bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4468: Cross-species analysis and immunophenotyping using of a focused panel of immune-responsive genes
Authors: De Velasco Marco A. , Kura Yurie , Sakai Kazuko , Nakagaki Hideki , Nishio Kazuto , Uemura Hirotsugu 
Published: September 2020

Abstract
Immunotherapy has transformed the landscape of cancer therapy, unfortunately, not all patients can reap the benefits and identifying those patients that may benefit remains challenging. It is the consensus that patients with inflamed tumors are more likely to benefit from immunotherapies targeting immune checkpoints, and therapies aiming to stimulate or boost T cell anti-tumor immunity and modulate tumor inflammation are being investigated. Determining which type of immune therapy to administer depends largely on the patients immunophenotype. Various methods aimed at determining a tumor's immune profile are emerging or are available, of these, immune profiling by gene expression analysis is common. Several platforms are available, however, methods to analyze results vary. We previously used a transgenic mouse model of prostate cancer to identify target genes and developed a focused panel of immune-related genes. In addition, we designed a scoring system to profile the tumor's immune phenotype and assess tumor immune responses. Our aim is to extend the applicability of this analysis model to any platform capable of measuring these gene targets. As proof of concept for our analytical approach, we extended our assessment to human cancer by defining cancer specific immune profiles and assessing their clinical relevance. Our focused panel consisted of 115 genes (six reference/normalization genes and 109 immune-related genes) and our scoring system was based on an enrichment algorithm using various immune cell-specific signatures and immune related processes. We evaluated the robustness of this immunophenotyping approach using mRNA data from a cohort consisting of 8477 patients spanning 28 cancer types from The Cancer Genome Atlas (TCGA) Research Network. Our computational pipeline utilized unsupervised and machine learning approaches to identify and evaluate phenotype clusters from gene expression or immune signatures. In this study, Louvain clustering outperformed traditional hierarchical clustering. Using Louvain clustering, we identified distinct clusters from which immunophenotypes could be defined and compared these to various molecular and clinical features. Here, we summarize our findings and show that a minimal gene set effectively identified cancer immunophenotypes. This cross-species analysis corroborates our previous observation and paves the way for further development of our analysis model.
Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Hideki Nakagaki, Kazuto Nishio, Hirotsugu Uemura. Cross-species analysis and immunophenotyping using of a focused panel of immune-responsive genes [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 4468.
Abstract 4499: Cancer targets early B-cell precursors to generate metastasis-promoting Bregs by promoting their premature emigration from the bone marrow and expansion in the circulation
Authors: Ragonnaud Emeline , Moritoh Kanako , Bodogai Monica , Garaud Soizic , Chen Chen , Wang Xin , Willard-Gallo Karen , Biragyn Arya 
Published: September 2020

Abstract
We previously reported that breast cancer (BC) generates metastasis-promoting regulatory B cells (CD25+ tumor-evoked Bregs). Because phenotypically these cells resembled bone marrow (BM) Rag+ B-cell precursors, such as large Pre-B cells, we hypothesized whether cancer uses them to generate Bregs. To investigate this idea, we used mouse and human BM aspirates, human PBMCs from BC patients, and mice with different orthotopic cancers, such as highly metastatic 4T1 breast cancer cells and EMT6. We report that breast cancer indeed uses BM B-cell precursors to generate Bregs. However, to do this, cancer expresses thymic stromal lymphopoietin (TSLP). Mechanistically, cancer-produced TSLP downregulates surface expression of CXCR4 and α4β1 (VLA-4) of B-cell precursors, thereby impairing their BM retention and increasing their exit into the circulation. TSLP also enables survival and proliferation of these BM emigrants, while other factors such as 5-lipoxygenase metabolites convert them into Bregs. The loss of TSLP expression in cancer cells alone or TSLPR deficiency in B cells not only reduce pre-B cells in the circulation, but also retard lung metastasis. Overall, our data reveal a previously unknown function of cancer-produced TSLP as inducers of premature B-cell precursor emigration from BM to support Breg generation. The results also suggest that the TSLP-pre-B cell axis can be an attractive therapeutic target.
Citation Format: Emeline Ragonnaud, Kanako Moritoh, Monica Bodogai, Soizic Garaud, Chen Chen, Xin Wang, Karen Willard-Gallo, Arya Biragyn. Cancer targets early B-cell precursors to generate metastasis-promoting Bregs by promoting their premature emigration from the bone marrow and expansion in the circulation [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 4499.
Abstract 4501: RNA seq analysis reveals altered immune specific gene signature in African American bladder cancer
Authors: reddy Karthik reddy kami , Karanam Balasubramanyam , Coarfa Cristian , Lotan Yair , Bollag Roni J. , Terris Martha K. , Putluri Nagireddy 
Published: September 2020

