bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 642: CSF-1R+ macrophages control the gut microbiome-enhanced liver NKT function through IL-18
Authors: Ma Chi , McCallen Justin , McVey John C. , Zhang Qianfei , Ruf Benjamin , Bauer Kylynda , Wang Sophie , Lai Chunwei Walter , Trinchieri Giorgio , Berzofsky Jay A. , Korangy Firouzeh , Greten Tim F. 
Published: April 2023

Abstract
The gut microbiome is an important modulator of the host immune system. Here, we found that altering the gut microbiome by oral vancomycin increases liver NKT cell function. Enhanced NKT cytokine production and activation marker expression were observed in vancomycin-treated mice following both antigen-specific and antigen-independent in vivo NKT stimulations, with a more prominent effect in liver as compared to the spleen. Fecal transplantation studies demonstrated that the NKT functional regulation is mediated by altering the gut microbiome but uncoupled from the modulation of NKT cell population size. Interestingly, when stimulated in vitro, NKT cells from vancomycin-treated mice did not show increased activation, suggesting an indirect regulation. NKT cells expressed high levels of IL-18 receptor, and vancomycin increased the expression of IL-18 in the liver. Blocking IL-18 by neutralizing antibody or using genetically deficient mice attenuated the enhanced NKT activation. Liver macrophages were identified as a major source of IL-18. General macrophage depletion by clodronate abolished this NKT activation. Using anti-CSF-1R depletion or LyzCrexCSF-1RLsL-DTRmice identified CSF-1R+ macrophages as a critical modulator of NKT function. Together, our results demonstrate that the gut microbiome controls liver NKT function via regulating CSF-1R+ macrophages to produce IL-18.
Citation Format: Chi Ma, Justin McCallen, John C. McVey, Qianfei Zhang, Benjamin Ruf, Kylynda Bauer, Sophie Wang, Chunwei Walter Lai, Giorgio Trinchieri, Jay A. Berzofsky, Firouzeh Korangy, Tim F. Greten. CSF-1R+ macrophages control the gut microbiome-enhanced liver NKT function through IL-18 [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 642.
Abstract 6505: ColoScape test: a molecular assay to detect early-stage colorectal cancer in plasma cell-free DNA
Authors: Tanaka Hiromi , Shen Shuo , Scimia Mauro , Pastor Larry , Li Jonathan , Fu Andrew Y. , Kim Daniel , Ni Rui , Zhang Aiguo , Sha Michael Y. 
Published: April 2023

Abstract
Colorectal cancer (CRC) is the second most common cause of cancer deaths when men and women are combined in the U.S. Early detection in the precancerous stage is key to reducing the CRC morbidity and mortality rates. Thus, there is a critical need for a cost-effective, time-efficient, and convenient clinical tool for early CRC detection. We have developed a multiplex qPCR assay (ColoScapeTM) to detect CRC-associated genetic and epigenetic changes from liquid biopsy samples (i.e., cell-free DNA) using our proprietary QClamp® XNA technology. The QClamp® XNA technology is very unique and enables the ColoScapeTM assay to selectively amplify the mutant and methylated DNA target sequences by using a synthetic DNA analog XNA (Xenonucleic Acid). This study demonstrates the analytical performance for detecting low-abundant mutated and methylated gene copies, as well as assess the clinical performance using plasma cell-free DNA samples from patients with CRC or advanced adenomas (≥1 cm) and from individuals with normal colonoscopies. The ColoscapeTM test is currently designed to detect mutations in 8 genes with 61 mutations and 7 methylated markers. The test consists of two parts: (i) the detection of mutations in 8 genes (APC, KRAS, BRAF, TP53, CTNNB1, NRAS, SMAD4, and PIK3CA) and (ii) the detection of 7 methylation targeted genes. For the assay analytical performance, the ColoScapeTM test shows that XNA effectively suppressed the wild-type background amplifications and led to amplify mutation and methylation target sequences dominantly, providing a high level of analytical sensitivity and specificity. The ColoScapeTM test is highly reproducible with intra- and inter-assay coefficient of variation of &lt;10% and the cross-reactivity within the assay was limited and negligible. The results for the assay analytical sensitivity indicated that each target could be detected between 0.1% and 0.5% variant allele frequency in 10 ng cfDNA. The preliminary assay clinical specificity and sensitivity were 100% (95% CI: 91.3-100%) and 86% (95% CI: 66-95%) respectively for CRC and 91% specificity (95% CI: 75%-98%) and 60% sensitivity (95% CI: 17%-93%) for advanced adenomas. In summary, the ColoScape test utilizing the XNA-based technology provides high sensitivity and high specificity to CRC and advanced adenomas with a great potential to be used as an early screening test.
