bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3546: Putting genes in context by linking gene signatures to established cancer hallmarks
Authors: Menyhart Otília , Kothalawala William , Győrffy Balázs 
Published: March 2024

Abstract
The concept of the "Hallmarks of Cancer" provides a valuable framework for understanding fundamental organizing principles common to various types of cancers. However, the absence of a consensus gene set for cancer hallmarks poses data comparison and integration challenges, resulting in diverse biological interpretations across studies.
Here, we first established a consensus cancer hallmark-gene set by merging data from available mapping resources. We searched the scientific literature for relevant publications from which a list of hallmark genes could be reconstructed. By consolidating data from seven publications, we identified 6,763 candidate cancer hallmark genes associated with ten cancer hallmarks. Of these, 1574 genes were part of at least two resources, forming a "core" hallmark gene set.
Then, we compared the enrichment of cancer hallmarks by analyzing the prognostic genes associated with overall survival across twelve solid tumor types. Notably, the hallmark "tissue invasion and metastasis" was most prominent in the stomach (p=1.2E-11), pancreatic (p=1.5E-09), bladder (p=1.8E-08), and ovarian cancers (p=0.0002), aligning with their heightened potential to spread. "Sustained angiogenesis" predominated in lung squamous carcinomas (p=4.5E-08), while "genome instability" showed strong enrichment in lung adenocarcinomas (p=1.3E-09), liver (p=1.4E-10), pancreatic (p=1E-5) and kidney cancers (p=0.0025). Compelling evidence links lifestyle choices like alcohol consumption and smoking to genomic instability across tumors, suggesting a potential common underlying mechanism of tumorigenesis.
Pancreatic cancers displayed the highest enrichment of hallmarks (8 out of 10), emphasizing the disease's complexity, while in melanomas, liver, and kidney cancer, a single hallmark (,,genomic instability”) was enriched among the prognostic markers of survival. These findings underscore the utility of the hallmark concept as an effective organizational tool, particularly when establishing a clear connection between genes and biological functions.
Finally, we integrated the data into a publicly accessible and user-friendly online tool (available at www.cancerhallmarks.com) that allows users to identify the most relevant cancer-associated "candidate hallmark genes" in their datasets.
In summary, we have established a consensus list of genes associated with cancer hallmarks. The analysis of survival-associated genes revealed a unique pattern of hallmark enrichment for each tumor type.
Citation Format: Otília Menyhart, William Kothalawala, Balázs Győrffy. Putting genes in context by linking gene signatures to established cancer hallmarks [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 3546.
Abstract 3550: PerturbDB: A resource for revealing gene functions and cancer-associated phenotypes
Authors: Yang Bing , Zhang Man , Shi Yanmei , Dong Yi-Ming , Ma Xingyu , Zhang Jingyuan , Lu Daning , Liao Jian-You , Yin Dong 
Published: March 2024

Abstract
Perturb-seq is a high-throughput technique that combines clustered regularly interspaced short palindromic repeats (CRISPR)-based screens with single-cell RNA sequencing (scRNA-seq) readouts for high-content phenotypic screens to comprehensively map the transcriptional effects of genetic perturbations, showing great advantages in revealing disease-associated gene functions and mechanisms in high volumes. Despite the rapid accumulation of Perturb-seq datasets, no dedicated database exists for reusing these valuable information. In this study, we developed a platform called PerturbDB (http://research.gzsys.org.cn/perturbdb) to facilitate users to unveil genotype-phenotype relations, especially gene functions and regulatory networks involved in several classical cancer associated phenotypes using 37 Perturb-seq datasets from 15 studies. By reanalyzing 3,429,829 single-cell transcriptomes from the knockdown of 3214 genes across 10 different cell lines, we identified 749 classical cancer phenotype-related genes and 373 functional gene clusters annotating potential novel functions. Utilizing Marker genes scoring and the InferCNV algorithm, we identified genes involved in 9 malignant phenotypes, which consists of sustaining proliferative signaling (362 genes), resisting cell death (120 genes), inducing angiogenesis (145 genes), tissue invasion and metastasis (321 genes), enabling replicative immortality (160 genes), deregulating cellular metabolism (247 genes), avoiding immune destruction (95 genes), unlocking phenotypic plasticity (231 genes), and chromosome instability (231 genes). Additionally, functional clusters were calculated utilizing Principal Component Analysis (PCAs) and the HDBSCAN package to introduce unknown gene functions related to the cancer associated phenotypes. Perturbation clusters (PCs) were identified by comparing similarities in the transcriptomes of perturbed cells, suggesting individual genes in the same functional cluster perform similar gene functions, and therefore novel functions of 735 genes can be inferred from the known functions of neighboring genes. The PGSEA tool was developed to facilitate functional analysis of genes not yet included, which helps users to predict gene functions through a combination of PerturbDB datasets and personalized RNA-seq datasets. This study will greatly expand our understanding of genes involved in emblematic cancer associated phenotypes and their coordinated functions and regulatory networks.
Citation Format: Bing Yang, Man Zhang, Yanmei Shi, Yi-Ming Dong, Xingyu Ma, Jingyuan Zhang, Daning Lu, Jian-You Liao, Dong Yin. PerturbDB: A resource for revealing gene functions and cancer-associated phenotypes [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 3550.
Abstract 3556: A pan-cancer ex vivo drug screen database for next-generation pharmacogenomics and functional precision oncology
Authors: Markus Anneliese , Pichotta Karl , Quinn Jeffrey , White Jessica , Tosh Christopher , Liu Jinrui , Coyne Erin , Tansey Wesley 
Published: March 2024

