bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3226: Facilitating personalized medicine with cloud-based storage and analytics
Authors: Howard Rachel , Hicks Kevin , Teer Jamie , Reisman Phillip , O'Leary Mandy , Eschrich Steven , Mitchell Ross , McLeod Howard , Rollison Dana 
Published: September 2020

Abstract
The vast wealth of medical data collected over the last decade holds great promise for accelerating novel research, discovery, and clinical translation. Specifically, the rapid expansion of genomic testing provides new opportunities for the clinical management of cancer patients, influencing diagnosis, risk stratification, and treatment planning. Moffitt Cancer Center's Personalized Medicine Clinical Service integrates next-generation sequencing test results into patient care, using the data to guide individualized treatment plans. To maximize the efficiency and efficacy of this service, creative solutions for data harmonization, storage, and management are required. We implemented a commercial molecular data warehouse (MDW), directly linked to our existing clinical data warehouse, to store and manage molecular data ranging from genotypic alterations to annotations from public resources (HUGO, COSMIC, Ensembl) and clinically actionable targets (4,256 records currently loaded). A centralized, cloud-based data and analytics platform is also being implemented at Moffitt that will integrate a broad range of multi-modal data. In the cloud environment, the data from the MDW will be linked to typically siloed data streams from the electronic health record, cancer registry management system, biospecimen management system, billing and scheduling systems, patient-reported information and outcomes, and patient-generated health data, creating a unique and customized Personalized Medicine Curated Data Mart (CDM). In addition to describing the features of the MDW and the challenges faced during its implementation, we will provide an overview of the extensive data cleaning and curation required to facilitate such a CDM. This includes the extraction of disease characteristics from unstructured clinical text via natural language processing, creation of new derived data fields, approaches to extracting and managing complex treatment data, and the inclusion of detailed, manually-abstracted recurrence and outcomes data for historical patients from existing institutional datasets such as the Clinical Genomics Action Committee (CGAC) database. Finally, we will present prototypes of analytics dashboards that will interface directly with our CDM, facilitating intuitive data exploration for all members of our personalized medicine teams.
Citation Format: Rachel Howard, Kevin Hicks, Jamie Teer, Phillip Reisman, Mandy O'Leary, Steven Eschrich, Ross Mitchell, Howard McLeod, Dana Rollison. Facilitating personalized medicine with cloud-based storage and analytics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3226.
Abstract 3258: Reconstituted functional Tim-3/Gal-9 immune checkpoint cell line to screen for novel Tim-3 ICBs
Authors: Zhang Fang , Wu Pei , Liu Jun , Wang Baiqiu 
Published: September 2020

Abstract
Background: Tim-3 (T-cell immunoglobin and mucin-domain containing-3) has emerged as a promising novel immune checkpoint target playing non-redundant and synergistic roles with PD-1 in triggering T cell exhaustion, however, the complexity of Tim-3-interacting ligands (Gal-9, Ceacam1 and others) has posed a challenge to reconstitute functional Tim-3-targeting immune checkpoint blockers (ICBs) cellular screening system.
Materials and methods: To address this challenge, we have engineered Tim-3 Advanced Genomic Manipulated human Jurkat T IL-2-Luc2P reporter cells (Tim-3 AGM T cells) via multiple steps of electroporation-mediated genomic manipulation, and validated the functionality of this reconstituted Tim-3 immune checkpoint cellular system using IL-2-Luc2P reporter assay and IL-2 ELISA following TCR and CD28 engagement.
Results: We found that anti-CD3/CD28-induced T cell activation in the Tim-3 AGM T cells as assessed by IL-2-Luc2P reporter was significantly suppressed (~80%) after over-expression of Gal-9 but not the empty vector control, validating functionality of the reconstituted Tim-3/Gal-9 immune checkpoint complex.
Conclusions: Such an innovative reconstituted functional Tim-3/Gal-9 immune checkpoint reporter cell line can enable high through-put screening for novel Tim-3 ICBs including small or large molecule therapeutics and following in-depth mechanistic studies.
Citation Format: Fang Zhang, Pei Wu, Jun Liu, Baiqiu Wang. Reconstituted functional Tim-3/Gal-9 immune checkpoint cell line to screen for novel Tim-3 ICBs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3258.
Abstract 3268: Anti-tumor effect of VSIG4 in conversion of immunosuppressive type II macrophage via repolarization
Authors: Kim Hye Jeong , Hwang Sunhee , Lee Seung-Hyun , Son HyunTae , Lee Joong Won , Kwon Byoung S. 
Published: September 2020