Citation Format: Hiromi Tanaka, Shuo Shen, Mauro Scimia, Larry Pastor, Jonathan Li, Andrew Y. Fu, Daniel Kim, Rui Ni, Aiguo Zhang, Michael Y. Sha. ColoScape test: a molecular assay to detect early-stage colorectal cancer in plasma cell-free DNA [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 6505.
Abstract 6522: Improved detection of low frequency mutations in ovarian and endometrial cancers by utilizing a highly accurate sequencing platform
Authors: Ragoussis Jiannis , Pezeshkian Nairi , Gilbert Lucy 
Published: April 2023

Abstract
Ovarian and endometrial cancers come within the top-4 for incident cancers as well as deaths in North American women. Cure rates have not improved in 30 years as high-grade subtypes continue to be diagnosed in Stage III/IV. Attempts at early diagnosis have failed because high-grade cancer cells exfoliate and metastasize while the primary cancer is small and undetectable by existing tests based on imaging and blood-based tumour markers. DOvEEgene (Detecting Ovarian and Endometrial cancers Early using genomics) is a genomic uterine pap test developed by a McGill team to screen and detect these cancers while they are confined to the gynecologic organs and curable by surgery. The test identifies pathogenic somatic mutations in uterine brush samples A high sensitivity error-reducing capture technology (DOvEEgene-SureSelectHS) utilizing duplex sequencing interrogates the exons of 23 genes involved in the development of sporadic and hereditary ovarian and endometrial cancers. We apply a combination of germline gene panel testing on saliva samples with deep duplex sequencing to detect somatic mutations at &lt;0.1% VAF, interrogation of microsatellite loci for instability and low coverage WGS for copy number analysis of uterine brush samples. Currently, DOvEEgene is the only test that can discriminate ovarian and endometrial cancers in peri- and postmenopausal women from benign gynecologic diseases common in that age group. This is important because pathogenic somatic driver mutations are also associated with increasing age and benign disease. DOvEEgene incorporates a deep machine-learning derived classifier that can discriminate the mutational signature of these cancers from benign disease aiming for a sensitivity of 70% and a specificity of 100% in a population with high background mutational burden. Here we tested the Onso system, a highly accurate sequencing technology from PacBio in order to potentially increase sensitivity while driving down sequencing costs by reducing required sequencing depth vs the current NGS standard. We sequenced 15 duplex Illumina sequencing libraries produced using the DovEE assay at PE 100bp mode and compared Onso data in non- duplex sequencing mode as well as duplex sequencing mode to the original duplex sequencing method. Here, we present this comparison and highlight the benefits of high accuracy sequencing for the detection of very low frequency (&lt;0.1%) somatic mutations.
Citation Format: Jiannis Ragoussis, Nairi Pezeshkian, Lucy Gilbert. Improved detection of low frequency mutations in ovarian and endometrial cancers by utilizing a highly accurate sequencing platform [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 6522.
