bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2179: Increased BCAT1 expression creates a pseudo-hypoxic environment that promotes cell proliferation in a subtype of glioblastoma
Authors: Fala Maria , Ros Susana , Sawle Ashley , Brindle Kevin M. 
Published: June 2022

Abstract
Background: BCAT1 (Branched Chain Amino Transferase 1) has been shown to be upregulated in human IDH (isocitrate dehydrogenase) wild-type glioblastoma (GBM) and BCAT1 knockdown leads to reduced cell proliferation in vitro and in vivo1. Here we investigated the role of BCAT1 in human patient-derived glioblastoma cells and the corresponding orthotopically implanted xenografts to understand how upregulation of the enzyme leads to a more aggressive phenotype.
Methods: The expression of BCAT1 was investigated in a panel of patient derived IDH wild-type glioblastoma cells and BCAT1 expression modulation was achieved using lentiviral expression of a doxycycline-inducible shRNA, to knockdown BCAT1 and expression of a BCAT1 cDNA to overexpress BCAT1. Effects of BCAT1 knockdown and overexpression were investigated in vitro in cell culture and in vivo, following intracranial implantation of mice with the relevant cells.
Results: Variable levels of BCAT1 expression were identified in different patient-derived cell lines. RNA sequencing analysis of BCAT1 knockdown in BCAT1 expressing glioblastoma cells revealed that knockdown led to significant downregulation of HIF 1α (Hypoxia Inducible Factor 1α) and its targets, which was confirmed by Western Blot analysis of Carbonic Anhydrase IX (CAIX) and Hexokinase II (HKII) in cell and tumor lysates. The opposite was observed following BCAT1 overexpression. BCAT1 knockdown also led to higher DNA demethylation levels. Treatment with membrane permeant dimethyl-alpha ketoglutarate mimicked the effect of BCAT1 knockdown. These data suggest that decreased cell proliferation following BCAT1 knockdown in BCAT1 expressing cells is mediated by accumulation of alpha-ketoglutarate, a substrate of BCAT1. Cells that had no BCAT1 expression showed a similar growth profile and overexpression had no effect on proliferation, suggesting that these cells are not dependent on BCAT1 expression.
Conclusion: We conclude that in a subtype of GBM characterized by upregulated BCAT1, BCAT1 expression results in lowered levels of alpha-ketoglutarate, leading to reduced prolyl hydroxylase activity and stabilization of HIF 1α and therefore a pseudo-hypoxic state, resulting in a transcriptome that favors a high proliferation rate. This makes BCAT1 a potential therapeutic target, for tumors that show BCAT1 upregulation.1. Tönjes M, Barbus S, Park YJ, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med. 2013;19(7):901-908. doi:10.1038/nm.3217
Citation Format: Maria Fala, Susana Ros, Ashley Sawle, Kevin M. Brindle. Increased BCAT1 expression creates a pseudo-hypoxic environment that promotes cell proliferation in a subtype of glioblastoma [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 2179.
Abstract 2195: A tissue atlas of oncogenic RAS mutation
Authors: Erdogan Ozgun , Counter Christopher 
Published: June 2022

Abstract
Despite over 50 possible oncogenic RAS mutations, cancers tend to have a bias towards a specific subset unique to each cancer type. As RAS mutations could arise from selection of an ideal level (quantitative) or type (qualitative) of oncogenic signaling, we generated four conditional Kras alleles with different oncogenic mutations, G12D or Q61R, coded with native rare or common codons to induce low or high protein expression to separate these two types of signaling. These alleles were crossed into a Rosa26-CreER background and globally activated, revealing tissues sensitive to quantitative signaling regulated by the RAS biochemical activity, qualitative signaling regulated by the specific mutation, and either both or none of these two types of signaling. Bulk RNAseq analysis further revealed that each allele induced a different cellular response, with the weakest allele induce transcriptional features of a plastic state while the strongest allele had all the transcriptional hallmarks of high oncogenic signaling and a stress response. In conclusion, this approach provides a mutational atlas of tissues dependent upon quantitative signaling, qualitative signaling, or both forms of signaling for tumorigenesis, as well as tissues generally resistant to oncogenic RAS. This tissue atlas can thus serve to define how specific cancers are initiated, and in turn, how to prevent such initiation events from taking hold to lead a normal cell down the path of tumorigenesis, which has important clinical implications for early cancer detection and prevention measures.
Citation Format: Ozgun Erdogan, Christopher Counter. A tissue atlas of oncogenic RAS mutation [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 2195.
Abstract 2199: Molecular dissection of a novel, highly proliferative lineage in a model of Helicobacter pylori-driven gastric metaplasia and dysplasia
Authors: O'Brien Valerie Phoebe , Young William C. , Finak Greg , Gottardo Raphael , Salama Nina R. 
Published: June 2022

