bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1149: Decitabine inhibits breast cancer cell proliferation through inhibition of endogenous retroviruses in vitro
Authors: Li Jiayi , Lin John , Andrada Leo , Grohol Bryce , Nong Serratt , Liu Yingguang 
Published: June 2022

Abstract
The purpose of the study is to elucidate the antineoplastic mechanisms of decitabine, a DNA methyltransferase inhibitor. Previous literature suggests that decitabine activates human endogenous retroviruses which subsequently enhances expression of interferons, thereby suppressing tumor cell proliferation. Contrary to this hypothesis, our in vitro study with human and mouse breast cancer cell lines showed a positive correlation between the antiproliferative effect of decitabine and its suppressive effect on two endogenous retroviruses, the human endogenous retrovirus type K (HERV-K) and the mouse mammary tumor virus (MMTV). Decitabine stimulated proliferation of the T47D human breast cancer cell line at lower doses but inhibited cell proliferation at higher doses. Correspondingly, HERV-K transcripts (env and pol) increased at lower doses and decreased at higher doses. Interestingly, expression of the E-cadherin gene, an indicator of epithelial differentiation, followed an opposite trend. Decitabine inhibited proliferation of the mouse 4T1 breast cancer cell line and its expression of MMTV in a dose-dependent manner, while enhancing expression of the mouse E-cadherin. 4T1 cells overexpressing MMTV env became more resistant to decitabine, so was a human breast cancer cell line (BT-20) overexpressing HERV-K env, while T47D cells with HERV-K knockdown became more susceptible to the drug. Meanwhile, in vivo studies showed that decitabine successfully suppressed tumor development in BALB/c mice inoculated with 4T1 cells. Surprisingly, expression of MMTV env was elevated in tumors of mice treated with decitabine, along with enhanced E-cadherin expression. These data suggest decitabine inhibits cancer cell proliferation (at least partially) through inhibition of endogenous retroviruses in vitro, but its mechanisms of action in vivo are different. Further studies of the interaction between decitabine and endogenous retroviruses using engineered 4T1 cells in BALB/c mice are currently underway.
Citation Format: Jiayi Li, John Lin, Leo Andrada, Bryce Grohol, Serratt Nong, Yingguang Liu. Decitabine inhibits breast cancer cell proliferation through inhibition of endogenous retroviruses in vitro [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 1149.
Abstract 1151: Pharmacogenomics genotyping from clinical somatic whole exome sequencing: Aldy, a computational tool
Authors: Osei Wilberforce A. , Shugg Tyler , Ly Reynold C. , Bray Steven M. , Salisbury Benjamin A. , Ratcliff Ryan R. , Pratt Victoria M. , Numanagić Ibrahim , Skaar Todd 
Published: June 2022

Abstract
Background Pharmacogenomics (PGx) testing can reduce toxicities and improve efficacy of several drugs used to treat cancer and associated symptoms. PGx results can be determined from germline whole-exome sequencing (WES), but somatic mutations may cause discordance between tumor and germline DNA. Since clinical diagnostic sequencing in oncology frequently only includes tumor DNA, there would be clinical value in calling germline PGx genotypes from tumor DNA. Thus, the purpose of this study was to assess the feasibility of using somatic WES data to call germline PGx genotypes.
Methods Germline and somatic WES data were obtained as part of the clinical workflow for 64 patients treated at the solid molecular tumor board clinic at Indiana University. Aldy v3.3 was implemented in LifeOmic’s Precision Health Cloud™ to call PGx genotypes from somatic WES. Somatic Aldy calls were compared with previously validated Aldy germline calls for 8 genes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, DPYD, and TPMT. Somatic read depth was &gt;100x, except for the intronic CYP3A4*22 variant, which was &gt;30x.
Results Somatic and germline Aldy calls were compared for a total of 512 genotypes and 56 (11%) calls were discordant. Discordant calls were most common for CYP2B6 (23.4%), followed by CYP2D6 (14.1%), CYP2C19 (10.9%), CYP2C8 (6.3%), and DPYD (6.3%). In contrast, all Aldy calls were concordant for CYP3A5 and TPMT. 38 out of 64 subjects (59%) had discordant calls for at least one gene. The most common first cancer diagnoses in our cohort were colorectal (9.3%), breast (7.8%), and pancreatic (7.8%), and the rates of discordant Aldy calls did not differ by cancer type (p&gt;0.05 for all cancer types). Based on our analyses of discordant calls, we anticipate that adjusting Aldy’s thresholds for variant calling may allow Aldy to determine genotypes from somatic WES data.
Conclusion In most cases, genotype calls of drug metabolism genes from tumor DNA reflected the germline genotypes; however, additional work needs to be done to determine if the remaining discordant calls can be corrected by modifying the informatics tools or if they are due to somatic mutations.
Citation Format: Wilberforce A. Osei, Tyler Shugg, Reynold C. Ly, Steven M. Bray, Benjamin A. Salisbury, Ryan R. Ratcliff, Victoria M. Pratt, Ibrahim Numanagić, Todd Skaar. Pharmacogenomics genotyping from clinical somatic whole exome sequencing: Aldy, a computational tool [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 1151.
Abstract 1156: Genome Nexus: A comprehensive resource for the annotation and interpretation of genomic variants in cancer
Authors: de Bruijn Ino , Li Xiang , Sumer Onur , Gross Benjamin , Sheridan Robert , Ochoa Angelica , Wilson Manda , Wang Avery , Zhang Hongxin , Lisman Aaron , Abeshouse Adam , Rodenburg Sander , van Hagen Sjoerd , Fijneman Remond , Meijer Gerrit , Schultz Nikolaus , Gao Jianjiong 
Published: June 2022