Abstract 6540: Multiscale protein networks: de novo aberrant protein interactions and oncogenic regulators in seven cancer types
Authors: Song Won Min , Elmas Abdulkadir , Farias Richard , Xu Peng , Zhou Xianxiao , Hopkins Benjamin , Huang Kuan-lin , Zhang Bin 
Published: April 2023

Abstract
We conducted integrative proteomic network analyses of 687 cases across 7 cancer types including breast cancer (115 tumor samples), clear cell renal carcinoma (100 tumor samples), colorectal cancer (91 tumor samples), hepatocellular carcinoma (101 tumor samples), lung adenocarcinoma (104 tumor samples), stomach adenocarcinoma (80 tumor samples), and uterine corpus endometrial carcinoma (96 tumor samples). Using Multi-scale embedded gene co-expression network analysis (MEGENA), we constructed co-expression protein network for each cancer type, and interrogated the network topology and co-expressed protein modules. For each cancer type, we identified disease-associated pathways as co-expressed protein modules enriched for differentially expressed proteins in tumor. Comparing with respective cancer transcriptome network models, this systematically revealed proteome-specific cancer subnetworks associated with heme metabolism, DNA repair, spliceosome, oxidative phosphorylation and KRAS oncogenic signaling pahways in several cancer types. Cross-cancer comparison identified highly preserved protein modules showing robust pan-cancer interactions and identified endoplasmic reticulum-associated degradation (ERAD) and N-acetyltransferase activity as the central functional axes. Then, we utilized these network models to predict pan-cancer protein network regulators in the up-stream of disease-associated pathways. The predicted pan-cancer regulators were experimentally validated by loss-of-function to confer anti-tumor effects in diverse cancer types: lung (H847), colon (HCT116), fetal kidney (HEK293T) and breast (MDA-MB-231) cancer cells. Overall, the study was designed to provide tractable network models of cancer proteome, and unlock the further potentials to understand oncogenic regulators and mechanisms in different cancer types.
Citation Format: Won Min Song, Abdulkadir Elmas, Richard Farias, Peng Xu, Xianxiao Zhou, Benjamin Hopkins, Kuan-lin Huang, Bin Zhang. Multiscale protein networks: de novo aberrant protein interactions and oncogenic regulators in seven cancer types [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 6540.
Abstract 6577: CARMEN: A pan-HLA and pan-cancer proteogenomic database on antigen presentation to support cancer immunotherapy
Authors: Kallor Ashwin Adrian , Waleron Michał , Bedran Georges , Eugénio Patrícia , Pesquita Catia , Faria Daniel , Zanzotto Fabio Massimo , Battail Christophe , Rajan Ajitha , Alfaro Javier 
Published: April 2023

Abstract
Cancer immunotherapy has greatly improved the quality of life of cancer patients and it hinges on the discovery of novel cancer antigens that could be targeted to improve disease outcomes. The creation of databases such as IEDB, SysteMHC, TANTIGEN, caAtlas, HLA Ligand Atlas, Cancer Antigenic Peptide Database, SPENCER and IEAtlas support the immunopeptidomics community in understanding the landscape of antigen presentation. We have developed a pan-cancer, pan-HLA, and pan-tissue database containing immunopeptidomics data mapped to transcriptomic, genomic, immunological and biochemical data. The database was generated from 80 different publicly available immunopeptidomics mass spectrometry datasets collected between 2015-2022 (76 cancer and 4 normal datasets), covering 15 different types of cancers and 152 different HLA-I alleles. The peptides contained in our database were obtained by a combination of closed, open and de novo searches using an in-house developed computational pipeline. Following rigorous false discovery rate estimation at 1% and a second-round search to eliminate any false signals that may not have been detected in the previous round of FDR estimation, we obtained a list of 11.2 million peptide-HLA combinations comprising both coding and non-coding regions of the genome as well as bacterial peptides. These peptides have been mapped to chromosomal coordinates to facilitate adoption by the genomics community of this useful resource on antigen presentation. Pathway/biochemical analysis of each peptide was performed using the rWikiPathways package. Finally, mutations associated with each peptide were annotated using COSMIC and dbSNP resources. Our database includes a FAIR knowledge graph which contextualizes and enriches the data to enable clinicians to take effective therapeutic decisions on the appropriate form of treatment for cancer immunotherapy with the case study of clear cell renal cell carcinoma (ccRCC). We will continue to expand our database with new data over the next two years and expand the scope of its applications to facilitate uptake by the larger scientific community.
