bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4826: Cancer mortality attributable to area-level socioeconomic inequalities in Japan from 2015 to 2020
Authors: Ito Yuri , Nakaya Tomoki , Inoue Manami , Sobue Tomotaka , Nakagama Hitoshi 
Published: March 2024

Abstract
Background: In the 3rd Healthy Japan 21 and the 4th National Cancer Plan, the government focused on reducing health inequalities. However, current monitoring of socioeconomic inequalities in cancer is still insufficient to set the targets for the plan. To prioritize strategy aimed at reducing socioeconomic inequalities in cancer mortality, we estimated the population attributable risk fraction (PAF) and excess death due to socioeconomic inequalities, by sex, age group and cancer site.
Method: We used the areal deprivation index (ADI) to establish area-based socioeconomic status. We categorized municipalities to ADI quintile weighted by the size of population, Q1 is the least deprived and Q5 the most deprived group. Excess death due to socioeconomic inequalities was calculated by the difference between observed number of deaths and expected death of Q2 to Q5 group with Q1 as standard population. We used cancer mortality data obtained from vital statistics in 2015-2020.
Results: In total, about 12000 male and 2800 female excess deaths per year due to socioeconomic inequalities were estimated; that is 5.5% and 1.8% as PAF. PAF due to socioeconomic inequalities limited to premature death, less than 75 years old, was estimated as 7.6% in men and 3.3% in women. By age group, the 0-39 years group showed the largest PAF at 15.7% in men and 16.6% in women. In men of all age groups, except 0-39 years, lung cancer was the highest excess death due to socioeconomic inequalities. For women, some cancer sites (breast, ovary, esophagus) showed an opposite association, Q1 was the highest mortality group. Therefore, total excess death was lower than in men. In women of all ages, the highest rate of excess death due to socioeconomic inequalities was gallbladder cancer. For the 0-39 years group, a high rate of excess death in stomach, leukemia, and cervical cancer was observed.
Discussion: Excess death and PAF due to socioeconomic inequalities differed by sex and age group. A greater impact of socioeconomic inequality on cancer mortality was observed in men than in women. Among women, further attention should be paid to areal variation of cancer death related to socioeconomic inequalities, based on the different area-based indices.
Citation Format: Yuri Ito, Tomoki Nakaya, Manami Inoue, Tomotaka Sobue, Hitoshi Nakagama. Cancer mortality attributable to area-level socioeconomic inequalities in Japan from 2015 to 2020 [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 4826.
Abstract 4897: Personalized cell surface target identification from pan-cancer RNA-seq and proteomics profiling of tumors
Authors: Marino Giacomo B. , Deng Eden Z. , Clarke Daniel J.B. , Ma Weiping , Wang Pei , Resnick Adam C. , Ma'ayan Avi 
Published: March 2024

Abstract
In its third phase, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) program collected pan-cancer data from 1,069 patients profiling the transcriptome, proteome, and phospho-proteome of tumors and adjacent tissues from ten cancer types. To identify potential immunotherapeutic candidates from this CPTAC cohort, we searched for cell-surface proteins that are highly expressed in tumor subtypes compared to their expression in normal tissues and cell types from ARCHS4 and the Genotype-Tissue Expression (GTEx) resources. For each cancer type, tumor samples were first clustered into subtypes based on RNA-seq data, and then cell surface targets were prioritized for each cluster. These targets were subsequently confirmed for high protein expression in the tumor subtypes. Tumor samples were also processed by their classification into immune subtypes to identify targets specific to hot (CD8+/IFNG+) and cold (CD8-/IFNG-) tumors of each cancer type. For each cancer type, the computational pipeline identified ~30 cell surface proteins that are highly expressed in the tumor and lowly expressed across tissues and cell types in both the ARCHS4 and GTEx backgrounds. Many of these targets are also robustly differentially expressed at the proteome level. Several targets were shared across tumor types, including VTCN1 and TMPRSS4. Altogether, this rational approach to identify potential targets demonstrates a pipeline that can be applied for personalized cancer diagnosis and therapeutic development.
Citation Format: Giacomo B. Marino, Eden Z. Deng, Daniel J.B. Clarke, Weiping Ma, Pei Wang, Adam C. Resnick, Avi Ma'ayan. Personalized cell surface target identification from pan-cancer RNA-seq and proteomics profiling of tumors [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 4897.
Abstract 4899: Interface-guided phenotyping of coding variants in the transcription factor RUNX1
Authors: Ozturk Kivilcim , Panwala Rebecca , Sheen Jeanna , Ford Kyle , Jayne Nathan , Zhang Dong-Er , Hutter Stephan , Haferlach Torsten , Ideker Trey , Mali Prashant , Carter Hannah 
Published: March 2024

