however, the immune microenvironment of HCC, especially which caused by cancerogenic substance has not been clarified so far. In this study, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC TME. Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas (TCGA) HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for the HCC.
Citation Format: Jian He. Leveraging single cell RNA-seq for uncovering immune landscape of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7039.
Abstract 7101: Remodeling of cancer cells by chemotherapy
Authors: Qian Gege , Schaffer Leah , Moon Kyung-Mee , Foster Leonard , Ideker Trey , Hu Mengzhou , Alkhairy Sahar , Lundberg Emma 
Published: March 2024

Abstract
Cisplatin is a commonly administrated chemotherapy drug for cancer treatment. Although the direct mechanism of cisplatin is largely well-defined, it is challenging to comprehensively assess its systemic effects. Cellular responses to perturbations are intricate processes involving modifications to protein complexes across diverse cellular compartments. Therefore, substantial research endeavors have been directed towards unraveling protein organization in cells. We recently built a multiscale integrated cell map, MuSIC, that combines fluorescence-stained images and interactions derived from affinity purification mass spectrometry to allow comprehensive characterization of cellular structure and functional networks of 5,254 proteins of the human bone osteosarcoma epithelial line (U2-OS). To exploit the biology of U2OS, we integrated dynamics into this map to determine the proteome reorganization upon cisplatin exposure. Thus, we developed a data-driven approach integrating high throughput size exclusion chromatography mass spectrometry (SEC-MS) data with large-scale cell maps built from static-state information to systematically map at all scales the remodeling of cell architecture in drug-treated cells. Here, we acquired drug-perturbed protein-protein interactions (PPIs) from the SEC-MS data by treating U2-OS with cisplatin. Integrating the differential interactions identified from SEC-MS PPIs with the scaffold large-scale hierarchy (MuSIC) allows retention of the upper cellular organization to systematically map drug impact on protein complexes in the cell. This pipeline serves as an explorative method to identify the drug-responsive organelles, alterations of hierarchical structures, and translocation of proteins. Apart from the well known alterations of DNA damage repair complexes, we also recapitulate remodeling in metabolism pathways, splicing, cAMP-dependent kinase activity, and histone modification. We identify 26 novel protein assemblies containing members that are previously associated with cisplatin biology. This pipeline exploits the potential of a well-established network by integrating the high throughput data modality, allowing for the screening of a range of chemical agents and stimuli to generate differential networks.
Citation Format: Gege Qian, Leah Schaffer, Kyung-Mee Moon, Leonard Foster, Trey Ideker, Mengzhou Hu, Sahar Alkhairy, Emma Lundberg. Remodeling of cancer cells by chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7101.
Abstract 7114: Exploring the landscape of PARP and PARG inhibitor selectivity in live cells using NanoBRET™ target engagement assays
Authors: Michaud Ani , Teske Kelly , Wilkinson Jennifer , Zimprich Chad , Vasta James , Corona Cesear , Zhou Min , Dominguez Elizabeth , Dunn-Hoffman Kaitlin , Robers Matthew 
Published: March 2024

Abstract
The 17-member poly(ADP-ribose) polymerase (PARP) family of proteins mediate a number of cellular processes including gene transcription, cell-division and DNA-repair. PARPs catalyze the addition of poly- or mono- ADP-ribose chains on target proteins, modifying their function and/or recruitment in various pathways. Poly(ADP-ribose) Glycohydrolase (PARG) catabolizes PAR units and facilitates the recycling of PARP and other modified effector proteins. A number of PARPS are implicated in human disease, and PARP inhibitors (PARPi’s) have seen major clinical success, however, many PARPs (especially mono PARPs) are understudied and chemical tools for understanding cellular PARPi selectivity and potency across the entire family are lacking. Similarly, several PARG inhibitors have been developed to date, but tools for directly assessing target engagement in a cellular context are sorely needed. Here we describe the development and application of target engagement assays for characterizing PARP and PARG inhibitor selectivity and affinity in live cells. This method is based on the NanoBRET™ assay platform, which is a proximity-based probe displacement assay that operates in live cells. Using NanoBRET™ technology, we have developed a single probe that covers 12 out of 17 PARP family members. We explored the family-wide selectivity of a diverse panel of clinical and preclinical PARP inhibitors in live cells, representing the first family-wide, cell-based method for profiling PARP selectivity. We also describe the development of a second probe that reports on PARG target engagement. Target engagement of PARG was observed for three out of five tested inhibitors, suggesting a potential indirect mode of action for certain inhibitors on PARG glycohydrolase activity. These assays offer a complementary approach for studying target engagement within the PARylation cycle.
Citation Format: Ani Michaud, Kelly Teske, Jennifer Wilkinson, Chad Zimprich, James Vasta, Cesear Corona, Min Zhou, Elizabeth Dominguez, Kaitlin Dunn-Hoffman, Matthew Robers. Exploring the landscape of PARP and PARG inhibitor selectivity in live cells using NanoBRET™ target engagement assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7114.
Abstract 7149: Discovery of a novel USP1 inhibitor: Targeted therapy for BRCA-mutated and PARPi-resistant cancers
Authors: Kim Jihye , Kim Sunkyu , Park Sejeong , Lee Sanghoon , Yoo Kiwoong , Lee Ho-Jeong , Kang Jaewoo , Lee Kwang-Ok 
Published: March 2024

Abstract
Harnessing synthetic lethality offers an innovative approach to targeted cancer treatment. USP1, a specific deubiquitinating enzyme, has gained attention as a potential synthetic lethality target for BRCA-mutated cancers. At AIGEN Sciences, Inc., we've integrated the advanced capabilities of our human-in-the-loop (HITL) AI drug discovery platform, AIGEN ChemTailor. This cutting-edge platform thrives on continuous learning enhanced by expert feedback, refining our approach to drug discovery. Using AIGEN ChemTailor, we synthesized a specific USP1 inhibitor. Its inhibitory capabilities were validated through the Ubiquitin-rhodamine 110 assay. Notably, our inhibitor presented remarkable anti-proliferative effects on BRCA1 mutant cells (MDA-MB-436) while showing no activity against BRCA wild-type cells (HCC1954), highlighting its specificity. The efficacy of our inhibitor was enhanced when combined with PARP inhibitors, such as olaparib or AZD5305, especially in UWB1.289 cells. Impressively, the USP1 inhibitor also effectively targeted PARPi-resistant cell lines, including A2780-ola, UWB1.289-nir, HCC38-ola, MDA-MB-468-ola, U251MG-ola, and OVCAR8-ola. Clonogenic assays with MDA-MB-436 and MCF-10A emphasized our inhibitor's selectivity towards BRCA mutant phenotypes. Subsequent studies demonstrated the compound's mechanism: inducing replication stress by impairing of DNA synthesis and activating DNA damage pathways via ATR signaling. Preclinical mouse studies highlighted favorable pharmacokinetics and involved the assessment of anti-tumor effects in animal models. In summation, our USP1 inhibitor, developed using AIGEN ChemTailor and advanced molecular modeling techniques, stands out as a potent therapeutic against BRCA-mutated cancers and PARP inhibitor-resistant strains.
Citation Format: Jihye Kim, Sunkyu Kim, Sejeong Park, Sanghoon Lee, Kiwoong Yoo, Ho-Jeong Lee, Jaewoo Kang, Kwang-Ok Lee. Discovery of a novel USP1 inhibitor: Targeted therapy for BRCA-mutated and PARPi-resistant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7149.