bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4472: A mouse model for GvHD: an excellent tool for evaluating the efficacy of anti-GvHD drugs and testing mechanisms of immunoregulation
Authors: Wu Meirong , Zhang Shiru , Zhu Fang , Sun Hongyan , Xu Jianming , Ju Cunxiang , Wang Hongyu , Chen Santi Suryani , Li Zhiying , Moore Mark Wade , Zhao Jing , Gao Xiang 
Published: April 2023

Abstract
Hematological malignancies, including leukemia, lymphoma and multiple myeloma, account for about 7% of all newly diagnosed cancers. Allogeneic hematopoietic stem cell transplantation (HSCT) is a traditional treatment for hematologic malignancies. Currently, CAR-T cell therapy has made a major breakthrough in the treatment of hematologic malignancies. However, the occurrence of acute Graft-versus-Host Disease (GvHD) represents a major obstacle for HSCT and limits the application of CAR-T cell therapy.
GemPharmatech established and characterized two murine models for anti-GvHD drug evaluation. In the first model, bone marrow from C57BL/6 donor mice was transplanted into a sublethally-irradiated BALB/c recipient mouse. In this model, T cell infiltration, tissue damage, and systemic inflammation were observed, similar to the clinical observations of patients receiving allogeneic HSCT. Efficacy evaluation of anti-GVHD drugs have been carried out based on this model. Our results showed that treatment with the anti-GVHD drug Ibrutinib, the survival rate and the lifespan of the mice was significantly prolonged, and the GvHD score was reduced by about 70% compared with the placebo group.
In the second model, human Peripheral Blood Mononuclear cells (PBMCs) were transplanted into irradiated severe immunodeficient NCG mice. The cohort was irradiated to accelerate GvHD occurrence. The reconstructed human T cells will recognize and attack mouse tissues to cause GvHD. Our results showed that hCD45+ cells infiltrated into heart, liver, and spleen of huPBMC-NCG mice. This model has also been successfully used for anti-GvHD efficacy evaluation. Upon treatment with an anti-GVHD drug, the lifespan of huPBMC-NCG mice was significantly extended and weight loss was alleviated.
Overall, the above-mentioned GvHD models show great potential for preclinical evaluation of anti-GvHD drug development in allogeneic HSCT.
Citation Format: Meirong Wu, Shiru Zhang, Fang Zhu, Hongyan Sun, Jianming Xu, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. A mouse model for GvHD: an excellent tool for evaluating the efficacy of anti-GvHD drugs and testing mechanisms of immunoregulation. [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 4472.
Abstract 448: Computational discovery and experimental validation of splicing-derived neoantigens
Authors: Zumrut Hasan Ekrem , Anderson Kendall , Manzanares Miguel , Smith Shaleigh , Gera Sakshi , Habib Nayab , Shah Sanjana , Trahan Devon , Akerman Martin , Arun Gayatri 
Published: April 2023

Abstract
RNA splicing is a central step in the regulation of gene expression, leading to the accurate assembly of viable mRNA isoforms. Errors in the splicing process are common in cancer and lead to the production of tumor-specific mRNAs that often encode for neoantigen peptides. Such neoantigens cannot be discovered using conventional DNA-based tools; they require specialized software for alternative splicing analysis using RNA-seq data. Envisagenics has developed SpliceIOTM, a proprietary software platform for splicing-derived neoantigen discovery. SpliceIO uses RNA-seq data to uncover extracellular neoantigens encoded by transmembrane proteins or presented to immune cells through the MHC complex. Using SpliceIO, we have analyzed roughly 8,000 RNA-seq samples from 4 different cancers and 14 normal tissue types. Each dataset first undergoes an unsupervised clustering analysis using SpliceSliceTM to stratify patients into subpopulations based on similar aberrations in splicing machinery. We then leverage SpliceIO to identify splicing-derived, tumor-specific neoantigens enriched in these cohorts. SpliceIO incorporates features, such as protein localization, MHC binding affinity, epitope accessibility and cancer relevance of the gene to help select tumor specific targets with the highest therapeutic potential. Here, we summarize the discovery and validation of novel splicing-derived neoantigens identified using SpliceIO. To validate neoantigen candidates, we performed isoform expression quantification at the RNA and protein levels using PCR, RNA-FISH, western blot and mass spectrometry. Our experiments confirmed several neoantigen candidates encoded by tumor-specific RNA isoforms, that are translated and localized to the cellular membrane. Interestingly, one of the candidates is an endoplasmic reticulum protein that exhibits cassette exon skipping in approximately 24% of TNBC tumors. Fluorescence microscopy experiments demonstrate that the TNBC-specific isoform of the protein is localized to plasma membrane but not the ER, suggesting that alternative splicing can alter protein localization. Together, our results demonstrate the potential of RNA splicing analysis for the discovery of novel immunotherapeutic targets.
