bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2024: High resolution limited proteolysis (HR-LiP), a novel structural proteomics approach for the prediction of small molecule-protein binding events
Authors: Beaton Nigel , Bruderer Roland , Feng Yuehan , Adhikari Jagat , Cornella-Taracido Ivan , Reiter Lukas 
Published: June 2023

Abstract
High resolution profiling of drug-protein interactions and binding mechanisms remains a major hurdle during lead selection and optimization. A key milestone in structure-based drug design is compound binding site identification and characterization. Structure-activity relationship (SAR) studies traditionally utilize time and cost intensive techniques such as nuclear magnetic resonance (NMR), x-ray crystallography (X-ray) and cryo-electron microscopy (cryo-EM). To date, hydrogen-deuterium exchange (HDX) is the only mass spectrometry-based approach that has been extensively utilized. Further, SAR studies are often complicated by protein size (large proteins and/or oligomers) and location (membrane proteins), which can lead to protocol adaptations that can introduce artifacts. High resolution limited proteolysis (HR-LiP) is a high-throughput, high-resolution approach based on LiP-Quant that utilizes peptide-level resolution to characterize drug-protein interactions. Two well-characterized drug target proteins, bromodomain-containing protein 4 (BRD4) and transitional endoplasmic reticulum ATPase (VCP), were selected for analysis as they represent both difficult targets for structural biology (size and oligomerization respectively). BRD4 was targeted with a well characterized inhibitor (JQ1), while VCP was investigated for binding with a known autophagy activator. Using HR-LiP we identify the binding site of the BRD4 inhibitor JQ1 in the full-length protein, which is typically too large to be used directly in with conventional methods. Further, we confirm binding of the autophagy activator to VCP at a site known to increase VCP activity. For both compounds tested, our data are in good accordance with orthogonal data obtained by other structural protein approaches including HDX-MS and “click” chemistry-based chemoproteomics. We demonstrate that HR-LiP can be used to dissect small molecule-protein binding events, including compound binding site prediction for protein targets classically considered to be difficult and time intensive. Further, we show that this data can be used to shed light on the biological mechanisms driving a phenotypic response. Given its biological power, broad applicability and ease of implementation, we envision the use of HR-LiP as a routine approach for target validation and lead optimization in small molecule drug discovery pipelines.
Citation Format: Nigel Beaton, Roland Bruderer, Yuehan Feng, Jagat Adhikari, Ivan Cornella-Taracido, Lukas Reiter. High resolution limited proteolysis (HR-LiP), a novel structural proteomics approach for the prediction of small molecule-protein binding events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2024.
Abstract 2092: Consensus analysis of associated target-biomarker pairs in cancers
Authors: Jeong Sumin , Park Yuna , Jeong Eunah , Yoon Sukjoon 
Published: June 2023

Abstract
The heterogeneity of cancers limits the reproducibility of target-biomarker relationships in diverse cohorts or sample groups. Here, we carried out consensus analyses of associated data pairs to improve the consistency (reproducibility) of prognostic power of biomarkers and anticancer efficacy of targets. All of RNA expression, patient survival, CRIRSPR/shRNA screening data were integrated from TCGA, GDSC and CCLE datasets. While &gt;90% of prognostic RNA expression found in given sample sets were not reproduced (i.e., not significant) in other test sets, those hits exhibiting consensus prognostic powers in diverse subtypes or lineages, were more significant in test sets than non-consensus hits. In the analysis of the association between CRISPR knockout and RNA expression data, the lineage consensus of the association increased the reproducibility in the validation using sh/siRNA knockdown and qPCR data. Further experimental validations reveal that ITGAV is an effective anticancer target in diverse lineages, significantly associated with prognostic RNA expression of several consensus biomarker genes. In conclusion, the consensus analysis was useful to prioritize reproducible targets and biomarkers from omics data. It has been implemented in Q-omics software (http://qomics.io) for general cancer research.
Citation Format: Sumin Jeong, Yuna Park, Eunah Jeong, Sukjoon Yoon. Consensus analysis of associated target-biomarker pairs in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2092.
Abstract 2106: Importance of alveolar epithelial cell type 2 populations in non-small cell lung cancer progression from localized to metastatic disease
Authors: Suvilesh Kanve Nagaraj 
Published: June 2023

