bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6129: Investigate the mechanism and treatment efficacy of regorafenib combined with anti-PD-L1 on bladder cancer
Authors: Pai Kai-Jen , Chang Yuan , Chiang I-Tsang , Hsu Fei-Ting 
Published: June 2022

Abstract
Bladder cancer is one of the most common cancer in urinary system in Taiwan. According to Ministry of Health and Welfare’s research, bladder cancer plays 15th leading causes of death in Taiwan in 2020. The patients who suffer from bladder cancer after undergoing resection surgery about 60% will relapse, and 80% of them will relapse in less than a year, 15% of the relapsing patients will aggravate and become invasive carcinoma spread all over the body. PD-L1 (Programmed death-ligand 1), also known as B7-H1 and CD274 is a transmembrane glycoprotein, which interacts with PD-1 (Programmed death-1) receptor on T cells to elicit the immune checkpoint response. Overexpression of PD-L1 suppresses the function of CD8+ T cells and facilitate tumor progression. Targeting tumor PD-L1 may be a possible treatment option; however, PD-L1 expression was only detected in small amount of population. Regorafenib is a multiple tyrosine kinase inhibitor, which has been approved by the US Food and Drug Administration to treat advanced HCC. In our research, we found that regorafenib may upregulation the surface PD-L1 expression in both mice and human cell line. Based on this finding, we suggested that regorafenib may show potential to enhance treatment efficacy anti-PD-L1. Therefore, we established MB-49 bearing animal model to identify the immune regulation and treatment efficacy of regorafenib combined with anti-PD-L1. In ours animal data we found that combination therapy effectively increased the tumor infiltrating population of NK cells and CD8+ lymphocytes which were determined by flow cytometry assay. Not only anti-tumoral leukocytes, we also detected the population of immune suppressor cells including regulatory T cells, MDSCs and M2 macrophage was suppressed by combination therapy. We also detected the tumor microenvironment related markers (VEGF, IDO-1, PD-L1, CD8, CD31, CD49b, FOXP3, granzyme B) to evaluate combination therapy effect by using immunohistochemistry staining. In conclusion, regorafenib may effectively enhance anti-PD-L1 efficacy via triggering positive immune regulation and increasing the interaction of anti-PD-L1 with tumor.
Citation Format: Kai-Jen Pai, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Investigate the mechanism and treatment efficacy of regorafenib combined with anti-PD-L1 on bladder 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 6129.
Abstract 6131: Harnessing resveratrol-mediated restoration of MHC-I in melanoma to enhance immunotherapy
Authors: Morehead Lauren C. , Koss Brian S. , Miousse Isabelle R. , Tackett Alan J. 
Published: June 2022

Abstract
The introduction of immunotherapy has drastically improved outcomes in cancer therapy, particularly in melanoma, the deadliest form of skin cancer. However, around half of melanoma tumors are initially resistant to treatment and a significant proportion of initial responders gain resistance later. This is in part because tumors are able to decrease their ability to be recognized by T-cells, an essential actor in immunotherapeutic action. There are two major types of T-cells: CD4+ helper and CD8+ cytotoxic. The most common method used by tumor cells to evade immune attack is to down-regulate major histocompatibility complex (MHC) class I molecules, which allow CD8+ T-cells to recognize cells to be eliminated. Thus, to increase immunotherapeutic efficacy, it is critical to identify how to safely restore MHC-I expression on cancer cells so that tumor antigens are presented to T-cells. I focused on finding potential adjuvants to immunotherapy for this purpose, and I found that resveratrol, a natural compound found in plants and associated with various medicinal properties, consistently elevated MHC-I expression in melanoma cells. Through a proteomics study, I identified that resveratrol also significantly affected pathways known to enhance MHC-I expression.
Citation Format: Lauren C. Morehead, Brian S. Koss, Isabelle R. Miousse, Alan J. Tackett. Harnessing resveratrol-mediated restoration of MHC-I in melanoma to enhance immunotherapy [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 6131.
Abstract 6142: Gain-of-function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy
Authors: Siolas Despina , Vucic Emily , Kurz Emma , Hajdu Cristina , Bar-Sagi Dafna 
Published: June 2022

