bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2488: PET imaging of innate immunity activation In Vivo with redox-tuned 4-[18F]fluoro-1-naphthol
Authors: Gammon Seth T. , Pisaneschi Federica , Paolillo Vincenzo , Qureshy Sarah , Piwnica-Worms David 
Published: June 2022

Abstract
High redox potential reactive oxygen and nitrogen species (ROS/RNS), such as O2 free radicals, superoxide, and hypochlorous acid, generated by activities of the NADPH oxidase-2 (NOX2)/myeloperoxidase (MPO) axis and related enzymes, are key effector molecules of innate immunity in physiological and diseased inflammatory states. Other lower energy species (H2O2, NO) provide adjuvant signaling functions. NOX2- and MPO-derived high energy radicals are known to oxidize naphthol species, wherein the naphthol products bind to proximate proteins and activated myeloid cells. Herein, we present 4-[18F]fluoro-1-naphthol ([18F]4FN), a novel redox-tuned radiopharmaceutical that selectively detects by positron emission tomography (PET) high energy radicals produced by activated innate immunity. The products of human MPO plus H2O2, but not H2O2 alone, rapidly and completely oxidized [18F]4FN. All-trans-retinoic acid-differentiated HL-60 "neutrophil-like" human cells activated with phorbol-12-myristate-13-acetate (PMA) retained [18F]4FN 5-fold over unstimulated cells. 4-ABAH, an MPO-specific inhibitor, or DPI, a broad oxidase inhibitor, blocked cellular retention by &gt;95%. [18F]4FN PET/CT imaging readily discriminated foci of inflammation in vivo in three distinct murine models of acute inflammation: endotoxin-induced whole-body toxic shock, PMA-induced mild contact dermatitis of the ear, and lipopolysaccharide (LPS)-induced ankle arthritis. Mechanistically, in mice in vivo, 4-ABAH reduced inflammation-induced [18F]4FN retention, and Cybb-/- (Nox2-/-) gene-deletion strongly and significantly abrogated PMA-induced [18F]4FN retention. Thus, [18F]4FN shows promise as a robust redox-tuned reporter for imaging activation states of innate immunity by PET/CT, is ready for translation. [18F]4FN PET imaging may find application in a variety of inflammatory states associated with cancer therapy, immunotherapy-related adverse events, as well as other diseases, including arthritis, hepatitis, atherosclerosis, COVID-19, as well as up-staging and monitoring multi-organ inflammation.
Citation Format: Seth T. Gammon, Federica Pisaneschi, Vincenzo Paolillo, Sarah Qureshy, David Piwnica-Worms. PET imaging of innate immunity activation In Vivo with redox-tuned 4-[18F]fluoro-1-naphthol [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 2488.
Abstract 2495: Clinical and demographic predictors of survival for fibrolamellar hepatocellular carcinoma patients - A patient-community registry-based study
Authors: Berkovitz Amichai , Migler Rachael D. , Qureshi Adam , Vaughan Roger , Marcotte Erin L. , Simon Sanford M. 
Published: June 2022

Abstract
Fibrolamellar Carcinoma (FLC), a rare liver cancer, has yet no specific tools to evaluate its prognosis. This study aims, in partnership with the patient community, to search for associations between various demographic and clinical factors and overall survival of patients, to assess prognostic factors. We performed a retrospective analysis on a community-based patient registry (The Fibrolamellar Registry http://fibroregistry.org) to examine relations between survival and different variables. The variables examined were demographic (gender), clinical (age at diagnosis, tumor size, number of tumors inside the liver, presence of positive lymph nodes or distant metastasis) as well as treatment modalities (surgery or systemic therapy). Kaplan-Meier survival plots were created for the overall research population and for stratifying by unadjusted variables. Cox proportional hazards model was used for multivariable analysis of hazard ratio (HR) for death at any time among groups, adjusting for variables found significant in the univariate analysis. Among 150 patients, (89 females and 61 males), median overall survival time from diagnosis to death or loss of follow-up was 8 years and 2 months. Features with independent positive effect on survival were female gender, as well as being treated with surgery alone. In contrast, having 10 or more tumors inside the liver had a negative effect on survival. Positive lymph nodes at diagnosis, and distant metastasis at diagnosis, were both associated with poorer prognosis, though did not remain independent when adjusting for covariables. We could not find an effect of age at diagnosis or tumor size at its largest measurement, on survival. In conclusion, our study suggests gender is a significant prognostic factor for FLC patients, with females having a better outcome than males. Surgical removal of the tumor, without additional systemic therapy is a positive prognostic factor as well. Having a large number of tumors of 10 and above, despite all being inside the liver, is a negative prognostic factor.