Abstract
At least 80% of gastric cancer cases are attributed to stomach infection with the bacterium Helicobacter pylori (Hp), which causes lifelong chronic inflammation. In some individuals, this inflammation can cause gastric atrophy, metaplasia (conversion of one normal cell type to another), dysplasia (presence of abnormal cells) and finally cancer, but the specific mechanism(s) through which Hp triggers this cascade are not well understood. Similar preneoplastic changes are recapitulated in a mouse model through tamoxifen-induced expression of active KRAS in the chief cells of the stomach (KRAS+ mice). We found that Hp infection of KRAS+ mice exacerbated disease: compared to Hp-KRAS+ mice, Hp+KRAS+ mice had an altered trajectory of metaplasia and accelerated dysplasia. In accordance with the hypothesis that Hp causes cancer through eliciting chronic inflammation, Hp+KRAS+ mice had severe inflammation marked by a ten-fold increase in T cells compared to Hp-KRAS+ mice. To understand gene expression changes in gastric cells in the context of metaplasia with and without active Hp infection, we performed single cell RNA-sequencing (scRNA-seq) on eight mouse stomachs (+/- Hp, +/- KRAS) using the 10x Chromium platform. Cluster analyses followed by UMAP (Uniform Manifold Approximation and Projection) visualization allowed us to identify 25 clusters, including epithelial and immune cell types. Hp+KRAS+ mice had a striking expansion of a population of metaplastic cells (most similar to surface mucus-producing “pit” cells), which comprised ~40% of epithelial cells in these mice. Metaplastic pit cells expressed markers of intestinal metaplasia and gastric cancer, and their abundance in the stomach was correlated with helper T cell abundance. Analysis of RNA velocity suggested that metaplastic pit cells arose from a progenitor cell type, rather than arising from pit cells directly. As well, a 10x Visium spatial gene expression experiment revealed the spatial organization of metaplastic pit cells near the lumen of the gastric epithelium. Finally, antibiotic eradication of Hp prevented metaplastic pit cell development and other disease phenotypes. Taken together, these studies provide new understanding of how Hp infection and inflammation cause gastric preneoplastic progression.
Citation Format: Valerie Phoebe O'Brien, William C. Young, Greg Finak, Raphael Gottardo, Nina R. Salama. Molecular dissection of a novel, highly proliferative lineage in a model of Helicobacter pylori-driven gastric metaplasia and dysplasia [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 2199.
Abstract 2209: HPV non-vaccination due to safety concerns/side effects: Variations in vaccination intentions by Parent-Child Gender, National Immunization Survey - Teen, 2010 - 2019
Authors: Chido-Amajuoyi Onyema , talluri rajesh , Jackson Inimfon , Shete Sahil , Domgue Joel Fokom , Shete Sanjay 
Published: June 2022