Abstract
V-set and immunoglobulin domain-containing 4 (VSIG4) is a B7 family-related protein which includes PDL1, VISTA and CTLA4 ligand. The known functions of VSIG4 are a receptor for complement iC3b and C3b to inhibit complement activity and negative regulation of proliferating T cell. Although VSIG4 is highly expressed in tissue-resident macrophage and tumor-associated macrophage (TAM), the mechanism of the signal transduction is not fully elucidated. Here we investigate the pivotal roles of anti-VSIG4 therapeutic antibody in TAM and tumor microenvironment. Anti-VSIG4 antibody engagement altered a broad range of type II macrophage (M2) transcriptome which related to immune-tolerance and increased the proliferation of cytotoxic CD8+T cells. Anti-VSIG4 antibody induced phosphorylation of JNK and p38MAPK and in consequence, decreased the expression of M2 marker CD14, CSF-1R and CD163 while type I macrophage (M1) marker CD86 and CD40 were increased. Furthermore, anti-VSIG4 antibody treatment to TAM in ovarian cancer patients, results in secretion of inflammatory cytokines and chemokines in a similar way to M1 macrophages. In the CD34+-based humanized mouse model, stimulation of VSIG4 attenuated tumor growth and promoted infiltration of IFN-gamma-producing CD8+ T cells into tumor tissue. Adopted transfer of differentiated M2 macrophages to immune-deficient NSG mice confirmed M2 conversion into M1 macrophage phenotype with anti-VSIG4 antibody. Our finding suggests that anti-VSIG4 antibody directly act on TAM and induce repolarization of TAM to tumor suppressive M1 macrophages, leading to a CD8+ T cell proliferation and tumor suppression. Overall, targeting the VSIG4 would be an advantageous candidate in cancer therapeutics.
Citation Format: Hye Jeong Kim, Sunhee Hwang, Seung-Hyun Lee, HyunTae Son, Joong Won Lee, Byoung S. Kwon. Anti-tumor effect of VSIG4 in conversion of immunosuppressive type II macrophage via repolarization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3268.
Abstract 3289: The status of the tumor microenvironment changes dynamics of the balance of CD8+ T cells and Treg cells in renal cell carcinoma
Authors: Sugiyama Daisuke , Muramatsu Tomoaki , Kobayashi Yoichi , Sassa Naoto , Maruyama Shoichi , Goto Momokazu , Akatsuka Yoshiki , Nishikawa Hiroyoshi 
Published: September 2020

Abstract
Immune checkpoint inhibitors (ICIs) are widely applied into the clinic based on their remarkable clinical effectiveness. Tumor mutation burden (TMB) and PD-L1 expression in the tumor microenvironment (TME) have been shown to be correlated with clinical responses of ICIs. In contrast, immunosuppressive cells, especially regulatory T (Treg) cells, in the TME are thought to be associated with the resistance to ICI therapy. In this study, we investigated the role of Treg cells in the TME in renal cancer (RCC). We have previously reported that the RCCs can be classified into three groups based on the frequency of CD3+CD4+CD45RA+FoxP3highcells; effector/activated Treg (eTreg) cells: high: &gt; 10%, moderate: &gt; 5%, and low: &gt; 0%, and high frequency of eTreg cells were correlated with the higher expression of PD-1, LAG-3, TIM-3 by CD8+ T cells. Based on the findings, we further investigated the frequency and phenotypes of Treg cells in the TME. We first compared flow cytometry analysis with immunohistochemistry analysis in the frequency of Treg cells. The frequency of Treg cells in the TME was well-correlated with FCM and IHC analyses. Then, the detailed phenotypes of tumor-infiltrating eTreg cells was examined. eTreg cells harbored high expression of activation markers such as TIGIT and CTLA-4, but low-moderate expression of exhausted molecules such as PD-1 and LAG-3. These data implicate that CD8+ T cells are exhausted, whereas Treg cells are activated in the TME. The clinical benefits by ICI therapy for RCC could be associated with the balance of CD8+ T cells and Treg cells. We are now analyzing the detailed mechanism controlling the balance to identify biomarkers of ICI therapy and to develop novel effective cancer immunotherapies.
Citation Format: Daisuke Sugiyama, Tomoaki Muramatsu, Yoichi Kobayashi, Naoto Sassa, Shoichi Maruyama, Momokazu Goto, Yoshiki Akatsuka, Hiroyoshi Nishikawa. The status of the tumor microenvironment changes dynamics of the balance of CD8+ T cells and Treg cells in renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3289.
Abstract 3308: SUMOylation-mediated enhancer activity regulates type I interferon pathway
Authors: Du Li , Chen Yuan , Rosen Steven 
Published: September 2020