Abstract
The immune microenvironment plays a critical role in cancer development, progression and resistance to therapy. Specific tumor genotypes can profoundly influence the composition of the immune microenvironment. After oncogenic KRAS, TP53 is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC). KRASG12D mutations in tumor cells are known to modify the immune landscape of PDAC, however the immune effects of neomorphic TP53 mutations have not been defined. Focusing on the most common neomorphic TP53 mutation in human PDAC, we sought to evaluate the non-cell-autonomous role of gain-of-function mutant Trp53R172H in modulating the immune microenvironment of pancreatic tumors by using KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDEC) genetically engineered to express the Trp53R172H gain-of-function. Orthotopically implanted tumors derived from CRISPR-generated KrasG12D/+;Trp53R172H/+ PDEC had a distinct immune profile in comparison to KrasG12D/+;Trp53+/+ tumors, characterized by an influx of intratumoral CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 (Th1) cells. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in neutrophil-related pathways in TP53-mutated tumors. Knockdown of CXCL2, a neutrophil chemoattractant, in the tumor epithelial compartment of CRISPR KrasG12D/+;Trp53R172H/+ PDEC tumors reversed the neutrophil phenotype. Depleting neutrophils in mice bearing CRISPR KrasG12D/+;Trp53R172H/+ PDEC tumors augmented sensitivity to combined CD40 immunotherapy and chemotherapy. Collectively, these data link gain-of-function mutant Trp53R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggests that tumor genotypes could inform patient selection for immunotherapy.
Citation Format: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi. Gain-of-function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy [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 6142.
Abstract 6169: Identification of molecules mediating natural killer cell-pancreatic stellate cell interactions
Authors: Malchiodi Zoe X. , Fitzgerald Allison , Galvano Elena , Weiner Louis M. 
Published: June 2022

Abstract
Pancreatic stellate cells (PSCs) are the main sources of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma (PDAC), which account for at least 50% of PDAC’s total tumor volume and its dense desmoplastic stroma. In recent years, immune-stromal cell interactions have been the subject of research in a variety of diseases. Interestingly, natural killer (NK) cells are relatively understudied in PDAC and may be exploited to identify new treatment opportunities. We have explored how NK cell-PSC interactions are mediated by known NK cell ligands. Human PSC (hPSC, CRC-811) or PDAC (MIA-PaCa-2, PANC-1) cell lines were co-cultured with DiO stained NK cells (NK-92, donor NK cells) for 4 hours, then target cells were assessed for apoptosis by flow cytometry using AnnexinV and Sytox stains. We found that although NK cells lyse both PSCs and PDAC cells, there was more NK cell-mediated lysis against PSCs. Using flow cytometry, we found that PSCs express the well-known MICA/B ligand, which binds the activating NKG2D receptor on NK cells to initiate its cytotoxic activity. In co-culture, neutralizing MICA/B in vitro did not completely inhibit NK cell-mediated lysis of PSCs, suggesting other interactions need to be explored. To identify other molecular determinants, NK cell ligand and receptor expression was evaluated by quantitative PCR in human PSC, PDAC, NK, and other leukocytic (K562) cell lines. Cell surface validation of highly expressed NK cell ligands and receptors were confirmed by flow cytometry and/or Western blot. NK cell ligands that were both highly expressed and localized to the cell surface were: NKG2D ligands—MICA and ULBP2 (both activating), KIR2DS4 (CD158I) ligand—HLA-A (activating), and NKp44 ligands—NKp44L and PCNA (activating and inhibitory, respectively). Their corresponding receptors were also expressed and localized to the cell surface by NK cells. These results highlight novel NK cell-PSC interactions that may mediate immune suppression in PDAC. These findings warrant further investigation.
Citation Format: Zoe X. Malchiodi, Allison Fitzgerald, Elena Galvano, Louis M. Weiner. Identification of molecules mediating natural killer cell-pancreatic stellate cell interactions [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 6169.
Abstract 6206: Discerning vasculature destruction caused by novel vascular disrupting agents examined by optical and multispectral optoacoustic imaging
Authors: Wanniarachchi Hashini I. , Schuetze Regan , Arango Lorena , Hamal Khagendra , Carlson Graham J. , Pavlich Cyprian , Deng Yuling , Trawick Mary L. , Pinney Kevin G. , Liu Li , Mason Ralph P. 
Published: June 2022

