bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7356: 3 UTR variations in esophageal squamous cell carcinoma in African Americans
Authors: Erkizan Ceyda , Wadleigh Robert 
Published: March 2024

Abstract
Esophageal squamous cell carcinoma (ESCC) predominantly affects African Americans (AA). Esophageal Cancer (EC) consists of two major histological subtypes: esophageal adenocarcinoma and squamous cell carcinoma. ESCC ranks among the most lethal cancers and is particularly aggressive among AA, comprising about 75% of total ESCC patients. The 5-year survival rate for localized EC in AA patients is 25%; in contrast, the survival rate for EC patients of Caucasian origin is 48%. However, for metastatic disease, the survival rate decreases dramatically to 5% regardless of race. To conduct an extensive mutation screening, we performed whole exome sequencing (WES) in 10 paired AA ESCC and control tissues. Mutations included nonsynonymous mutations in multiple genes and copy number variations. Here, we report on further analysis of the WES data to identify 3 UTR noncoding region alterations, comprising the highest proportion of noncoding variations. Whole exome sequencing was performed using Agilent SureSelect XT Human All Exon V6 + UTR kit on matched normal-tumor samples from 10 AA patients (nine males and one female) with advanced-stage ESCC. The ages of patients ranged from 53 to 80 years. All patients, except for one, reported tobacco use and alcohol consumption. Our analysis yielded 5378 variants in noncoding regions in our cohort. The most variations were found in the 3UTR location, with 46% of all noncoding variations. In our dataset, variations in the 3UTR region of 48 genes were predicted by CScape to assert an oncogenic effect. The highest ten oncogenic predictive scores are for ETV1, FOXO3, MSI2, TCF7L2, KAT6A, FOXO1, IRF4, TRIM24, ELK4, and FGFR1 genes. Approximately 2500 genes having 3’UTR variations are over-presented in intracellular signaling and cell-cell communications, transcriptional regulation of pluripotent stem cells by OCT4, SOX2, NANOG, generic RNA polymerase II transcription, RHO GTPase cycle, and regulation of cytoskeletal remodeling. The combined effects of noncoding and coding region mutations may largely impact poor prognosis in AA with ESCC and yield targets for developing candidate therapeutics.
Citation Format: Ceyda Erkizan, Robert Wadleigh. 3 UTR variations in esophageal squamous cell carcinoma in African Americans [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 7356.
Abstract 7359: Priority targets in pancreatic cancer
Authors: Nwosu Zeribe Chike , di Magliano Marina Pasca , Lyssiotis Costas 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a drug resistant and lethal cancer. To better understand this disease, we separately analyzed five published human PDAC microarrays, determined the differential genes in each dataset and defined a gene as ‘consistent’ if it is ‘upregulated’ or ‘downregulated’ in &gt;4 datasets (adjusted P&lt;0.05). We identified 2,010 consistently upregulated- and 1,928 downregulated genes, over 50% of which were previously uncharacterized in PDAC. These genes span multiple processes, including cell cycle, immunity, transporters, metabolism, signaling, transcription factors and epigenetics. - with cell cycle and glycolysis being the most altered. Many consistent genes correlated with tumor subtype, proliferation, metastasis, and ~41% predicted survival, notably, OGN, PLOD2, DIAPH3, C2orf40, ADM, UPP1, ZNF189, DCBLD2, PLAG1, and glycolysis genesALDOA, GAPDH, PKM and LDHA. We identified 451 high priority targets, including 185 upregulated genes (notably in cell cycle and glycolysis) whose knockdown suppressed PDAC cell growth in prior RNAi screen studies. Our results represent an important milestone in the quest for mechanisms, drug targets and biomarkers and could enable the discovery of novel mechanisms and therapies in PDAC.
Citation Format: Zeribe Chike Nwosu, Marina Pasca di Magliano, Costas Lyssiotis. Priority targets in pancreatic 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 7359.
Abstract 7364: Comprehensive multi-omics analysis for resectable hepatocellular carcinoma uncovers biomarkers to predict microvascular invasion
Authors: Kang Incheon , Kwon Woo Young , Lee Sung Hwan 
Published: March 2024

Abstract
Introduction: Microvascular invasion (MVI) is a well-known prognostic factor in predicting cancer relapse after curative resection of resectable hepatocellular carcinoma (HCC).Therefore, there is a clear unmet need for a precision strategy based on cancer-specific multi-omics features to predict the MVI feature at the initial diagnosis of HCC.
