bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2343: Adapting gene set enrichment analysis to single cell data
Authors: Wenzel Alexander T. , Jun John , Mesirov Jill P. 
Published: March 2024

Abstract
Gene Set Enrichment Analysis (GSEA) is a method for quantifying the activation of pathways and processes in gene expression data. GSEA works by ranking genes and testing if genes in annotated gene sets representing molecular pathways are overrepresented at the top or bottom of the ranked list. Standard GSEA assumes a gene-by-sample matrix with samples falling in two phenotype class labels and ranks genes based on correlation of expression and sample class labels. Single sample (ssGSEA) uses a similar approach to enrichment scoring but ranks genes in a single sample based on their expression. There has been recent interest in using the ssGSEA modality to measure pathway activity in individual cells from single cell RNA-sequencing (scRNA-seq) data. However, we have observed that ssGSEA scores in scRNA-seq cells are prone to uncertainty due to the characteristic sparsity of scRNA-seq data. This is because sparse data leads to large groups of tied genes, that is, genes with equal expression and subsequently equivalent positions in the ranked list. Because ssGSEA, which was designed for bulk gene expression technologies which yield much less sparse data, breaks ties arbitrarily, these ties can lead to variability in enrichment scores that is purely algorithmic and not a result of the underlying biology. To address this issue, we performed benchmarking to characterize the stability of scores using different enrichment scoring statistics, normalization methods, and aggregation of similar single cells. We have implemented the best practices identified using this analysis as Single Cell GSEA (scGSEA), a software tool which we will make freely available to researchers as open-source software to enable robust gene set enrichment scoring in scRNA-seq data.
Citation Format: Alexander T. Wenzel, John Jun, Jill P. Mesirov. Adapting gene set enrichment analysis to single cell data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2343.
Abstract 2364: Anti-CADM1 chimeric antigen receptor (CAR) is a novel therapeutic strategy against small cell lung cancer
Authors: Katkam Shiva Krishna , Zolov Sergei , Shield Delaney , Chuikov Sergei , Keshamouni Venkateshwar G 
Published: March 2024

Abstract
Small cell lung cancer (SCLC) is a highly aggressive form accounting for 15% of all lung cancers. SCLC is characterized by high proliferative rates, early metastasis, and poor prognosis. The median survival is less than 2 years even in patients with early-stage disease and less than a year in patients with metastatic disease which highlights the need for new therapeutic strategies. Cell Adhesion Molecule (CADM) 1 encodes a glycoprotein which belongs to an immunoglobulin superfamily of cell adhesion molecules responsible for epithelial cell adhesion through its homophilic trans-interaction between the adjacent cells. CADM1 is highly expressed on the cell surface of 80% of the SCLC cells, associated with its neuroendocrine features, along with the expression of Neural Cell Adhesion Molecule (NCAM). CADM1 is known to act as tumor promoter through its interactions with actin binding proteins. Consistently, we observed CADM1 expression in H69, H82, and H510 SCLC cell lines as assessed by western immuno blot. More importantly they were all susceptible to NK mediated cytotoxicity when assessed against NK cell line, NK92. We previously demonstrated that CADM1 mediates NK-mediated immune surveillance in non-small cell lung cancer, suggesting that CADM1 could be a potential immunotherapeutic target for SCLC. Here we report the development of an anti-CADM1 chimeric antigen receptor (CAR) specific for T and NK cells engineered with T and NK cell specific adaptor domains. Assessed the specificity of CARs by expressing them in NK92 cells and testing them against CADM1 expressing and CADM1-null A549 cells as targets. Finally, we evaluated the efficacy of anti-CADM1 CAR-T and CAR-NK cells against SCLC targets and observed a robust killing, largely proportionate to the levels of CADM1 expression in them. We are further assessing the efficacy of anti-CADM1 CAR-T and CAR-NK products in inhibiting tumor growth in NSG mice against SCLC xenografts. Together, these observations demonstrate that targeting CADM1 with CAR-T and CAR-NK cells is a potential new therapeutic strategy for SCLC.
Citation Format: Shiva Krishna Katkam, Sergei Zolov, Delaney Shield, Sergei Chuikov, Venkateshwar G Keshamouni. Anti-CADM1 chimeric antigen receptor (CAR) is a novel therapeutic strategy against small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2364.
Abstract 2382: KY-CLC-mouse: a common light chain bispecific antibody discovery platform
Authors: Peng Hao , Wu Guojin , Hao Feng , He Feng , Gu Yi , Ning Jinying 
Published: March 2024