Abstract
Tumor growth requires a functioning vascular network and offers an attractive therapeutic target. The invasive proliferating neovasculature of tumors lacks pericyte support and exhibits increased permeability thereby offering a unique, potentially selective target for anticancer therapy. Most vascular disrupting agents (VDAs) inhibit microtubule formation, causing rapid morphological changes in endothelia cells resulting in dramatically increased vessel permeability, cellular detachment, vessel occlusion, and vessel wall damage [doi: 10.3390/molecules26092551]. Highly vascular kidney tumors are expected to be particularly sensitive to VDAs. We are evaluating OXi8007, a water soluble indole phosphate pro-drug derivative of the first generation VDA combretastatin. The prodrug OXi8007 is stable in saline but releases active OXi8006 is the presence of alkaline phosphate. Preliminary pharmacokinetic data benchmarked using 13C-labeled OXi8006 and OXi8007 show rapid vascular clearance and conversion to the glucuronide conjugate in vivo. Doses up to 700 mg/kg were tolerated by mice. Luciferase-expressing RENCA tumor cells were implanted orthotopically in the right kidney capsule of syngeneic BALB/c mice. Bioluminescence Imaging (BLI) was applied weekly to assess tumor growth and acute response to OXi8007. Following addition of luciferin substrate subcutaneously BLI signal from the tumor reached a maximum within 10 minutes. When BLI was repeated 4 hrs after 250 or 350 mg/kg OXi8007 IP, the generated signal was &lt;1% of baseline signal indicating acute vascular disruption. Multispectral Optoacoustic Tomography (MSOT) revealed matching acute changes in tumor vascular oxygenation and additionally showed distinct heterogeneity. An oxygen gas breathing challenge indicated lower oxygen saturation in the tumor following treatment. Histology showed massive hemorrhage following both doses. BLI signal recovered after 1 to 2 days and repeated administration of OXi8007 again caused acute vascular shutdown. These results match previous observations in breast tumor models [doi: 10.1016/j.canlet.2015.08.021] indicating opportunities for therapeutic application.
Citation Format: Hashini I. Wanniarachchi, Regan Schuetze, Lorena Arango, Khagendra Hamal, Graham J. Carlson, Cyprian Pavlich, Yuling Deng, Mary L. Trawick, Kevin G. Pinney, Li Liu, Ralph P. Mason. Discerning vasculature destruction caused by novel vascular disrupting agents examined by optical and multispectral optoacoustic imaging [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 6206.
Abstract 6212: Multiomics analyses reveal multimodal Fusobacterium DNA damage perturbations in colorectal cancer
Authors: Kataria Radhika , Quist Jelmar , Lee Sunjae , Megalios Anargyros , Sawyer Elinor , Hardiman Thomas , Liu Chang , Kelly Katherine , Portlock Theo , Shoaie Saeed , Grigoriadis Anita 
Published: June 2022