Abstract
Interpreting genomic variants in tumor samples presents a challenge in research and the clinical setting. A major barrier is that information about variants is fragmented across disparate databases, and aggregating information from these requires building extensive infrastructure. To this end, we have developed Genome Nexus, a one stop shop for variant annotation, equipped with a powerful API for bulk annotation of variants and a user friendly interface for cancer researchers.
Genome Nexus is available at https://www.genomenexus.org. It a) aggregates variant information from a large number of sources that are relevant to cancer research and clinical applications; b) allows high-performance programmatic access to the aggregated data via a unified API; c) provides a search interface and a reference page for individual cancer variants; d) provides user-friendly tools for annotating variants in patients; e) is freely available under an open source license and can be installed in a private cloud or local environment.
Genome Nexus contains annotations from more than a dozen resources, including those that provide variant effect information (VEP), protein sequence annotation (Uniprot, Pfam, dbPTM), functional consequence prediction (Polyphen-2, Mutation Assessor, SIFT), population prevalence (gnomAD, dbSNP, ExAC), cancer population prevalence (Cancer Hotspots, SignalDB) and clinical actionability (OncoKB, CIViC, Clinvar). The annotations can be accessed through the website, the API, and a command line client.
Genome Nexus is unique in providing a user friendly interface specific to cancer that allows high performance annotation of any variant. It is the main annotation service for the popular cancer genomics tool cBioPortal, which serves thousands of users daily. It is also offered as a standalone tool for annotation, allowing researchers and clinicians as well as genomic infrastructure developers to leverage it directly in their own workflows. For example, a local installation of Genome Nexus is used for annotating all variants in AACR Project GENIE.
Citation Format: Ino de Bruijn, Xiang Li, Onur Sumer, Benjamin Gross, Robert Sheridan, Angelica Ochoa, Manda Wilson, Avery Wang, Hongxin Zhang, Aaron Lisman, Adam Abeshouse, Sander Rodenburg, Sjoerd van Hagen, Remond Fijneman, Gerrit Meijer, Nikolaus Schultz, Jianjiong Gao. Genome Nexus: A comprehensive resource for the annotation and interpretation of genomic variants in 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 1156.
Abstract 120: HIF-1α regulation by Smurf2-mediated protein degradation in a VHL-independent manner
Authors: Zhao Shuai , El-Deiry Wafik S. 
Published: June 2022