Citation Format: Amichai Berkovitz, Rachael D. Migler, Adam Qureshi, Roger Vaughan, Erin L. Marcotte, Sanford M. Simon. Clinical and demographic predictors of survival for fibrolamellar hepatocellular carcinoma patients - A patient-community registry-based study [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 2495.
Abstract 2499: Identifying DNA methylation signatures of retinoblastoma via aqueous humor, a novel ocular liquid biopsy
Authors: Xu Liya , Li Hongtao , Weisenberger Dan , Liang Gangning , Berry Jesse 
Published: June 2022

Abstract
Introduction: Retinoblastoma (Rb) is the most common childhood intraocular cancer. Tissue biopsy of Rb can cause tumor spread, so it is contraindicated. We demonstrated that aqueous humor (AH), an ocular fluid, is a high yield liquid biopsy enabling in vivo detection of tumor-derived cell free DNA (cfDNA) thus overcoming the contraindication to biopsy. Prognostic genomic cfDNA biomarkers in Rb AH enables objective real time disease monitoring.
In ~13% of Rb, tumor progression is driven by epigenetic deregulation of tumor-promoting pathways without detectable genomic alterations. However, epigenetic studies have been done only on tumor from surgically removed eyes. The frequency and effect of epigenomic regulation in eyes that have been saved with therapy is not clear due to no access to in vivo tumor. Therefore, epigenetic analysis of AH cfDNA is highly desired to understand the broader spectrum of Rb tumorigenesis and prognosis.
Materials and Methods: 16 AH samples and 4 Rb tumors from 12 patients with 14 Rb eyes were included in the study. We conducted global DNA methylation profiling of tumor tissues from surgically removed Rb eyes, AH samples collected from different clinical stages with different treatment outcomes using the Illumina Infinium EPIC DNA methylation BeadArray platform. Publicly available DNA methylation data of normal retina, Rb eyes, and Rb patients were obtained from Gene Expression Omnibus (GEO, GSE57362) for cell type DNA methylation comparisons.
Results: Our preliminary studies revealed a high degree of concordance in genome-wide differential DNA methylation patterns between paired AH and tumor samples. Integrating our data with large public datasets, we identified reliable RB DNA methylation signatures in cfDNA that have potential diagnostic and prognostic values. We also identified hypermethylation at RB1 promoter, which suggested RB1 is druggable to DNA methylation inhibitors. By integrating DNA methylation data with gene expression data, we identified over 300 differentially expressed genes potentially regulated by DNA methylation change. Pathway analysis indicated several tumor suppressor pathways (e.g., RB1 and P53 pathways) were suppressed and some oncogenic pathways were activated (e.g., E2F pathways).
Conclusions: Our study sets the stage for exploiting epigenetic markers in AH and identifying potential therapeutic targets to improve the clinical management of patients with RB.
Citation Format: Liya Xu, Hongtao Li, Dan Weisenberger, Gangning Liang, Jesse Berry. Identifying DNA methylation signatures of retinoblastoma via aqueous humor, a novel ocular liquid biopsy [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 2499.
Abstract 2504: Next generation sequencing identifies novel potential biomarkers for DICER1 syndrome
Authors: Wu Mona K. , Lopez Raphael D. , Warren Mikako , Shah Rachana , Neviani Paolo , Amatruda James F. 