Citation Format: Hasan Ekrem Zumrut, Kendall Anderson, Miguel Manzanares, Shaleigh Smith, Sakshi Gera, Nayab Habib, Sanjana Shah, Devon Trahan, Martin Akerman, Gayatri Arun. Computational discovery and experimental validation of splicing-derived neoantigens [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 448.
Abstract 4531: Clinical translation of biomarkers for ZL-1211, an anti-CLDN18.2 antibody, in patients with advanced solid tumors from a phase I dose-escalation study
Authors: Luo Zhen , Wang Xiao , Zeng Xuehuo , Yi Jiaqing , Burns Tegan , Liu Herman , Zhang Xinyu , Liu Wenyu , Hsu Karl , Gong Hua 
Published: April 2023

Abstract
ZL-1211, a humanized monoclonal IgG1 antibody targeting CLDN18.2, induces cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). We developed ex vivo ADCC and CDC assays to study the mechanism of actions of ZL-1211. Our preclinical data has demonstrated greater antitumor activities than the clinical leading benchmark via enhanced ADCC by mutation in Fcγ domain and potent CDC activities. We used those ex vivo assays to further profile the clinical specimens from patients collected at baseline (pre-infusion) and the following cycles (post-infusion) in our phase 1 study (NCT05065710). Preliminary results in clinical samples indicated that baseline ADCC and CDC capabilities were correlated with anti-tumor activity of ZL-1211 in patients with CLDN18.2-positive locally advanced or metastatic solid tumors, suggesting probable predictive biomarkers. Results also showed that changes in circulating ZL-1211 mediated ADCC and CDC activities were dose-dependent and in accordance with the pharmacokinetic (PK) profile. In addition, we performed differential gene expression analysis and real-time PCR to compare gene expression in ZL-1211 responder and non-responder PDX models and CCLE cell lines. Our findings reveal that several immune-related genes may serve to predict the responses to ZL-1211 treatment. Other potential predictive biomarkers such as Fcγ receptor CD16A polymorphism and baseline stromal CD8 expression were also evaluated in clinical samples. Taken together, analytical approaches developed and validated from preclinical studies were successfully translated to characterize clinical samples in the current Phase 1 trial. The exploratory analysis indicated the clinical relevance of multiple biomarkers and their potential as predictive biomarkers of ZL-1211.
Citation Format: Zhen Luo, Xiao Wang, Xuehuo Zeng, Jiaqing Yi, Tegan Burns, Herman Liu, Xinyu Zhang, Wenyu Liu, Karl Hsu, Hua Gong. Clinical translation of biomarkers for ZL-1211, an anti-CLDN18.2 antibody, in patients with advanced solid tumors from a phase I dose-escalation study. [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 4531.