Abstract
Bispecific antibodies (BsAbs) have emerged as a potent therapeutic tool in cancer treatment, gaining increasing centrality in therapeutic applications. However, the development of bispecific antibodies is hindered by the mispairing of light and heavy chains. In response to this challenge, our company developed the KY-CLC-mouse, featuring an identical κ light chain without the expression of the λ light chain. This mouse shows great promise in bispecific antibody development, as the identical κ light chain, modified from a frequently occurring light chain in mice, pairs with multiple heavy chains. The advantages of such a light chain include good solubility and stability, as well as ease of humanization without post-translational modifications in the complementary-determining regions (CDRs). Furthermore, the CDRs were modified to reduce immunogenicity. This KY-CLC-mouse platform has facilitated the identification of antibodies that specifically target over a dozen antigens, such as PD-1, LAG33, MET, PSMA, and CD28, with KD ranging from 0.1 nM to 10 nM. We apply the knob-in-hole technology to assemble bispecific antibodies, targeting two antigens or different epitopes of the same antigen, following their humanization. Prime examples include fully humanized BsAbs PD1xLAG-3, PDL1xEGFR, PSMAxCD28, and EGFRxB7H3. These bispecific antibodies have an identical light chain and were developed with knob-into-hole technology. With different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, the BsAbs show neither aggregation nor degradation, suggesting good developability of these antibodies. Additionally, these BsAbs have a half-life of more than five days in the blood of both mice and monkeys. In conclusion, our common light chain KY-CLC-mouse is a powerful bispecific antibody discovery platform.
Citation Format: Hao Peng, Guojin Wu, Feng Hao, Feng He, Yi Gu, Jinying Ning. KY-CLC-mouse: a common light chain bispecific antibody discovery platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2382.
Abstract 2391: Towards better prediction of treatment resistance: Directly modeling progression from multiple lesions
Authors: Protich Samuel , Stoddard Madison , Yuan Lin , White Douglas , Bottino Dean , Chakravarty Arijit 
Published: March 2024

Abstract
Late-stage cancers in the clinic present as a set of dispersed tumors, each with distinct growth kinetics. As most patients enrolled in trials of experimental anticancer therapeutics have late-stage malignancies, it is important to understand the impact of data analysis methodologies on the ability to detect treatment effect. In particular, we are interested in the potential risk posed by aggregating individual tumor measurements from multiple-lesion clinical data into a single tumor burden measurement, as this may cause a loss of information. In this work, we use quantitative modeling to assess how analyzing multiple lesions separately versus using an aggregated readout affects tumor response and detection of progression free survival and relapse. To assess the impact of data aggregation, we built a two-population clonal dynamics model consisting of sensitive and resistant tumor cells undergoing growth in the presence or absence of treatment. We performed parameter sweeps to assess the impact of individual model parameters on progression free survival and relapse. We then extended these sweeps to the multi-lesion situation, using nonlinear regression to compare parameter values of aggregated models and the parameter values of the individual models that comprised it. From our simulations, the most influential parameters in determining rebound are the growth rate of the resistant cells and the fraction of these cells, while growth rate of sensitive cells and growth rate inhibition affect effectiveness of treatment. In analyzing the multiple lesion model in different situations, we found that estimates for progression free survival were significantly more sensitive when the lesions were analyzed separately, rather than being aggregated. Our work suggests that aggregating the lesions into a single readout loses impact of individual lesion growth rate inhibitions, impairing early detection as the ability to detect fast growing, small, resistant lesions (despite overall tumor burden decreasing) is lost. Taken together, our findings suggest that data aggregation causes a loss of information. Relapse can be predicted at earlier times when using the multiple lesion model compared to an aggregated model.
Citation Format: Samuel Protich, Madison Stoddard, Lin Yuan, Douglas White, Dean Bottino, Arijit Chakravarty. Towards better prediction of treatment resistance: Directly modeling progression from multiple lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2391.
Abstract 2394: Significance of regional lymph node dissection in patients with clear cell sarcoma and epithelioid sarcoma
Authors: Takemori Toshiyuki , Kobayashi Eisuke , Iwata Shintaro , Ogura Koichi , Osaki Shuhei , Fukushima Suguru , Kawai Akira 
Published: March 2024