Methods: Using gene expression profiling for resected human HCC (Discovery cohort, n=240), we identified the transcriptomic signature predicting the MVI feature. Comprehensive analyses were performed using the dataset from the cancer dependency map (DepMap) project, including cancer-specific molecular characterization with multi-omics data, and drug sensitivity with compound screening, and integrative in-silico prediction methods to uncover MVI. The transcriptomic signature predicting the MVI feature were validated in independent translational cohorts (TCGA-LIHC; n=373, KOREA; n=188, TOKYO; n=183, MODENA; n=78, ZHONGSHAN; n=159).
Results: The MVI signature with 1028 genes was identified from robust statistical testing from the discovery cohort, and robust validation for the prediction performance of the MVI signature showed significant accuracy in the validation cohort (AUC=0.865, p&lt;0.01). Multi-omics analysis revealed aggressive tumor biology associated with the MVI signature and specified biomarkers.
Conclusions: Integrative multi-omics profiling for resectable HCC uncovers biomarkers to predict MVI. A novel combination of biomarkers performs in sorting out the tumor with aggressive tumor biology. A precision strategy to discover resectable tumors beneficial from surgical resection can be established from consecutive clinical trials based on this translational study.
Citation Format: Incheon Kang, Woo Young Kwon, Sung Hwan Lee. Comprehensive multi-omics analysis for resectable hepatocellular carcinoma uncovers biomarkers to predict microvascular invasion [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 7364.
Abstract 7399: Development of a reproducible AI-based spatial biomarker of the tumor immune infiltrate on H&E slides
Authors: Di Proietto Valentina , El-Khoury Jean , Adjadj Benjamin , Gillet Lucie , Marteau Ulysse , Schutte Kathryn , Von Loga Katharina 
Published: March 2024

Abstract
Background: The immune infiltrate in the tumor microenvironment (TME) has been shown to be associated with prognosis in several studies. However, a comprehensive assessment of the TME composition is not performed in routine practice due to the lack of standardized methods and tools for quantification. The aim of our study is to develop a reproducible, artificial intelligence (AI)-based, spatial biomarker of the tumor related immune response to predict patients outcome on routine Hematoxylin & Eosin (H&E) slides. To the best of our knowledge, this is the first study that implements a robust H&E pipeline to assess, across multiple cohorts, the prognostic power and the added-value of a spatial marker in comparison to non-spatial measures such as the overall lymphocytes density on the slide.
Methods: We trained AI models on both publicly available (NuCLS and Lizard) and proprietary datasets to automatically detect cells and tissue types on H&E stained Whole Slide Images of cancers from different origins.
We used these models on TCGA COAD and TCGA BRCA and computed spatial measures related to the lymphocyte densities in the tumor core versus the invasive margin as well as the immune infiltration in the tumor stroma (in between tumor islets) versus in the tumor islets themselves.
Univariate and multivariate survival analysis is performed through repeated cross-validation. A log-rank test on the stratified groups is performed for each evaluated marker, using the median value as cutoff.
Preliminary results on TCGA-COAD and TCGA-BRCA show that spatial markers of the tumor-related immune response are individually associated with overall survival, reinforcing findings from prior studies emphasizing the importance of the spatial relationship between tumor and immune cells. Multivariate analysis with both linear and non-linear models is currently ongoing across selected cohorts.
Citation Format: Valentina Di Proietto, Jean El-Khoury, Benjamin Adjadj, Lucie Gillet, Ulysse Marteau, Kathryn Schutte, Katharina Von Loga. Development of a reproducible AI-based spatial biomarker of the tumor immune infiltrate on H&E slides [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 7399.