Abstract
Understanding specific functional gene signature among bladder cancer (BLCA) patients of diverse race/ethnicities remain largely unexplored. Even though the incidence rate of BLCA in African Americans (AA) is nearly half as that of European Americans (EA), but AA have the worst survival. This survival difference can be attributed to unequal access to health care, and social economic status, which in turn delays the treatment in AA patients. Here, we analyzed RNA-seq data from AA and EA patient cohort compare with adjacent benign tissues and identified a set of signature genes which are significantly altered in AA patients. Gene Set Enrichment Analysis (GSEA) reveals that these genes are significantly enriched in immune pathways. Several known cytokines, cell differentiated markers and transcription factors including, growth differentiation marker 2 (GDF2), Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) were downregulated and fibroblast growth factor 1 (FGF1), Caudal type homeobox 1 (CDX1) were upregulated in AA compare to EA. To interrogate the function of specific genes in tumor, we have used an integrated repository portal for tumor-immune system interactions (TISIDB). Using this disease association analysis, we identified a common relationship of these genes with immune response, cytokine signaling and regulation of lymphocyte activation. Our findings indicate that an altered tumor-immune interplay could be a factor for AA BLCA progression and provide the rationale to examine immune specific checkpoint inhibitors to target BLCA on subset of patients from the AA community.
Key words: Racial disparity, Immune system, Bladder cancer.
Citation Format: Karthik reddy kami reddy, Balasubramanyam Karanam, Cristian Coarfa, Yair Lotan, Roni J. Bollag, Martha K. Terris, Nagireddy Putluri. RNA seq analysis reveals altered immune specific gene signature in African American bladder cancer [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 4501.
Abstract 4512: Mouse model for in vivo evaluation of efficacy and potential cytokine release syndrome of chimeric antigen receptor (CAR) T cell therapy
Authors: Jiao Jing , Ye Chunting , Cai Danying , Cheng Mingshan , Keck James 
Published: September 2020

Abstract
Chimeric antigen receptor (CAR) T-cell therapy holds great promise as cancer immunotherapy. While impressive responses have been achieved in patients with hematological malignancies there are challenges for CAR T therapy such as toxicity complications due to cytokine release syndrome (CRS) and limitations due to CAR T cell exhaustion. As increasing number of novel CAR T products are in the discovery and preclinical phase of development, preclinical models to assess efficacy as well as potential toxicity of CAR T in vivo are needed. Here, we describe a new NSG™ mice model to examine CAR T cells for efficacy and potential CRS.
Immunodeficient NSG™ mice are commonly used to evaluate CAR T functions. However, human T cells can cause acute xeno-GVHD in NSG™ limiting the use of the model system. A system to study human T cell function in the absence of xeno-GVHD is required. A new NSG™ derivative NSG-MHC Class I/II knockout (KO) strain has MHC class I and MHC class II deficiency in addition to B, T and NK cell deficiency. NSG-MHC Class I/II KO mice are known to have a delayed onset of GVHD and can provide a useful background to study human immunity in the absence of GVHD [M. A. Brehm et al., FASEB J. 33, 3137–3151 (2019)]. Human B-cell lymphoma Raji tumor cells express high levels of CD19 and CD22 which are targets for CAR T therapy. Using NSG-MHC Class I/II KO mice and luciferase-tagged Raji-Luc tumor model we found that compared to controls CD22 CAR T and CD19 CAR T showed significant tumor growth inhibition by Xenogen imaging analysis. No body weight loss was observed with the CAR T treatments. As high tumor burdens are usually associated with the potential of causing CRS we examined CD19 CAR T cells on low and high tumor burdens and the data will be presented in context of efficacy. We have established a new mouse model using NSG-MHCI/II KO mice to enable evaluation of CAR T efficacy and propensity to induce cytokines simultaneously in vivo. Furthermore PBMC-humanized NSG-MHCI/II KO mice can also be established and used to examine CAR T cells prepared from the same PBMC donor to mimic autologous CAR T cell therapy.
Citation Format: Jing Jiao, Chunting Ye, Danying Cai, Mingshan Cheng, James Keck. Mouse model for in vivo evaluation of efficacy and potential cytokine release syndrome of chimeric antigen receptor (CAR) T cell therapy [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 4512.
Abstract 4562: Next generation Oncos oncolytic adenovirus with novel anti-cancer double-transgenes shows synergistic anticancer effect in melanoma mouse model
Authors: Kuryk Lukasz , Moller Anne-Sophie 
Published: September 2020

