bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1195: BC-BET v2.0: Updates to an online Bladder Cancer Biomarker Evaluation tool
Authors: Dancik Garrett M. 
Published: June 2022

Abstract
The Bladder Cancer Biomarker Evaluation Tool (BC-BET) is a web application for quickly evaluating candidate diagnostic and prognostic biomarkers in bladder cancer, based on publicly available gene expression datasets. Specifically, BC-BET evaluates whether a selected gene is differentially expressed between normal cells and tumor samples; between low- and high- grade tumors; and between non-muscle invasive and muscle-invasive tumors. BC-BET also evaluates whether a selected gene is significantly associated with survival, and whether the gene is associated with survival in two clinically important patient subsets: patients with low-grade, non-muscle invasive tumors; and patients with high-grade, muscle invasive tumors. Here we describe updates to BC-BET that include the inclusion of additional patient cohorts, and new features including multi-gene search, data visualization, additional data export options, and faster search times. BC-BET v2.0 contains gene expression data from 17 cohorts (N = 1846), and users can now query up to 500 genes at a time in order to quickly identify genes associated with bladder cancer. For single gene queries, dot plots can be generated for visualization of gene expression across groups; while Kaplan-Meier curves can be generated for survival analyses. BC-BET v2.0 also allows users to export the gene expression and clinical data, which would allow researchers to generate their own visualizations or to carry out additional analyses. Finally, the BC-BET backend was re-designed, resulting in more than a 2x fold increase in performance efficiency. We hope that this tool will continue to serve the bladder cancer research community and will ultimately lead to a better understanding of and treatment of this disease. The BC-BET web application as well as its source code is freely available from https://gdancik.github.io/BC-BET/.
Citation Format: Garrett M. Dancik. BC-BET v2.0: Updates to an online Bladder Cancer Biomarker Evaluation tool [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1195.
Abstract 1196: Elucidating compound mechanism of action and polypharmacology with a large-scale perturbational profile compendium
Authors: Hu Lucas Zhongming , Douglass Eugene , Realubit Ron , Karan Charles , Alvarez Mariano , Califano Andrea 
Published: June 2022

Abstract
Traditional approaches to elucidate small molecule mechanism of action (MoA) are usually based on affinity binding assays. These often fail to detect lower affinity binding targets and secondary effectors that are usually highly tissue context-dependent. As such, these can vary dramatically across different cancer types. To address this challenge and facilitate more quantitative approaches to targeted cancer therapy, a more comprehensive picture of drug MoA, including poly-pharmacology and toxicity effects mediated by the full range of its high-affinity (primary), as well as its context-specific lower-affinity (secondary) and downstream effector (tertiary) targets. For this purpose, we generated transcriptional genome-wide RNA-Seq profiles of cancer cell lines, following compounds perturbation with FDA approved and late-stage experimental oncology drugs using a fully automated and highly efficient PLATE-Seq technology1. Compared to prior approaches, this provides (a) genome-wide readouts, rather than readouts limited to a small set of landmark genes, (b) in cell lines that were specifically selected as the highest-fidelity models for published human cancer cohorts, using the OncoMatch algorithm2, and (c) for a drug repertoire that is clinically relevant. In addition, to avoid confounding effects from drug stress/death response pathway activation—a common issue in previous studies—drugs were titrated at their maximum sub-lethal concentration (48-hr IC20) using 10-point dose response curves in each cell line. The ~20,000 molecular profiles generated by these assays were analyzed using the VIPER algorithm3 to reproducibly assess the effect of each drug on the activity of ~6,500 regulatory and signaling proteins compared to vehicle control. The resulting PanACEA (Pancancer Activity-based Compound Efficacy Analysis), a database comprising drug perturbation profiles for 23 different cancer cell lines and &gt; 700 oncology drugs, representing the largest resources of functionally annotated, genome-wide perturbational profiles for clinically relevant drugs. Systematic analysis identified critical drug mechanism of action and drugs capable of reproducibly targeting undruggable proteins, such as MYC or KRAS. We also leveraged graph theory-based network approach to generate a conserved drug functional network and drug functional networks in different cancer contexts, which pinpoint critical novel poly-pharmacology effects.
Citation Format: Lucas Zhongming Hu, Eugene Douglass, Ron Realubit, Charles Karan, Mariano Alvarez, Andrea Califano. Elucidating compound mechanism of action and polypharmacology with a large-scale perturbational profile compendium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1196.
Abstract 1218: HOPE2Net: Integrating histological features and position embeddings in spatially resolved transcriptomics to predict gene expression and pathway activities from histology images in tumors
Authors: Su Kenong , Pang Minxing , Li Mingyao 
Published: June 2022