Abstract 7428: S2Map: An online interactive analytical platform for quantitative signal measurement of cell Secretion Signal Map
Authors: Yue Zongliang , Zhou Lang , Huang Fengyuan , Chen Pengyu 
Published: March 2024

Abstract
Cell communication is predominantly governed by secreted proteins, whose diverse secretion patterns often signify underlying physiological irregularities. Unraveling the intricacies of these secreted signals at the single-cell level is crucial for a comprehensive understanding of regulatory mechanisms involving various molecular agents. To elucidate the array of cell secretion signals, encompassing both anisotropic and isotropic biomolecular cues from individual immune cells or disparate cell types, we introduce the Secretion Signal Map (S2Map). S2Map is an innovative online interactive analytical platform that incorporates qualitative metrics, the signal inequality index (SII) and the signal coverage index (SCI), which are exquisitely sensitive in facilitating the measurement of dissymmetry and diffusion of cumulative signals and signal dynamics in temporal analysis. S2Map's innovation lies in its depiction of signals through real-time secretion hotspots, and cumulative secretion contour lines, complemented by the visualization of potential cell secretion signal velocities via stream plots generated by regression models. We evaluated the SII and SCI performance in distinguishing the simulated signal diffusion model. Presently, S2Map hosts a repository of 12 datasets that map single-cell and two-cell secretion dynamics. These datasets serve as a resource to explore secretion signal types. We anticipate that S2Map will be a powerful approach to delve into the complexities of physiological systems, providing insights into the regulation of protein production, such as cytokines at the remarkable resolution of single cells. The S2Map server is publicly accessible via https://au-s2map.streamlit.app/.
Citation Format: Zongliang Yue, Lang Zhou, Fengyuan Huang, Pengyu Chen. S2Map: An online interactive analytical platform for quantitative signal measurement of cell Secretion Signal Map [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 7428.
Abstract 753: CEACAM1 induces microbiome and metabolite driven diversion of TGF-β signaling to promote colon cancer
Authors: Bhowmick Krishanu , Ohshiro Kazufumi , Xiang Xiyan , John Sahara , Yang Xiaochun , Idicula Kevin , Beauchemin Nicole , Mazumder Raja , Crandall Keith A. , Hassan Mohammad I. , Mohammad Taj , Mishra Lopa 
Published: March 2024

Abstract
Background: Colon cancer is rising in younger individuals in the United States. Potential causal factors are altered diets and gut microbiomes. Yet key signaling pathways, host-microbe interactions, and metabolites such as ammonia in cancer remain unclear. CEACAM1 responds to pathogenic microbes, interacts with the TGF-β/SPTBN1 and levels are raised in invasive colon cancer. Alterations in the TGF-β pathway occur ~40% of human GI cancers, and mouse models with disrupted TGF-β signaling (Tgfbr2−/−, Smad4+/−Sptbn1+/−, and Tgfb1−/−) develop colorectal cancer (CRC) that is dependent upon an altered gut microbiome. Our previous studies indicate the lipid metabolites (reactive aldehydes) form toxic adducts with cleaved SPTBN1 and divert TGF-β signaling to pro-oncogenic process. Poor prognosis CRC is associated with raised levels of microbial metabolites, such as ammonia. Thus, we hypothesized that “the intricate relationships among pathogen-binding CEACAM1, the gut microbiome, metabolites such as ammonia, and βII-Spectrin drive colon cancer development”.
Methods: We examined gut microbiota composition, immune cell population, inflammation, and cancers in Smad4+/−Sptbn1+/− and Sptbn1LSKO mice fed a normal chow diet or a high-fat diet (HFD). We evaluated CEACAM1 and TGF-β member alterations in in CRCs using TCGA datasets. Alphafold-based molecular modeling predicted interaction sites between βII-Spectrin and CEACAM1 was followed by functional studies.
Results: Increased CEACAM1 levels with alterations in TGF-β members were associated with lower survival (TCGA). Mice with disrupted TGF-β signaling (Smad4+/−Sptbn1+/−) develop CRC, have high CEACAM1 levels, and an altered gut microbiome signature. CEACAM1 interacts with βII-Spectrin, and levels are restored to normal in βII-Spectrin LSKO which restores the gut microbiome and blocks inflammation and cancer. Ammonia induces CASPASE-3 mediated cleavage of βII-Spectrin, forms toxic adducts and divert TGF-β signaling to pathological pro-oncogenic signaling, triggering CRC.
Conclusion: We have found a critical role for CEACAMs in CRC cancer development, through diverting the TGF-β signaling pathway to a pro-oncogenic phenotype. CEACAM1 and βII-Spectrin are attractive therapeutic targets for CRC.
