bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3512: Joint probabilistic modeling of multimodal metabolic data with UnitedMet
Authors: Xie Amy X. , Bradshaw Casey , Tosh Christopher , Tansey Wesley , Reznik Ed 
Published: March 2024

Abstract
Metabolites play a crucial role in the functioning of biological systems. Measurements of metabolite abundances by metabolomics and metabolic pathway activity by isotope-tracing are powerful approaches to study metabolic phenotypes. However, large-scale measurements of metabolite levels and pathway activity remain extremely scarce due to the technical challenges. Motivated by the strength of RNA-metabolite covariation, we present UnitedMet, a Bayesian probabilistic method for end-to-end joint modeling of RNA-sequencing and metabolic datasets that is capable of dimensionality reduction, data integration and metabolic modality prediction. UnitedMet demonstrates high accuracy predicting metabolite levels and isotopologue distributions from gene expression data in human tumor samples. To evaluate UnitedMet’s efficacy in clinical applications, we inferred metabolomic profiles and isotope labeling patterns from the RNA sequencing data of clear cell renal cell carcinoma (ccRCC) patients enrolled in TCGA and clinical trials. Correlation analysis between genetic mutations and predicted metabolic phenotypes revealed that BAP1 mutations were associated with increased contribution of glucose to TCA cycle in ccRCC. Increased TCA cycle activity was found to be associated with disease progression and poorer clinical outcome. UnitedMet, therefore, provides a solution that could be broadly applicable to enhance multimodal metabolomic datasets and facilitates comprehensive study of interplays between metabolic profiles, molecular alterations and human phenotypes.
Citation Format: Amy X. Xie, Casey Bradshaw, Christopher Tosh, Wesley Tansey, Ed Reznik. Joint probabilistic modeling of multimodal metabolic data with UnitedMet [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 3512.
Abstract 3600: Reversal of iNKT cell dysfunction in cholangiocarcinoma
Authors: Htwe Khin Su Su , Soontrapa Kitipong , Jirawatnotai Siwanon , Prasopporn Sunisa , More-Krong Pimkanya , Sampattavanich Somponnat , Wongkajornsilp Adisak 
Published: March 2024

Abstract
Invariant natural killer T (iNKT) cells are CD1d-restricted unconventional T cells possessing innate and adaptive immunity with high anti-tumor activities. Yet, the effectiveness of iNKT cell therapy in clinical trials is limited due to iNKT cell dysfunction after exposure to the tumor microenvironment. Aggressive cholangiocarcinoma (CCA) cell lines were used to study iNKT cell reactivity. These CCA cell lines lacked CD1d molecules and responded poorly to iNKT cells. The iNKT cells became dysfunctional after the exposure to CCA by 48 h. In this study, we overcame iNKT cell dysfunction by searching for a small molecule to prevent or reverse the gene sets regulating iNKT cell dysfunction, thus prolonging anti-tumor activity. It was found that P53 and estrogen early response pathway gene sets were enriched in dysfunctional iNKT cells which were reversed by vorinostat, an HDAC inhibitor. Anti-CCA activity of iNKT cells was regained with a subtherapeutic dose of vorinostat as protection. Interestingly, vorinostat could not totally recover the anti-tumor effect of iNKT cells that have already developed into the dysfunctional stage. Significant tumor size reduction was seen in the humanized mouse model after iNKT cell adoptive therapy was given in combination with vorinostat compared to monotherapy with either iNKT cell or vorinostat alone. This study demonstrated that inhibiting the gene sets regulating iNKT cell dysfunction by vorinostat could prevent iNKT cell dysfunction, and prolong its anti-tumor activities. This combination could be a novel treatment option for CD1d-negative CCA patients resistant to standard chemotherapy.
Citation Format: Khin Su Su Htwe, Kitipong Soontrapa, Siwanon Jirawatnotai, Sunisa Prasopporn, Pimkanya More-Krong, Somponnat Sampattavanich, Adisak Wongkajornsilp. Reversal of iNKT cell dysfunction in cholangiocarcinoma [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 3600.
Abstract 3630: Measuring EGFr on extracellular vesicles in human plasma samples
Authors: Olsen Dorte Aa. , Hansen Torben F. , Brandslund Ivan , Madsen Jonna S. 
Published: March 2024

