tbuckley/cabot-search huggingface dataset:
Abstract 5471: CNSigs: An R package for the identification of copy number signatures
Authors: David Tallman, Sinclair Stockard, Zachary T. Weber, Sarah Asad, Katharine Collier, Elizabeth Adams, Jerome Bey, Daniel G. Stover
Journal: Cancer Research (2020)

Abstract Copy number aberrations (CNAs) are gains and losses of large genomic segments present across most cancer types and are a hallmark of cancer genomic alterations. However, the processes underlying CNAs and characteristic patterns of CNAs are poorly understood. Using single nucleotide variant (SNV) data, bioinformatic advances have identified underlying mutational signatures resulting from distinct mutational processes. Mutational signatures have led to a variety of discoveries, several of which are being investigated in clinical management of cancer. The development of algorithms able to uncover similar signatures for CNAs, rather than SNVs, is still in its infancy. Here we present an analysis package for the R programming language called CNSigs that allows for the robust and reproducible derivation of copy number signatures. Based on a list of extracted copy number features previously verified in ovarian cancer, we utilize mixed model approaches and non-negative matrix factorization to derive CNA signatures across cancer types. The development of a package to derive signatures from copy number data allows further investigation of underlying processes that may be responsible for these CNA fingerprints. To verify the reproducibility of the signatures, we derived signatures from two independent breast cancer datasets that use distinct copy number segmentation approaches. From these independent datasets we were able to recover the same signatures with high accuracy. We identified five signatures that are distinct from known breast cancer receptor-based or expression-based subtypes, yet reveal unique associations with underlying mutations, mutational processes, and transcriptional programs. To validate robustness, we applied the pipeline to 11 different cancer types from the TCGA dataset and showed that we were able to derive signatures from all of these cancer types of varying sample sizes. We identified certain signatures that cut across tumor types, while others are distinct to individual cancers. This work lays the groundwork for further analysis into the underlying molecular processes leading to these copy number signatures seen across cancer types. The CNSigs package also allows researchers to easily analyze their own samples to look for signatures in their copy number profiles and to compare these to signatures previously derived for their cancer type. Citation Format: David Tallman, Sinclair Stockard, Zachary T. Weber, Sarah Asad, Katharine Collier, Elizabeth Adams, Jerome Bey, Daniel G. Stover. CNSigs: An R package for the identification of copy number signatures [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 5471.
Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer
Authors: Junbao Zhang, Ying Ying, Meiqi Li, Maolin Wang, Xiaoyan Huang, Min Jia, Junhui Zeng, Canjie Ma, Yixiang Zhang, Chen Li, Xiaomei Wang, Xing-sheng Shu
Journal: Theranostics (2020)

Tumor-initiating cells (TICs) maintain heterogeneity within tumors and seed metastases at distant sites, contributing to therapeutic resistance and disease recurrence. In colorectal cancer (CRC), strategy that effectively eradicates TICs and is of potential value for clinical use still remains in need. Methods: The anti-tumorigenic activity of a small-molecule inhibitor of KDM6 histone demethylases named GSK-J4 in CRC was evaluated by in vitro assays and in vivo imaging of xenografted tumors. Sphere formation, flow cytometry analysis of cell surface markers and intestinal organoid formation were performed to examine the impact of GSK-J4 on TIC properties. Transcriptome analysis and global profiling of H3K27ac, H3K27me3, and KDM6A levels by ChIP-seq were conducted to elucidate how KDM6 inhibition reshapes epigenetic landscape and thereby eliminating TICs. Results: GSK-J4 alleviated the malignant phenotypes of CRC cells in vitro and in vivo, sensitized them to chemotherapeutic treatment, and strongly repressed TIC properties and stemness-associated gene signatures in these cells. Mechanistically, KDM6 inhibition induced global enhancer reprogramming with a preferential impact on super-enhancer-associated genes, including some key genes that control stemness in CRC such as ID1. Besides, expression of both Kdm6a and Kdm6b was more abundant in mouse intestinal crypt when compared with upper villus and inhibition of their activities blocked intestinal organoid formation. Finally, we unveiled the power of KDM6B in predicting both the overall survival outcome and recurrence of CRC patients. Conclusions: Our study provides a novel rational strategy to eradicate TICs through reshaping epigenetic landscape in CRC, which might also be beneficial for optimizing current therapeutics.
Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial
Authors: Nathalie Baize, Isabelle Monnet, Laurent Greillier, Margaux Geier, Hervé Lena, Henri Janicot, Alain Vergnenegre, Jacky Crequit, Regine Lamy, Jean-Bernard Auliac, Jacques Letreut, Hervé Le Caer, Radj Gervais, Eric Dansin, Anne Madroszyk, Patrick-Aldo Renault, Gwenaëlle Le Garff, Lionel Falchero, Henri Berard, Roland Schott, Patrick Saulnier, Christos Chouaid
Journal: The Lancet Oncology (2020)
Functional analysis of RIC8A, a candidate tumor suppressor, mutated or inactivated in a subset of breast carcinomas
Authors: Chang-Dong Zhang, Aslaug Muggerud, Henrik Edgren, Kristine Kleivi, Maija Wolf, Therese Sorlie, Olli Kallioniemi, Marko Kallio
Journal: Cancer Research (2007)

3651  To identify novel tumor suppressor genes in breast cancer, we integrated data from microarray screening of genomic and transcriptomic outlier genes as well as from non-sense mediated RNA decay analysis of six breast cancer cell lines. The top candidates were analyzed for sequence variation, which resulted in the identification of a truncating mutation of the RIC8A gene in the ZR-75-1 breast cancer cell line.  RIC8A (Resistance to Inhibitors of Cholinesterase 8 homolog A) is a guanine nucleotide exchange factor which functions in the G protein signal pathway. It has multiple potential functions in cells commensurate with a possible role in mitosis and cancer. For example, it has been implicated in the asymmetric cell division in Drosophila and C. elegans. It is involved in regulation of microtubule pulling forces during mitotic movement of chromosomes by stimulating G(i)-alpha protein. It also acts as an activator for G(q)-alpha (GNAQ) protein by enhancing the G(q)-coupled receptor-mediated ERK activation.  In order to explore its role in cancer, we first determined its expression across our database of microarray data from 250 breast cancers. This indicated that down-regulation of RIC8A was seen in ~7% of primary breast cancers. Interestingly, analysis of the genes coexpressed with RIC8A supported its possible role in mitotic processes in vivo. We then set out to functionally explore the role of hRIC8A in breast cancer cells in biochemical and cellular assays utilizing various fusion proteins of hRIC8A and hRIC8Aβ (an alternative splice form). We show here that hRIC8Aβ interacts with Pin1, the peptidyl-prolyl isomerase implicated in Wnt-signalling, tumorigenecity and cell transformation. We speculate that this association may be one of the ways by which hRIC8A functions in mitosis and may contribute to its association with cancer.
Abstract 759: RNA Complete BCT: A novel blood collection tube targeting circulating RNA and extracellular vesicles
Authors: Nicholas M. George, Lisa Bartron, Nursen Binbuga, Sean Salamifar, Eunju Seong
Journal: Cancer Research (2020)

Abstract Precision medicine, specifically in medical oncology, has been significantly enabled and the pace accelerated with the advent of liquid biopsy-based diagnostics. While liquid biopsy assays targeting circulating cell-free DNA (cfDNA) provide useful diagnostic information, such as mutational burden, they are limited to a static assessment of the disease state due to cfDNA derivation from dying cells. Assays exploiting circulating extracellular vesicles (EVs) and EV-associated cargo, such as cell-free RNA (cfRNA), provide a comprehensive and dynamic view of the disease as these analytes derive from both living and dying cells. A significant hurdle in making liquid biopsy testing with EVs and cfRNA commonplace is donor specimen integrity. Collected patient blood samples undergo time-dependent degradation leading to increases in disease non-specific EVs and cfRNA thereby compromising the accuracy and reproducibility of analyte measurement. To overcome this vulnerability we have developed the Streck RNA Complete BCT, a first of its kind blood collection tube intended for stabilizing draw-time concentrations of extracellular vesicles and cell-free RNA. Intended uses include direct analysis of EV populations and indirect analysis of cfRNA through RT-PCR or Next-generation Sequencing-based methods. Incorporation of this blood collection tube into the pre-analytical workflow will allow for delayed sample processing without effect on sample integrity or downstream analyte analysis. Citation Format: Nicholas M. George, Lisa Bartron, Nursen Binbuga, Sean Salamifar, Eunju Seong. RNA Complete BCT: A novel blood collection tube targeting circulating RNA and extracellular vesicles [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 759.