Published: June 2022

Abstract
MicroRNAs (miRNAs) are small RNA molecules that play a critical role in regulating gene expression. The DICER1 enzyme is a key component of the microRNA biogenesis pathway. Reflecting this central role, patients who inherit or acquire mutations in the DICER1 gene have an increased risk of developing a spectrum of benign and malignant tumors —thereby earning the recognition as a pediatric cancer predisposition syndrome known as DICER1 syndrome (OMIM 601200). DICER1 syndrome is definitively diagnosed by DNA sequencing demonstrating presence of a loss of function mutation on one copy of DICER1 plus a “hotspot” mutation on the other copy of DICER1. As tumor and germline DNA sequencing can pose logistical and/or cost difficulties, a complementary diagnostic method based on marker expression is valuable for both diagnostics and surveillance. Biomarkers that are candidate therapeutic targets are also appealing as these may offer a more tailored approach for therapy. As there are no approved biomarkers for identification of DICER1-associated tumors, we performed RNAseq and miRNAseq in an engineered murine mesenchymal cell model that incorporates a specific DICER1 hotspot mutation to identify candidates. We validated candidate biomarkers at the RNA (Eya2, Vipr1, miR-139-3p, and miR-30d-3p) and protein (Eya2, and Vipr1) levels in vitro, to provide proof of principle data for their eventual clinical utility. The miRNA candidate biomarkers levels were evaluated in both total and small extracellular vesicle-enriched fractions. These novel data pave the way for additional tools for diagnosis and surveillance in patients with DICER1 syndrome.
Citation Format: Mona K. Wu, Raphael D. Lopez, Mikako Warren, Rachana Shah, Paolo Neviani, James F. Amatruda. Next generation sequencing identifies novel potential biomarkers for DICER1 syndrome [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 2504.
Abstract 2505: Predicting prognosis in PFA ependymoma and group 3/4 medulloblastoma methylomes using interpretable epigenetic models
Authors: Ng Indy , Fricke Alexander , Pai Shraddha 
Published: June 2022

Abstract
Introduction: Our goal is to develop interpretable, prognostic models for Group 3/4 medulloblastoma (G3/4 MB) and PFA ependymomas (PFA-EP) using brain tumor DNA methylomes. Our models use prior knowledge of genome regulation and may identify cellular processes that help develop molecular therapies. We previously developed a classifier algorithm, netDx, which uses similarity networks to integrate heterogeneous patient data and predict outcome1. netDx demonstrates excellent performance and allows measures to be grouped into biologically meaningful features (e.g. grouping genes into pathway features).
Ependymoma Methods: We predicted survival in PFA-EP using 569 methylomes2 (Illumina 450K). Using netDx, we evaluated a model that grouped CpG-level methylation into sets reflecting 25 cell types from the developing human cerebellum, 3 chromatin states, EZH2 binding sites, and brain super enhancers (80:20 train/test split, feature selection &gt;=8/10; 10 splits). This model was compared to a baseline lacking prior knowledge.
Preliminary Results: Organizing methylomes by prior knowledge significantly improves prognostic prediction (Table 1, p &lt; 5x10-3, one-sided WMW). Features that predict prognosis are consistent with known dysregulation in PFA-EP2 (Table 1).
G3/4 MB Methods: We predicted binarized survival using 285 methylomes3 (Illumina 450K), using identical methods as above.
Preliminary results: Tumor methylomes carry predictive signal for survival prediction (Table 1), consistent with previous findings. We are currently evaluating the effect of including prior knowledge.
Interim Conclusion: Prior knowledge can improve survival prediction in PFA-EP and identifies features reflecting tumor biology. We are interested in extending interpretable modeling to other tumours.1. Pai et al. (2019) Mol Sys Biol. 15. 2. Pajtler et al. (2018) Acta Neuropathol. 136. 3. Northcott et al. (2017) Nature 547.
Table 1. Average model performance and top features. Dataset Predictor design AUPR (mean+/- SD, 10 train/test splits) Predictive features PFA-EP; 252 good/317 poor survivors2 DNAm, no prior knowledge 64.2 +/- 2.3 n/a * Covariates: CXOrf67 mutation status, sex DNAm, prior knowledge* 67.5 +/- 3.5(p &lt; 5x10-3; one-sided WMW test compared to baseline model) CXOrf67mut, methylation in: {H3K9me3 sites; marker genes for ependymal cells of choroid plexus; marker genes for multiple interneuron classes} G3/4 MB: 146 good/139 poor survivors3 DNAm, no prior knowledge 0.61 +/- 6.3 n/a ** Covariates: age, sex DNAm, prior knowledge** In progress
Citation Format: Indy Ng, Alexander Fricke, Shraddha Pai. Predicting prognosis in PFA ependymoma and group 3/4 medulloblastoma methylomes using interpretable epigenetic models [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 2505.