Citation Format: Ashwin Adrian Kallor, Michał Waleron, Georges Bedran, Patrícia Eugénio, Catia Pesquita, Daniel Faria, Fabio Massimo Zanzotto, Christophe Battail, Ajitha Rajan, Javier Alfaro. CARMEN: A pan-HLA and pan-cancer proteogenomic database on antigen presentation to support cancer immunotherapy. [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 6577.
Abstract 6654: Association PD-L1 overexpression with immune checkpoint inhibitor effect in triple-negative breast cancer
Authors: Park A Young , Kim Ju Hee , Lee Sangen , Kim Hong Kyu , Lee Han-Byoel , Han Wonshick 
Published: April 2023

Abstract
Background: Recently, studies on the antitumor effects of PD-L1 inhibitors have gained importance in difficult to treat solid tumors. In particular, the expression of PD-L1 could be an important factor in evaluating the possibility of immunotherapy in triple-negative breast cancer where targeted therapy is not possible and the prognosis is poor. Accordingly, this study investigated the effect of PD-L1 overexpression on the immune checkpoint inhibitor effect in triple-negative breast cancer.
Method: The relationship between T stage and N stage according to PD-L1 mRNA expression was analyzed in the TCGA and METABRIC datasets of breast cancer. To evaluate the role of PD-L1, PD-L1-overexpressing breast cancer cell lines for in vitro and in vivo experiments were established.
Result: Using TCGA and METABRIC datasets, we found that PD-L1 showed the highest expression in breast cancer of the basal subtype, but the correlation between T stage and N stage according to PD-L1 expression was not statistically significant. To determine the functional importance of PD-L1 in breast cancer, we established 4T1-PD-L1-overexpressing breast cancer cell lines. We observed that the overexpression of PD-L1 promoted cell proliferation, migration, and invasion. In the orthotopic tumor mouse model, PD-L1 showed no significant difference in tumor growth compared to the control group, but anti-PD-L1 treatment showed a significant antitumor effect.
Conclusion: We confirmed that overexpression of PD-L1 in an orthotopic breast cancer model did not induce increased tumor growth. Above all, it was confirmed that a high PD-L1 level enhances the antitumor effect of immune checkpoint inhibitors. Our findings show that the expression level of PD-L1 in breast cancer has a significant effect on the immune checkpoint inhibitor effect. We need to further investigate the role of PD-L1 in breast cancer.
Citation Format: A Young Park, Ju Hee Kim, Sangen Lee, Hong Kyu Kim, Han-Byoel Lee, Wonshick Han. Association PD-L1 overexpression with immune checkpoint inhibitor effect in triple-negative 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 6654.
Abstract 6656: Expression pattern and clinicopathological implication of B7 family immune checkpoints, VTCN1 and HHLA2, in non-small cell lung cancer
Authors: Lim Sojung , Koh Jaemoon , Song Seung Geun , Yim Jeemin , Han Bogyeong , Kim Young A , Chung Doo Hyun , Jeon Yoon Kyung 
Published: April 2023

Abstract
Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of current immunotherapies. VTCN1 (B7-H4/B7x/B7S1) and HHLA2 (B7-H7/B7y) are B7 family co-inhibitory molecules reported to be expressed in PD-L1-negative or EGFR-mutant lung adenocarcinoma (LUAD). To elucidate the clinicopathological implications of these two immune checkpoints, we checked their detailed expression patterns including intratumoral heterogeneity.
Methods: VTCN1 and HHLA2 expression were evaluated in public single-cell RNA sequencing (scRNAseq) and The Cancer Genome Atlas (TCGA) dataset. Their immunohistochemistry (IHC) was performed on tissue microarrays of 413 LUAD and 382 lung squamous cell carcinoma (LUSC) specimens. Intratumoral heterogeneity was evaluated by IHC on representative sections of 59 surgically resected LUAD and 49 LUSC specimens.