Abstract
Background: Gender-generated disparities in HPV vaccination uptake have the potential to further perpetuate existing disparities in HPV-associated cancers. This study examines the influence of parent-child gender on intent to not vaccinate against HPV due to safety/side effect concerns.
Methods: Study data was from the National Immunization Survey-Teen (2010 - 2019). Weighted prevalence of intention to refuse HPV vaccination due to safety/side effect concerns were stratified by parent-child gender. Multivariable logistic regressions were used to examine for associations between intentions to refuse HPV vaccination due to safety concern/side effects and parent-child gender.
Results: Over the study period, intentions to refuse HPV vaccination due to safety concerns rose among all parent-child gender pairings but was highest among respondent mothers when pertaining to their unvaccinated daughters. Results revealed statistically significant increased likelihood of having intentions to refuse HPV vaccination due to safety concerns among all parent-child combinations, compared to father-son pairs. These odds were consistently highest among mother-daughter pairs; 9.25 times more likely (95% CI: 6.34-13.51) than father-son pairs in 2010. In 2019, compared to father - son pairs, fathers were 1.94 (95% CI: 1.21-3.12) times more likely to report intention to not vaccinate against HPV for their daughters; while mothers were 2.23 (95% CI: 1.57-3.17) times more likely to report intentions to refuse HPV vaccination for their sons; and 2.87 (95% CI: 2.02-4.07) more likely for their daughters.
Conclusions: Intentions to refuse HPV vaccination due to safety concern/side effects varied by gender of the responding parent and pertinent child. Study findings are persistent and constantly increased over a 10-year period. Interventions aimed at correcting gender-based misperceptions, as well as to counter misinformation about the safety of the HPV vaccine are warranted.
Citation Format: Onyema Chido-Amajuoyi, rajesh talluri, Inimfon Jackson, Sahil Shete, Joel Fokom Domgue, Sanjay Shete. HPV non-vaccination due to safety concerns/side effects: Variations in vaccination intentions by Parent-Child Gender, National Immunization Survey - Teen, 2010 - 2019 [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 2209.
Abstract 2228: A multi-omic perspective of how selection shapes blood cancer risk phenotypes in aging populations
Authors: Skead Kimberly , Soave David , Fave Marie-Julie , Bruat Vanessa , Morris Quaid , Awadalla Philip 
Published: June 2022

Abstract
The genetic architecture of blood is highly complex with germline polymorphisms, somatic point mutations, and larger chromosomal alterations playing a role in shaping the fitness of the immune cells. Many advances have been made in understanding how the age associated acquisition of point mutations and somatic structural variants (SSVs) in blood, termed Age-Related Clonal Hematopoiesis (ARCH), predispose individuals to hematological cancer or cardiovascular disease. Yet, ARCH is commonly observed in healthy individuals and our ability to predict who is at risk of progressing to disease remains limited. A previous study which integrated deep learning and population genetics methods to evaluate the complex interplay of selection on point mutations in deeply sequenced blood samples highlighted the role that negative selection plays in prevention progression to hematological cancer. Here, we interrogate the mutational and selective pressures within blood to better understand how the full spectrum of somatic changes within an individual impact clonal fitness and disease outcomes. We evaluate how selection shapes the prevalence of large somatic structural variation in blood sampled from 15,910 individuals across over 20 different genetic ancestries, including the Thousand Genomes Study and the Canadian Partnership for Tomorrow’s Health study. Using dense genotyping arrays, we capture SSVs among 20 populations and find that ARCH attributed to somatic structural variation is three times as high as previously reported with up to 14% of individuals harbouring at least one large SSV in their blood. We estimate the rate at which SSVs accrue in blood cells and find that selection impacts the size and frequency of SSVs within individual blood populations. To determine the functional impact of clonal mutations on molecular phenotypes, we investigate the relationship between structural variation and the transcriptome. We show that gains, losses and copy number neutral variants impact gene expression distinctly, with stabilizing selection shaping the penetrance of copy number alterations in gene expression. Our work shows how different classes of selection shape clonal dynamics in blood thus enabling us to better understand why certain individuals are at a high risk of malignancy.
Citation Format: Kimberly Skead, David Soave, Marie-Julie Fave, Vanessa Bruat, Quaid Morris, Philip Awadalla. A multi-omic perspective of how selection shapes blood cancer risk phenotypes in aging populations [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 2228.
Abstract 2236: A novel integrated predictive model for pancreatic cancer
Authors: Ke Temin , Lophatananon Artitaya , Muir Kenneth , Yu Xinzhu 
Published: June 2022