Abstract
Introduction: Extracellular vesicles (EVs), secreted extracellularly by almost all types of cells, play a pivotal role in intercellular communication and have emerged as valuable indicators in disease progression. Their potential for cancer diagnostics and monitoring is particularly noteworthy. Epidermal growth factor receptor (EGFr) is a major driver of several cancers and serve as an important target or co-target in cancer treatment. The purpose of this study was to develop an assay for measuring EGFr on EVs directly in plasma samples. Additionally three assays were developed to measure the total concentration of plasma EVs.
Methods: Recognizing the expected low concentrations of EGFr on EVs, the immunoassays were developed using Single molecule array (Simoa) technology, which has shown up to a 1000-fold improvement in sensitivity as compared to conventional immunoassay approaches. Commercial available calibrator material and antibodies against surface markers (EGFr, CD9, CD63 and CD81) were used to develop four assays: CD81-EGFr, CD81-CD9, CD81-CD63, and CD9-CD63. Plasma samples from healthy individuals (n=13) and small cohorts of various cancer patients (n=30, lung, colorectal, ovarian) were used for development, validation and testing.
Results: Each assay was tested for dilution linearity, limit of detection, analytical variation and pre-analytical stability of EVs. EGFr on EVs was lower in cancer patients (median: 489 × 106 EVegfr/mL) compared with healthy individuals (median: 663 × 106 EVegfr/mL). Conversely, total EV concentrations were markedly higher in plasma from cancer patients compared with healthy individuals (CD81-CD9: 9157 vs 4088, CD81-CD63: 3634 vs 1582, CD9-CD63: 9538 vs 1210, median values x106 EV/mL). Positive correlations were observed among the total EV assays (r=0.6, p&lt;0.0001).
Conclusion: The developed assays allow measurement of EGFr on EVs and total EVs in human plasma samples. Notable, total EV concentrations were highly increased in cancer as compared with healthy individuals. The assays are now ready for a comprehensive validation using large cohorts of cancer samples.
Citation Format: Dorte Aa. Olsen, Torben F. Hansen, Ivan Brandslund, Jonna S. Madsen. Measuring EGFr on extracellular vesicles in human plasma samples [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 3630.
Abstract 3634: Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer
Authors: Henick Brian S. , Georgis Yohanna , Herzberg Benjamin O. , Concepcion-Crisol Carla P. , Taylor Alison M. 
Published: March 2024

Abstract
Deleterious mutations in STK11/LKB1, KEAP1, and SMARCA4 have been shown to be associated with adverse response to immunotherapy in several lung cancer cohorts. However, the biological and clinical implications of deletions of these genes, which all reside on chromosome 19p (chr19p), has not been extensively described. We sought to first characterize the association between immune infiltration and these copy number changes in chr19p. To do this, we analyzed mutation, copy number, and gene expression data from non-small cell lung cancer cohorts in the Cancer Genome Atlas (TCGA). Chr19p is frequently deleted across cancers in the TCGA dataset, with higher rates in lung adenocarcinoma. In both lung adenocarcinoma and squamous cell carcinoma, nearly half of TCGA tumors have deletion of chr19p including STK11, KEAP1, and SMARCA4, and these tumors are enriched for STK11 mutation. Immune infiltrate (estimated by methylation patterns) was not significantly associated with STK11 mutation but was significantly reduced in tumors with chr19 deletion when controlling for tumor type and overall copy number load. In addition, low-level deletion of any of these genes correlated with decreased expression of immune signaling pathways.
Based on these findings, we next wanted to characterize the association between chr19p copy number and immunotherapy response. We previously reported that low-level deletion of STK11 correlated with an immunosuppressive, treatment-refractory phenotype in samples collected from non-small cell lung cancer (NSCLC) patients with resectable disease in a phase II study of neoadjuvant atezolizumab + chemotherapy. To confirm these findings in a larger cohort, we examined the AACR GENIE NSCLC biopharma collective (BPC) dataset. A subset of this cohort included patients treated with immunotherapy (atezolizumab, nivolumab, and/or pembrolizumab) and with copy number data available or GISTIC analysis of individual genes (n = 204). Here, deletion of any of these three genes correlated with worse overall survival, and this was statistically significant for STK11 deletion. Overall, our data suggests that a broader set of patients, defined by copy number changes in these genes, may experience this adverse immunobiology. Further study to elucidate the mechanistic implications of this association is warranted.
Citation Format: Brian S. Henick, Yohanna Georgis, Benjamin O. Herzberg, Carla P. Concepcion-Crisol, Alison M. Taylor. Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer [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 3634.
Abstract 3646: A spatially resolved single cell proteomic atlas of small bowel adenocarcinoma
Authors: Dereli Zeynep , Bozorgui Behnaz , Wang Huamin , Weinstein John , Overman Michael , Korkut Anil 
Published: March 2024