Association Between Drug Use and Subsequent Diagnosis of Lupus Erythematosus
Authors: Jeanette Halskou Haugaard, Kristian Kofoed, Gunnar Gislason, Lene Dreyer, Alexander Egeberg
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> It has been estimated that up to 30% of all subacute cutaneous lupus erythematosus (CLE) cases and up to 15% of systemic lupus erythematosus (SLE) cases are drug induced. Based on numerous case reports and several epidemiologic studies, more than 100 drugs from more than 10 drug classes are suspected to cause drug-induced lupus erythematosus. <h3>Objective</h3> To examine the association between drug use and a subsequent diagnosis of CLE or SLE based on a systematic screening process of the drugs in the Anatomical Therapeutic Chemical classification system in a nationwide setting. <h3>Design, Setting, and Participants</h3> A matched case-control study was conducted using all incident cases of CLE and SLE registered in the Danish National Patient Register between January 1, 2000, and December 31, 2017. Patients with CLE and patients with SLE were matched (1:10) on age and sex, with individuals from the general population serving as controls. <h3>Exposures</h3> To select which drugs to examine for an association with CLE or SLE, a screening process of all drugs was performed, including drugs filled at pharmacies and drugs administered in hospitals. <h3>Main Outcomes and Measures</h3> Odds ratios (ORs) were calculated for the association between exposures to certain drugs and the subsequent diagnosis of CLE or SLE. <h3>Results</h3> In all, 3148 patients with CLE (n = 1298; 1022 women [78.7%]; median age at diagnosis, 50.5 years [interquartile range, 39.4-62.2 years]) or SLE (n = 1850; 1537 women [83.1%]; median age at diagnosis, 45.0 years [interquartile range, 33.6-56.4 years]) and 31 480 controls (25 590 women [81.3%]; median age, 47.5 years [interquartile range, 35.9-59.5 years]) were found. Many significant associations between drug use and a subsequent diagnosis of CLE and SLE were observed. Many associations were likely due to protopathic bias. However, new plausible causal associations were observed between CLE or SLE and some drugs, including fexofenadine hydrochloride (SLE: OR, 2.61 [95% CI, 1.80-3.80]; CLE: OR, 5.05 [95% CI, 3.51-7.26]), levothyroxine sodium (SLE: OR, 2.46 [95% CI, 1.97-3.07]; CLE: OR, 1.30 [95% CI, 0.96-1.75]), metoclopramide hydrochloride (SLE: OR, 3.38 [95% CI, 2.47-4.64]; CLE: OR, 1.47 [95% CI, 0.85-2.54]), and metronidazole hydrochloride (SLE: OR, 1.57 [95% CI, 1.09-2.27]; CLE: OR, 1.93 [95% CI, 1.25-2.97]). <h3>Conclusions and Relevance</h3> The study's findings suggest that physicians should be cognizant about whether a new case of CLE or SLE could be drug induced. Furthermore, the results highlight that the reported associations in the published literature may be due to publication or protopathic bias.