Abstract
Oncolytic virotherapy is a promising anti-cancer strategy utilizing genetically engineered viruses to preferentially infect, replicate in and lyse cancer cells. To date, Talimogene laherparepvec is the only FDA approved oncolytic virus (OV), however, many other types of OVs are showing promising results in clinical studies. One example is ONCOS-102, an adenovirus serotype 5/3 chimera expressing GM-CSF as a transgene, which recently reported 33% ORR in advanced anti-PD1 refractory melanoma.
Genetically engineered OVs can be armed with different co-stimulatory molecules in order to boost the anti-tumour immune responses. Building on the ONCOS-102 backbone, we have engineered two next generation ONCOS viruses, ONCOS-210 and ONCOS-212, expressing novel double transgenes designed to inhibit tumor growth and metabolism. Here, we describe the characterization and pre-clinical in vitro and in vivo testing of ONCOS-210 and ONCOS-212.
The oncolytic properties of ONCOS-210 and ONCOS-212 were confirmed in 4 melanoma cell lines in vitro, demonstrating robust cell lysis and induction of immunogenic cell death. Anti-cancer effects of the viruses were also assessed in i) immunodeficient xenograft and ii) humanized xenograft mouse models to further understand the anti-cancer and immune stimulatory potency of the constructs. Intra-tumoral ONCOS-210 and ONCOS-212 resulted in robust anti-tumor activity in both immune-deficient and immune-competent mice. The double transgenes were shown to act synergistically in vivo, in line with the design hypotheses and proposed mode of action to induce cell lysis and prevent tumor growth. Moreover, the vectors were able to increase tumor infiltration of various immune subsets including CD4+, CD8+, CD8+ expressing PD1+ or CD8+ expressing Granzyme B T cells and reduction of regulatory T-cells and MDSC in the tumour microenvironment, suggesting an ability to prime immune-suppressive tumors to better respond to immunotherapy.
These encouraging preclinical findings will be further investigated to elucidate the mode of action and perform toxicological studies to bring ONCOS-210 and ONCOS-212 towards clinical testing.
Citation Format: Lukasz Kuryk, Anne-Sophie Moller. Next generation Oncos oncolytic adenovirus with novel anti-cancer double-transgenes shows synergistic anticancer effect in melanoma mouse model [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 4562.
Abstract 4585: LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses and prevents tumor growth
Authors: Rosean Claire Buchta , Sinha Pratima , Koelle David M. , Nghiem Paul , Heiland Teri 
Published: September 2020