Abstract
Understanding the consequences of single amino acid substitutions in cancer driver genes remains an unmet need. Perturb-seq provides a tool to investigate the effects of individual mutations on cellular programs. Here we deploy SEUSS, a Perturb-seq like approach, to generate and assay mutations at physical interfaces of the RUNX1 Runt domain. We measured the impact of 115 mutations on RNA profiles in single myelogenous leukemia cells and used the profiles to categorize mutations into three functionally distinct groups: wild-type (WT)-like, loss-of-function (LOF)-like and hypomorphic. Notably, the largest concentration of functional mutations (non-WT-like) clustered at the DNA binding site and contained many of the more frequently observed mutations in human cancers. Hypomorphic variants shared characteristics with loss of function variants but had gene expression profiles indicative of response to neural growth factor and cytokine recruitment of neutrophils. Additionally, DNA accessibility changes upon perturbations were enriched for RUNX1 binding motifs, particularly near differentially expressed genes. Overall, our work demonstrates the potential of targeting protein interaction interfaces to better define the landscape of prospective phenotypes reachable by amino acid substitutions.
Citation Format: Kivilcim Ozturk, Rebecca Panwala, Jeanna Sheen, Kyle Ford, Nathan Jayne, Dong-Er Zhang, Stephan Hutter, Torsten Haferlach, Trey Ideker, Prashant Mali, Hannah Carter. Interface-guided phenotyping of coding variants in the transcription factor RUNX1 [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 4899.
Abstract 5182: Exploiting tumor RNA-sequencing data for prediction of immune checkpoint inhibition response
Authors: Mestdagh Pieter , Van Dam Pieter-Jan , De Baene Frederick , Fierro Carolina , Van Hoof Elise , Rivière Emmanuel , Dangreau Hanne , Van Cauwenberge Reindert , Vandesompele Jo 
Published: March 2024