Diagnostic Yield of Colonoscopy in Patients With Symptoms Compatible With Rome IV Functional Bowel Disorders
Authors: Zohaib Asghar, Mo Thoufeeq, Matthew Kurien, Alex J. Ball, Anupam Rej, Foong Way David Tai, Shima Afify, Imran Aziz
Journal: Clinical Gastroenterology and Hepatology (2020)
Abstract B70: Rac1 as a therapeutic target in ovarian cancer
Authors: Melanie Rivera, Martha M. Grimes, Dayna Dominguez, S. Ray Kenney, Yuna Guo, Elsa Romero, Kathryn J. Brayer, Yan Guo, Scott A. Ness, Sarah F. Adams, Carolyn Muller, Laurie G. Hudson, Angela Wandinger-Ness
Journal: Clinical Cancer Research (2020)

Abstract Rac1 is a high-value therapeutic target for cancer based on its tumor-promoting activities, yet clinical applications targeting Rac1 are in their infancy. High expression and hyperactivation of Rac1 in ovarian cancer, along with our identification of R-ketorolac as a novel Rac1 and Cdc42 selective inhibitor with translational potential, prompt us to test the hypothesis that targeting Rac1 has therapeutic utility for ovarian cancer. Ascites tumor cell samples from ovarian cancer patients in a prospective study receiving racemic ketorolac for clinically indicated use in pain relief were previously reported to show time-dependent reduction of Rac1 and Cdc42 activities post-treatment. New RNA seq data of these patient samples reveals significant downregulation of genes involved in endocytosis, regulation of actin cytoskeleton, ER protein processing, TNF and NOD signaling. Conversely, the identified downregulated genes were overexpressed and associated with worse survival in ovarian cancer patients analyzed through The Cancer Genome Atlas (TCGA). Among the downregulated genes in the NOD pathway are chemokines and proinflammatory cytokines. Follow-up cytokine panels from patients confirm that racemic ketorolac treatment reduces the levels of immunosuppressive cytokines IL-6, IL-10, and RANTES in ascites fluids. Together, these data indicate there may be a benefit to the anti-inflammatory activity of the S- enantiomer, as well as the GTPase inhibitory activity of the R-enantiomer of ketorolac for ovarian cancer treatment. Citation Format: Melanie Rivera, Martha M. Grimes, Dayna Dominguez, S. Ray Kenney, Yuna Guo, Elsa Romero, Kathryn J. Brayer, Yan Guo, Scott A. Ness, Sarah F. Adams, Carolyn Muller, Laurie G. Hudson, Angela Wandinger-Ness. Rac1 as a therapeutic target in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B70.
Abstract LB-220: Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes
Authors: Dina Hesham AbouRaya, Shahenda El-Naggar
Journal: Cancer Research (2020)

Abstract Embryonal tumor with multilayered rosettes (ETMR) is an aggressive and rare variant of embryonal brain tumors. Amplification of C19MC microRNA cluster and expression LIN28 are distinctive features of ETMR. Despite the increasing efforts to decipher ETMR, the biology remains poorly understood. To date, the role of aberrant alternative splicing in ETMR is not thoroughly investigated. In the current study a comprehensive analysis was performed on published unprocessed RNA-seq reads of tissue- matched ETMR (SRP032476), and fetal controls from the Human Developmental Biology Resource (HDBR) (E-MTAB-4840) datasets. Gene expression was quantified in samples using kallisto/sleuth pipeline. For the alternative splicing analysis, reads were mapped to the genome (hg38) using STAR. Identification and quantification of alternative splicing events (skipped exon, alternative 5′ and 3′splice sites, mutually exclusive exons, multi Exons Skip and retained intron) were carried out using SplAdder. Functional enrichment analysis for the differentially expressed and the differentially spliced genes was subsequently performed using Metascape. All statistical values reported were corrected for multiple hypothesis testing by Benjamini-Hochberg false discovery rate (q-values).The expression analysis revealed a total of 2205 differentially expressed genes (DEGs) between ETMR and fetal controls while 2446 showed differential alternative splicing patterns. DEGs with significant alternative splicing events were identified to be involved in ubiquitin mediated proteolysis, endocytosis, RNA transport, regulation of actin cytoskeleton pathways as well as histone modification. Interestingly, DEGs with intron retention events were involved in various signaling pathways including TGF-beta signaling pathway, MAPK signaling pathway and ErbB signaling pathway. These findings highlight the role of defective alternative splicing in shaping ETMR tumor landscape, and the identified pathways constitute potential therapeutic targets. Citation Format: Dina Hesham AbouRaya, Shahenda El-Naggar. Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes [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 LB-220.
