bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6195: Assessing replication stress as an actionable therapeutic opportunity in chordoma
Authors: Punturi Nindo , Dolat Lee , Leung Wendy , Levy Joan , Zou Lee , Freed Daniel M. , Cote Gregory M. 
Published: April 2023

Abstract
Chordoma is a rare bone cancer with a high rate of disease recurrence and no approved systemic therapies. Tumor profiling studies indicate a significant number of chordomas are characterized by alterations in SWI/SNF chromatin remodeling and DNA damage repair genes, which have been associated with replication stress in other cancer types. We demonstrate here that preclinical chordoma models exhibit a replication stress phenotype and dependence on ATR activity. To assess the effect of ATR inhibition on cell viability, a panel of chordoma cell lines were treated with the ATR inhibitor elimusertib (BAY 1895344). In a subset of cell lines, elimusertib inhibited viability with low-nanomolar IC50 values. Upon treatment with the ATR inhibitor ceralasertib (AZD6738), DNA fiber assays revealed a mild decrease in replication fork speed and a significant increase in fork asymmetry in cells sensitive to ATR inhibitor, suggesting possible fork stalling or collapse in response to ATR inhibition. To assess genomic instability as a consequence of ATR inactivation and fork stalling or collapse, alkaline and neutral comet assays were performed to determine the presence of genome-wide ssDNA and/or dsDNA breaks, respectively. In a panel of chordoma PDX models, striking differential sensitivity to ATR inhibition was observed. In sensitive models, elimusertib (50 mg/kg, po, bidx3) promoted 85-90% tumor growth inhibition, in contrast to resistant models, where elimusertib treatment had no effect on tumor growth. Moreover, PDX models sensitive to ATR inhibition were sensitive to other therapies that exacerbate replication stress; for example, gemcitabine promoted multiple complete responses in a pediatric chordoma PDX model. Coupled with preclinical efficacy data, genomic and transcriptomic sequencing of differentially-sensitive chordoma models provided insight into the molecular factors associated with the replication stress phenotype in chordoma - illuminating potential biomarkers for patient selection. Finally, we explore various combination therapies and show that combining elimusertib with cisplatin or gemcitabine synergistically inhibits the viability of chordoma cell lines. Collectively, our data indicate that a subset of chordomas are characterized by intrinsic replication stress that can be therapeutically exploited by inhibiting ATR.
Citation Format: Nindo Punturi, Lee Dolat, Wendy Leung, Joan Levy, Lee Zou, Daniel M. Freed, Gregory M. Cote. Assessing replication stress as an actionable therapeutic opportunity in chordoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6195.
Abstract 6205: Visualizing dynamics of long non-coding RNA TUG1 in live glioblastoma cells
Authors: Minematsu Ayaka 
Published: April 2023

Abstract
Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. lncRNA TUG1 (taurine upregulated gene 1) is highly expressed in various cancers, including glioblastoma. Previously we found that TUG1 is an essential molecule for cancer cells to cope with excessive replication stress in the S phase. Albeit its importance to cell cycle-related function, how it is dynamically regulated during the cell cycle is entirely unknown. Here, we established a system visualizing endogenous TUG1 molecules in live cells. TUG1 was tagged with stem-loop motifs recognized by a specific binding protein fused with GFP. We tracked TUG1 RNA by the GFP signal for 22 hours in T98G glioblastoma cells and found that the expression started from the later G1 phase. When cells were treated with Hydroxy Urea, a chemical that interferes with replication and increases replication stress, the expression of TUG1 was further upregulated in the S phase within 20 mins. We also observed some TUG1 molecules accumulated in several nuclear locations. It may indicate that TUG1 assembles to protect damaged DNA loci efficiently. Our results suggest that the expression of TUG1 is regulated in a cell cycle-dependent manner and is strongly connected with its function of TUG1. The current live-cell imaging system could help further discover the critical roles of TUG1 in cancer cells.
Citation Format: Ayaka Minematsu. Visualizing dynamics of long non-coding RNA TUG1 in live glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6205.
Abstract 621: Aging dampens lymphoma-provoked phenotypic and epigenomic changes to the adaptive immune system
Authors: Hesterberg Rebecca S. , Cheng Chia-Ho , Yao Jiqiang , Song Xiaofei , Yu Xiaoqing , Cleveland John L. 
Published: April 2023