Abstract
Immune checkpoint inhibitors (ICI) have become the standard of care as a first- or second-line systemic treatment for patients with various cancer types. Unfortunately, many patients do not respond to this treatment and the occurrence of immune-related adverse events varies widely. There is an urgent need for robust predictive biomarkers for ICI response to identify patients with likely clinical benefit from this costly treatment. Several biomarkers, aimed at predicting response to ICI, have been proposed, including PD-L1 expression, tumor mutation burden (TMB), infiltration of cytotoxic T-cells in the tumor, Microsatellite Instability (MSI) and expression of various immune gene signatures. However, these individual biomarkers have suboptimal performance and multiple complementary omics technologies are required to properly quantify them. Integration of these multi-omic biomarkers has proven valuable in increasing the accuracy and robustness of ICI response prediction.We have developed a computational pipeline that determines the expressed mutation burden (eTMB), MSI status, fraction of infiltrating immune cells and various immune gene expression signatures directly from the RNA-sequencing profile of the tumor. Each biomarker is quantified using a dedicated algorithm that applies machine learning (eTMB and MSI) or computational deconvolution (infiltrating immune cells) and integrates external data sources to maximize performance. Algorithm performance has been validated on large cohorts of tumor RNA-sequencing data with matching gold standard quantification of said biomarkers.
As a proof of concept, we applied our pipeline to tumor RNA-sequencing data of 45 gastric cancer patients treated with pembrolizumab. Responders showed significantly higher eTMB scores and were enriched among the MSI-H patients. Fractions of CD8 T-cells and M1 Macrophages, together with interferon gamma and cytotoxic T-cell gene expression signatures, were significantly increased in responders. Notably, integrating these biomarkers into a single prediction model improved prediction of response to checkpoint inhibition therapy compared to predictions based on eTMB or MSI alone.
Taken together, our approach enables the quantification of various ICI response biomarkers from a single omics layer (RNA-sequencing) and can contribute to ICI response prediction.
Citation Format: Pieter Mestdagh, Pieter-Jan Van Dam, Frederick De Baene, Carolina Fierro, Elise Van Hoof, Emmanuel Rivière, Hanne Dangreau, Reindert Van Cauwenberge, Jo Vandesompele. Exploiting tumor RNA-sequencing data for prediction of immune checkpoint inhibition response [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 5182.
Abstract 5246: Therapeutic efficacy of glypican-3 peptide-linked chimeric antigen receptor-macrophages in hepatocellular carcinoma
Authors: Leung Wing Hei , Leung Oi Ning , Wong Tsun Ting , Lee Kin Wah 
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is the third most lethal cancer and sixth most diagnosed cancer worldwide. Recently, chimeric antigen receptor-T cell (CAR-T) therapy has been demonstrated to be a promising immunotherapy for the treatment of hematologic malignancies such as leukemia. However, its application in solid tumors has proven to be challenging. To overcome this limitation, chimeric antigen receptor-macrophages (CAR-Ms) have emerged as a new immunotherapy against solid cancers, capitalizing on the unique attributes of macrophages in penetrating the tumor microenvironment, promoting antigen presentation, and priming T cells. Traditionally, CAR-M therapy involves the transfer of an edited CAR gene into macrophages via viral infection. However, this method is expensive, involves tedious procedures, and has long-term safety concerns. In the present study, we employed peptides to mimic the genetic approach for producing CAR-Ms to reduce the above uncertainties. To achieve this, we developed a novel bioconjugation method called the phthalaldehydeamine capture (PAC) reaction to produce peptidic CAR-Ms (pCAR-Ms) targeting Glypican-3 (GPC3) in HCC cells. This was achieved by linking GPC3 specific peptides to Raw264.7 murine macrophages. Using an in vitro co-culture system, we demonstrated the specificity and efficacy of pCAR-Ms against GPC3, as evidenced by a significant increase in the number of phagocytosed cells with high GPC3 expression when compared to their low-expression counterparts, by flow cytometry and confocal microscopy. The specificity of pCAR-Ms was further proven in GPC3-knockdown HCC cells, with a significant decrease in the phagocytic rate. Using an HCC xenograft model derived from MHCC97L cells, we confirmed the specific homing of pCAR-Ms to tumor sites via intravenous injection of lipopolysaccharide (LPS)-differentiated pCAR-Ms. Strikingly, pCAR-Ms suppressed HCC tumor growth when compared with untagged macrophages and PBS control. In conclusion, we provided evidence of the potency and specificity of non-viral-based pCAR-Ms in targeting HCC with simple and short production time and increased flexibility.
Citation Format: Wing Hei Leung, Oi Ning Leung, Tsun Ting Wong, Kin Wah Lee. Therapeutic efficacy of glypican-3 peptide-linked chimeric antigen receptor-macrophages in hepatocellular carcinoma [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 5246.
Abstract 5280: Minimizes T cells DNA damage induced by PARP inhibitors and enhances its anti-tumor efficacy
Authors: Liu Jiahao , Jiao Xiaofei , Mu Wei , Li Huayi , Zhu Li , Zhao Xuejiao , Mills Gordon B. , Gao Qinglei , Fang Yong 
Published: March 2024

Abstract
Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for ovarian and breast cancer. The sustained remission induced by PARP inhibitors largely depends on T cell activity. However, the direct effects of PARP inhibitors on T cells, as well as their precise impact on T cell DNA integrity and subsequent anti-tumor immune responses, have not been fully elucidated.
Method & Result: Following treatment with 25 μM olaparib or 15 μM niraparib for 48 hours, T cell viability decreased by 39.20% and 41.89%, respectively. Reduced proliferation and increased cell death were also observed, as indicated by reduced Ki-67 and elevated cleaved Caspase-3 levels. RNA sequencing further revealed a significant enrichment of DNA damage pathways in T cells after olaparib treatment, which was validated by elevated γH2AX levels in T cells using western blots and immunofluorescence. To assess PARP inhibitor-induced DNA damage in clinical settings, paired ovarian cancer samples pre- and post-niraparib monotherapy were obtained from the NANT trial (NCT04507841). Post-treatment tumor samples exhibited a higher number of γH2AX+ T cells compared to their pre-treatment counterparts. To identify the key protein mediating T cell inhibition induced by PARP inhibitors, a whole genomic CRISPR knock-out screening was conducted in human T cells, revealing an enrichment of sgRNAs targeting PARP1 after PARP inhibitor treatment. This outcome was further confirmed by the knockout of PARP1 in human T cells in vitro, leading to the restored viability and reduced levels of DNA damage after olaparib treatment. Importantly, following cytosine base editors (CBEs) of PARP1 in CAR-T cells, improved anticancer activity was observed both in vitro and in two ovarian cancer patient-derived xenografts (PDX) models when combined with PARP inhibitors.
Conclusion: This study observed that PARP inhibitors can cause significant DNA damage in human T cells, resulting in cell death, inhibited proliferation, and impairment of anti-cancer immunity. PARP1 was identified as the target for PARP inhibitor-induced T cell death, and its knockout or point mutation led to improved anticancer efficacy of T cells when used in combination with PARP inhibitors. [JH Liu and XF Jiao contributed equally as co-first authors.]
Citation Format: Jiahao Liu, Xiaofei Jiao, Wei Mu, Huayi Li, Li Zhu, Xuejiao Zhao, Gordon B. Mills, Qinglei Gao, Yong Fang. Minimizes T cells DNA damage induced by PARP inhibitors and enhances its anti-tumor efficacy [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 5280.
Abstract 5396: Vascularized gastric cancer 3D co-culture model using a microphysiological system as an oncolytic virus testing platform
Authors: Kim YeLin , Song Youngsook , Choi Yeongmin , Jang Jinhwan , Kim Suryong , Liu Tsung-Li , Baek Kyusuk , Oh Keunhee , Ma Seunghyun , Kim Tae Soo , Kwon Woo Sun , Yoo Sanghee , Kim Jee Hung , Rha Sun Young 
Published: March 2024