Abstract
Type I interferon (IFN) pathway plays an important role in innate immunity and anti-tumor immune response. Previous study has reported that SUMOylation represses type I interferon production, and that deletion of the E2 enzyme Ubc9 or SUMO2 or 3 greatly enhanced type I interferon response. However, the detailed mechanism of how SUMOylation regulates type I interferon response in controversial in the literature. In this study, we found that inhibition of the SUMO E1 enzyme with ML-792 significant enhanced type I cytokine IFNβ expression in human monocytes THP1 cell line, up to 1,500 folds. Similar induction was observed in human peripheral blood mononuclear cells (PBMCs). However, ML-792 treatment showed no effect in IFNβ promoter reporter assay, indicating that ML-792 induced IFNβ expression is not through activation of the transcription factors, such as through the STING pathway, that act on the promoter region. Genome browser ENCODE analysis showed SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1) binds at a ifnb1 enhancer region, known as L2, located ~9kb upstream of ifnb1 transcription start site (TSS). Knockdown of SETDB1 increased IFNβ level resulting in enhanced type I IFN downstream gene expression, indicating that SETDB1 is a transcriptional suppressor of ifnb1 gene. Chromatin immunoprecipitation (ChIP) assay determined that ML-792 treatment or knockdown of the catalytic subunit of the SUMO E1 greatly reduced SETDB1 SUMOylation and occupancy at ifnb1 gene enhancer region. Mutation of SETDB1 SUMOylation sites (4KR, with all 4 SUMOylation sites mutated: K355R, K1032R, K1050R, K1069R) also reduced SETDB1 binding at ifnb1 gene enhancer region shown by ChIP assay, demonstrating that SUMOylation is required for SETDB1 binding to ifnb1 gene enhancer region. In conclusion, our study identified SETDB1 as a novel transcriptional suppressor of ifnb1gene. In addition, we found that at least one mechanism of SUMOylation in preventing type I IFN production is through regulating SETDB1 binding to the enhancer of ifnb1 and consequently histone methylation.
Citation Format: Li Du, Yuan Chen, Steven Rosen. SUMOylation-mediated enhancer activity regulates type I interferon pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3308.
Abstract 331: Biology reconstructed: Testing immuno-oncology agents in tumor-specific 3D cell culture
Authors: Kirshner Julia , Parikh Mukti R. 
Published: September 2020