Abstract 2513: MDSC-derived TNF is a novel regulator of T-cell dysfunction in pancreatic cancer
Authors: Bianchi Anna , De Castro Silva Iago , Deshpande Nilesh U. , Mehra Siddharth , Singh Samara , Dosch Austin R. , Garrido Vanessa T. , Rafie Christine I. , Nagathihalli Nagaraj , Merchant Nipun , Datta Jashodeep 
Published: June 2022

Abstract
Introduction: Abundance of myeloid-derived suppressor cells (MDSC) and a dysfunctional T-cell compartment are defining hallmarks of therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC). Using congenic in vivo murine models to phenocopy extremes of T-cell enrichment or exclusion, we sought to interrogate central MDSC-mediated mechanisms that govern immune tolerance in PDAC.
Methods: Orthotopically implanted T-cell-excluded (Tcelllo) vs T-cell-enriched (T-cellhi) congenic KPC tumors, and intratumoral Ly6G+F4/80- MDSCs from both clones, were subjected to RNA sequencing. Ex vivo co-cultures evaluated the effects of intratumoral MDSC on splenic T-cells. Orthotopically injected KPC-T-celllo mice were treated with etanercept vs. vehicle, and immunophenotyping via flow cytometry was performed.
Results: RNA-seq of KPC T-celllo vs. T-cellhi tumors revealed enrichment of myeloid immunoregulatory pathways, and downregulation of leukocyte activation/cytotoxicity pathways. Flow cytometry revealed a dramatic increase in MDSCs infiltrating KPC-Tcelllo tumors (P&lt;0.001). To decipher MDSC-intrinsic mechanisms associated with T-cell exclusion, RNA-seq of MDSCs infiltrating T-cellhi clones revealed relative downregulation of MAPK signaling, and cytokine profiling of MDSCs conditioned with MAPK inhibitor trametinib revealed marked reduction in TNF secretion. Confocal microscopy confirmed striking decrease in TNF in MDSCs isolated from KPC- T-cellhi vs. Tcelllo tumors. Ex vivo MDSC-T-cell co-cultures significantly attenuated T-cell proliferation and activation (via IFN-γ release) while favoring T-cell apoptosis, which could be rescued by pre-conditioning MDSCs with either etanercept (TNFR2 decoy receptor) or MAPK pathway inhibitors. Orthotopically injected KPC-T-celllo tumor-bearing mice treated with etanercept demonstrated a remodeled TME vs. vehicle-treated mice, with attenuation in MDSC trafficking, enrichment in CD4+/CD8+ T-cell infiltration, and reduction in T-cell exhaustion.
Conclusion: MDSC-derived TNF regulates T-cell dysfunction in PDAC via a MAPK-dependent mechanism. Compartment-specific inhibition of TNF may be a provocative strategy to overcome immune tolerance in PDAC.
Citation Format: Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Samara Singh, Austin R. Dosch, Vanessa T. Garrido, Christine I. Rafie, Nagaraj Nagathihalli, Nipun Merchant, Jashodeep Datta. MDSC-derived TNF is a novel regulator of T-cell dysfunction 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 2513.