Abstract
Recent developments in spatially resolved transcriptomics (SRT) technologies have enabled the profiling of transcriptome-wide gene expression while retaining spatial location information of each measured spot within a tissue. Meanwhile, the corresponding histopathology images of tissue sections are readily available and can be aligned to the measured spots. Given that the histology images are practically more convenient and affordable to obtain, we designed HOPE2Net, a multi-layer perceptron architecture, that leverages information provided by SRT data to predict gene expression and pathway activities from histology images. Through systematic evaluations of different approaches for extracting deep image features and cellular morphology features, HOPE2Net performs feature selections from a pre-trained Vision Transformer, which is the state-of-art deep learning model for image recognition. After extracting histological image features, HOPE2Net further integrates with position embeddings, to optimize the gene expression and pathway activity prediction tasks. Through analyzing breast cancer and prostate cancer SRT datasets obtained from numerous tissue sections in multiple patients, we demonstrate that HOPE2Net can accurately predict the gene expression patterns for highly variable genes and the activities for significantly enriched domain-specific pathways. We further show that the predicted gene expression and pathway activities can help detect cancer subtypes and aid in treatment decision-makings. Given the growing interest in applying SRT in cancer genomics, we believe HOPE2Net holds the potential in identifying biomarkers from direct screenings of tissue histology images, which may be implemented in clinical studies for cancer diagnoses and decision-making processes.
Citation Format: Kenong Su, Minxing Pang, Mingyao Li. HOPE2Net: Integrating histological features and position embeddings in spatially resolved transcriptomics to predict gene expression and pathway activities from histology images in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1218.
Abstract 1224: UMIBB: A novel nonparametric Bayesian method improves robustness and sensitivity of analysis in pooled CRISPR-Cas9 screens leveraging unique molecular identifiers
Authors: Choi Ashley , Meier Samuel , Fenoglio Silvia , Feng Tianshu , Engel Justin , Shen Binzhang , Liu Shangtao , Teng Teng , Khendu Tenzing , Huang Alan , Andersen Jannik , Pan Xuewen , Yu Yi 
Published: June 2022

Abstract
CRISPR-based functional genomics screens are a powerful tool for identifying synthetically lethal cancer drug targets. Current strategies for analyzing pooled CRISPR screens usually rely on signals from single guide RNAs (sgRNA) with differential relative abundance between two experimental conditions. However, conventional approaches are susceptible to false positives and false negatives driven by outlier cell clones, since the sgRNA abundance does not account for the heterogeneous phenotypes resulting from different editing outcomes of the same sgRNA. To overcome this, we added DNA barcodes to each sgRNA to create unique molecular identifiers (UMIs) for CRISPR libraries and developed a companion analytical platform that enables robust, industry-scale CRISPR screens. Here, we present UMIBB, a novel nonparametric Bayesian approach for analyzing UMI-CRISPR data. The number of UMIs with normalized count depletion or enrichment compared to the control experimental condition for each sgRNA is modeled by a beta-binomial distribution. The gene level statistics are derived by combining z-scores of the sgRNAs level posterior probabilities weighted by the number of UMIs in each sgRNA. This approach minimizes the impact of outlier cell clones on statistics and prioritizes genes with consistent count differentials across multiple UMIs in each gene. To assess the power of UMIBB, we benchmarked it on a low coverage (200X) genome-scale negative-selection screen, comparing with results from a high coverage (1000X) screen. These screens were conducted on KRAS mutant cancer celllines (A549) treated with trametinib or vehicle control. Despite the high noise level usually observed in lower coverage screens, our method was able to uncover most of the validated sensitizer genes for trametinib and achieved the highest sensitivity compared to conventional methods. Furthermore, we applied UMIBB on a genome-scale positive-selection screen and successfully identified novel genes (RAD18 and UBE2K) as key mediators of USP1 dependency in BRCA1 mutant cell lines. Our studies demonstrate that UMIBB is highly robust against false positives due to clonal heterogeneity and is more likely to identify true genetic interactions.
Citation Format: Ashley Choi, Samuel Meier, Silvia Fenoglio, Tianshu Feng, Justin Engel, Binzhang Shen, Shangtao Liu, Teng Teng, Tenzing Khendu, Alan Huang, Jannik Andersen, Xuewen Pan, Yi Yu. UMIBB: A novel nonparametric Bayesian method improves robustness and sensitivity of analysis in pooled CRISPR-Cas9 screens leveraging unique molecular identifiers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1224.
Abstract 1288: STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer
Authors: Jadhav Heta , Pantelidou Constantia , Kothari Aditi , Liu Renyan , Wulf Gerburg , Guerriero Jennifer L. , Shapiro Geoffrey I. 
Published: June 2022

Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors exert their efficacy by inducing synthetic lethal effects, as well as cGAS/STING-mediated immune responses in BRCA- and other homologous recombination repair-deficient cancer cells. Here, we investigated whether the immunologic and therapeutic effects of PARP inhibition in BRCA-deficient breast cancer models could be augmented by synthetic cyclic dinucleotide agonists of STING. In in vitro experiments, combined olaparib-mediated PARP inhibition and ADU-S100-mediated STING agonism induced a greater degree of STING pathway activation and proinflammatory cytokine production compared to monotherapies in BRCA1-deficient human MDA-MB-436 cells and mouse triple-negative breast cancer cell lines derived from a genetically engineered model of BRCA-deficient breast cancer. In vivo experiments were conducted in mice bearing completely established tumors derived from the genetically engineered mouse model expanded syngeneically. In this model, the combination also induced an improved immune response compared to either monotherapy alone, evidenced by a greater degree of cytotoxic T cell recruitment and activation, and enhanced dendritic cell activation and antigen presentation. Nanostring mRNA analysis indicated that combinatorial effects were the result of augmented interferon signaling and antigen processing, as well as heightened leukocyte and dendritic cell functions. The combination markedly improved anti-tumor efficacy in vivo compared to monotherapy treatment, with evidence of complete tumor clearance and prolongation of survival. Finally, in mice treated with the combination, tumors could not be re-established upon rechallenge, indicating the induction of immunologic memory. These results support the development of combined PARP inhibition and STING agonism in BRCA-associated breast cancer.
Citation Format: Heta Jadhav, Constantia Pantelidou, Aditi Kothari, Renyan Liu, Gerburg Wulf, Jennifer L. Guerriero, Geoffrey I. Shapiro. STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1288.
Abstract 1302: Priming tumors using pH sensitizers potentiates the anti-tumor T cell response induced by immune checkpoint blockade therapy
Authors: Chin Renee , de la Cerda Jorge , Schuler William , Pagel Mark D. 
Published: June 2022

Abstract
While immune checkpoint blockade (ICB) treatments such as nivolumab and ipilimumab have spelled hope for many cancer patients, not all patients benefit from this form of therapy. One mechanism by which tumors suppress the anti-tumor T cell activity that results from ICB is through decreasing extracellular tumor pH (pHe), a function inherent to tumor cells due to the Warburg effect. We thus hypothesize that increasing pHe prior to ICB therapy potentiates the T cell-mediated anti-tumor effect of ICB treatment. To undergo this study, we first screened a panel of six inhibitors termed pH sensitizers, and found that esomeprazole significantly reduced the proton efflux rate (PER) of 4T1, but not B16-F10 cells. Furthermore, esomeprazole did not significantly reduce cell viability of either 4T1 or B16-F10 cells, and did not significantly inhibit T cell activity. Moving forward, our next objectives are to investigate the effects of esomeprazole and the combination of esomeprazole and ICB on tumor-bearing mice. Assessment of the tumor growth in response to esomeprazole and ICB and ex vivo interrogation of the immune cell infiltrate into the tumors will elucidate the efficacy of the treatment combination in terms of tumor control and anti-tumor immunity. Modification of pHe by esomeprazole will be examined by acidoCEST MRI, which will also provide insights as to the ideal pHe parameters for optimal ICB therapy in patients.
Citation Format: Renee Chin, Jorge de la Cerda, William Schuler, Mark D. Pagel. Priming tumors using pH sensitizers potentiates the anti-tumor T cell response induced by immune checkpoint blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1302.
Abstract 1326: Loss of p53 sensitizes tumor cells to immune checkpoint blockade therapy via upregulation of IL-33
Authors: Gao David Shihong , Li Yang , Shoush Jason , Sun Runzi , Lu Binfeng 
Published: June 2022

Abstract
Recent studies suggest p53 contributes to poor survival in the context of immune checkpoint blockade (ICB). Mutations to p53 significantly improve the response rate to PD-1 ICB in lung cancer patients. Tumor-derived IL-33 is required for the anti-tumor immune response and efficacy of ICB. However, the relationship between p53 and IL-33 during ICB is unknown. In this study, we characterize the role of the p53/IL-33 axis in regulating the response of the tumor microenvironment to ICB. We use CRISPR-Cas9 to delete Trp53 from murine MC38 colon adenocarcinoma. Deletion of Trp53 and PD-1 ICB synergistically inhibits tumor growth. Il33 is upregulated in the Trp53-deficient and treated tumor cells, and its expression increases with time and response to treatment. Cd4+ and Cd8+ T cell infiltration increases adjacent to IL-33 expressing tumor cells, while Treg infiltration is decreased. Simultaneous deletion of Il33 in MC38 tumors reverses the efficacy PD-1 ICB. Trp53-deficient MC38 in ST2-/- (IL-33 receptor) mice also show no response to PD-1 ICB. Our findings depict a novel mechanism by which the loss of p53 in tumors treated with ICB unleashes the expression of tumoral IL-33 and induces downstream signaling. p53 mutations may be a double-edged sword for cancer, i.e. the loss of the tumor suppressor initially facilitates tumorigenesis, but eventual buildup of mutations and activation of damage pathways, such as NF-kB, leads to upregulation of danger signals in the tumor. These danger signals, such as IL-33, mediate the anti-tumor effect of ICB.
Citation Format: David Shihong Gao, Yang Li, Jason Shoush, Runzi Sun, Binfeng Lu. Loss of p53 sensitizes tumor cells to immune checkpoint blockade therapy via upregulation of IL-33 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1326.
Abstract 1342: Evaluating the role of antibody in pancreatic tumorigenesis
Authors: Foote Jeremy 
Published: June 2022