Abstract 4632: Spatial whole transcriptome analysis of differential expression for biomarker discovery in colorectal cancer
Authors: Cheung Elim , Sundaram Vidyodhaya , Zhang Baowen , Zhang Lutong , Lu Tong 
Published: April 2023

Abstract
Background: Colorectal cancer (CRC) is one of the leading causes of cancer death, which is frequently caused by genetic or epigenetic changes. The study of tumor microenvironment (TME) profiling may provide a better knowledge of spatial gene expression patterns of known CRC markers, visualize the cell composition and localization, and serve to aid the understanding of the mechanisms of tumor formation. BioChain Institute, Inc. is currently investigating the TME profiling of CRC through tissue-wide, whole transcriptome analysis for the ability to discover potential therapeutic targets.
Methods: BioChain’s formalin-fixed paraffin-embedded (FFPE) tissue samples from 3 primary colon adenocarcinoma tumors (PT), and their matched adjacent normal tissues (PN), were used to investigate the TME. The images of Hematoxylin and Eosin (H&E)-stained tissue sections were annotated by our pathologist. The spatial whole transcriptome was analyzed using 10x Genomics Visium Spatial Gene Expression for FFPE. This assay provided about 5,000 spatially barcoded spots with mRNA-binding oligonucleotides to capture the gene expression. The integration of the imaging and sequencing data enabled a spatially resolved transcriptome of CRC heterogeneity.
Results: The annotations of both PT and PN tissue samples were found to be correlated with the spatial gene expression clustering. With the overlaying of total gene counts for each spot on the H&E-stained tissue image, about 16,000-17,000 genes were detected in each sample. The median of ~5,500 and ~1,600 genes per spot were expressed in PT and PN samples respectively. The study of gene expression levels revealed the overexpression of several well-known CRC markers (APOE, SCD, IGFBP3, TIMP1, SPARC) and the down-regulation of numerous markers (DES, CA1, KLF4) in PT samples significantly.
Conclusion: Our spatial analysis results provide insight into tumor heterogeneity, spatial organization of cells within the TME and biomarker identification. BioChain is in a unique position to facilitate researchers with a plethora of oncologic and other diseased tissue types, as well as the spatial whole transcriptome analysis. Our study enables the understanding of the TME, discovery of potential diagnostic and prognostic targets, especially for the development of personalized therapy.
Citation Format: Elim Cheung, Vidyodhaya Sundaram, Baowen Zhang, Lutong Zhang, Tong Lu. Spatial whole transcriptome analysis of differential expression for biomarker discovery in colorectal cancer. [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 4632.
Abstract 4640: CAF contributes to cancer progression through its immunomodulatory role within the tumor microenvironment
Authors: Núñez Muriel Antonieta , Corrales Oreste , Velasquez Victoria , Ernst Daniel , Viviana Montecinos , Nualart Francisco , Yuseff María Isabel , Cerda-Infante Javier 
Published: April 2023

Abstract
Introduction: Cancer progression and metastatic spread is modulated by the tumor microenvironment. Cancer-associated fibroblasts (CAF) are the most abundant cell type within the tumor microenvironment. Little is known about the specific mechanisms by which CAF would exert its cancer progression, through the high secretory capacity of soluble pro-tumorigenic molecules and remodeling of the extracellular matrix. Recent studies in our laboratory have shown for the first time that CAF derived from patients without metastasis express a different genetic profile than those with metastases (mCAF). This study seeks to evaluate the contribution of mCAF to tumor progression through its immunomodulatory role.
Methodology: mCAFs were obtained from patients with metastatic disease and BAF from benign patients. The fibroblasts were functionally characterized by the generation of fibroblast-derived matrices (FDM) and secretory profiles by cytokine array. CD8 T lymphocytes were obtained from healthy patients and treated with fibroblast-secretome. Markers were studied by flow cytometry: activation (CD25 and CD69) and repression (LAG3 and PD1). The migration of CD8 T lymphocytes was studied by transwell and agarose drop migration assay.