Abstract
Objective Clear cell sarcoma (CCS) and epithelioid sarcoma (ES) are common as soft-tissue sarcoma subtypes causing lymph node metastasis (LNM), but the role of regional lymph node dissection is still unclear especially in these patients without imaging evidence of LNM. Here we retrospectively investigated the significance of lymph node dissection for patients with CCS and ES. Methods Forty-one patients (CCS: 13, ES: 28) with no distant metastasis other than in the regional lymph nodes were enrolled in this study. Of these 41 patients, those without LNM on imaging findings were categorized into two groups: "with dissection (WD)" group and "no dissection (ND)" group, respectively. Overall survival (OS), lymph node metastatic-free survival (LNMFS), progression-free survival (PFS), and post-operative LNM rate were compared between two groups. Results There were 26 patients who had undergone regional lymph node dissection and 15 patients who had not undergone regional lymph node dissection (ND group). Histopathological examination revealed metastasis to the lymph nodes in 9 of the 26 patients (38.5%). 9 patients were suspected of having LNM based on preoperative imaging findings such as CT or FDG PET/CT. Among the remaining 17 patients (WD group) in whom LNM was not suspected based on preoperative imaging findings, 6 patients (35.3%) had LNM. OS (p=0.03), LNMFS (p&lt;0.01), and PFS (p&lt;0.01) were all significantly better in the WD group. The postoperative LNM rate was significantly lower in the WD group than in the ND group (p=0.03), and there were no significant differences in OS, LNMFS, or PFS between the CCS and ES groups in terms of histological type. Discussion Even in cases where LNM was not suspected on preoperative imaging, LNM was present in more than 30% of cases. The possibility of regional LNM should be borne in mind in soft-tissue sarcomas, which frequently present with LNM, regardless of imaging findings. We also suggested that simultaneous dissection of the regional lymph nodes at the time of resection of the primary tumor improves the prognosis. Although ES and CCS are ultra-rare sarcomas, further validation with the accumulation of case series is desirable.
Citation Format: Toshiyuki Takemori, Eisuke Kobayashi, Shintaro Iwata, Koichi Ogura, Shuhei Osaki, Suguru Fukushima, Akira Kawai. Significance of regional lymph node dissection in patients with clear cell sarcoma and epithelioid sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2394.
Abstract 2437: Distinct DNA methylation patterns in male urogenital cancers
Authors: Yu Guopeng , Wang Jiangyi , Li Long , Xie Wenchuan , Liu Yushan , Yang Qing , Xu Bin 
Published: March 2024

Abstract
Background: Male urogenital cancers including prostate cancer (PCa), bladder cancer (BLCA) and kidney renal cancer (KIRC), account for 38% of the total number of new male cancers. Previous studies have shown that changes in DNA methylation patterns are associated with the occurrence and progression of these cancers. Here, we performed whole-genome bisulfite methylation sequencing (WGBS) on tissue samples from these cancers to comprehensively characterize the methylation patterns to provide insights into the potential biological functions of methylation and to identify possible early detection biomarkers.
Methods: Tissue samples were collected from patients with PCa, BLCA and KIRC who had not received any treatment prior to surgery from Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine. Samples with the cancer cells content ≥30% in cancer tissues and no cancer cells in the adjacent tissues was deemed qualified. A total of 43 samples were sequenced by whole-genome bisulfite methylation sequencing (WGBS) with a depth of 30X, including PCa, BLCA, KIRC cancer tissues, and their adjacent cancer tissues.
Results: Distinct methylation patterns were observed in the 3 cancers. By comparing cancer and adjacent tissues, the numbers of differentially methylated sites (DMSs) were 21,195 (31% hyperDMSs and 69% hypoDMSs), 587,010 (23% hyperDMSs and 77% hypoDMSs) and 7,855,162 (5% hyperDMSs and 95% hypoDMSs) in PCa, BLCA and KIRC, respectively. The distribution of hyperDMSs and hypoDMSs across various chromosomes was relatively consistent in KIRC and BLCA. However, in PCa, the hypoDMSs were mainly located on chromosome 8 (5265/14666, 36%). Among the three cancers, only 2-3% of hypoDMSs were located in gene promoter regions, while the proportions of hyperDMSs in gene promoter regions were higher with 4%, 8% and 17% for PCa, BLCA and KIRC, respectively. Among the above DMSs, 1901 DMSs-related genes were shared by PCa, BLCA and KIRC and 251, 4252, 2475 DMSs-related genes were unique in PCa, BLCA and KIRC, respectively. Gene Ontology analysis revealed that the shared DMSs-related genes were enriched in Wnt signaling pathway and positive regulation of MAPK cascade.
Conclusions: Our present study demonstrated the differential methylation patterns in male urogenital cancers, which may provide insights into the potential biological functions of methylation and to identify possible early detection biomarkers.
Citation Format: Guopeng Yu, Jiangyi Wang, Long Li, Wenchuan Xie, Yushan Liu, Qing Yang, Bin Xu. Distinct DNA methylation patterns in male urogenital cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2437.
Abstract 2445: Peripheral blood immune phenotypes in pancreatic ductal adenocarcinoma
Authors: Pavelko Kevin D. , Villasboas Jose C. , Taylor William R. , Doering Karen A. , Kisiel John B. , Majumder Shounak 
Published: March 2024

Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a major cancer killer with a low 5-year survival rate of 12%. Diagnosing PDAC at an early stage is one of the strongest predictors of long-term survival. Therefore, novel methods for early detection of PDAC must be explored. In this pilot study we aimed to compare the peripheral blood immune cell phenotypes in PDAC cases and cancer-free controls.
Method: CyTOF (cytometry by time-of-flight) was used to evaluate peripheral blood mononuclear cells (PBMC) from newly diagnosed treatment naïve patients with PDAC and sex and age matched cancer-free controls using a 29-marker immune phenotyping panel. Multiple analysis approaches including dimensionality reduction using tSNE and clustering using Phenograph were used to evaluate the results. Immune subsets having differential abundance differences were verified by manual gating.
Results: Twenty patients were included in this pilot study (15 PDAC cases; 5 Cancer-free controls). Among the 15 PDAC cases, 5 were early stage (Stage 1-2). Thirty-two unique immune cell clusters were identified using the Phenograph algorithm: 10 unique clusters with properties consistent with monocytes/macrophages, 9 CD4 T cell clusters, 6 CD8 T cell clusters and 4 NK cells clusters. When comparing the case and control groups we noted lower percentages of CD8+CD27+ T-cells in cases. This was further verified by manual gating that confirmed the distribution of CD8+CD27+ T-cells relative to all T-cells were decreased in PDAC patients. In addition, a 57% increase in naïve CD4 T cells was found in case samples compared to controls. A principal component analysis of the clustering results identified two unique clusters of immune profiles that emerged providing a potential peripheral blood immune cell signature that could stratify and differentiate PDAC cases from controls. A CD14+CD16+CD4LoCD38+CD45RO+ population of monocytes was the primary cell population driving this difference.
Conclusion: This study provides early evidence to indicate that a distinct PBMC immune phenotype may differentiate PDAC patients from control subjects. Further analysis in larger sample sets is warranted for in-depth characterization and identification of unique immune based biomarkers for PDAC detection.
Citation Format: Kevin D. Pavelko, Jose C. Villasboas, William R. Taylor, Karen A. Doering, John B. Kisiel, Shounak Majumder. Peripheral blood immune phenotypes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2445.
Abstract 2447: Identification of tumor marker gangliosides for early cancer detection: A mass spectrometry approach
Authors: Culp-Hill Rachel , Hill Collin , Blackler Adele , Ricketts William 
Published: March 2024

Abstract
Tumor-marker gangliosides (TMGs) have enormous potential for early-stage cancer detection as diagnostic biomarkers despite being relatively understudied in this context. AOA Dx is focused on the development of a mass spectrometry platform for the quantitation of TMGs in human serum, particularly disialogangliosides GD2 and GD3. The development of a mass spectrometry platform for TMG quantitation may allow for the identification of diagnostic signatures for early-stage cancer detection. Briefly, we monitored fragment moieties characteristic of gangliosides in an untargeted fashion by mass spectrometry. We then identified those differentially altered in cancerous groups compared to normal, and subsequently performed targeted MRM analysis. Through these investigations, we have identified multiple TMGs, specifically multiple types of GD2 and GD3 species characterized by unique lipid tails across different cancer types in human serum from confirmed cancer diagnoses. Other ganglioside classes including GMs and relatively understudied GTs were also identified in this study. Notably, the serum of melanoma and ovarian cancer patients exhibited significantly increased levels of several ganglioside species compared to age-matched healthy serum, highlighting the potential of TMGs as a promising avenue for cancer diagnosis. Further experiments will focus on refining this mass spectrometry method and expand demographic representation to confirm our initial findings and identify additional TMGs of interest. In addition, we intend to apply immune-based platforms such as thin-layer chromatography and ELISA, which have already shown promising results in the detection and quantitation of these compounds. Taken together, AOA Dx is advancing the development of a high-throughput mass spectrometry platform designed for the detection of TMGs, with a primary focus on GD2 and GD3. Our objective is the identification of a diagnostic disease signature for early-stage cancer detection. The validation of this type of diagnostic panel would allow for expedited diagnosis and treatment of cancers currently diagnosed at late stages, ultimately reducing healthcare costs and increasing survival rates. Future research will aim to validate these biomarkers in independent prospective studies.
Citation Format: Rachel Culp-Hill, Collin Hill, Adele Blackler, William Ricketts. Identification of tumor marker gangliosides for early cancer detection: A mass spectrometry approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2447.