Abstract
HIF-1α is the main mediator of hypoxic response in cells and contributes to angiogenesis, metastasis and therapy resistance in cancer. The canonical pathway of HIF-1α degradation in normoxia is through the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. We previously found that knockdown of CDK4 decreased HIF-1α expression in a VHL-independent manner. To explore the mechanism of CDK4-induced HIF-1α stabilization, we performed a proteomic analysis on HIF-1α-interacting proteins with palbociclib treatment, a bioinformatic prediction of HIF-1α-targeting E3 ubiquitin ligases and identified SMAD specific E3 ubiquitin protein ligase 2 (Smurf2) to be involved in a non-canonical HIF-1α regulation mechanism. Overexpression of Smurf2 enhanced the ubiquitination of HIF-1α and reduced expression of HIF-1α in HCT116 colorectal cancer cells. Smurf2 overexpression downregulated HIF-1α target gene SLC2A1 but not HIF1A mRNA level in hypoxia. Knockdown of SMURF2 increased HIF-1α expression in normoxia even when CDK4 was knocked-down. TCGA analysis showed correlation between high SMURF2 mRNA and better prognosis in kidney renal clear cell carcinoma (KIRC). In KIRC, VHL loss is a frequent mutational event that leads to high constitutive expression of HIF-1α and HIF-2α. Thus, we investigated a role for Smurf2 in HIF regulation in this cancer type. Overexpression of Smurf2 suppressed HIF-1α expression in RCC4 VHL-deficient clear cell renal cancer line in normoxia. Knockdown of SMURF2 increased HIF-1α expression in RCC4 cells. Treatment of RCC4 cells with Smurf2 inhibitor Heclin also increased HIF-1α expression in normoxia. HIF-2α expression was reduced upon Smurf2 overexpression in RCC4 cells under normoxia and in SW480 colorectal cancer cells under hypoxia. In summary, Smurf2 mediates VHL-independent HIF-1α degradation, which provides new insights for HIF-1α targeting in cancers especially with VHL deficiency, and targeting of Smurf2 to increase HIF activity may have functional consequences in non-neoplastic disorders.
Citation Format: Shuai Zhao, Wafik S. El-Deiry. HIF-1α regulation by Smurf2-mediated protein degradation in a VHL-independent manner [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 120.
Abstract 1207: Bento: A toolkit for subcellular spatial analysis of RNA organization
Authors: Mah Clarence , Ahmed Noorsher , Lam Dylan , Carter Hannah , Yeo Gene 
Published: June 2022

Abstract
We present Bento, a Python toolkit for subcellular spatial analysis of RNA, implementing tools for ingesting highly-multiplexed spatial transcriptomics data, visualization, detection of RNA localization patterns, identification of cell states, and subcellular spatial statistics. We applied our methods to analyze multiple spatial transcriptomics datasets from a variety of platforms, including seqFISH+ (10k RNA in cultured mouse fibroblast cells) MERFISH (130 RNA in cultured U2-OS cells), and the Spatial Molecular Imager (980 RNA in FFPE of NSCLC and breast cancer tumors) to show how subcellular spatial analysis can be leveraged to understand RNA localization and behavior. We use tensor factorization to perform unsupervised clustering analysis of subcellular patterns in each dataset, demonstrating how cell type and morphology are consistently linked to spatial RNA organization.
Citation Format: Clarence Mah, Noorsher Ahmed, Dylan Lam, Hannah Carter, Gene Yeo. Bento: A toolkit for subcellular spatial analysis of RNA organization [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 1207.
Abstract 1208: Denoising spatial expression profiling data based on in situ position and image information
Authors: Wang Yunguan , Song Bing , Wang Shidan , Chen Mengyi , Xie Yang , Xiao Guanghua , Wang Li , Wang Tao 
Published: June 2022

Abstract
Spatial expression profiling (SEP) technologies provide gene expression close to or even superior to single-cell resolution while retaining the physical locations of sequencing and often also providing matched pathology images. However, the expression data captured by SEP technologies suffer from high noise levels, including but not limited to dropouts as in regular single-cell RNA-sequencing (scRNA-seq). The extra experimental steps for preserving the spatial locations of sequencing could result in even more severe noises, compared to regular scRNA-seq. Fortunately, such noises could be largely reduced by leveraging information from the physical locations of sequencing and the tissue and cellular organization reflected by corresponding pathology images. In this work, we demonstrated the extensive levels of noise in SEP data. We developed a mathematical model, named Sprod, to reduce such noises based on latent space and graph learning of matched location and imaging data. We comprehensively validated Sprod and demonstrated its advantages over prior methods for removing dropouts in scRNA-seq data. We further showed that, after adequately de-noising by Sprod, differential expression analyses, pseudotime analyses, and cell-to-cell interaction inferences yield significantly more informative results in various biological application settings. In particular, with Sprod, we discovered 3-4 times more RNA transcripts that were actively transported in mouse hippocampus neurons. We also showed that the tumor cells at the tumor-stroma boundaries demonstrate differential transcriptomic features from the tumor cells in the central regions, caused by their interactions with the stroma/immune cells. Overall, we envision denoising by Sprod to become a key first step to empower SEP technologies for biomedical discoveries and innovations.
Citation Format: Yunguan Wang, Bing Song, Shidan Wang, Mengyi Chen, Yang Xie, Guanghua Xiao, Li Wang, Tao Wang. Denoising spatial expression profiling data based on in situ position and image information [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 1208.
Abstract 1234: PD-L1 PET: A potential biomarker of checkpoint inhibitor sensitivity in renal cancer
Authors: Mulgaonkar Aditi , Woolford Layton , Elias Roy , Nham Kien , Guan Bing , Hao Guiyang , Stevens Christina , Tcheuyap Vanina Toffessi , Haldeman Sydney , Miyata Jeffrey , Carrillo Deyssy , Qin Qian (Janie) , Singla Nirmish , Bowman Isaac , Cadeddu Jeffrey , Margulis Vitaly , Christie Alana , Kapur Payal , Pedrosa Ivan , Dakanali Marianna , Oz Orhan , Sun Xiankai , Brugarolas James 
Published: June 2022

Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Program death-ligand 1 (PD-L1) and its corresponding receptor (PD-1) are the target of most FDA-approved ICIs. Perhaps unsurprisingly, PD-L1 levels are predictive of response to targeting drugs in lung and other cancers. However, PD-L1 is not predictive in other tumor types including renal cell carcinoma (RCC). PD-L1 is typically measured on tumor biopsies or archival tissues and we hypothesized that the lack of PD-L1 predictive power is due to tumor heterogeneity and tumor evolution. To test this notion, we embarked upon the generation of a PD-L1 probe that would enable real time assessment of PD-L1 across sites of disease using molecular imaging. We leveraged atezolizumab, a highly specific PD-L1 therapeutic antibody with a mutant Fc. Atezolizumab (ATZ) was labeled with 89Zr after conjugation with a bifunctional chelator and evaluated by positron emission tomography (PET). In extensive preclinical studies using multiple patient-derived xenografts (PDXs) with variable PD-L1 levels, we show that 89Zr-ATZ PET is able to distinguish RCC with variable PD-L1 expression. These data set the foundation for an investigator new drug (IND) approval from the FDA and an ongoing clinical trial in RCC patients (NCT04006522). Consistent with our hypothesis, 89Zr-ATZ PET shows substantial PD-L1 heterogeneity not only across but also within patients at different sites of disease. Furthermore, preliminary data suggest that PD-L1 levels may be predictive of response to ICI. By assessing PD-L1 expression in real time, 89Zr-ATZ PET may enable: (1) the identification of patients most likely to respond to PD-L1/PD-1 targeted therapies; (2) tailored management of the disease across different sites; (3) the evaluation of interventions that modulate PD-L1 levels; (4) insights into toxicities; and (5) probing resistance.
Citation Format: Aditi Mulgaonkar, Layton Woolford, Roy Elias, Kien Nham, Bing Guan, Guiyang Hao, Christina Stevens, Vanina Toffessi Tcheuyap, Sydney Haldeman, Jeffrey Miyata, Deyssy Carrillo, Qian (Janie) Qin, Nirmish Singla, Isaac Bowman, Jeffrey Cadeddu, Vitaly Margulis, Alana Christie, Payal Kapur, Ivan Pedrosa, Marianna Dakanali, Orhan Oz, Xiankai Sun, James Brugarolas. PD-L1 PET: A potential biomarker of checkpoint inhibitor sensitivity in renal 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 1234.
Abstract 1266: Circulating immune biomarkers in peripheral blood reflect the effect of a CD200 immune checkpoint targeted immunotherapy in pet dogs with high-grade glioma
Authors: Puerta Martinez Francisco W. , Schnell Sathya , Arnold Susan , Pluhar Elizabeth G. , Olin Michael 
Published: June 2022