Abstract
Background: Pancreatic cancer is the 7th leading cause of cancer-related mortality and the 12 th most common cancer globally. Many studies have identified risk factors for pancreatic cancer, nevertheless, there have been few combined risk factor models developed for the UK specific population. Due to the high incidence with a poor survival rate together with the potential high preventable rate, it is important to establish an accessible predictive risk factor model for identifying potential high-risk populations.
Study aim: To establish a pancreatic cancer risk prediction model by integrating the current risk factors together with established genomic biomarkers.
Method:Using data from the UK biobank we have investigated the role of established and suggested risk factors for pancreatic cancer. The established risk factors include age, BMI, smoking, alcohol consumption, diabetes and pancreatitis. We also calculate the added prediction from the current polygenic risk score (PRS) to evaluate the risk for genetic predisposition. Last, we utilise the multivariate logistic regression models to establish a novel risk model by integrating the well-known risk factors such as cigarette smoking, heavy alcohol consumption, increased BMI, chronic pancreatitis, diabetics, some germline mutation, and our new evaluated PRS and biological clocks.
Results: We will present the performance of the novel integrated model which will be useful for use in primary care to identify the at-risk population. This will assist in the promotion of prevention recommendations and for future health check follow-up.
Citation Format: Temin Ke, Artitaya Lophatananon, Kenneth Muir, Xinzhu Yu. A novel integrated predictive model for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2236.
Abstract 229: Elucidating arsenic dependent carcinogenesis in humans
Authors: Poceros-Coba Alma A. , Estrada-Florez Ana , Toal Ted , Lott Paul , Garrido Macarena , Steinmaus Craig , Ferrecio R. Catterina , Carvajal-Carmona Luis 
Published: June 2022

Abstract
Arsenic contamination in drinking water is one of the major health issues worldwide. Over 140 million people from 50+ countries are exposed to drinking water containing arsenic at levels above “safe” levels of 10 μg/L. Several studies indicate that chronic arsenic exposure is associated with the development of carcinogenic changes in the lungs, bladder, liver, and skin and other potential health problems. In this project, we aim to characterize bladder cancer mutational signatures and somatic mutations in a cohort of bladder cancer patients known to have been highly exposed to arsenic in northern Chile by using whole-exome sequencing (WES). We analyzed WES data and identified somatic mutations and mutational signatures using Mutec2 and SigProfiler. Preliminary analyses from a small number of exposed patients identified two mutational signatures, previously described as having “unknown” etiology, that showed an association with arsenic exposure. We are currently validating these findings in additional samples and with functional studies. Alma Poceros-Coba Ph.D. Candidate is the recipient of the Conacyt-UC-MEXUS Doctoral Fellowship and is the recipient of the UCDCCC Travel Award.
Citation Format: Alma A. Poceros-Coba, Ana Estrada-Florez, Ted Toal, Paul Lott, Macarena Garrido, Craig Steinmaus, Catterina Ferrecio R., Luis Carvajal-Carmona. Elucidating arsenic dependent carcinogenesis in humans [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 229.
Abstract 2291: microRNA/mRNA integrated analysis of multiple myeloma transcriptomics
Authors: Koduru Srinivas V. 
Published: June 2022