Citation Format: Krishanu Bhowmick, Kazufumi Ohshiro, Xiyan Xiang, Sahara John, Xiaochun Yang, Kevin Idicula, Nicole Beauchemin, Raja Mazumder, Keith A. Crandall, Mohammad I. Hassan, Taj Mohammad, Lopa Mishra. CEACAM1 induces microbiome and metabolite driven diversion of TGF-β signaling to promote colon 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 753.
Abstract 7560: Microsatellite instability (MSI) detection using flow-based sequencing
Authors: Lithwick-Yanai Gila , Benjamin Hila , Cano-Nistal Jorge , Geisler Shir , Jaimovich Ariel , Iremadze Nika , Kessler Dror , Soifer Ilya , Lebanony Danit , Simhon Keren Ben , Gilad Shlomit , Meiri Eti , Lipson Doron , Maruvka Yosef E. 
Published: March 2024

Abstract
Background: Microsatellite instability (MSI) is an important genomic biomarker associated with various cancers and hereditary conditions. Accurate and efficient classification of MSI status is essential for diagnosis, prognosis, and treatment decisions. Different approaches for testing MSI have been presented in the literature, including NGS-based methods which either rely on comparison with a matched control sample, a set of reference control samples, or the reference genome (no control). In this study, we explore the feasibility of accurately identifying MSI status using the UG100 platform, which utilizes flow-based sequencing chemistry. Since MSI detection is typically based on long homopolymers, we examined here whether the flow-based sequencing data can be effectively used for MSI classification.
Methods: We performed whole genome sequencing (WGS) on a cohort of 24 cell lines with known MSI status, as well as on 15 tumor tissue samples, encompassing various cancer types, including colon, lung, bladder, and endometrial cancer. To determine the MSI status, polyA/T homopolymer loci were considered. We measured the MSI status in these loci using two methods: 1) Counting short indel variants detected using somatic Deep Variant, in comparison with matched blood normal, and 2) a novel MSI score based on the difference of the polyA/T homopolymer length, in comparison to the reference genome. We assessed the ability to evaluate the score for the full sequenced coverage (~100X) as well as when limiting to exome boundaries, and when sampling down to 1X coverage.
Results and Conclusions: We established the performance of the MSI score on the cell lines with known MSI status. The score was verified on cell line mixtures (simulating lower tumor purity) as well as on clinical samples from various tissue sources, including colon samples annotated as mismatch-repair deficient. We demonstrate the ability to use the cost-effective UG100 sequencing combined with the two methodologies to identify MSI-high samples in these scenarios.
Citation Format: Gila Lithwick-Yanai, Hila Benjamin, Jorge Cano-Nistal, Shir Geisler, Ariel Jaimovich, Nika Iremadze, Dror Kessler, Ilya Soifer, Danit Lebanony, Keren Ben Simhon, Shlomit Gilad, Eti Meiri, Doron Lipson, Yosef E. Maruvka. Microsatellite instability (MSI) detection using flow-based sequencing [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 7560.
