bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3114: PDX tumor growth comparisons in the ultra-immunodeficient NOD.CB17-PrkdcscidIL2rgtm1/Bcgen (B-NDG) mouse model
Authors: Melton Michele , Jiang Hongmei , Hyddmark Emma M. , Rothrock Travis 
Published: June 2022

Abstract
The purpose of the study was to compare the growth of various PDX models in the two ultraimmunodeficient mouse models NSG™ (Jackson Laboratory) and B-NDG (Inotiv). Four breast cancer PDX models from the Washington University Human in Mouse (WHIM) collection, ER+ WHIM20 and WHIM81, Her2+ WHIM43, and triple negative WHIM5, and one melanoma PDX models generated by the Wistar institute, WM4071-2, was utilized. For models WHIM20, WHIM5, and WM4071-2 all mice were injected with tumor cells on the same day, whereas for WHIM43 BND-G mice were injected in two separate batches. The WHIM81 studies were carried out at different times for the NSG™ and B-NDG animal cohorts. Studies utilizing WHIM5, WHIM20, WHIM43 and WM4071-2, included a group of athymic nude mice as well. For all models, mice were injected with 1.5x106 cells/mouse. The cells were mixed 1:1 with PBS:Corning Matrigel GFR and the injection volume was 100 µL/mouse. Mice were housed in Innovive individually vented cages and consumed Teklad Global Rodent Diet 2019 throughout the study. Tumors were measured multiple times per week using Biopticon’s TumorImager™. For all models except WHIM81, the tumors grew well and with very similar rate in both B-NDG and NSG™ mice. WHIM20 and WHIM43 grew significantly slower in the Athymic nude mice compared to both of the ultraimmunodeficient mouse models, however, the growth of WHIM5 was comparable between all three models. The results from the WHIM81 model suggests faster growth in the B-NDG model compared to the NSG™, however, it is also possible that this is due to the different batches of tumor cells utilized at each implantation event. Thus, the B-NDG model represents a novel ultraimmunodeficient mouse model that can have great utility for tumor studies, particularly for hard to grow or slower growing tumor models.
Citation Format: Michele Melton, Hongmei Jiang, Emma M. Hyddmark, Travis Rothrock. PDX tumor growth comparisons in the ultra-immunodeficient NOD.CB17-PrkdcscidIL2rgtm1/Bcgen (B-NDG) mouse model [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 3114.
Abstract 3205: Role of RIG-I in tumor endothelium
Authors: Baris Adrian M. , Fraile-Bethencourt Eugenia , Khou Sokchea , Ruhl Rebecca , Hudson Clay , Anand Sudarshan 
Published: June 2022

Abstract
The immune microenvironment plays a critical role in the efficacy of cancer treatment. The manipulation of cytosolic nucleic acid sensors has become a strategy to boost the immune response in cancer therapy, but it is critical to understand how these nucleic acid sensors work in the tumor microenvironment. One aspect of the immune microenvironment is the nucleic acid sensor, which recognizes pathogenic nucleic acids and activates an immune response. Retinoic acid-inducible gene I (RIG-I) is an RNA sensor that responds to dsRNA by activating a type I interferon response. It has been found that RIG-I activation can induce an anti-tumor immune response, but its role in the tumor microenvironment is unknown. Prior studies show regulation of the innate immune response in endothelium can increase the anti-tumor response. Understanding the role of RIG-I in endothelial cells, and how this can be used to potentially reprogram the tumor microenvironment, is critical for developing more effective cancer treatments. In addition, my research on the effects of RIG-I in endothelium has wide-reaching implications beyond cancer treatment. I hypothesize RIG-I activation in endothelial cells will produce an anti-tumor immune response. My findings show that endothelial RIG-I activates a robust type I interferon response and inhibits EC function including, inducing apoptosis and inhibiting migration, which is indicative that RIG-I plays a role in the endothelial immune response. RIG-I also plays a role in the expression of the several angiogenic regulators in a tissue-specific manner. This research will provide critical knowledge about the role of RIG-I in tumor angiogenesis, and provide novel treatment avenues for solid tumors.
Citation Format: Adrian M. Baris, Eugenia Fraile-Bethencourt, Sokchea Khou, Rebecca Ruhl, Clay Hudson, Sudarshan Anand. Role of RIG-I in tumor endothelium [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 3205.
Abstract 3238: GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair
Authors: Li Ming , Xu Hui 
Published: June 2022