Abstract
Introduction: Infiltrating pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall 5-year survival rate of 10%. The PDAC tumor microenvironment (TME) is characterized by a fibroinflammatory response mediated by a complex mix of cancer-associated fibroblast (CAF) subsets resulting significant deposition of extracellular matrix (ECM), poor vascularization, T cell exclusion, and recruitment of immune-suppressive myeloid cells. Collectively, these factors contribute to a resistance to aggressive chemotherapeutics and failure of checkpoint inhibitors. Preclinical studies as well as clinical efforts designed to deplete the dense tumor stroma or ECM have been successful, but unexpectedly accelerated tumor progression underscoring critical gaps in our understanding of the dynamics between tumor, stromal elements, and infiltrating immune cell subsets.
Rationale: In some cancer subtypes, B cells have been shown to suppress cancer progression through secretion of antibodies targeted to aberrantly expressed self-, stress-associated-, or tumor-specific antigens on neoplastic cells. A considerable body of literature also indicates that B cells may play a role in promotion of pancreatic tumor progression, however, the role of antibodies in PDAC progression is unclear. The major objective of our studies is to understand the significance of anti-tumor antibody responses in pancreatic tumorigenesis.
Methods: To address this question, we crossed the spontaneous mouse model of pancreatic cancer where Pdx1 drives Cre-mediated activation of a mutant KrasG12D allele on a heterozygous Tp53+/FL mutant background (KPC-WT mice) with animals that retain B cells that lack the ability to secrete antibody of any immunoglobulin (Ig) isotype (KPC-μS-AID mice).
Results: Kaplan-Meier survival studies demonstrate that loss of all circulating antibody accelerates progression to lethal PDAC in KPC-μS-AID versus KPC-WT mice (median survival of 3- versus 5-months, respectively), with increased incidence of lung and liver metastases. Further, loss of circulating antibodies increased the density of intratumoral neutrophils, reduced numbers of podoplanin+ CAFs and reduced ECM density. IgG subclass antibodies were localized at higher densities within stroma/ECM in pancreata from both mice and surgically resected tumor specimens from human PDAC patients. Loss of AID-dependent class switched antibodies similarly accelerated lethal PDAC in KPC-AID versus KPC-WT mice.
Conclusions: These findings implicate class-switched antibodies in delaying pancreatic tumor progression through potential regulation of intratumoral neutrophil density and ECM production within the PDAC TME.
Citation Format: Jeremy Foote. Evaluating the role of antibody in pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1342.
Abstract 1356: In vivo epigenetic CRISPR screen identifies PRMT5 as an immune suppressor in pancreatic cancer
Authors: Hu Hai , Deng Jiehui , Li Fei , wang wei , Khodadadi-Jamayran Alireza 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a devastating disease in which the mortality rate approaches the incidence rate. Desmoplasia is a hallmark of PDA, which creates a mechanical barrier surrounding the tumor cells, prevents appropriate vascularization and leads to pool immune infiltration. PDA exhibits a “cold” tumor microenvironment characterized by a prominent myeloid cell infiltration, which is extremely immune suppressive. Therefore, PDA has been demonstrated to be resistant to immunotherapy. Indeed, single-agent immune checkpoint inhibitor therapy has failed in clinical trials for PDA patients. Targeting epigenetic modification is an attractive approach to enable the response to immunotherapy in multiple solid tumor models. To identify epigenetic modulators as potential novel immunotherapeutic targets in PDA, we performed an orthotopic in vivo epigenetic CRISPR screen. Prmt5 was screened out as one of the top candidates. Further validation studies showed that Prmt5 knockdown (KD) alone or in combination with anti PD-1 treatment significantly inhibited the tumor progression. PRMT5 shRNA in combination with PD1 blockade can dramatically altered the tumor immune microenvironment (TME) with influx of effector CD8 T cells and changes in the macrophage/myeloid populations. Collectively, our work describes PRMT5 as an attracting target which governs tumor immunity in PDA.
Citation Format: Hai Hu, Jiehui Deng, Fei Li, wei wang, Alireza Khodadadi-Jamayran. In vivo epigenetic CRISPR screen identifies PRMT5 as an immune suppressor in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1356.