Abstract
The majority of Merkel cell carcinomas (MCC), a rare and highly-aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of a truncated form of the viral large T antigen (LT) in infected cells and making LT an attractive target for therapeutic cancer vaccines. While induction of tumor-reactive CD8+ T cells is a major goal of cancer therapy, CD4+ T cells provide essential support to CD8+ T cells by promoting their expression of cytotoxic effector molecules and increasing their migratory capacity. Cytokines secreted by CD4+ T cells, such as IFNγ, can also exert desirable effects on the tumor microenvironment. Therefore, we set out to design a cancer vaccine that promotes potent, antigen-specific CD4+ T cell responses to MCPyV-LT. To activate antigen-specific CD4+ T cells in vivo, we utilized our nucleic acid platform, UNITE (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and a balanced T cell response. LTS220A, encoding a mutated form of MCPyV-LT that abrogates its pro-oncogenic properties, was introduced into the UNITE platform. Intradermal vaccination with LTS220A-UNITE promoted a potent, antigen-specific CD4+ T cell response to MCPyV-LT. Additionally, prophylactic vaccination with LTS220A-UNITE prevented growth of B16F10 tumors expressing LTS220A in 100% of mice. Therefore, we find that DNA vaccination using the UNITE platform enhances CD4+ T cell responses to MCPyV-LT and prevents tumor growth when given prophylactically. Future studies will test the efficacy of LTS220A-UNITE for use as a therapeutic cancer vaccine.
Citation Format: Claire Buchta Rosean, Pratima Sinha, David M. Koelle, Paul Nghiem, Teri Heiland. LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses and prevents tumor growth [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 4585.
Abstract 4609: TP53, PIK3CA, and BRAF somatic mutations in airway epithelial field of injury associated with lung cancer risk
Authors: Craig Daniel J. , Morrison Thomas , Khuder Sadik , Crawford Erin L. , Wu Leihong , Xu Joshua , Blomquist Thomas M. , Willey James C. 
Published: September 2020

Abstract
Background: Lung cancer is the leading cause of cancer-related death in men and women, and cigarette smoking is the most significant preventable risk factor. Early detection through annual low dose CT screening reduces mortality but has low positive predictive value and specificity, in part due to low lung cancer incidence (&lt;10%) among those who currently meet screening criteria. Thus, there is a need for biomarkers that reliably detect those at highest lung cancer risk, thereby enabling more effectivescreening. The purpose of this study was to test the hypothesis that high risk for lung cancer is characterized by high prevalence of low variant allele frequency (VAF) somatic mutations among known lung cancer driver genes in normal airway epithelial cells (AEC).
Methods: Synthetic DNA internal standards (IS) were prepared for each of 11 lung cancer driver genes and mixed with each AEC genomic (g)DNA specimen prior to competitive multiplex PCR amplicon NGS library preparation. A custom Perl script was developed to separate IS reads and respective specimen gDNA reads from each target into separate files for parallel variant frequency analysis. This approach enabled reliable detection of mutations with VAF as low as 5 x 10-4 (0.05%). This method was then applied in a retrospective case-control study. Specifically, AEC specimens were collected by bronchoscopic brush biopsy from the normal airways of 19 subjects, including eleven lung cancer cases and eight non-cancer controls, and the association of lung cancer risk with AEC driver gene mutations was tested.
Results: TP53 mutations with 0.05-1.0% VAF were more prevalent (p&lt;0.005) and significantly more enriched for tobacco smoke and age-associated mutation signatures in AEC from lung cancer cases compared to non-cancer controls matched for smoking and age. Further, PIK3CA and BRAF mutations in this VAF range were identified in AEC from cases but not controls.
Conclusions: Measurement of very low frequency mutations in the 0.05-1.0% VAF range enabled identification of an AEC somatic mutation field of injury associated with lung cancer risk. A biomarker comprising TP53, PIK3CA, and BRAF somatic mutations may better stratify individuals for optimal lung cancer screening and prevention outcomes.
Citation Format: Daniel J. Craig, Thomas Morrison, Sadik Khuder, Erin L. Crawford, Leihong Wu, Joshua Xu, Thomas M. Blomquist, James C. Willey. TP53, PIK3CA, and BRAF somatic mutations in airway epithelial field of injury associated with lung cancer risk [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 4609.
Abstract 464: Allicin, a potent new ornithine decarboxylase inhibitor in neuroblastoma
Authors: Schultz Chad R. , Gruhlke Martin C. , Slusarenko Alan J. , Bachmann Andre S. 
Published: September 2020