Abstract
Glioblastoma is the most common malignant brain cancer with dismal survival and prognosis. Temozolomide (TMZ) is a first-line chemotherapeutic agent for glioblastoma, but the emergence of drug resistance limits its anti-tumor activity. We previously discovered that the interferon inducible guanylate binding protein 3 (GBP3) is highly elevated and promotes tumorigenicity of glioblastoma. Here, we show that TMZ treatment significantly upregulates the expression of GBP3 and stimulator of interferon genes (STING), both of which increase TMZ-induced DNA damage repair and reduce cell apoptosis of glioblastoma cells. Mechanistically, relying on its N-terminal GTPase domain, GBP3 physically interacts with STING to stabilize STING protein levels, which in turn induces expression of p62 (Sequestosome 1), nuclear factor erythroid 2 like 2 (NFE2L2, NRF2), and O6-methlyguanine-DNA-methyltransferase (MGMT), leading to the resistance to TMZ treatment. Reducing GBP3 levels by RNA interference in glioblastoma cells markedly increases the sensitivity to TMZ treatment in vitro and in murine glioblastoma models. Clinically, GBP3 expression is high and positively correlated with STING, NRF2, p62, and MGMT expression in human glioblastoma tumors, and is associated with poor outcomes. These findings provide novel insight into TMZ resistance and suggest that GBP3 may represent a novel potential target for the treatment of glioblastoma.
Citation Format: Ming Li, Hui Xu. GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair [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 3238.
Abstract 3350: TSEEN genes database
Authors: Matyunina Ekaterina , Makashov Andrei , Kozlov Andrei P. 
Published: June 2022

Abstract
According to the hypothesis of the evolutionary role of tumors, evolutionarily new genes should be specifically expressed in tumors [A.P. Kozlov, 2014]. Indeed, TSEEN (tumor specific evolutionarily novel) genes were described by us [Kozlov, 2016]. 1015 genes were identified by the Protein Historian program as evolutionary novel for humans, that is, originated in humans, and 1392 as evolutionarily young, that is, originated in primates. As a result of analyzing the GTEx database data, we have shown that out of 1015 evolutionarily new human genes and 1392 evolutionarily young human genes, 309 genes and 592 genes are not expressed in any of 33 normal tissues, respectively. The expression level of 101 evolutionarily new human genes originated in humans and 233 evolutionarily young human genes originated in primates is significant in most tumors, according to transcriptome data from the TCGA database. Samples of 101 evolutionarily novel human genes and 233 evolutionarily young human genes were selected, which are present only in the genomes of humans and primates, not expressed in normal tissues, and expressed in one or more tumors in 10-100% of patients.For Theria and Eutheria, the similar distribution was as follows: among 365 and 896 genes novel for these taxons, 71 and 124 genes, respectively, are not expressed in normal human tissues, respectively, but at the same time have tumor-specific expression pattern (inclusion criteria of expression - fpkm &gt;2 in 10-100% of patients).There are also 898 genes, originated in mammalia and not expressed in normal human tissues. 119 of them are expressed in at least 1 or more tumors in 10-100% of patients.The TSEEN genes database allows [us] to select genes according to their evolutionary age and expression pattern in normal and tumor tissues. We can retrieve gene(s), which are expressed tumor-specifically and are evolutionarily young or novel.As far as TSEEN genes have many immunogenic epitopes they could be promising targets for development of universal prophylactic and therapeutic antitumor vaccines, as well as universal markers for cancer laboratory diagnostics.Created TSEEN genes database is available at: https://tseendb.org/#/
Citation Format: Ekaterina Matyunina, Andrei Makashov, Andrei P. Kozlov. TSEEN genes database [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 3350.
Abstract 3351: Identification of a NOTCH transcriptomic signature for basal-like breast cancer
Authors: Braune Eike-Benjamin , Geist Felix , Wienke Dirk , Seshire Anita , Lendahl Urban 
Published: June 2022