Abstract
Large-scale drug screens across thousands of drugs and biological models enable pan-cancer analyses that can reveal novel insights into therapeutic response and resistance. Existing databases, such as the Cancer Dependency Map only screen established 2D cell lines, which are known to poorly translate to patients. Ex vivo models such as patient-derived cells, spheroids, and organoids, have consistently demonstrated superior translatability from drug screening responses as they better replicate the original tumor. However, the cost, complexity, and difficulty of developing and screening ex vivo models has thus far prevented the establishment of any large-scale database comparable to existing cell line databases. We present the pan-preclinical (PPC) project, a large pan-cancer database of ex vivo drug responses comprising 2.1M raw dose-response measurements with curve-level summary statistics and metadata. The PPC database is assembled from over 30 previously published ex vivo studies and contains 2,880 ex vivo models spanning 106 cancer subtypes tested against subsets of 3,023 drugs. Compounds are harmonized across studies and paired with detailed chemoinformatics derived from PubChem. Each ex vivo sample is matched to an underlying patient and paired, where available, with genomics, transcriptomics, and clinical information such as sex, treatment history, and overall survival. Two thirds of the underlying studies did not originally make the underlying drug screening data available at publication time, making the PPC database a novel resource beyond data integration. Results: To investigate the power of the PPC database, we developed a preliminary computational modeling and statistical analysis pipeline. A hierarchical Bayesian factor model was developed to estimate dose-response curves, remove batch effects across studies, and impute missing drugs. Low-dimensional projections of ex vivo drug responses show biologically meaningful clustering. Statistical analyses of both observed and imputed drug responses recapitulate standard of care drugs as significantly effective across several cancer types. Overall, we envision the PPC project laying the foundation for the next generation of large-scale pharmacogenomic analyses and aiding in the coming era of functional precision oncology.
Citation Format: Anneliese Markus, Karl Pichotta, Jeffrey Quinn, Jessica White, Christopher Tosh, Jinrui Liu, Erin Coyne, Wesley Tansey. A pan-cancer ex vivo drug screen database for next-generation pharmacogenomics and functional precision oncology [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 3556.
Abstract 356: Developing a multiplex assay to monitor apoptosis and necrosis using the Cellaca® PLX Image Cytometer
Authors: Mukherjee Joydeep , Pierce Mackenzie , Huang Yongyang , Lin Allen , Chan Leo Li-Ying 
Published: March 2024