Abstract
The purpose of this study was to test if allicin inhibits ornithine decarboxylase (ODC) in pediatric neuroblastoma (NB). The natural product allicin is a reactive sulfur species (RSS) from garlic (Allium sativum L.). NB is an early childhood cancer arising from the developing peripheral nervous system. In up to 25% of cases MYCN gene amplification is correlated to high tumor stage and poor patient prognosis. High stage NB relapses frequently despite multimodal therapy and relapsed tumors are virtually untreatable. Therefore, there is a clear need for specific, novel therapeutics. MYCN transactivates the E-box gene ODC1, and the gene product ODC is a rate-limiting enzyme in polyamine biosynthesis. The increase of polyamines (putrescine, spermidine, spermine) triggers cell hyperproliferation in NB and other MYC-driven cancers through the activation of Rb-regulated cell cycle progression. ODC is a validated drug target and α-difluoromethylornithine (DFMO) is an ODC inhibitor under investigation in phase II NB trials. Although a safe drug with clinical promise, DFMO has various challenges including the need for exceptionally high treatment doses and rapid renal clearance in the urine. In an effort to identify pharmacologically superior ODC inhibitors, we identified allicin as a potent ODC inhibitor using a specific radioactive in vitro activity assay with purified ODC. Allicin also inhibited ODC activity in actively growing NB cells, reduced polyamine levels, and induced apoptosis in cell cultures. ODC is a homodimer with 12 cysteines per monomer and allicin S-thioallylates cysteines. Allicin reacts with, and is titrated-out by, low molecular weight thiols like dithiothreitol (DTT). Removal of DTT from the ODC activity assay reaction resulted in significantly higher allicin potency (IC50 at 11 nM). Although allicin has multiple cellular targets, our data reveal that one mode of action is ODC inhibition, which suppresses polyamine accumulation and induces apoptosis. The natural product allicin could be used in conjunction with other anticancer treatments, the latter at a lower than usual dosage, to achieve drug synergism with good prognosis and less side-effects.
Citation Format: Chad R. Schultz, Martin C. Gruhlke, Alan J. Slusarenko, Andre S. Bachmann. Allicin, a potent new ornithine decarboxylase inhibitor in neuroblastoma [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 464.
Abstract 4641: Association between dietary tomato intake and the risk of hepatocellular carcinoma: Findings from a prospective cohort study
Authors: Thomas Claire E. , Luu Hung N. , Wang Renwei , Adams-Haduch Jennifer , Yuan Jian-Min , Jin Aizhen , Koh Woon-Puay 
Published: September 2020

Abstract
Background: Intake of tomato and/or lycopene have been found to be associated with reduced risk of several cancer types, but epidemiological data on risk of hepatocellular carcinoma (HCC) are sparse.
Methods: The associations of tomato and lycopene consumption with risk of HCC were examined in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45-74 years at enrollment in 1993-1998 with 25 years of follow-up. Tomato and lycopene consumption was evaluated using a validated semi-quantitative food frequency questionnaire. Incident HCC cases were ascertained through the linkage analysis with the nationwide Singapore cancer registry. Cox proportional hazard regression was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of HCC with the consumption of tomato and lycopene among all cohort participants, and unconditional logistic regression was used to assess the association among individuals negative for hepatitis B surface antigen (HBsAg).
Results: After a mean follow-up of 17.6 years, 561 incident HCC cases were identified. Higher tomato intake was associated with lower risk of HCC after adjustment for multiple potential confounders (Ptrend&lt;0.001). Compared to the lowest quartile, HRs (95% CIs) of HCC for the 2nd, 3rd, and 4th quartile of tomato intake were 0.70 (0.56-0.88), 0.73 (0.58-0.92), and 0.63 (0.49-0.81). Among HBsAg-negative individuals, the inverse association remained (Ptrend=0.03). There was no association between lycopene intake and HCC risk (Ptrend=0.54).
Conclusion: Tomato intake may offer protection against the development of HCC, particularly among individuals without chronic infection with hepatitis B virus.
Citation Format: Claire E. Thomas, Hung N. Luu, Renwei Wang, Jennifer Adams-Haduch, Jian-Min Yuan, Aizhen Jin, Woon-Puay Koh. Association between dietary tomato intake and the risk of hepatocellular carcinoma: Findings from a prospective cohort study [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 4641.