Abstract
Introduction: Non-small cell lung cancer (NSCLC) is by far the leading cancer killer. Identifying personalized treatment strategies to prevent and treat metastases remains an unmet clinical need. Alveolar epithelial type II (AT2) cells are self-renewing epithelial stem cells that have been identified to initiate a majority NSCLCs. Previously, we have reported the presence of multiple AT2 cell types in micrometastatic circulating tumor cell-derived xenograft (CDX) models and patient metastatic tumors. These findings provide a rationale to further study whether and how AT2 cells contribute to metastatic progression.
Hypothesis: We hypothesize that AT2 cell types have a functional role in metastasis tumorigenicity of NSCLC.
Methods: A library of NSCLC patient-derived circulating tumor cell (CTC) lines, xenograft (PDX) models, and publicly available data sets of patients’ NSCLC tumor tissues were subjected to single cell/bulk RNA sequencing and analysis to determine the frequencies and expression patterns of AT2 subclones. Using magnetic bead sorting AT2 cells were enriched and AT2-associated tumorigenicity, migratory and invasion capacity determined using 3D culture and PDX models. The effects of AT2 depletion on PDX tumor characteristics were evaluated histologically. Frequencies of AT2 phenotypes in primary and metastatic tumors were validated in human tissue microarrays and patient CTCs.
Results: An additional AT2 population was identified in NSCLC brain metastases and primary lung tumors that had metastasized already. However, this additional AT2 cell population was absent in primary lung tumors of patients that had not metastasized and in patients with lymph node, pleural and liver metastases. AT2-depleted NSCLC cell lines had reduced tumorigenicity in PDX models in comparison to tumors derived from whole cell populations. In addition, tumors derived from AT2 depleted cell lines were highly necrotic. AT2-depleted cell lines showed decreased migratory and invasion capacity in 3D models. Further, AT2 phenotypes were identified at high rates in NSCLC patients’ metastases and CTCs.
Conclusion: Findings indicate an important role of AT2 cells in metastatic progression, beyond their known role in NSCLC initiation. The role of AT2 in metastasis migration, invasion and growth offers unique opportunities to identify novel therapeutic targets. Expansion of translational findings on AT2 cells has high potential for clinical impact to prevent or treat metastatic disease in NSCLC patients.
Citation Format: Kanve Nagaraj Suvilesh. Importance of alveolar epithelial cell type 2 populations in non-small cell lung cancer progression from localized to metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2106.
Abstract 2113: The age-dependent intratissue accumulation of cholesterol, resulting in reduced squalene epoxidase, is associated with a high colorectal cancer risk population
Authors: Jun Soo Young , Yoon Ji-Yong , Lee Jeong-Ju , Kim Nam-Soon 
Published: June 2023

Abstract
Objective: we recently reported that cholesterol accelerates CRC aggravates via the dissociation of GSK3β/p53 by the degradation of squalene epoxidase (SQLE). However, despite its clinical reports, the underlying mechanisms between age, cholesterol, and CRC aggravation have never been evaluated in human cohorts.
Design: tissue lysates and human specimens collected prospectively from CRC patients and controls were grouped according to CRC grade and divided into two groups based on age 50, the average risk for CRC. The intra-tissue content of total cholesterol and cholesteryl ester were measured using CRC lysates. We then used fluorescence-based multiplex immunohistochemistry with digital image analysis and machine learning to measure the quantitative expression of SQLE, GSK3β, p53wt, and p53mt.
Results: through an epidemiological study, we estimated age-dependent increases in CRC incidence and the percentage of a group with high cholesterol around age 50. Considering this age-dependency, we demonstrated age and CRC-grade-dependent manner cholesterol accumulated inside CRC tissues, SQLE, p53wt, and p53mt degraded, and GSK3β inactivated. SQLE and GSK3β were clinically associated with increased risk and showed good diagnostic and prognostic performance in CRC patients older than 50. Furthermore, the combined value for four variables exhibited superior diagnostic performance in discriminating from CRC patients after age 50 to controls.
Conclusion: this study provides new biological perceptions explaining the effects of age in the progression of CRC aggravation and potential biomarkers associated with a high CRC-risk population.
Citation Format: Soo Young Jun, Ji-Yong Yoon, Jeong-Ju Lee, Nam-Soon Kim. The age-dependent intratissue accumulation of cholesterol, resulting in reduced squalene epoxidase, is associated with a high colorectal cancer risk population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2113.
Abstract 2302: Detection of tumor-associated methylation and mutation signatures for early colorectal cancer diagnosis
Authors: Bains Pushpinder , Kulak Mikhail , Cui Zhen , Babu Alisha , Tran Stella , Lee Bongyong , Zhang Aiguo , Sha Michael 
Published: June 2023