Abstract
Lymphoma is a disease that principally afflicts older individuals and also impairs the immune system, yet how aging and cancer interact to affect the immune system remains poorly understood. This is particularly the case for malignancies that arise within hematopoietic tissues that closely interact with immune cells. We hypothesized that lymphoma-provoked changes to the adaptive immune system would differ based on age. To explore how the immune system is altered by both B-cell lymphoma and the aging process, we transplanted Eμ-Myc lymphoma B-cells into mice aged 6-12 weeks or 20-24 months. Interestingly, as marked by reduced splenomegaly and lymphoma cell numbers, tumor burden was significantly reduced in aged hosts, suggesting lymphoma cells grow more slowly in the aged tissue microenvironment. Further, while lymphoma progression provoked losses in total numbers of normal T-cells, NK-cells, and B-cells in young individuals, aged lymphocytes were surprisingly resistant to lymphoma. Similarly, profound phenotypic changes in T-cell subpopulations that are provoked by Eμ-Myc lymphoma in young individuals, such as increases in expression of CD44, CD69, PD-1, Foxp3, and Tox, were not manifest in lymphoma-bearing aged mice. In addition, immature NK cell population dynamics were altered by lymphomas differently among aged mice when compared to young mice. Finally, analyses of the chromatin state of enriched CD4+ T cells from young and aged mice by ATAC-seq revealed that the aging process provoked marked alterations in the epigenome, and that lymphoma only provoked significant changes to the epigenome among young CD4+ T cells. We conclude that aging-driven epigenetic alterations manifest in the adaptive immune system renders these cells surprisingly resilient to lymphoma-mediated immune suppression.
Citation Format: Rebecca S. Hesterberg, Chia-Ho Cheng, Jiqiang Yao, Xiaofei Song, Xiaoqing Yu, John L. Cleveland. Aging dampens lymphoma-provoked phenotypic and epigenomic changes to the adaptive immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 621.
Abstract 6213: Disruption of XPF function by HPV promotes alternative end joining and sensitivity to cisplatin in HNSCC
Authors: Liu Qi , Zuo Nan , Ma Lin , Wei Lanlan 
Published: April 2023

Abstract
Human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC) usually show a tremendous better clinical outcome compared to their HPV-negative counterparts. Although the HPV associated survival advantage is partially explained by the enhanced cisplatin sensitivity in HNSCC (Clin Ca Res 2018, 24(23): 6001), the underlying mechanisms are still poorly elucidated. Cisplatin causes DNA interstrand crosslinks (ICLs) that requires Fanconi anemia (FA) pathway for DNA repair. Consistently, our study showed that HPV-positive HNSCC cells exhibited a FA defective cellular phenotype. In clonogenic cell survival assay, 1h treatment with 5μM cisplatin eliminated approximately 56.7% more HPV-positive HNSCC cells than HPV-negative ones. Furthermore, HPV-positive cells treated with cisplatin showed prolonged G2/M cell cycle arrest and more 53BP1 foci, indicating profound deficiency in repairing ICLs. Consistent with these findings, increased aberrant chromosome formation was observed in HPV-positive cells following Mitomycin C treatment. In order to reveal the mechanism, we further interrogated HPV-labeled HNSCC samples in TCGA database, and identified XPF, an endonuclease protein in FA pathway, was downregulated in HPV-positive HNSCC. Further analysis of cellular and clinical samples confirmed that both mRNA and protein expressions of XPF were significantly lower in HPV-positive HNSCC (P&lt;0.001). To test the importance of XPF in HPV-induced cisplatin sensitivity, we performed a cell viability assay, and found that knock-down of XPF increased the effects of cisplatin on HPV-negative HNSCC by 39.54% (± 4.42%), while no significant change was observed in HPV-positive HNSCC (P&gt;0.05). Notably, inhibition of XPF function by a small molecule inhibitor recapitulated the effect of HPV, resulted in enhanced error-prone DNA repair with alternative end-joining (alt-EJ). In a probe-based ddPCR assay, XPF inhibition increased 32.02% (± 5.80%, P&lt;0.001) alt-EJ events in HPV-negative HNSCC cells, while little difference was detected in HPV-positive cells. Thus, we speculated that combined inhibition of XPF and alt-EJ may improve clinical outcome in the difficult-to-treat, HPV-negative HNSCC, which worth further research efforts.
Citation Format: Qi Liu, Nan Zuo, Lin Ma, Lanlan Wei. Disruption of XPF function by HPV promotes alternative end joining and sensitivity to cisplatin in HNSCC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6213.
Abstract 6520: Combination of serum human satellite RNA and miR-21 levels as a biomarker for diagnosis of pancreatic cancer
Authors: Seimiya Takahiro , Kishikawa Takahiro , Otsuka Mtoyuki , Fujishiro Mitsuhiro 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to the difficulty of its diagnosis. Because human satellite II (HSATII) RNA, a satellite repeat RNA, is highly and specifically expressed in human PDAC, the serum HSATII RNA level may be a biomarker for diagnosis of PDAC. To measure the serum HSATII RNA level with high sensitivity and reproducibility, we previously developed a convenient method, tandem repeat amplification by nuclease protection (TRAP) combined with droplet digital PCR (ddPCR). Here, we refined the original method by simultaneously measuring the serum miR-21 level to enhance the detection of PDAC. A total of 135 patients were enrolled in this study, including 65 patients with pancreatic cancer and 70 healthy controls. We developed the PDAC-Index as a combination of the HSATII RNA and miR-21 levels to discriminate PDAC from healthy controls. The PDAC-Index demonstrated good diagnostic performance (AUC: 0.92 (95% CI: 0.86-0.99); sensitivity: 0.94; specificity: 0.85) which was significantly better than HSATII RNA alone (AUC: 0.92 vs 0.82, p=0.004). Importantly, the PDAC-index was elevated in an early-stage PDAC case that was negative for CA19-9. The PDAC-index also discriminated PDAC from chronic pancreatitis and intraductal papillary mucinous neoplasm more accurately than CA19-9. These results suggest that the PDAC-Index may be a promising biomarker for diagnosis of PDAC.
Citation Format: Takahiro Seimiya, Takahiro Kishikawa, Mtoyuki Otsuka, Mitsuhiro Fujishiro. Combination of serum human satellite RNA and miR-21 levels as a biomarker for diagnosis of pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6520.
Abstract 6568: Extended support for model organisms: The next frontier for the molecular signatures database
Authors: Castanza Anthony S. , Recla Jill M. , Eby David , Wenzel Alexander T. , Thorvaldsdottir Helga , Bult Carol J. , Mesirov Jill P. 
Published: April 2023