Abstract
Apoptosis is a critical pathway for programmed cell death that cancer cells can evade to ensure survival. For pharmaceutical drug discovery, it is important to characterize and compare cancer therapeutics (i.e., small molecules, antibody drugs, cell therapies) that can initiate the process of apoptosis, allowing for the identification of potential therapeutic candidates. In this work, we developed and demonstrated a multiplex detection method for monitoring apoptosis and necrosis with Annexin V, Caspase 3/7, and Propidium Iodide (PI) using the Cellaca® PLX Image Cytometer. First, apoptosis was induced in Jurkat and K562 cell lines with staurosporine over the course of 24 h, and were monitored at 0, 1, 1.5, 2, 4, 20, and 24 h timepoints. Samples were stained with Hoechst 33342 (total dye), Annexin V-APC (early-stage apoptosis), Caspase-3 488 (late-stage apoptosis), and PI (necrosis) at each timepoint and evaluated using the Cellaca® PLX. Results showed that apoptotic factors and cascades were successfully detected along the pathway from early to late-stage apoptosis, and ultimately necrosis. A clear trend was observed during the first 2 h showing differences of up to 25% between the single Annexin V+ and Caspase-3+ populations in treated Jurkat cells, however, a significant increase in double positive apoptotic/necrotic cells for Annexin V+PI+ and Capase-3+PI+ was not observed until 20 h. Upon further analysis amongst apoptotic populations, Annexin V+ only populations were higher than Caspase-3+ only populations by up to 30% between 0-2 hours. Conversely, K562 cells did not exhibit a notable change in apoptotic and necrotic populations due to low sensitivity to staurosporine. The proposed image-based detection method using the Cellaca® PLX may provide an effective and efficient tool for rapid and reliable simultaneous detection of early, late-stage apoptosis, and necrosis. This may allow researchers to better characterize and screen potential cancer therapeutic drug candidates in a high-throughput manner to determine their treatment efficacy.
Citation Format: Joydeep Mukherjee, Mackenzie Pierce, Yongyang Huang, Allen Lin, Leo Li-Ying Chan. Developing a multiplex assay to monitor apoptosis and necrosis using the Cellaca® PLX Image Cytometer [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 356.
Abstract 3581: IGFR1 and MEK inhibition synergize to mediate anti-tumor activity in adrenocortical carcinoma
Authors: Kumar Suresh , Sun Nai-Yun , Arakawa Yasuhiro , Varghese Diana , Hoang Chuong D. , Hernandez Jonathan M. , Pommier Yves , Thomas Craig , Rivero Jaydira Del , Roper Nitin 
Published: March 2024

Abstract
Adrenocortical carcinoma (ACC) is an aggressive and rare endocrine malignancy with limited treatment options and poor prognosis. IGF2, the ligand for IGFR1, is highly expressed in ACC. However, linsitinib, an IGFR1 inhibitor, failed to improve overall survival over placebo in a randomized, phase 3 clinical trial of metastatic ACC. We hypothesized that combination therapy with IGFR1 inhibition may have greater anti-tumor efficacy in ACC than IGFR1 inhibition alone. To test this hypothesis, we performed high-throughput cell toxicity screening of 2803 clinical-stage compounds with linsitinib in an ACC cell line. MAPK inhibitors were among the top screening hits. MEK inhibitors were chosen for further evaluation given the safety, tolerability, and broad clinical activity of these FDA-approved agents. IGFR1 and MEK inhibitors were strongly synergistic in cytotoxicity across ACC cell lines, ACC organoid short-term cultures derived from surgical tissue resections (PDOs), and PDX-derived organoids (PDXOs). Genetic depletion of IGF2 significantly inhibited growth with cobimetinib and genetic depletion of MEK1 inhibited growth with linsitinib in ACC cell lines. Combination IGFR1 and MEK inhibition downregulated ERK phosphorylation and increased apoptosis compared to either IGFR1 or MEK inhibition alone. Linsitinib combined with cobimetinib significantly reduced tumor growth compared to either linsitinib or cobimetinib alone in an ACC xenograft model. Our study provides preclinical support for testing the combination of IGFR1 and MEK inhibition in patients with ACC.
Citation Format: Suresh Kumar, Nai-Yun Sun, Yasuhiro Arakawa, Diana Varghese, Chuong D. Hoang, Jonathan M. Hernandez, Yves Pommier, Craig Thomas, Jaydira Del Rivero, Nitin Roper. IGFR1 and MEK inhibition synergize to mediate anti-tumor activity in adrenocortical 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 3581.
Abstract 36: The discovery of a novel CD19xCD22 dual-targeting CAR for the development of an IPSC-derived cell therapy
Authors: Carton Jill M. , Wheeler John , Dower Chris , Campion Liam , Millar Hillary J. , Beqiri Marilda , Morse Barry , Gurung Buddha , Genovese Rebecca , DeLuca Steven , Dominick Charles , Naso Michael , Levitsky Hy 
Published: March 2024