Results: In LUAD scRNAseq, VTCN1 and HHLA2 were predominantly expressed on epithelial cells and were not co-expressed with PD-L1. However, IHC showed their expression in both tumor and immune cells. In TCGA analysis, there was a negative correlation between VTCN1 and PD-L1 (LUAD, r = -0.094, p = 0.033; LUSC, r = -0.227, p &lt;0.001). VTCN1 and HHLA2 showed positive correlations in both TCGA (LUAD, r = 0.211, p &lt;0.001; LUSC, r = 0.182, p &lt;0.001) and IHC analysis (LUAD, p &lt;0.001; LUSC, p = 0.016). They were more frequently expressed in EGFR-mutant LUAD (52.9% vs. 40.3%, p = 0.015 for VTCN1 in EGFR-mutant vs. wildtype; 59.8% vs. 40.5%, p &lt;0.001 for HHLA2). CD8+ T-cell infiltration was significantly higher in VTCN1- or HHLA2-positive EGFR-mutant LUAD, but there was no significant relationship in EGFR-wildtype. In 60% of cases expressing both VTCN1 and HHLA2, the two showed spatially concordant expression (15 out of 24 LUAD; 3 out of 6 LUSC). However, VTCN1 and PD-L1 showed concordant expression in 37.2% of cases expressing both (6 out of 16 LUAD; 10 out of 27 LUSC). HHLA2 expression was associated with better overall survival in LUSC, but there was no significant difference in survival according to VTCN1 expression.
Conclusions: VTCN1 and HHLA2 are frequently co-expressed in PD-L1-negative NSCLC, especially EGFR-mutant LUAD rich in CD8+ T-cells and can serve as potential novel immunotherapeutic targets.
Citation Format: Sojung Lim, Jaemoon Koh, Seung Geun Song, Jeemin Yim, Bogyeong Han, Young A Kim, Doo Hyun Chung, Yoon Kyung Jeon. Expression pattern and clinicopathological implication of B7 family immune checkpoints, VTCN1 and HHLA2, in non-small cell lung 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 6656.
Abstract 6681: XNA increases assay sensitivity in sanger sequencing, qPCR, NGS and CRISPR mutant screening
Authors: Liu Wei , Brown Robert , Fu Andrew , Shen Shuo , Sha Michael , Zhang Aiguo 
Published: April 2023

Abstract
The proprietary XNA (xeno nucleic acid) technology has wide applications in sensitive detection of rare mutations in different genomic platforms. These target-specific DNA oligo analogs increase assay sensitivity by blocking the polymerase-dependent amplification of wildtype sequence so only amplification of the mutant sequence occurs. Here we show that the XNA technology helps enrich rare somatic mutations in different human specimen types such as FFPE and plasma samples, using technology platforms such as Sanger sequencing, TaqMan qPCR, and NGS. XNA increases assay sensitivity to 0.1% for Sanger sequencing and qPCR. For NGS, XNA allows detection of the mutant sequence at a lower sequencing depth, thus combining XNA technology with NGS for MRD (molecular residual disease) detection could improve cancer management. In addition, We also show CRISPR mutant screening using a target-specific XNA in a SYBR Green qPCR assay. XNA can be used for rapid CRISPR mutant screening for DNA from pool or individual clones generated from gene editing experiments. In summary, XNA technology is a powerful tool when combined with existing genomic mutation detection platforms to screen for rare somatic mutations and for rapid CRISPR mutant screening. The technology is customizable as a service for easy integration with current technology platforms and applications.
Citation Format: Wei Liu, Robert Brown, Andrew Fu, Shuo Shen, Michael Sha, Aiguo Zhang. XNA increases assay sensitivity in sanger sequencing, qPCR, NGS and CRISPR mutant screening [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 6681.