Abstract
Small bowel adenocarcinoma (SBA) is a rare malignancy associated with poor prognosis. The cellular and proteomic heterogeneity within the tumor immune microenvironment (TIME) of SBA is a likely driver of prognosis, disease progression and response to therapy. There is, however, a major gap in our knowledge of tumor and immune interactions in SBA. Cyclic Immunofluorescence (CycIF), an antibody-based, highly multiplexed imaging technology for spatially resolved single cell level proteomic profiling, is well suited to map the proteomic heterogeneity and organization of TIME in SBA. Here, using CycIF, we have generated a spatially resolved single-cell proteomic atlas of TIME for 136 tumor and normal samples from clinically and genomically annotated SBA patients (N=37). The SBA TIME Atlas covers information on expression levels, spatial position, and cell morphology for &gt; 40 proteomic markers of tumor-intrinsic processes and states, diverse immune cell types, immune checkpoints, and tumor vascularization. In total, we collected proteomics data from &gt; 600,000 cells. Using a hierarchical decision tree of cell type markers, we have generated the cell identity annotations for &gt; 350,000 cells, with positional information. A comprehensive computational analysis of the SBA atlas revealed various spatial and heterogeneity features that may impact the TIME organization in fine detail. Using those features, we have compared the proteomic heterogeneity in tumor vs. normal cell populations, identifying spatial and single-cell correlates of key clinical variables (e.g., patient survival, age, sex, disease stage, metastatic status). We have also performed differential analyses of spatial features involving protein markers and cell types with respect to genomic alteration states and have mapped the spatial enrichment of likely actionable immune check proteins to immune and tumor cells. Such mapping may guide future therapeutic decisions. Overall, we expect that the SBA TIME Atlas will provide a useful resource and inform future translational studies, as well as basic research for better mechanistic understanding and treatment of this disease.
Citation Format: Zeynep Dereli, Behnaz Bozorgui, Huamin Wang, John Weinstein, Michael Overman, Anil Korkut. A spatially resolved single cell proteomic atlas of small bowel adenocarcinoma [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 3646.
Abstract 3685: Improved detection of minimal residual disease in colorectal cancer patients using adaptive noise cancellation algorithm
Authors: Bao Hua , Tang Wanxiangfu , Li Ningyou , Wu Min , Zhang Jinfeng , Zhu Baihan , Wu Xue , Shao Yang 
Published: March 2024

Abstract
Objective: Existing methods for detecting circulating-tumor DNA (ctDNA) through fixed panels exhibit constrained sensitivity, while customized panels are time-consuming and rely on prerequisite tumor mutation profiles. Here, we aimed to introduce an adaptive noise cancellation approach for efficient Minimal Residuals Disease (MRD) detection in colorectal cancer patients employing a fixed panel under both tumor-informed and tumor-naïve situations.
Methods: 108 plasma samples were collected from 52 colorectal cancer patients (11 relapse, 41 non-relapse) at various post-surgical timepoints. Comprehensive mutational profiling of plasma samples was conducted using a fixed MRD panel (SHIELDINGTM ULTRA) that encompasses hotspots in 2365 cancer-related genes. Background errors were removed by an adaptive noise cancellation algorithm relying on DNA fragment profiling, normal pool, and white blood cell background and intra-run plasma sampling. Variants were called both with (tumor-informed) and without (tumor-naïve) the present of tumor tissue.
Results: Our longitudinal analysis of 108 plasma samples yielded 90.9% sensitivity, 97.6% specificity and 97.6% negative predictive value in the tumor-informed scenario. The ctDNA positive patients exhibited significantly higher risk than those with negative ctDNA status (Hazard Ratio = 87.2, p = 3.5 × 10^(-5)). For landmark analysis, 33 plasma samples (≤7 days post-operation) were assessed, yielding a remarkable performance of 66.7% sensitivity and 100% specificity. Our approach showed robustness under tumor-naïve scenario, illustrating 90.9% sensitivity, 92.7% specificity and 97.4% NPV for the longitudinal analysis. This corresponded to an increased risk of 49 times in the ctDNA positive patients (HR = 49.0, p = 2.2 × 10^(-4)). Notably, the results of tumor-naïve samples closely aligned with those of tumor-informed samples, showing a concordance of 92.6% and substantial agreement (Cohen’s Kappa = 0.691).
Conclusion: Our method stands as an ultra-sensitive tool for identifying colorectal patients at high risk of recurrence. By employing an adaptive noise cancellation algorithm, our fixed panel approach demonstrates superiority over existing fixed panels in accuracy and proves to be a cost-effective alternative to personalized panels. Significantly, it extends potential clinical utilization towards tumor-naïve patients, which is not feasible for personalized panels.
Citation Format: Hua Bao, Wanxiangfu Tang, Ningyou Li, Min Wu, Jinfeng Zhang, Baihan Zhu, Xue Wu, Yang Shao. Improved detection of minimal residual disease in colorectal cancer patients using adaptive noise cancellation algorithm [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 3685.
Abstract 3745: Metabolomic profiling of lipid and metabolite in cirrhosis patients with and without hepatocellular carcinoma
Authors: Powell Hannah , Ruiz Elisa , Grimm Sandra L. , Najjar Omar , Olivares Luis , Scheurer Michael , Serag Hashem B. El , Coarfa Cristain , Kaochar Salma 
Published: March 2024