Abstract
The extent to which immune cell phenotypes in the peripheral blood reflect intratumoral immune activity prior to and early in cancer immunotherapy is unclear. Here we studied the population dynamics of immune cells and immune phenotypic changes, using clinical blood samples and a multicolor flow cytometry analysis. These samples were serially obtained from a cohort of high-grade glioma canine patients enrolled in a trial with an immunotherapy that targets the CD200/CD200R immunological synapse. This therapy consists of an alternative checkpoint inhibitor peptide (CD200AR-L) that modulates the CD200 immune checkpoint, currently being used in an adult phase I safety trial for recurrent glioblastoma trial (NCT04642937) and a canine high-grade spontaneous glioma trial (U01CA224160-01). We found evidence of a strong effect of the therapy on peripheral immune cells in responder versus nonresponder dogs. Upon initiation of therapy, immune effector cell proliferation increased in responsive patients, whereas in nonresponders immune cell populations either didn’t change significantly or an increase in immunosuppressive phenotypes was observed. Cell populations such as MDSC, regulatory T cells and exhausted T cells were predominantly higher in nonresponder dogs. These data showed that peripheral immune cell phenotypes were linked to the outcome of the immunotherapy, thus dogs with better immune cell profiles, including increased cytotoxic differentiation, had a better prognosis and longer overall survival rates. Taken together, these results suggest that variation in patient responsiveness can be explained by differences in peripheral immune cell proliferation and differentiation soon after the initiation of immunotherapy.
Citation Format: Francisco W. Puerta Martinez, Sathya Schnell, Susan Arnold, Elizabeth G. Pluhar, Michael Olin. Circulating immune biomarkers in peripheral blood reflect the effect of a CD200 immune checkpoint targeted immunotherapy in pet dogs with high-grade glioma [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 1266.
Abstract 1289: Systemic immune response of prostate cancer patients to alpha-emitting radiotherapy
Authors: Lunj Sapna , Mistry Hitesh , Song YeePei , Patel Kamlesh , Nightingale Hannah , Smith Tim , Hoskin Peter , West Catharine , Choudhury Ananya 
Published: June 2022

Abstract
Targeted alpha therapy (TAT) is a type of radiotherapy (RT) that uses alpha-emitting radionuclides. These radionuclides have a natural affinity for areas of bone metastases (i.e., radium-223, Ra-223) or can label specific tumour targets (i.e., prostate-specific membrane antigen). Conventional photon irradiation (i.e., external beam) can activate or suppress immune responses. The resulting immune response is dictated by the release of soluble markers such as cytokines (i.e., IL-6) and damage associated molecular patterns, DAMPs (calreticulin). Less is known about the immune response induced by alpha-emitters. With increased interest in using TAT for cancer patients, it is important to gain a more in depth knowledge regarding the immune response of alpha emitters.
Aim: Explore the systemic immune response of prostate cancer (PCa) patients to alpha-emitting RT by studying circulating cytokines, checkpoint molecules, matrix metalloproteinases (MMPs) and DAMPs. Methods: The cohort comprised of 43 patients with metastatic castration-resistant PCa treated with up to six four-weekly injections of the alpha emitter, Ra-223. We measured longitudinal changes in 61 plasma markers using the Luminex assay. The plasma markers included cytokines, checkpoint molecules and DAMPs.
Results: Ra-223 induced longitudinal changes in 14 plasma markers over the course of treatment (T2-T6) compared with pre-treatment levels (T1). Most of the observed RT-induced changes occurred after four injections of Ra-223 (T5), where 9 of the 14 plasma markers changed significantly. The table summarises T5 findings (presented as mean concentration, pg/ml; statistical analysis using Wilcoxon matched-pairs signed rank test).
Conclusion: Our data demonstrates that alpha-emitting RT induces systemic immune responses that can be measured in the plasma of patients. Given the diverse role of these markers, further study is needed to explore the biological implications of these systemic changes on patient outcome.
Changes in plasma markers in patients treated with Ra-223 T1 T5 P value IL-8 6.7±0.9 9.7±1.3 0.0009 IL-2R 293.5±42.9 364.5±69.7 0.0247 IP-10 18.4±2.3 21.8±2.5 0.0243 RANTES 2668.8±173.4 2944.7±164.6 0.0455 BTLA 549.9±153.5 527.7±265.2 0.0319 CD137 49.6±8.9 39.1±13.5 0.0099 Calreticulin 7868±3514.9 9238.4±808.5 0.0386 RAGE 63.9±4.7 52.3±5.1 0.0014 MMP1 66.1±7.5 84.9±12.6 0.0245
Citation Format: Sapna Lunj, Hitesh Mistry, YeePei Song, Kamlesh Patel, Hannah Nightingale, Tim Smith, Peter Hoskin, Catharine West, Ananya Choudhury. Systemic immune response of prostate cancer patients to alpha-emitting radiotherapy [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 1289.