Abstract
Myeloma is plasma cell disorder, mostly effects adults over 60 years. Non-coding RNAs are emerging field and play vital role in development of disease. Major non-coding RNAs are miRNAs, lncRNAs, circRNAs and sn/snoRNAs. We analyzed restricted and publically available RNA-seq and small RNA-seq data sets for biomarkers identification and their involvement in myeloma. We obtained restricted data from “BluePrint”, which contains 11 myeloma plasma cells and 4 normal tonsil plasma cells (EGAS00001001110). We identified 1534 genes are differentially regulated (2-fold cut-off, &gt;10-FC 218 genes). Top 10 upregulated genes were: EDNRB (1246-FC), SCUBE1 (737-FC), MC4R (691-FC), NDNF (601-FC), PTGS2 (567-FC), GPRC5D (531-FC), MFAP3L (467-FC), CCND1 (381-FC), CXCL12 (344-FC) and BTBD3 (326-FC) ; top 10 downregulated were: EBF1 (-111-FC), HLA-DRB1(-133-FC), CPXM1 (-171-FC), LOC642131 (-171-FC), IGHV1OR15-3 (-171-FC), HLA-DRB5 (-204-FC), PRAMENP (-210-FC), DTX1 (-220-FC), CD22 (-337-FC) and RFTN1 (-356-FC). Publically available small RNA-seq data downloaded and analyzed for miRNAs, lncRNAs, circRNAs and sn/snoRNAs which contains 3 healthy donor’s plasma cells and 3 newly diagnosed myeloma patient plasma cells (PRJNA377345). We used mirDIP portal to analyze miRNA and mRNA differentially expressed data, predicated from more than 13 databases showed major role of miR-152-3p (targets 28 mRNAs), miR-93-5p (targets 19 mRNAs), miR-301a-3p (targets 13 mRNAs), miR-29c-3p (targets 12 mRNAs), and miR-144-3p (targets 9 mRNAs). Integrated analysis can provide valuable information from the transcriptomics data and effect of miRNAs on mRNAs.
Citation Format: Srinivas V. Koduru. microRNA/mRNA integrated analysis of multiple myeloma transcriptomics [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 2291.
Abstract 2294: Genomic landscape and immunological profile of glioblastoma in East Asians
Authors: Deng Davy 
Published: June 2022

Abstract
While it is well known that Glioblastoma (GBM) shows profound inter- and intra-tumoral heterogeneity, the ancestry disparities among races have been largely overlooked. By comparing the predominantly caucasian TCGA GBM dataset (EUR, n=383) with a large genomic and transcriptomic East Asian GBM dataset (EAS, n=443), we identified numerous significant differences between EAS-GBM and EUR-GBM. Transcriptomic clustering also established a novel EAS-GBM molecular classification system and the discovery of a new EAS-specific GBM subtype. We characterized each subtype comprehensively including genomic alterations, immune profile and TCR/BCR repertoire analysis. This study elucidates important ancestry-dependent biological and molecular differences between GBMs and proposes a new transcriptome-based EAS-GBM classification. Understanding these unique features contribute to a more comprehensive characterization of the heterogeneity in GBM patients and could facilitate more careful patient stratification during targeted therapy and drug development.
Citation Format: Davy Deng. Genomic landscape and immunological profile of glioblastoma in East Asians [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 2294.
Abstract 23: Will novel systemic treatments alter the benefit of lung cancer screening?: A microsimulation study
Authors: Gogebakan Kemal Caglar , Lange Jane , Slatore Christopher , Etzioni Ruth 
Published: June 2022

Abstract
Background: The U.S. Preventive Services Task Force has recently updated its 2013 lung cancer screening guidelines with low-dose computed tomography. In the last decade, population level mortality for advanced non-small cell lung cancer fell significantly due to the novel targeted and immunotherapy-based treatments. Moreover, with detection of new molecular targets, these therapies are expected to become the ultimate curative options. However, how these treatments might impact the benefits of lung cancer screening is unknown.
Methods: We utilize a computer microsimulation modeling framework to screen the U.S. population aged 50 to 80 who had a 20 pack-year smoking history and currently smoked or had quit within the past 15 years under both standard treatments (chemotherapy and radiotherapy) and novel treatments (immunotherapy and targeted therapy) settings. The corresponding mortality reductions associated with the stage shift via low-dose computed screening are projected for each setting.
Results: Over 25 years, risk-targeted screening saves 243 lives per 20,000 under standard therapies (12% mortality reduction) and 99 per 20,000 under fully adopted novel therapies (6% mortality reduction). Under standard treatment, 1.28 cancers are over-diagnosed per life saved; under fully adopted novel therapies, this increases to 3.46. Over 25 years the number needed to screen to avert one death is 82 under standard treatment and 202 under fully adopted novel therapies.
Conclusions: Ongoing transition from chemotherapy and radiotherapy to novel immunotherapies and targeted therapies may reduce the expected lives saved by low-dose computed tomography screening. Screening recommendations might need to be reconsidered as novel treatments become widespread.
Citation Format: Kemal Caglar Gogebakan, Jane Lange, Christopher Slatore, Ruth Etzioni. Will novel systemic treatments alter the benefit of lung cancer screening?: A microsimulation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 23.