Abstract 2514: Pancreatic cancer subtype-specific secreted factors determine the immunosuppressive tumor microenvironment
Authors: Bärthel Stefanie , Falcomatà Chiara , Widholz Sebastian A. , Toska Albulena , Boniolo Fabio , Schmitt Constantin , Gölling Vanessa , Swietlik Jonathan , Mir Jonas , Jesinghaus Moritz , Meissner Felix , Rad Roland , Schmidt-Supprian Marc , Saur Dieter 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a complex disease displaying genetic heterogeneity along with a tumor microenvironment (TME) unique in its composition. Whereas the PDAC TME is known to be highly immunosuppressive, it remains elusive how distinct genetic alterations affect TME cell type recruitment and how this, in turn, influences progression and treatment outcome. Therefore, we systematically investigated the TME composition and tumor-immune crosstalk in molecular PDAC subtypes. We delineated the TME landscape of a comprehensive tumor cohort derived from Kras-driven PDAC mouse models by integrating single cell RNA-sequencing (scRNA-seq) with histopathological analysis, tissue RNA-seq followed by deconvolution and flow cytometry immunophenotyping. Our results show that distinct molecular PDAC subtypes recruit divergent subpopulations of infiltrating immune cells, most notably evidenced by major differences in frequency and phenotype of macrophages and neutrophils. Functional secretome analysis of well-characterized Kras-driven mouse and primary human PDAC cell lines revealed subtype-specific factors which differ between the two main transcriptional subtypes of PDAC (classical and mesenchymal). Accordingly, crosstalk between tumor and immune cells inferred by interaction probability analysis through ligand-receptor pairs from scRNA-seq data nominates the CSF signaling network as a key player in mesenchymal PDAC, whereas CXCL signal hubs mediate higher infiltration of immunosuppressive neutrophils in classical tumors. Our findings contribute to the understanding of PDAC subtype-specific biology and aid the identification of potential immunotherapeutic vulnerabilities thereof.
Citation Format: Stefanie Bärthel, Chiara Falcomatà, Sebastian A. Widholz, Albulena Toska, Fabio Boniolo, Constantin Schmitt, Vanessa Gölling, Jonathan Swietlik, Jonas Mir, Moritz Jesinghaus, Felix Meissner, Roland Rad, Marc Schmidt-Supprian, Dieter Saur. Pancreatic cancer subtype-specific secreted factors determine the immunosuppressive tumor microenvironment [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 2514.
Abstract 2515: Estrogen regulates the immune microenvironment of colorectal cancer liver metastases
Authors: Benslimane Yasmine , Lapin Sarah , Chambon Julien , Leibovitch Matthew , Perrino Stéphanie , Brodt Pnina 
Published: June 2022

Abstract
Liver metastases (LM) remain a major cause of cancer-related death and many cancers preferably metastasize to the liver due to its unique anatomical location, rich blood supply and immune-tolerant microenvironment. Up to 50% of colorectal carcinoma patients develop LM during their disease and this is associated with a poor prognosis. Our laboratory previously identified a sexual dimorphism in the regulation of the immune microenvironment (IME) of LM and showed that estrogen could promote the accumulation of myeloid-derived suppressor cells (MDSCs) and Tregs in the liver in response to invading cancer cells. The objective of this study was to elucidate the role of estrogen in the recruitment and polarization of monocytes/macrophages and in the accumulation and phenotype of natural killer (NK) cells in the IME of colorectal carcinoma LM (CRCLM). Moreover, we sought to determine the therapeutic potential of Selective Estrogen Receptor Degrader (SERD) therapy in tumor bearing female mice. In estrogen-competent female mice bearing CRCLM, we found increased gene and protein expression of the immunosuppressive cytokine TGF-β, and inversely a decrease in the pro-inflammatory cytokine TNF-alpha. Furthermore, we identified a significant increase of newly recruited, immunosuppressive CD68+F4/80+CD163+ M2 macrophages, as compared to estrogen-depleted (ovariectomized) mice. The recruitment of pro-inflammatory CD68+F4/80+TNF-alpha+ M1 macrophages, and the accumulation of the highly cytotoxic NK1.1+ CD49a+ liver NK cells were increased in estrogen-depleted female mice and could be restored upon estrogen supplementation. Moreover, treatment of female mice with the SERD Fulvestrant, markedly reduced the number of CRCLM compared to vehicle-treated mice, and significantly reduced the cell frequencies and counts of recruited myeloid cells and M2 macrophages in the liver. Taken together, our results identify estrogen as a critical regulator of an immunosuppressive tumor ME in the liver and a potential therapeutic target. Funding by the Canadian Institute of Health Research is gratefully acknowledged.
Citation Format: Yasmine Benslimane, Sarah Lapin, Julien Chambon, Matthew Leibovitch, Stéphanie Perrino, Pnina Brodt. Estrogen regulates the immune microenvironment of colorectal cancer liver metastases [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 2515.