Abstract 7576: Exemestane and its primary metabolite 17-hydroexemestane inhibit synergically the tumor growth of ER/AR positive breast cancer tumors
Authors: Santacana-Font Gemma , Kedra Darek , del Carmen García-Macías Maria , Cornelus-Reitsma Laurens , Lyngra Marianne , Sauer Torill , Kristensen Vessela , Hurtado Antoni , Geisler Jürgen 
Published: March 2024

Abstract
Exemestane, an aromatase inactivator of the third generation, plays a crucial role in breast cancer therapy by targeting the P450 aromatase enzyme and, thus, decreasing estrogen synthesis. Exemestane (Aromasin™) is currently the only steroidal aromatase inactivator widely used in clinical routine treatment of ER+ breast cancer in all phases of the disease in a global perspective. However, the complex mechanisms underlying its therapeutic effects, besides being an aromatase inhibitor, remain incompletely understood. In this study, we employed a combination of human samples and in vitro data to unveil a compelling insight: Exemestane (EXE) and its primary metabolite, 17β-hydroxyexemestane (HEXE), exhibit potent inhibitory effects on tumor growth when present together in patient serum. Our biochemical analysis establishes a critical threshold—20% HEXE metabolite of the total EXE in patient serum—to trigger a tumor growth inhibition exceeding 90%, as evidenced by Ki67 staining. Mechanistically, our data reveals that both HEXE and EXE bind to the Androgen Receptor (AR), triggering a synergistic activation that induces a transcriptional program leading to cell death while diminishing the intracellular signaling activated by the oncogene Ras. Notably, patients with tumors characterized by a minimum of 20% AR+ epithelial cancer cells stand to benefit the most from exemestane and HEXE. Intriguingly, the binding of AR to chromatin in tumors gives rise to a molecular signature capable of distinguishing responsive from non-responsive patients to both EXE and HEXE. Collectively, our findings elucidate a dual therapeutic role for Exemestane in selected patients: it not only restrains estrogen-driven proliferation by estrogen suppression but also stimulates cell death by establishing a specific interactome with the AR at the genomic level. These insights suggest that both EXE and HEXE are necessary to achieve the best therapeutic effects in ER+/AR+ breast cancer tumors. Moreover, our findings suggest that AR-expression and targeting should be investigated further to potentially add novel strategies to our existing algorithms in ER+/AR+ MBC.
Citation Format: Gemma Santacana-Font, Darek Kedra, Maria del Carmen García-Macías, Laurens Cornelus-Reitsma, Marianne Lyngra, Torill Sauer, Vessela Kristensen, Antoni Hurtado, Jürgen Geisler. Exemestane and its primary metabolite 17-hydroexemestane inhibit synergically the tumor growth of ER/AR positive breast cancer tumors [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 7576.
Abstract 7579: Dual inhibition of enhancer of zeste homolog 1 2 induces pyroptosis, modulates oncogenic signaling pathways & sensitizes hepatocellular carcinoma to valemetostat & docetaxel treatments
Authors: Harira Asmaa Elkhder , Maher Adham , Sultan Ahmed 
Published: March 2024

Abstract
HCC is a global health concern, with chemotherapy resistance and patient recurrence posing significant challenges to liver cancer treatment. EZH2 is a crucial part of the polycomb repressive complex 2 (PRC2). It, along with its homolog EZH1, is a focus for cancer therapeutic targets. Dysregulation of EZH1/2 can cause cancer development due to significant changes in geneexpression. The current study aims to investigate the interaction between EZH1/2 and oncogenic signals responsible for HCC progression and pyroptosis induction. Two cell lines, HepG2 and SK-Hep1, were subjected to two FDA-approved drugs, Valemetostat (Val) and Docetaxel (Doc), to determine the impact of EZH1/2 on tumorigenicity and drug resistance. The WST-1 assay was utilized to gauge cell proliferation. The results indisputablydemonstrated a synergistic effect of the drugs after 48 h of treatment. The inhibition of viability was attributed to apoptosis induction in both tested cell lines, and the maximum effect was observed in the combined treatment as compared to either the control or each drug alone. Furthermore, our datashowed activation of caspase-3, upregulation of BAX, indicating apoptotic induction, and downregulation of Bcl-2, Bcl-XL, AKT, S6k, oncogenic β-catenin, and Stat3 protein expression levels, suggesting a modulation of oncogenic signaling pathways at the protein level. After 24 h of Val/Doc treatment, pyroptosis was observed, characterized by cell swelling and bubbles on themembrane and a significant release of lactate dehydrogenase, indicating pyroptotic cell cytotoxicity. The antitumor effects and pyroptosis were enhanced by using a dual inhibitor, UNC1999, for EZH1/2, resulting in a marked increase in the sensitivity of tested cells to the Val/Doc treatment invitro. The present study unequivocally demonstrated that dual inhibition of EZH1/2 acts as a potent sensitizer of HCC cells to Val/Doc treatment, which might be a promising therapeutic approach for inducing cellular pyroptosis in HCC cell lines.
Citation Format: Asmaa Elkhder Harira, Adham Maher, Ahmed Sultan. Dual inhibition of enhancer of zeste homolog 1 2 induces pyroptosis, modulates oncogenic signaling pathways & sensitizes hepatocellular carcinoma to valemetostat & docetaxel treatments [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 7579.