Abstract
Early detection of hepatocellular carcinoma (HCC) is crucial for improving patient outcomes, as curative treatments are most effective at the early stages of the disease. The lack of robust biomarkers, particularly a non-invasive diagnostic tool, precludes significant improvement of clinical outcomes for HCC patients. Serum metabolites are one of the best non-invasive means for determining patient prognosis. Established biomarkers for HCC including alpha-fetoprotein (AFP), have shown suboptimal performance in early disease stages. This study aimed to develop a combined metabolite and lipid panel to differentiate early-stage HCC from cirrhosis. Unbiased metabolomic and lipidomic analyses of serum samples were performed for 28 and 30 patients with early HCC and cirrhosis, respectively. We developed an unbiased high-resolution liquid chromatography mass spectrometry (LC-MS) based metabolic profiling platform and evaluated differences in the serum global metabolome and lipidome. This method enabled the detection of over 1200 metabolites and up to 800 lipid molecules in this select cohort. We identified 124 metabolites and 246 lipids that were upregulated and 208 metabolites and 73 lipids that were downregulated in HCC compared to cirrhosis. Using multiomic integrative analysis, we identified the overlap between differentially expressed metabolites and lipid and previously published transcriptomic signatures and illustrate that the overlapping signature associates with clinical disease progression. Lastly, we leveraged machine learning models to identify a minimal panel of lipids and metabolites that accurately distinguish between cirrhosis patients with HCC and without HCC. The best performing classifier was derived using Support Vector Machines, achieving a median AUC of 0.98 over 100 cross-validation iterations, and we showed that we need as little as 12 metabolite and lipids for effective discrimination between cirrhosis and early HCC.
Citation Format: Hannah Powell, Elisa Ruiz, Sandra L. Grimm, Omar Najjar, Luis Olivares, Michael Scheurer, Hashem B. El Serag, Cristain Coarfa, Salma Kaochar. Metabolomic profiling of lipid and metabolite in cirrhosis patients with and without 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 3745.
Abstract 3755: Impact of antigen retrieval and other parameters on detection of FGFR2b in various solid tumors on a BenchMark ULTRA automated staining platform: Development of a new IHC assay for FGFR2b
Authors: Watson Autumn Sky , Le Catherine , Wertheimer Anne M. , Escobedo Spencer , So Lisa , Siddegowda Bhavani Bagevalu , Palting John D. , Marion Susan , Stratton Steven P. , Aggeler Birte 
Published: March 2024

Abstract
Background: Fibroblast growth factor receptor 2b (FGFR2b) is part of the FGFR transmembrane tyrosine kinase receptor family. This protein has gained more attention in recent years as a tumor progression biomarker in numerous solid tumors. The detection of FGFR2b by immunohistochemistry (IHC) has been used recently in immunotherapy clinical trials with multiple tumor types. During IHC assay development on formalin-fixed paraffin embedded tissue, a thorough study of antigen retrieval through cell conditioning or enzyme incubation, primary antibody incubation, and detection parameters is critical to evaluate staining performance.
Design: A study of an investigational anti-FGFR2b (FPR2-D) assay developed on a BenchMark ULTRA automated staining platform explored the effect of antigen retrieval and detection parameters on staining performance. VENTANA System Software was used to modify steps in the IHC staining protocol resulting in 42 permutations. Ten different solid tumors were stained with these modifications to the assay and subsequently evaluated for FGFR2b expression.
Result:s The results demonstrate that the staining clarity, intensity, and dynamic range within tissue cases of FGFR2b staining can vary widely between different solid tumor types. While most permutations of the initial assay parameters had minimal impact on the staining performance and readability by a pathologist, the order of the enzyme treatment and the cell conditioning steps (in addition to increased incubation time of primary antibody) had a significant impact when comparing across different solid tumors. Detection of FGFR2b seemed to have a greater susceptibility by tumor type to the antigen retrieval process than has traditionally been observed in other biomarkers.
Conclusion: The overall results of this investigation show the importance of an extensive parameter screening approach when evaluating new antibody targets and indication combinations in IHC to ensure optimal staining performance. This is critical to downstream testing and the potential use of new assays in the context of in vitro diagnostics.
Citation Format: Autumn Sky Watson, Catherine Le, Anne M. Wertheimer, Spencer Escobedo, Lisa So, Bhavani Bagevalu Siddegowda, John D. Palting, Susan Marion, Steven P. Stratton, Birte Aggeler. Impact of antigen retrieval and other parameters on detection of FGFR2b in various solid tumors on a BenchMark ULTRA automated staining platform: Development of a new IHC assay for FGFR2b [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 3755.