Abstract
In 2005, we introduced the Gene Set Enrichment Analysis (GSEA) method to enable the identification and estimation of significance of activated biological pathways and processes in molecular data. Serving a community of over 300,000 registered users, and contributing scientific analysis to more than 30,000 publications, GSEA has become ubiquitous in gene expression analysis and particularly in cancer research. The power of GSEA relies, in a large part, on the Molecular Signatures Database (MSigDB) that provides tens of thousands of expertly curated and annotated gene sets representing cellular processes, canonical pathways, response signatures, etc., derived from prior studies, public data, and curated pathway databases. Here we describe an important recent addition to the GSEA/MSigDB resource.
Historically, the GSEA-MSigDB resource has focused specifically on human data, offering guidance and support for analysis of model organism data through limited provision of orthology mapping files. In recognition of the importance of the mouse as a model organism for cancer research, we recently significantly expanded our support for mouse data in two ways.
(1) We introduced Mouse MSigDB with a total of about 15,000 sets that are provided in the native mouse gene symbol space and are derived from published mouse datasets and mouse-focused resources. This allows GSEA analysis of mouse datasets without the need for orthology conversion.
(2) For investigators who wish to use MSigDB’s human gene sets to analyze mouse data, or vice versa, we also implemented a new procedure for orthology mapping gene identifiers in an input dataset to match the identifiers of the gene sets. The new mapping considers the particular requirements of gene set enrichment analysis, and incorporates high confidence gene ortholog data from the Alliance of Genome Resources and ortholog-match refinement utilizing Ensembl’s ortholog datasets.
Together, these new additions offer a substantial step forward for making mouse a first-class citizen of the GSEA-MSigDB ecosystem. The new Mouse MSigDB, and the full GSEA-MSigDB resource, is available at gsea-msigdb.org.
Citation Format: Anthony S. Castanza, Jill M. Recla, David Eby, Alexander T. Wenzel, Helga Thorvaldsdottir, Carol J. Bult, Jill P. Mesirov. Extended support for model organisms: The next frontier for the molecular signatures database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6568.
Abstract 6571: Mammonc-DB: A web based user-friendly tool for comprehensive multi-omics data analysis in breast cancer
Authors: Karthikeyan Santhosh Kumar , Chandrashekar Darshan S. , Manne Upender , Creighton Chad , Qin Zhaohui S. , Kumar Sidharth , Varambally Sooryanaraya 
Published: April 2023