Abstract
Fusobacterium nucleatum is an opportunistic bacterial pathogen and oncogenic microbe. To systematically investigate Fusobacterium-host interactions in colorectal cancers (CRCs), using host sequencing data, we developed a multi-omics PAThogen CHaracterization tool (PATCH) allowing for gene-level annotations. In 1,020 CRC transcriptomes and 28 genomes from The Cancer Genome Atlas (TCGA), we detected 9 Fusobacterium species and genes encoding 2,346 proteins, including carcinogenic virulence factors, oxidative stress chaperones, and immune response modulators. Fusobacterium was absent in tumor-adjacent normal tissue, however showed variable intra-tumor heterogeneity. PATCH-defined Fusobacterium-positive CRCs confirmed known and revealed novel perturbations in several host DNA damage responses (DDR) mechanisms, including deficiencies in telomere maintenance pathways, elevated cytosolic DNA/RNA sensing signaling, and mutations in genes involved in multiple oncogenic-related pathways. Moreover, PATCH uncovered Fusobacterium’s DNA integrated into the coding regions of tumor suppressor genes in the cancer genome and in non- coding regions significantly enriched in close proximity to Long Interspersed Elements (LINE-1), suggesting a potential rationale for LINE-1 hypomethylation in Fusobacterium-positive CRCs. Collectively, our analytical approaches have delineated Fusobacterium’s multimodal contribution to disrupting genomic stability, which ultimately could facilitate tailored treatment options targeting several DDR pathways in Fusobacterium-positive CRC.
Citation Format: Radhika Kataria, Jelmar Quist, Sunjae Lee, Anargyros Megalios, Elinor Sawyer, Thomas Hardiman, Chang Liu, Katherine Kelly, Theo Portlock, Saeed Shoaie, Anita Grigoriadis. Multiomics analyses reveal multimodal Fusobacterium DNA damage perturbations in colorectal 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 6212.
Abstract 6269: A cell double barcoding system for quantitative evaluation of primary tumors & metastasis in animals: Uncovers clonal-specific anti-cancer drug effects
Authors: Hesin Arkadi , Kumar Santosh , Gahramanov Valid , Becker Maria , Vilenchik Maria , Alexandrov Ilya , Yaglom Julia , Sherman Michael 
Published: June 2022

Abstract
Imaging in monitoring metastasis in mouse models have low sensitivity and is not quantitative. Cell DNA barcoding, demonstrating high sensitivity and resolution, allows monitoring effects of drugs on the number of tumor and metastatic clones. However, this technology is not suitable for comparison of sizes of metastatic clones in different animals, e.g. drug treated and untreated, due to high biological and technical variability upon tumor and metastatic growth and isolation of barcodes from tissue DNA. Yet, both numbers of clones and their sizes are critical parameters for analysis of drug effects. Here we developed a modification of the barcoding approach for monitoring drug effects on tumors and metastasis that is quantitative, highly sensitive and highly reproducible. This novel cell double barcoding system allows simultaneously following the fate of two or more cell variants or cell lines in xenograph models in vivo, and also following the fates of individual clones within each of these populations. This system allows comparing effects of drugs on different cell populations, and thus normalizing drug effects by drug-resistant lines, which corrects for both biological and technical variabilities and significantly increases the reproducibility of results. Using this barcoding system, we uncovered that effects of a novel DYRK1B kinase inhibitor FX9847 on primary tumors and metastasis is clone-dependent, while a distinct drug osimertinib demonstrated clone-independent effects on cancer cell populations. Overall cell double barcoding approach can significantly enrich our understanding of drug effects in basic research and preclinical studies.
Citation Format: Arkadi Hesin, Santosh Kumar, Valid Gahramanov, Maria Becker, Maria Vilenchik, Ilya Alexandrov, Julia Yaglom, Michael Sherman. A cell double barcoding system for quantitative evaluation of primary tumors & metastasis in animals: Uncovers clonal-specific anti-cancer drug effects [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 6269.
Abstract 627: Custom Vectra® Polaris™ fluorescent multiplex IHC panel identifies mature tertiary lymphoid structures in colorectal cancer
Authors: Pollan Sara G. , Hanifi Arezoo , Hargrove James , Parnell Erinn A. , Lin Jessica , Ragheb Josette William , Au Qingyan 
Published: June 2022