Abstract
Introduction: The ability to identify epigenetic signatures, together with genetic alterations, has expanded the translational utility of genomic sequencing in clinical settings. Epigenetic changes may appear at very early stages before diagnosis. Thus, they could be used as epigenetic biomarkers for early detection or risk of cancer development. Circulating cell-free DNA (cfDNA) profiling has emerged as a promising biomarker for cancer diagnosis and prognosis. Herein, we developed targeted next-generation sequencing (NGS) based assays for assessing multiple DNA methylated and mutated regions in both low-quantity (plasma cfDNA) and low-quality formalin-fixed paraffin-embedded (FFPE) tissue for colorectal cancer (CRC) detection.
Methods: For the OptiSeqTM CRC methylation panel, we assessed the methylation status of CpG dinucleotides in 42 genes. With this panel, we profiled 6 CRC samples (matching cfDNA and FFPE), 2 primary colon tumors with adjacent normal, and 6 advanced adenomas (AA) FFPE tissue DNA. For healthy individuals, we profiled 12 normal colon FFPE samples and 31 plasma cfDNA (26 matching buffy coat DNA samples). For the OptiSeqTM CRC mutation panel, the mutation status was assessed in 43 genes. Here, we profiled 6 CRC samples (matching cfDNA and FFPE), 19 CRC plasma cfDNA, 4 AA FFPE and 42 healthy individuals’ plasma cfDNA (26 matching buffy coat DNA samples). The analytical and clinical performance for both panels (separately and combined) were calculated using advanced adenoma (AA), CRC, and cancer-free individuals.
Results: For CRC cfDNA samples, clinical samples testing showed that the methylation panel had a sensitivity of 50% (95% CI: 13.9-86.0) and specificity of 100% (95% CI: 86.2-100) while the mutation panel yielded the sensitivity 88% (95% CI: 67.7-96.8) and specificity 100% (95% CI: 89.5-100). Combining the mutation panel with the methylation panel, the sensitivity increased to 100% (95% CI: 51.6-100) and specificity to 100% (95% CI: 65.1-93.3). For AA FFPE samples, the methylation panel analysis yielded a sensitivity of 100% (95% CI: 39.5-100.0) and a specificity of 100% (95% CI: 67.8-100).
Conclusion: We have developed and validated the targeted NGS-based panels to detect clinically relevant mutation and methylation patterns and demonstrate its potential as a highly sensitive assay for early CRC diagnosis.
Citation Format: Pushpinder Bains, Mikhail Kulak, Zhen Cui, Alisha Babu, Stella Tran, Bongyong Lee, Aiguo Zhang, Michael Sha. Detection of tumor-associated methylation and mutation signatures for early colorectal cancer diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2302.
Abstract 2653: ABN501, a novel anti-claudin-3 antibody, shows potent anti-cancer activity in vitro and in vivo
Authors: Lee Saehyung , Choi Jae , Hong Sunghyun , Sim Euni , Kim Jaemun , Lee Sangin , Hong Sungyoul , Yang Hobin , Jo Jiwon , Kim Na Young , Shin Young Kee , Choi Jun Young 
Published: June 2023