Abstract
Dual-targeting cell therapies to address CD19 antigen loss in heme malignancies are being explored by Century Therapeutics and others for unmet clinical need in hematological malignancies. CD22 chimeric antigen receptor (CAR) T-cell therapies have shown promising efficacy in relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) alone and in combination with CD19 CAR-T cell therapies (1,2). CD22 is a multi-domain glycoprotein expressed on B-cells. Natural splice variants of CD22 can exclude domains near the N-terminus, allowing for therapeutic resistance when these domains are targeted. We identified novel single domain antibodies (VHH) to CD22 that bind to multiple epitopes on different domains of CD22, including membrane proximal binders. The VHHs were affinity matured to enhance cell-based binding and formatted as CARs in monovalent and tandem, bivalent formats. Our data demonstrates the best efficacy against CD22+ tumor cells with a biparatopic, tandem VHH CAR format. Through additional engineering, bispecific CARs that combined three CD22-binding VHH and the anti-CD19 scFv, FMC63, in a loop CAR configuration were designed and tested. This CD19xCD22 bispecific, CD22 biparatopic CAR was engineered into primary T-cells and demonstrated cytotoxicity activity against CD19 and CD22 positive tumor cells as well as CD19 knockout and CD22 knockout cell lines. CD19xCD22 bispecific primary CAR-T cells were efficacious in controlling tumors in mouse xenograft models. This novel CAR is being tested in IPSC-derived iT and iNK cells for off-the-shelf allogeneic cell therapy to expand patient access beyond CD19 CAR-T cell therapies. Ref: 1. Nat Med. 2018;24(1):20-28. doi: 10.1038/nm.4441. 2. Blood. 2018;132(suppl 1). Abstract 27
Citation Format: Jill M. Carton, John Wheeler, Chris Dower, Liam Campion, Hillary J. Millar, Marilda Beqiri, Barry Morse, Buddha Gurung, Rebecca Genovese, Steven DeLuca, Charles Dominick, Michael Naso, Hy Levitsky. The discovery of a novel CD19xCD22 dual-targeting CAR for the development of an IPSC-derived cell therapy [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 36.
Abstract 3606: Tumor-specific CD8+ Tc9 cells activate host CD4+ T cells to control antigen-lost tumors
Authors: Xiao Liuling , Yi Qing 
Published: March 2024

Abstract
Cancer immunotherapies relying on targeted destruction of cancer cells by potent antitumor T cells have achieved unprecedented success in recent years. As a main form of cancer immunotherapies, adoptive T cell therapy (ACT) has shown a durable response in certain cancer patients. However, this response is often short-lived and tumor relapse occurs due to the outgrowth of antigen-lost-variant (ALV) tumors and poor antitumor immune response. Here, We reported that adoptively transfer of murine tumor-specific CD8+ Tc9 but not Tc1/CTL cells achieved long-term control of tumor growth in vivo. Here, we demonstrated that murine tumor-specific Tc9 cells not only killed antigen-expressing primary tumors but also controlled the outgrowth of antigen-lost relapsed tumors by recruiting and activating host effector CD4+ T cells that recognized relapsed tumors. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type-2 dendritic cells (cDC2) into tumor-draining lymph nodes to prime host CD4+ T cell response against relapsed tumors. Depleting host CD4+ T cells or deficiency in CCR7 expression impaired Tc9 cell ability to control the outgrowth of relapsed tumor. We also observed that intratumoral IL24 expression was positively correlated with gene signatures of cDC2 and CD4+ T cells in human cancers and expression of IL24 and cDC2 and CD4+ T cell gene signatures were associated with patient’s overall survival. Thus, this study uncovers a novel mechanism underlying activation of tumor-specific CD4+ T cells in vivo.
Citation Format: Liuling Xiao, Qing Yi. Tumor-specific CD8+ Tc9 cells activate host CD4+ T cells to control antigen-lost 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 3606.
Abstract 3624: A low-cost kit for gentle, effective and timely extracellular vesicle (GET EVs) isolation: Accelerating development of RNA-based liquid biopsies for neuroendocrine neoplasms
Authors: Su Boyang , Jeyhani Morteza , Yang Xiaojing , Nanayakkara Jina , Wunsche Reese , Renwich Neil , Tsai Scott , Leong Hon 
Published: March 2024