Results and conclusion: FDM of mCAF are different in their composition and organization. Furthermore, the secretome of each type of fibroblast presents a differential effect on the activation of CD8 T cells according to the markers highlighted. Regarding migration, it has been observed that the mCAF-secretome can attract lymphocytes. However, it would lead them to apoptosis. Our results suggest that mCAF, within the tumor microenvironment, has an immunomodulatory role on CD8 T lymphocytes.
Acknowledgment: Beca Doctorado Nacional ANID 21181427
Citation Format: Muriel Antonieta Núñez, Oreste Corrales, Victoria Velasquez, Daniel Ernst, Montecinos Viviana, Francisco Nualart, María Isabel Yuseff, Javier Cerda-Infante. CAF contributes to cancer progression through its immunomodulatory role within the tumor microenvironment. [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 4640.
Abstract 4688: Comprehensive analysis of natural killer cell-associated markers using MultiOmyxTM immunofluorescence assay
Authors: Parnell Erinn A. , Fei Jiong , Nunns Harry , Leones Eric , Yeung Elaine , Russell Blair , Sahafi Flora , Au Qingyan 
Published: April 2023

Abstract
As a promising alternative platform for cellular immunotherapy, natural killer cells (NK) have recently gained attention as an important type of innate immune regulatory cell. NK cell immunotherapy approaches have been translated into clinical applications, and clinical trials of NK cell infusion in patients with hematological malignancies (HM) and solid tumors have thus far yielded many encouraging clinical results. Understanding the pattern of NK expression and the relationship to different states of NK cells may have direct relevance for immune responses in cancer. Approaches capable of simultaneously detecting NK cells with detailed information on NK differentiation state, however, remain limited. In this study, we used MultiOmyx hyperplexed immunofluorescence (IF) assay to classify and characterize the spatial arrangement of NK cell markers in a pan-cancer cohort including 9 tissue microarrays (TMAs) from breast, head and neck, prostrate, colon, bladder, lung, kidney, ovarian and melanoma indications. The panel includes CD3, CD4, CD8, CD16, CD45, CD56, CD57, CD137, FoxP3, Granzyme B, HLA-E, NKG2A, NKP46 and tumor segmentation marker. The panel enables the detection of NK cells expressing CD56 and/or NKP46 in the 9 different tumor indications. We also studied the expression of activating and inhibiting receptors, such as CD16 and NKG2A, in NK cell population. The active cytotoxic subsets of mature NK cells were evaluated using co-expression of NK cell surface markers with CD57 and the cytotoxic molecule expression in NK cells was assessed using co-expression with Granzyme B. Using proprietary deep-learning-based image analysis, we were able to quantify the densities of these different NK cell population and study the prevalence of these NK cells in different cancer indications included in this study. Many strategies have been developed for exploiting NK-mediated anti-tumor activities. CAR-NK cell therapy and antibodies that directly target NK cell inhibitory receptors such as NKG2A and TIGIT, are currently being evaluated in the clinical trials. The MultiOmyx NK cell panel reported in this study enables the comprehensive profiling of the NK population and can provide greater understanding of NK cell biology during cancer progression. The panel can be further used to explore the efficacy of the NK cell-based immune therapy.
Citation Format: Erinn A. Parnell, Jiong Fei, Harry Nunns, Eric Leones, Elaine Yeung, Blair Russell, Flora Sahafi, Qingyan Au. Comprehensive analysis of natural killer cell-associated markers using MultiOmyxTM immunofluorescence assay. [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 4688.
Abstract 4691: Spatially resolved transcriptomics deconvolutes histological prognostic subgroups in patients with colorectal cancer and synchronous liver metastases
Authors: Wood Colin S. , Pennel Kathryn A. , Leslie Holly , Legrini Assya , Cameron Andrew J. , Horgan Paul , Edwards Joanne , Steele Colin W. , Jamieson Nigel B. 