Abstract
Claudin-3, one of the tight junction proteins, could be a potential therapeutic target and biomarker. Since it is not only overexpressed in various types of malignant solid cancers but also exposed externally during tumorigenesis. Previously, we developed a fully human monoclonal antibody (ABN501) with sub-nanomolar affinity against the native claudin-3 protein. In this study, we confirmed that ABN501 is highly specific for the extracellular loop (ECL) 2 domain of claudin-3 using stable cell lines expressing two chimeric claudins fused to claudin-3 and claudin-4. Followed by, we evaluated in vitro ADCC activity of ABN501 using NK cells expressing CD16a (NK-92MI-CD16a), in various cancer cell lines, expressing claudin-3. ABN501 exhibited potent in vitro ADCC activity in diverse cancer cell lines. We also confirmed in vivo anti-tumor activity of ABN501 in xenograft mice bearing claudin-3-expressing tumors. In summary, we suggest that ABN501 can be used as promising tissue-agnostic drug candidates as therapeutics for various types of claudin-3-positive cancers. ABN501 is currently developed with various antibody engineering platforms.
Citation Format: Saehyung Lee, Jae Choi, Sunghyun Hong, Euni Sim, Jaemun Kim, Sangin Lee, Sungyoul Hong, Hobin Yang, Jiwon Jo, Na Young Kim, Young Kee Shin, Jun Young Choi. ABN501, a novel anti-claudin-3 antibody, shows potent anti-cancer activity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2653.
Abstract 2869: The role of regulatory T cells in NASH-mediated HCC development
Authors: Yang Ming , Kimchi Eric T. , Staveley-O’Carroll Kevin F. , Li Guangfu 
Published: June 2023

Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, ranging from simple steatosis to an advanced form of non-alcoholic steatohepatitis (NASH) without effective treatment. NASH can progress to liver cirrhosis and hepatocellular carcinoma (HCC) in association with increased production of liver-resident regulatory T cells (Treg). This study aims to identify the role of Tregs in NASH-driven HCC development.
Methods Wild-type C57BL/6 mice were fed with a choline-low high-fat high-sugar diet (CL-HFS), which recapitulates the Western-pattern diet, to induce NASH, then received transplantation of oncogenic hepatocytes by intrasplenic injection to induce an orthotopic HCC. Wild-type mice fed with a normal diet were used for control. Hepatic immune cell profiling was characterized by flow cytometry to identify the cellular basis mediating CL-HFS-induced NASH. The metagenomic assay was applied to identify NASH-relevant gut microbiota in the liver tissue.
Results CL-HFS caused successful development of NASH and liver fibrosis in wild-type mice. Fast orthotopic tumor growth was detected in NASH-bearing mice compared to wild-type mice. Strongly positive staining of glypican 3 (GPC3), increased frequency of Tregs, and increased expression of Col1α1, Col4α1, and α-SMA were detected in livers and tumors from NASH-bearing mice compared to wild-type mice by IHC and flow cytometry. Metagenomic assay detected the lipid-producing bacterial genus Bacillus in NASH liver, which was demonstrated to increase the frequency of Tregs in healthy spleen cells.
Conclusion CL-HFS-caused NASH promotes HCC growth likely by increasing liver-resident Tregs and liver-infiltrating Bacillus.
Keywords: Non-alcoholic fatty liver disease (NAFLD), Non-alcoholic steatohepatitis (NASH), choline-low high-fat high-sugar diet (CL-HFS), regulatory T cells (Tregs), Bacillus, hepatocellular carcinoma (HCC).
Citation Format: Ming Yang, Eric T. Kimchi, Kevin F. Staveley-O’Carroll, Guangfu Li. The role of regulatory T cells in NASH-mediated HCC development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2869.
Abstract 2914: iPSC-derived CAR-NK cell therapy: nominating clinical candidate clones through integrated multi-functional analysis
Authors: Hall Matthew S. , Manor Ohad , Campion Liam , Bullaughey Chiamin , Morse Barry A. , Gurung Buddha , Borges Luis 
Published: June 2023