Abstract
Extracellular vesicles (EVs) are cell fragments released by all cells, making them promising platforms for cancer biomarker development. Effective isolation of ultra-pure EVs for downstream analyses is key for EV-based liquid biopsy development. However, current EV isolation methods such as ultracentrifugation (UC) and other commercialized EV isolation kits are lackluster because of damage to EVs, length of time required, and low EV recovery rates. In response, we developed an “GET EV” kit which is based on the principles of lipid energy states, also known as the aqueous two-phase system (ATPS) to isolate EVs from any media. Nanoscale flow cytometry (nFC) analysis revealed that ATPS has greater EV enrichment capability (21.4 × vs. 10.9 × times fold enrichment) and higher EV recovery efficiency (97.6% vs. 69.3% recovery) than UC. Other EV isolation kits were tested and were inferior to ATPS in terms of EV recovery and EV-RNA recovery. EV subpopulations as determined by EV biomarkers (CD9, CD63, CD81, etc.) were confirmed by nFC. “Omics” studies (small RNA sequencing and proteomics) also confirmed the presence of expected EV markers. We developed an RNA-based liquid biopsy for Neuroendocrine Neoplasms (NENs) by quantitating the presence of EVs containing miR-375, an established biomarker for NENs. Using the GET EVs kit, we isolated EVs from healthy volunteer and patient plasma samples of NEN patients. RT-qPCR demonstrated enriched expression of miR-375 in EVs isolated from Lung and GI NEN patient plasma samples. Our study establishes the use of GET EV kits to efficiently, rapidly, and gently isolate EVs from small plasma samples (250 uL). This is a low-cost innovation that will finally enable the development of other RNA-based Liquid Biopsies for other disease sites with significant diagnostic and prognostic implications.
Citation Format: Boyang Su, Morteza Jeyhani, Xiaojing Yang, Jina Nanayakkara, Reese Wunsche, Neil Renwich, Scott Tsai, Hon Leong. A low-cost kit for gentle, effective and timely extracellular vesicle (GET EVs) isolation: Accelerating development of RNA-based liquid biopsies for neuroendocrine neoplasms [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 3624.
Abstract 370: BACH1 metastatic activity is regulated by oxygen-dependent proline hydroxylation in triple-negative breast cancer
Authors: Li Thomas , Nguyen Long Chi , Dann Christopher , Henn Madeline , Yang Dongbo , Shi Emily , Robinson-Mailman Lydia , Igarashi Kazuhiko , Rosner Marsha R. 
Published: March 2024

Abstract
Hypoxia, low oxygen availability at the tissue level, is a key driver of metastasis in solid tumors. Oxygen-sensitive activation of hypoxia-induced transcription factors is in part regulated by prolyl hydroxylase domain proteins (PHDs). We and others previously showed that the BTB and CNC homolog 1 (BACH1) transcription factor promotes metastasis in various cancer types. In accompanying work, we show that BACH1 is prolyl-hydroxylated and degraded in an oxygen-dependent manner in triple-negative breast cancer (TNBC). Here we show that BACH1 lacking its hydroxylated proline sites (i.e., mutant BACH1) expressed in TNBC cells exhibits increased DNA binding to a canonical BACH1 binding site as well as greater transcriptional output of metastasis and hypoxia-response-related genes relative to wild-type BACH1. Furthermore, in vivo assays showed that mutant BACH1 promotes greater tumor metastasis of TNBC cells than wild-type BACH1. Our findings suggest that the proline hydroxylation of BACH1 directly regulates BACH1’s transcriptional activity by modulating its DNA-binding activity. Together, these results reveal a mechanism underlying oxygen-sensitive regulation of BACH1 that could potentially contribute to BACH1-mediated pro-metastatic signaling and therapeutic resistance under hypoxia in TNBC.
Citation Format: Thomas Li, Long Chi Nguyen, Christopher Dann, Madeline Henn, Dongbo Yang, Emily Shi, Lydia Robinson-Mailman, Kazuhiko Igarashi, Marsha R. Rosner. BACH1 metastatic activity is regulated by oxygen-dependent proline hydroxylation in triple-negative breast 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 370.