Abstract 2757: Analysis of stromal myofibroblasts identifies secreted proteins that promote pancreatic ductal adenocarcinoma
Authors: Kelly A. Martin, Aimy Sebastian, Nicholas R. Hum, Stephen Byers, Elizabeth K. Wheeler, Matthew A. Coleman, Gabriela G. Loots
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most incurable types of cancer. Cancer that develops in the acinar cells of the pancreas is typically not diagnosed until later stages, such as stage 3 or 4. As such, this form of cancer is particularly lethal with only 9% of patients reaching 5-year survival. PDAC is known to have a particularly dense extracellular matrix composed of fibroblasts, which have been previously shown to play an important role in promoting resistance to drug therapy. Characterization of the stromal networks involved in PDAC tumor development as well as protein markers of fibroblast subpopulations within the tumor stroma are critical to developing new fibroblast-targeted therapeutic approaches as well as understanding key signaling molecules that ultimately promote tumor progression and drug resistance. Single-cell RNA sequencing (scRNAseq) was utilized to analyze cancer-associated fibroblasts (CAFs) from KPC mouse-derived, MT3 subcutaneous murine allografts along with two fibroblast lines derived from human PDAC tumors: CRC-811 and IA-1340. Single cell gene expression profiling and subsequent analysis of MT3-derived CAFs resulted in the identification of three CAF subpopulations including a myofibroblast subpopulation that expressed high levels of smooth muscle actin (Acta2), which was also observed in both human samples. Fibroblast subpopulations enriched in Acta2 expression, expressed high levels of Wnt5a along with several other secreted factors including Tgfb1, Tgfb2 and Ctgf. Wnt5a is a secreted protein that activates non-canonical Wnt signaling pathways and is known to regulate normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However Wnt5a is not natively expressed in MT3 cancer cells derived from syngeneic tumors, but potentially in the stroma. We hypothesize it is exclusively derived from fibroblasts. Previously it has been shown that Wnt5a inhibition suppressed gastric cancer metastasis, therefore further validation of the role of myofibroblast-derived Wnt5a on PDAC disease progression is warranted. This study received funding by LDRD 19-SI-003. This work was conducted under the auspices of the USDOE by LLNL (DE-AC52-07NA27344). IM Release Number: LLNL-ABS-798442. Citation Format: Kelly A. Martin, Aimy Sebastian, Nicholas R. Hum, Stephen Byers, Elizabeth K. Wheeler, Matthew A. Coleman, Gabriela G. Loots. Analysis of stromal myofibroblasts identifies secreted proteins that promote pancreatic ductal adenocarcinoma [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 2757.
Development of a Synthetic Population Model for Assessing Excess Risk for Cardiovascular Disease Death
Authors: Mary G. Krauland, Robert J. Frankeny, Josh Lewis, LuAnn Brink, Eric G. Hulsey, Mark S. Roberts, Karen A. Hacker
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Evaluating the association of social determinants of health with chronic diseases at the population level requires access to individual-level factors associated with disease, which are rarely available for large populations. Synthetic populations are a possible alternative for this purpose. <h3>Objective</h3> To construct and validate a synthetic population that statistically mimics the characteristics and spatial disease distribution of a real population, using real and synthetic data. <h3>Design, Setting, and Participants</h3> This population-based decision analytical model used data for Allegheny County, Pennsylvania, collected from January 2015 to December 2016, to build a semisynthetic population based on the synthetic population used by the modeling and simulation platform FRED (A Framework for Reconstructing Epidemiological Dynamics). Disease status was assigned to this population using health insurer claims data from the 3 major insurance providers in the county or from the National Health and Nutrition Examination Survey. Biological, social, and other variables were also obtained from the National Health Interview Survey, Allegheny County, and public databases. Data analysis was performed from November 2016 to February 2020. <h3>Exposures</h3> Risk of cardiovascular disease (CVD) death. <h3>Main Outcomes and Measures</h3> Difference between expected and observed CVD death risk. A validated risk equation was used to estimate CVD death risk. <h3>Results</h3> The synthetic population comprised 1 188 112 individuals with demographic characteristics similar to those of the 2010 census population in the same county. In the synthetic population, the mean (SD) age was 40.6 (23.3) years, and 622 997 were female individuals (52.4%). Mean (SD) observed 4-year rate of excess CVD death risk at the census tract level was –40 (523) per 100 000 persons. The correlation of social determinant data with difference between expected and observed CVD death risk indicated that income- and education-based social determinants were associated with risk. Estimating improved social determinants of health and biological factors associated with disease did not entirely remove the excess in CVD death rates. That is, a 20% improvement in the most significant determinants still resulted in 105 census tracts with excess CVD death risk, which represented 24% of the county population. <h3>Conclusions and Relevance</h3> The results of this study suggest that creating a geographically explicit synthetic population from real and synthetic data is feasible and that synthetic populations are useful for modeling disease in large populations and for estimating the outcome of interventions.