Abstract
Breast cancer (BC) accounted for 15% cancer related death among women, in the United States last year. It is a highly heterogeneous and complex diseases with multiple molecular events occurring during cancer initiation and progression. It is important to unravel the heterogeneity of breast cancer and the molecular events to develop diagnostic biomarkers and targeted therapies. There is need for comprehensive and user-friendly tool for the utilization of available breast cancer data including metastatic and treatment response data. We have earlier created a highly used pan-cancer proteogenomic portal called UALCAN (ualcan.path.uab.edu). Based on the current unmet need for comprehensive BC data analysis and visualization resource, we developed an integrated proteo-genomicbreast cancer data analysis portal, called Mammonc-DB (http://resource.path.uab.edu/MammOnc-ge.html). For Mammonc-DB, we collected data from public repositories like NCBI Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) for collecting and analysis of genomics and epigenetics data, and, PRIDE, and, ProteomeXchange for proteomics data. We procured and processed multi-omics studies related to normal, primary, and metastatic human breast cancer data with other clinical information available, for different clinical models. We also collected and analyzed different therapy, and treatment studies that are currently employed in treating BC patients. Mammonc-DB has user friendly interface that aid breast cancer researchers and clinicians in, a) allows users to identify potential biomarkers in breast cancer, b) accessing publicly available breast cancer multi-omics data, c) Visualizing the expression pattern of gene or protein of interest with clinical feature stratification in each dataset among others This resource serves as a one-stop resource to study gene expression (protein-coding and non-coding) analysis along with epigenetic regulation, and protein expression patterns in BC. With this platform, we tend to create global user base that will accelerate discovery of biomarkers in BC that might be involved in diagnosis, therapeutic target identification and treatments of breast cancer.
Citation Format: Santhosh Kumar Karthikeyan, Darshan S. Chandrashekar, Upender Manne, Chad Creighton, Zhaohui S. Qin, Sidharth Kumar, Sooryanaraya Varambally. Mammonc-DB: A web based user-friendly tool for comprehensive multi-omics data analysis in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6571.
Abstract 672: A genetic defect in phenylalanine hydroxylase (PAH) affects the immune system in kidney
Authors: Kim Seojeong , Kang Chaelin , Park Jihyun , Han Seung Seok , Koh Youngil , Yoon Sung-Soo 
Published: April 2023

Abstract
PAH, one of the genes associated with inborn error of metabolism (IEM), codes for phenylalanine hydroxylase and is specifically expressed in the liver and kidney. When PAH is dysfunctional, phenylalanine (Phe) cannot be converted to tyrosine (Tyr), and it produces toxic metabolites such as phenylpyruvate by a metabolic shift. We previously analyzed germline variants of IEM-related genes using public cancer multi-omics data. As a result, there was a high frequency of mutations in the PAH gene, and germline variants were particularly high in renal cell carcinoma (RCC). Based on this data, we suggest that kidney-specific expressed PAH mutations could change the kidney tissue microenvironment, which makes them more vulnerable to chronic kidney disease (CKD) and affects cancer development. We used the PAH enu2 mice model, which has a missense mutation in the PAH gene. PAH homozygous mutant mice display phenylketonuria (PKU) when not maintained on a Phe-free diet. PAH enu2 mice were maintained a normal diet. The concentration of phenylalanine in the mice's serum was measured each week. Then, the proportions of immune cells were analyzed in peripheral blood and kidney. Next, Jurkat cells, which are well-known as human T-cell lines, were applied to the in vitro experiment. Jurkat cells were cultured in a medium containing Phe or PPA and were activated by PHA/PMA or anti-CD3/CD28. Then after, the expression of immune-related markers was evaluated. Additionally, the expression of the PAH enzyme in human RCC and normal tissue was assessed by immunohistochemistry (IHC). The concentration of Phe in mice serum was higher when the PAH gene was defective; homozygous mutant, heterozygous mutant. As PAH-defective mice got older, the T cell population decreased in the blood and kidney immune cells. When Jurkat T cells were cultured with Phe or PPA, the expression of IL-2, a cytokine related to T cell expansion, decreased in the PPA-treated and activated group. There were more significant changes when treated with PPA rather than Phe. IHC data shows the expression of PAH was significantly decreased in RCC tissues compared to non-tumor tissue. These results suggest that the immune system could be changed by PAH dysfunction bearing a germline mutation. Moreover, the kidney tissue microenvironment with PAH defects is vulnerable to the development of kidney disease, which can lead to RCC. This is a novel discovery that can explain the importance of the role PAH gene in kidney disease.
Citation Format: Seojeong Kim, Chaelin Kang, Jihyun Park, Seung Seok Han, Youngil Koh, Sung-Soo Yoon. A genetic defect in phenylalanine hydroxylase (PAH) affects the immune system in kidney [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 672.