Abstract
Breast cancer is a heterogeneous disease, where different subtypes differ in terms of biology, treatment options and prognosis. It is an emerging view that dysregulation of major signaling pathways, including Notch signaling, contributes to breast cancer development and progression, but precisely how and in which subtypes Notch signaling is hyperactivated still largely remains to be determined. To gain further insights into dysregulation of Notch in cancer, we set out to identify and evaluate a novel Notch transcriptomic signature focusing initially on breast cancer. We first established Notch-regulated transcriptomes from six breast cancer cell of the basal subtype in response to activation of Notch (by culturing on immobilized Notch ligand) or blockade of Notch (by γ-secretase inhibitors) for 8 and 72 hours. Our data reveal that a core set of Notch-responsive genes can be identified from both time-points and we are validating the transcriptomic signature on a broader set of additional 19 breast cancer cell lines from various breast cancer subtypes. The Notch transcriptomic signature showed robust coherence scores in breast cancer patient data, and robust correlation with basal-like transcriptomes was demonstrated. Analysis of single cell transcriptomic data from breast cancer patients demonstrated that the Notch signature showed additionally good correlation with immune cells in the tumor stroma, notably tumor associated macrophages, indicating that Notch signaling is upregulated in specific cell types of the tumor stroma. Collectively, the data provide a robust transcriptional signature to read out activation of the Notch signaling pathway in basal-like breast cancer and the signature will be important to better stratify patients and to evaluate and predict outcome of future Notch-based therapies for breast cancer.
Citation Format: Eike-Benjamin Braune, Felix Geist, Dirk Wienke, Anita Seshire, Urban Lendahl. Identification of a NOTCH transcriptomic signature for basal-like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3351.
Abstract 3364: Diagnosing Li-Fraumeni syndrome from the somatic genome
Authors: Laverty Brianne , Subasri Vallijah , Light Nicholas , Malkin David 
Published: June 2022

Abstract
Background: Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in the tumor suppressor gene TP53. LFS is estimated to occur in 1:1000 - 1:5000 people and is associated with a 80% lifetime cancer risk. This syndrome is diagnosed using familial cancer history and germline TP53 sequencing; however, clinical heterogeneity and variants of unknown significance limit diagnostic precision. Accurate diagnosis is imperative to implement surveillance for secondary malignancies and familial genetic testing.
Methods: We hypothesized that LFS cancers evolve uniquely from sporadic cancers, implying that the somatic genomes of LFS patients exhibit distinct characteristics that can infer the predisposition syndrome. To investigate this, we interrogated mutational signatures, TP53 copy number, TP53 loss of heterozygosity, ploidy, and the incidence of chromothripsis in tumor compared to normal samples (blood or fibroblast) of individuals with germline TP53 mutations (n=27), somatic TP53 mutations (n=17) and WT for TP53 (n=158). We created a random forest model with 10-fold cross validation to determine if somatic features could diagnose LFS.
Results: No signatures were significantly associated with LFS (Wilcoxon rank-sum test, Benjamin-Hochberg FDR correction). As previously reported in the literature, LFS compared to non-LFS cancers in our cohort were more likely to: be hyperdiploid (odds ratio (OR) = 11.83, FDR &lt; 0.0001, Fisher exact test), have undergone TP53 loss of heterozygosity (OR = 23.15, FDR &lt; 0.0001, Fisher exact test) and experience chromothripsis (OR = 7.76, FDR &lt; 0.001, Fisher exact test).
The area under the receiver operating curve (AUROC) for our random forest model with 10-fold cross validation was 0.90, the area under the precision recall curve (AUPRC) was 0.59, the positive predictive value (PPV) was 0.70, the negative predictive value (NPV) was 0.93 and the F1-score was 0.52. This implies that the somatic genomic features are reliable indicators of this germline syndrome. We have obtained access to a future 50 LFS samples from the Pediatric Cancer Genome Project dataset, which we hope will improve our model’s performance.
Conclusion: We have developed a machine learning tool that uses somatic features to identify LFS, a germline cancer predisposition syndrome. As the importance of precision oncology becomes apparent, a tool to identify LFS patients from the somatic genome will facilitate early diagnosis. This will allow individuals to enter a surveillance program for early detection of secondary tumors, leading to improved outcomes.
Citation Format: Brianne Laverty, Vallijah Subasri, Nicholas Light, David Malkin. Diagnosing Li-Fraumeni syndrome from the somatic genome [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 3364.
Abstract 3384: Combined DNA methylation analysis in size based CTC fraction and matched plasma-cfDNA provides prognostic information in early stage NSCLC
Authors: Markou Athina N. , Londra Dora , Tserpeli Victoria , Kollias John , Tsaroucha Emilia , Pateras Ioannis , Potaris K , Vamvakaris Ioannis , Kotsakis Athanasios , Georgoulias Vasilis , Lianidou Evi 
Published: June 2022