Abstract
Introduction: Tertiary lymphoid structures (TLS) are promising prognostic indicators of positive outcomes for patients with solid tumors including colorectal cancer (CRC) [1]. Large-scale retrospective analysis shows patients with mature TLS in particular respond to PD-1/PD-L1 antibody treatment with improved objective response, progression-free and overall survival [2]. Since not all patients respond to PD-1/PD-L1 antibody treatment, identifying patients with mature TLS is clinically relevant as it enables selection of patients likely to respond to immune checkpoint blockade. Mature TLS are composed of T cells (CD3+), follicular B cells (CD20+), germinal center B cells (CD23+), and follicular dendritic cells (CD21+) [3]. The ability to identify and evaluate TLS is limited by detection methods which traditionally employ hematoxylin and eosin (H&E) staining for visual quantification of immune aggregates, potentially significantly underestimating their quantity [4]. Multiplexed fluorescent immunohistochemistry (IHC) detection assays have the capability to precisely quantify mature TLS within the TME. Colorectal cancer specimens expressing a dynamic range of TLS are stained with a novel custom Vectra® Polaris™ multiplex immunofluorescence panel detecting CD20, CD21, CD23, CD3 and pan-cytokeratin. Identification of mature TLS with CD3+CD20+CD21+ and CD3+CD20+CD23+ expression in the TME is reported.
Results: Vectra® Polaris™ TLS multiplex immunofluorescence panel successfully identified mature TLS in the TME of colorectal cancer patient samples. TLS were quantified via custom analytics algorithms generated with Indica HALO software.
Conclusion: Characteristics of TME immunity in colorectal cancer differentially impact an individual patient’s odds of survival [5]. The novel Vectra® Polaris™ multiplex assay in this study shows a detailed picture of mature TLS in patient cancer samples. Future applications of this panel include investigations of TLS associated with successful anti-tumor immune development and therapeutic response to treatment. [1] Oncoimmunology. 2020; 9(1): 1724763 [2] Nat Cancer. 2, 794-802 (2021) [3] Oncoimmunology. 2021; 10(1): 1900508. [4] Mod Pathol 2017 Sep;30(9):1204-1212. doi: 10.1038/modpathol.2017.43. [5] Cell. 2020 Sep 3;182(5):1341-1359.e19. doi: 10.1016/j.cell.2020.07.005
Citation Format: Sara G. Pollan, Arezoo Hanifi, James Hargrove, Erinn A. Parnell, Jessica Lin, Josette William Ragheb, Qingyan Au. Custom Vectra® Polaris™ fluorescent multiplex IHC panel identifies mature tertiary lymphoid structures in colorectal 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 627.
Abstract 6312: The adverse events atlas, towards a strategy to predict synergistic adverse events of combination therapies
Authors: Kucukosmanoglu Asli , Scoarta Silvia , Wijnands Thomas , Kanev George , Westerman Bart , Kiewit Bert , Noske David , Wurdinger Tom 
Published: June 2022

Abstract
The current gold-standard of estimating adverse events of a drug are clinical trials. However, these trials fail to represent real-life practice where patients have additional diseases (comorbidities) and commonly use numerous drugs when entering the clinic. Therefore, there is a rise of interest in combinational therapies, also because effective combinations are expected to prevent therapy resistance. At this moment it is not feasible to predict the adverse events of new combination therapies due to lack of available information both from a dimensionality (i.e., number of adverse events recorded per patient) as well as from a patient-number perspective. When available, this information allows to choose combinational therapies with acceptable adverse events.
In this study we developed a preliminary method to predict adverse events of drug combinations in order to select combinations with a mild adverse event profile.
We used the FAERS, an FDA post-marketing adverse events registry as data source containing 15 million adverse-event records. First, we developed a method to visualize the adverse events profiles of monotherapy and combination therapy using dimension reduction to accurately represent the relation between adverse events over many patients. These adverse-event profiles are then fed to a convolutional neural network (CNN) to generate an explainable prediction-model for adverse events occurring in combination therapies.
The CNN trained on monotherapy is able to learn from the data and recognize adverse event patterns. The learned pattern information, as stored in the so-called latent space, can be converted back onto the original adverse event profiles. This showed a high similarity to the original data, also for unseen combination therapy effects. Furthermore, a t-SNE analysis on the latent space of the CNN is able to separate additive and synergistic adverse event patterns in combination therapy.
Our CNN model can successfully learn complex adverse-event patterns for single drugs and their combinations, which are all encoded in the latent space. The developed method is therefore applicable to determine the combinatorial effects of highly complex adverse event profiles.
Citation Format: Asli Kucukosmanoglu, Silvia Scoarta, Thomas Wijnands, George Kanev, Bart Westerman, Bert Kiewit, David Noske, Tom Wurdinger. The adverse events atlas, towards a strategy to predict synergistic adverse events of combination therapies [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 6312.