Abstract
In recent years, immuno-oncology had emerged as a promising strategy to control tumor growth and spread. However, the advancement of immuno-oncology and development of immuno-oncology agents are hindered by the lack of in vitro models capable of supporting an intact immune compartment. Here we describe a tumor-specific 3D cell culture platform where the human tumor microenviroment is reconstructed ex vivo. Our patient-derived 3D culture approach comprehensively accounts for the major components of the cellular and extracellular tissue microenvironment preserving the critical interactions between tumors and their surroundings. Our 3D tumor-spectific models incorporate tissue-specific extracellular matrix(ces) (ECM) and tumor-specific medium supplements allowing for a true reconstruction of tumor microenvironment. The system is complete with the immune along with tumor and stromal, elements embedded within the tumor-specific ECM. Our platform retains the characteristics of the in vivo tissue demonstrating long-term viability, proliferation, and maintenance of the cellular heterogeneity appearing within the native microenvironment. Our approach is compatible with multiple classes of immuno-oncology agents from naked antibodies and antibody-drug conjugates, to bi- and tri-specific compounds, and CAR-T cells. The experimental set-up for testing immuno-oncology agents is comprized of 3 step: (1) embed tumor, stromal, and immune cells within the tissue-specific ECM and overlay with growth medium; (2) add the treatment agents to the culture medium and allow to infiltrate the ECM; and (3) evaluate the effects of the test agents either in situ, by microscopy and/or cell-based assays, or after isolation from the ECM by FACs and omics approaches. The rate of agent infiltration into the ECM was dependent on the therapeutic modality and was observed within 24-96 hours of treatment. Measurable T cell activation was detected at 48 hours post treatment and anti-tumor effects were evident within 5-9 days of exposure to therapeutic agents. Importantly, activation of the T cells in response to treatment occurred without exogenous priming. Taken together, this data position our 3D platform as a superior alternative to the currently used methods for testing of immuno-oncology agents.
Citation Format: Julia Kirshner, Mukti R. Parikh. Biology reconstructed: Testing immuno-oncology agents in tumor-specific 3D cell culture [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 331.
Abstract 3338: Intra-tumoral microbes correlate with immune cell fractions in lung cancer biopsies not other cancers
Authors: Mo Xiaokui , Spakowicz Daniel , Hoyd Rebecca 
Published: September 2020

Abstract
Exogenous sequences in bacteria have been found in many tumors, but their effect on outcomes remains largely unknown. We hypothesize that intratumoral microbes elicit effects through the recruitment of immune cells, such as CD8+ T-cells that are important for immunotherapy response. Through ORIEN (Oncology Research Information Exchange Network), we obtained RNA-seq data from biopsies of 480 tumors (Melanoma=16, Bladder=104, Colorectal=20 Renal Cell Carcinoma=20, Sarcoma=118, Lung=202) from patients treated at The Ohio State University Comprehensive Cancer Center. Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. Human gene expression was deconvolved to relative abundances of immune cells using CIBERSORT. Across cancers, an average of 99.87% of reads were aligned to the human reference genome. The immune cell types CD8+ T-cells, activated dendritic cells and M1 macrophages were significantly enriched in lung cancer (p-values &lt;0.0001), and M2 macrophages were significantly enriched in sarcoma (p-values&lt;0.0001). On the other hand, exogenous reads were aligned to 1328 genomes of bacteria, archaea, viruses and fungi. The phyla with the largest average relative abundances were Proteobacteria, Firmicutes and Actinobacteria, with average relative abundances of 39.5%, 20.1%, and 5.16% respectively. In lung cancer, there was a significant positive correlation between the fraction of CD8+ T-cells and Acinetobacter junii (p-value=0.035), and between activated NK cells and Acidipropionibacterium virtanenii (p-value=0.035). This suggests a mechanism by which intratumoral microbes may affect the immune system and thereby cancer outcomes.
Citation Format: Xiaokui Mo, Daniel Spakowicz, Rebecca Hoyd. Intra-tumoral microbes correlate with immune cell fractions in lung cancer biopsies not other cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3338.
Abstract 3344: The human commensal lactobacillus rhamnosus GG orchestrates an anti-tumor immune response
Authors: Owens Josh , Saeedi Bejan , Naudin Crystal , Hunter-Chang Sarah , Darby Trevor , Robinson Brian , Jones Rheinallt 
Published: September 2020