Abstract
Background: Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) analysis represents a liquid biopsy approach for real-time monitoring of tumor evolution. DNA methylation is considered to be an early event in the process of cancer development and progression. The aim of the present study was to evaluate whether detection of DNA methylation of selected tumour suppressor genes in size-based CTC fraction and matched ctDNA could provide prognostic information in early stage NSCLC.
Methods: The methylation status of five selected gene promoters (APC, RASSFIA1, FOXA1, SLFN11, SHOX2) was examined by highly specific and sensitive real time methylation specific PCR assays in: a) a training group of 35 primary tumours and their corresponding adjacent non-cancerous tissues of early stage NSCLC patients, b) a validation group of 22 primary FFPEs tumor tissues and 42 peripheral blood samples of early stage NSCLC patients that gDNA was isolated from FFPEs, sized-based CTCs and plasma, and c) a control group of healthy blood donors (n=12).
Results: All five gene promoters tested were highly methylated in the training group of primary tumours; methylation of SHOX2 promoter in the primary tissues was associated with unfavorable outcome. RASSFIA and APC were found methylated in plasma-cfDNA samples at 14.3% and 11.9% respectively, whereas in the corresponding size-based CTC-enriched fractions SLFN11 and APC promoters were methylated in 7.1%. The incidence of relapse was higher in patients with i) promoter methylation of APC and SLFN11 in plasma-cfDNA (P=0.037 and P=0.042 respectively) and ii) at least one gene promoter was methylated in the sized-based CTC fraction or plasma-cfDNA.
Conclusions: Although in liquid biopsy components methylation of these gene promoters was significantly lower than in the primary tumors, the combination of DNA methylation analysis in sized-based CTC fraction and plasma-cfDNA revealed clinical relevance. Additional studies are required to validate our findings in a large cohort of early stage NSCLC patients.
Citation Format: Athina N. Markou, Dora Londra, Victoria Tserpeli, John Kollias, Emilia Tsaroucha, Ioannis Pateras, K Potaris, Ioannis Vamvakaris, Athanasios Kotsakis, Vasilis Georgoulias, Evi Lianidou. Combined DNA methylation analysis in size based CTC fraction and matched plasma-cfDNA provides prognostic information in early stage NSCLC [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 3384.
Abstract 3392: Rapid, scalable isolation of human tumor nuclei for single cell genomics
Authors: Gibbons Michael , Puleo Alaina , Herschleb Jill , Taylor Sarah 
Published: June 2022