Abstract
CNTY-101 is an induced Pluripotent Stem Cell (iPSC) derived Chimeric Antigen Receptor (CAR) NK cell clinical candidate for the treatment of B-cell malignancies. It incorporates six gene edits. A CAR targeting CD19 mediates tumor cell engagement and killing, the homeostatic cytokine IL-15 improves functional persistence, and EGFR acts as a safety switch, providing an antibody target for elimination of the engineered cells, if ever necessary. Further edits are designed to reduce graft rejection due to alloreactivity, including disruption of beta-2-microglobulin (B2M) to prevent major histocompatibility complex class I (MHC-I) surface expression, disruption of class II major histocompatibility complex transactivator (CIITA), and expression of HLA-E fused with B2M. Our data indicate that iPSC lines show significant functional variability dependent on the original somatic cell and donor used for reprogramming. Additional functional variability is induced when the iPSC are genetically edited and differentiated to NK cells. This complexity necessitates careful methodology for nominating clinical candidate clones with desirable functional attributes and presents an opportunity for future refinement. Here, we evaluate 28 clinical candidate clones for CNTY-101, integrating in-process data from genetic engineering, differentiation, and a battery of functional assays into a unified analysis framework. We find that the donor and the number of integrated transgene alleles (ex. monoallelic vs biallelic) have a large impact on clone function. In silico correction for donor and allele number reveals that transgene surface expression correlates with functions including short-term killing, serial-killing, and persistence. We show that IL-15 transgene expression, serial-killing, and persistence correlate along one functional axis, while CAR expression, short-term killing, and cytokine secretion correlate on a second functional axis. In addition, we identify biomarkers measured during the differentiation process that are correlated with functional performance, such as the level of CD94 surface expression and tumor killing. Finally, we discuss the application of functional multi-omics to candidate clone nomination for Century Therapeutics’ pipeline of future products.
Citation Format: Matthew S. Hall, Ohad Manor, Liam Campion, Chiamin Bullaughey, Barry A. Morse, Buddha Gurung, Luis Borges. iPSC-derived CAR-NK cell therapy: nominating clinical candidate clones through integrated multi-functional analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2914.
Abstract 2915: Intratumoral co-injections of NK cells and neutralizing antibodies against the NKG2A inhibitory pathway achieve efficacious anti-tumor responses in a CD8 T cell and cDC1-dependent manner
Authors: Alvarez Maite , Ochoa Maria C. , Molina Carmen , Teijeira Alvaro , Garasa Saray , Sanchez-Gregorio Sandra , Olivera Irene , Glez-Vaz Javier , Cirella Asunta , Gomis Gabriel , Gonzalez-Gomariz Jose , Berraondo Pedro , Melero Ignacio 
Published: June 2023

Abstract
Local intratumoral NK cell activity is known to foster adaptive T cell-mediated immunity against cancer, that conceivably is inhibited by the interactions of the inhibitory receptor NKG2A with the MHC class I molecule HLA-E in humans or Qa-1b in mice. In this study, we found that intratumoral delivery of NK cells significantly attains therapeutic effects only if co-injected with anti-NKG2A and anti-Qa1b blocking monoclonal antibodies (mAb) in two solid mouse tumors models. Such therapeutic activity was contingent on endogenous CD8 T cells and on type-1 conventional dendritic cells (cDC1), which mediate cross-priming of tumor antigens. Moreover, the anti-tumor effects can be enhanced upon combination with anti-PD-1 mAb. This combination achieves at least partial abscopal efficacy against distant untreated tumors. In xenografted mice with HLA-E-expressing human cancer cells, intratumoral co-injection of allogeneic human NK cells and the clinical-grade anti-NKG2A mAb monalizumab synergistically achieved therapeutic effects and gave rise to stronger antibody-dependent cellular cytotoxicity (ADCC) in conjunction with cetuximab. In conclusion, these studies provide evidences for the therapeutic potential of on-site NK cell-based immunotherapies that may recruit endogenous T-cell responses.
Citation Format: Maite Alvarez, Maria C. Ochoa, Carmen Molina, Alvaro Teijeira, Saray Garasa, Sandra Sanchez-Gregorio, Irene Olivera, Javier Glez-Vaz, Asunta Cirella, Gabriel Gomis, Jose Gonzalez-Gomariz, Pedro Berraondo, Ignacio Melero. Intratumoral co-injections of NK cells and neutralizing antibodies against the NKG2A inhibitory pathway achieve efficacious anti-tumor responses in a CD8 T cell and cDC1-dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2915.