Abstract
Only 10% of patients with colorectal cancer (CRC) are approved for immunotherapy and only 50% of approved patients are responsive to this treatment. The 95% of CRC patients that are refractory to immunotherapy are so because of low anti-tumor immune responses in the gut mucosa. Mucosal immunity is sensitive to changes in the microbiome community structure, and to dietary supplementation with beneficial bacteria, known as ‘probiotics' which are known to augment mucosal immunity. Therefore, we supplemented the murine microbiome by daily oral gavage with the human commensal bacteria, Lactobacillus rhamnosus GG (LGG). We discovered that LGG increases colonic CD8 T cell responses by flow cytometry and immunofluorescence analysis. We did not believe that LGG was having a direct effect on CD8 T-cell function but was being augmented through an innate cell population. Using BATF3-null mice which lack conventional dendritic cells, we did not detect LGG-induced CD8 T-cell changes determining that this response is dendritic cell dependent. In addition, we sought to determine how LGG was being sensed by dendritic cells. Based off preliminary data and published reports, we utilized Toll like Receptor 2 (TLR2)-null mice and found that LGG-induced CD8 T cell induction also required TLR2 signaling. These data describe a novel mechanism whereby LGG induces colonic CD8 T cells activation through a dendritic cell and TLR2-dependent manner. As CD8 T-cells are critical in the anti-tumor response, we induced colonic tumors in mice by performing the DSS-AOM model. After tumors were established, we administered LGG daily by oral gavage. LGG supplementation resulted in significantly reduced tumor burden compared to control mice fed vehicle or a non-probiotic bacterium. Furthermore, this reduction in tumor burden was CD8 T cell dependent, as depletion of CD8 T cells abrogated this effect. In summary, oral supplementation with LGG may hold clinical promise in augmenting colonic anti-tumor immune responses and may increase immunotherapy response rates in patients.
Citation Format: Josh Owens, Bejan Saeedi, Crystal Naudin, Sarah Hunter-Chang, Trevor Darby, Brian Robinson, Rheinallt Jones. The human commensal lactobacillus rhamnosus GG orchestrates an anti-tumor immune response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3344.
Abstract 336: Organotypic co-cultures as a novel 3D model for head and neck squamous cell carcinoma
Authors: Thierauf Julia C. , Engelmann Luca , Laureano Natalia Koerich , Stark Hans-Jürgen , Prigge Elena-Sophie , Horn Dominik , Freier Kolja , Grabe Niels , Federspil Philippe , Plinkert Peter K. , von Knebel Doeberitz Magnus , Hess Jochen , Affolter Annette 
Published: September 2020

Abstract
Background. Head and neck squamous cell carcinomas (HNSCC) are histologically and molecularly heterogeneous tumors and frequently develop resistance mechanisms against treatment. Reliable patient-derived 3D tumor models are urgently needed to further study the complex pathogenesis of these tumors and how to overcome treatment failure.
Methods. We developed a 3D organotypic co-culture (OTC) model for HNSCCs that maintains the architecture and cell composition of the patients' tumor. A dermal equivalent, composed of healthy, human-derived fibroblasts embedded into viscose fibers, grows in an insert for approximately 10 days in culture and serves as a scaffold for the patient sample. After outgrowth of fibroblast within the dermal equivalent, we cultivated vital HNSCC tumor explants from 13 patients (non-HPV driven, n=7; HPV-driven HNSCC, n=6) by carefully placing them on top of the scaffold. Fractionated irradiation (IR) was applied to 5 samples. To evaluate tumor proliferation and areas of apoptosis, we performed immunohistochemistry and immunofluorescence with antibodies against ki-67, cleaved caspase-3, pan-cytokeratin (PanCK), p16INK4a, and vimentin.
Results. All 3D OTC models of non-HPV driven samples encompassed proliferative cancer cells during cultivation for up to 21 days. Proliferation indices of primary and 3D-OTC models were comparable and consistent over time. Overall, tumor explants displayed heterogeneous growth and invasion patterns. Radioresistant and clonally expanding tumor cells were enriched in 3D-OTC models after fractionated IR. HPV DNA was detectable in both primary and OTC (day 14) of HPV-driven tumors; However, p16INK4a expression levels were varying.
Conclusion. Our 3D-dimensional organotypic co-culture model for HNSCC supports cancer cell survival and proliferation in their original microenvironment. The model enables investigation of invasive cancer growth as well as clonal expansion of resistant cancer cells upon treatment. In the future, the introduced model might serve as a platform to perform sensitivity testing upon treatment to predict the patients' individual response to therapy.
Citation Format: Julia C. Thierauf, Luca Engelmann, Natalia Koerich Laureano, Hans-Jürgen Stark, Elena-Sophie Prigge, Dominik Horn, Kolja Freier, Niels Grabe, Philippe Federspil, Peter K. Plinkert, Magnus von Knebel Doeberitz, Jochen Hess, Annette Affolter. Organotypic co-cultures as a novel 3D model for head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 336.