Abstract
Sample preparation remains a significant roadblock to the implementation and scaling of single cell technologies in clinical and translational research. Time consuming, custom dissociation protocols performed on fresh tissue by experts are often utilized to obtain high quality single cell data. However, these complex protocols result in low sample throughput and high variability driven by logistical challenges and user variability. Additionally, many samples that are of interest for clinical and translational studies arrive in research labs snap frozen, leaving nuclei extraction as the only viable path to generate single cell/nuclei data. To overcome these challenges, we present a scalable, easy to use, spin column-based nuclei isolation platform that generates single nuclei that are ready for input into downstream 10x Genomics single cell assays in under an hour.
We processed eight unique human tumors in parallel (skin melanoma, breast, ovary, prostate, lung, kidney, colorectal, and pancreas). Starting from snap frozen tissue, we were able to generate single nuclei suspensions for all samples, in parallel, within 90 minutes. The resulting single nuclei were run through the 10x Genomics Single Cell Gene Expression, Single Cell Immune Profiling, and Single Cell ATAC workflows.
Single cell gene expression data retained high data complexity across all tumor types tested. Expected cell type clusters, including tissue-specific tumor cells, surrounding/infiltrating immune cells and stromal cells were easily identified and profiled via gene expression analysis. Even fragile cell types often missing in single-cell data (e.g. mature adipocytes) were preserved and profiled in this experiment. Additionally, epigenetic changes as measured by Single Cell ATAC profiling were consistent with both general and tissue-specific epigenetics of each cancer type analyzed.
In summary, this platform streamlines sample preparation for single cell studies from snap frozen tissue, enabling these samples to be used much more routinely and unlock biobanked sample cohorts. The findings presented here demonstrate that this fast and easy to use nuclei isolation system provides a consistent platform for generating high quality single nuclei data at scale for clinical, translational and basic research studies alike.
Citation Format: Michael Gibbons, Alaina Puleo, Jill Herschleb, Sarah Taylor. Rapid, scalable isolation of human tumor nuclei for single cell genomics [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 3392.
Abstract 3408: Longitudinal measurement of HPV copy number in cell free DNA predicts progression free survival in HPV positive oropharyngeal cancer
Authors: Adamowicz Martyna Joanna , Warlow Sophie J. , Thomson John P. , Carey Lara M. , Thain Helen , Wescott Robert , Cuschieri Kate , Li Lucy Q. , Conn Brendan , Hay Ashley , Nixon Iain J. , Aitman Timothy J. 
Published: June 2022

Abstract
Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in global prevalence and is divided into two types dependent on association with human papillomavirus (HPV), with a more favorable prognosis in HPV+ve tumors. Assay of HPV copy number in plasma cell-free DNA (cfDNA) provides a minimally invasive method for detecting and monitoring tumor-derived HPV, with potential for enhancing clinical care. We have evaluated the utility of cfDNA droplet digital PCR (ddPCR) as a method for characterisation and longitudinal monitoring of patients with OPSCC in a prospectively recruited cohort of 104 OPSCC patients. ddPCR assay of cfDNA for five HPV types showed overall 95% concordance with p16 immunohistochemistry (IHC) and PCR analysis of solid tumor tissue. Longitudinal sampling in 48 HPV+ve patients, with median follow-up of 20 months, strongly predicted patient outcomes. Progression-free survival, stratified respectively by the presence or absence of detectable HPV cfDNA at a median of 13 weeks post-treatment, was 50% and 88% (p=0.001, hazard ratio 10.0 (95% CI 2.1-47.1)). In two patients, greater reliance on sequential HPV measurement would have avoided surgical intervention which ultimately did not confirm disease recurrence. The high concordance of pre-treatment plasma cfDNA-HPV analysis with p16 IHC and HPV-PCR of solid tissue, together with the predictive value and utility of sequentially measured post-treatment cfDNA-HPV copy number, provide a compelling case for the routine use of cfDNA-HPV ddPCR in management of OPSCC and for clinical trials to assess its impact on treatment outcomes.
Citation Format: Martyna Joanna Adamowicz, Sophie J. Warlow, John P. Thomson, Lara M. Carey, Helen Thain, Robert Wescott, Kate Cuschieri, Lucy Q. Li, Brendan Conn, Ashley Hay, Iain J. Nixon, Timothy J. Aitman. Longitudinal measurement of HPV copy number in cell free DNA predicts progression free survival in HPV positive oropharyngeal 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 3408.