Published: April 2023

Abstract
Patients demonstrating strong immune responses to primary colorectal cancer (CRC) have a survival benefit following surgery, while those with predominantly stromal microenvironments do poorly. Biomarkers to identify patients with colorectal cancer liver metastases (CRLM) who have good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary CRC and CRLM, and to interrogate the underlying functional biology that drives disease progression. Patients undergoing synchronous resection of primary CRC and CRLM underwent detailed histological assessment, panel genomic and bulk transcriptomic assessment, immunohistochemistry (IHC) and GeoMx Spatial Transcriptomics (ST) analysis. Integration with genomic features, pathway enrichment analysis and immune deconvolution were performed. High-immune metastases were associated with improved cancer specific survival (HR, 0.36, P=0.01). Bulk transcriptomic analysis was confounded by stromal content but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for Type II Interferon signaling (NES=-2.05 P.Adj&lt;0.005) and MHC-Class II Antigen Presentation (NES=-2.09 P.Adj&lt;0.005). In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T-cells and neutrophils with enrichment of Notch (NES=2.2 P.Adj=0.022) and TGF-β (NES=2.2 P.Adj=0.02) signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcome in patients undergoing synchronous resection of CRLM and ST analysis has revealed significant intra-tumoral and inter-lesional heterogeneity with underlying transcriptomic programs identified in driving each phenotype.
Citation Format: Colin S. Wood, Kathryn A. Pennel, Holly Leslie, Assya Legrini, Andrew J. Cameron, Paul Horgan, Joanne Edwards, Colin W. Steele, Nigel B. Jamieson. Spatially resolved transcriptomics deconvolutes histological prognostic subgroups in patients with colorectal cancer and synchronous liver metastases. [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 4691.
Abstract 4698: Reproducibility in spatial biology: reducing variables to improve the reliability of insight generation
Authors: Arvidson Lisa , Prioli Reginaldo , Jensen Samuel , Hoying James B. , Golway Michael W. , Smith Michael J. , White Katie O. , Heil-Chapdelaine Richard A. , Huang Chi-Chou , Phan Tuan H. , Sasaki Hideki , Angus-Hill Melinda 
Published: April 2023

Abstract
There is an ongoing crisis in reproducibility in scientific studies, and studies in spatial biology are no exception. Cell DIVETM Multiplex imaging solution (Leica Microsystems) provides reliable workflow solutions to minimize variability from study to study. Cell DIVE allows probing and imaging of dozens of biomarkers on a whole tissue section with an iterative staining and dye inactivation workflow. At its core, Cell DIVE is designed to provide methods reproducibility, from tissue preparation, antigen retrieval, and sample imaging and slide storage. Cell DIVE is designed to work with directly conjugated primary antibodies, another source of variability. However, conjugated antibodies from Cell Signaling Technology (CST) are rigorously validated using stringent acceptance criteria to reduce variability. In addition, the use of recombinant antibodies, the consistent conjugate brightness and antibody degree-of-labeling reduce lot to lot variability, ensuring reliable conjugated antibodies for spatial biology studies. High resolution imaging results are obtained by consistent round to round imaging, consistent calibration and corrections, and reduction of human error using the BAB 200 liquid handling solution (Advanced Solutions Life Sciences). We present here, an iterative biomarker study using adjacent tissue sections probed with distinct lots of CST antibody panels, imaged in temporally separated batches using a Cell DIVE imager fitted with a BAB200 liquid handler. Following robust analysis (segmentation, phenotyping and statistical analysis), we report the reproducibility findings across parameters. Methods and results reproducibility in spatial biology is essential for reliable insight generation, giving confidence in the quality of future studies aimed at improving patient outcomes.
Citation Format: Lisa Arvidson, Reginaldo Prioli, Samuel Jensen, James B. Hoying, Michael W. Golway, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Melinda Angus-Hill. Reproducibility in spatial biology: reducing variables to improve the reliability of insight generation. [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 4698.