Abstract
Introduction: Angiogenesis is a critical aspect of cancer growth and metastasis. Consequently, inhibiting angiogenesis has garnered substantial attention in oncology research. JX-594 (pexastimogene devacirpvec; Pexa-Vec®), engineered from the Wyeth vaccine strain, has emerged as an attractive oncolytic virotherapy and demonstrated oncolytic, immunotherapeutic, and tumor vasculature-disrupting capacities. In our previous study, we found that JX-594 reduced the amount of vasculature in gastric tumors using a xenograft mouse model. In the present study, we investigate the effect of JX-594 on tumor vasculature using an in vitro human cell 3D co-culture model of vascularized gastric cancer, to determine if this tool provides improved accuracy in evaluating the mechanism of action and biological activity of JX-594 as compared to traditional animal models.
Methods: The Curio-Spheroid chip is a Microphysiological System (MPS) that can grow tumor organoids or spheroids in 3D using physiologically relevant hydrogels and culturing them with other human cell types such as fibroblasts, endothelial cells, and immune cells. We evaluated nine human gastric cancer cell lines (YCC-18, YCC-19, YCC-22, YCC-30, YCC-32, YCC-38, Hs746T, NUGC-3, SNU-620) for their ability to form spheroids and induce angiogenesis inside Curio-Spheroid chips. We selected YCC-32 for the oncolytic virus testing. Serial increases of M.O.I (multiplicity of infection) of JX-594 disrupted the tumor-induced angiogenesis in a dose-dependent manner.
Results: JX-594 treatment of the YCC-32 spheroid resulted in decreased levels of Ki-67 and cytopathic effects in a dose-dependent manner inside the Curio-Spheroid MPS system. Angiogenesis was observed surrounding the spheroid when co-cultured with endothelial cells and fibroblasts. JX-594 decreased YCC-32 spheroid-induced angiogenesis in a dose-dependent manner in the vascularized gastric cancer 3D co-culture model.
Conclusion: JX-594 had an inhibitory effect on tumor-induced angiogenesis in our vascularized gastric cancer in vitro 3D human cell co-culture model, demonstrating the utility of the platform as a tool to interrogate the effects of an oncolytic virus on both tumor cell killing and tumor-induced angiogenesis.
Citation Format: YeLin Kim, Youngsook Song, Yeongmin Choi, Jinhwan Jang, Suryong Kim, Tsung-Li Liu, Kyusuk Baek, Keunhee Oh, Seunghyun Ma, Tae Soo Kim, Woo Sun Kwon, Sanghee Yoo, Jee Hung Kim, Sun Young Rha. Vascularized gastric cancer 3D co-culture model using a microphysiological system as an oncolytic virus testing 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 5396.
Abstract 5402: Understanding the role of exercise in lymphatic vessel regulation in melanoma
Authors: Tirumala Priya , Lee Jonghae , Schadler Keri L. 
Published: March 2024

Abstract
Exercise has been demonstrated to be an effective method to remodel tumor blood vessels and to improve immune cell infiltration in multiple tumor models in mice. However, it is unclear whether aerobic exercise alters lymphatic vasculature in tumors. The lymphatic system plays an important role in tumor growth and metastasis because it regulates interstitial fluid pressure via lymph flow and immune cell trafficking, in conjunction with blood vessels. Lymphatic vessels are particularly important during metastasis because tumor cells frequently escape the primary tumor through lymphatic vasculature to establish the first site of metastasis in the lymph nodes. Here, we evaluated the effect of aerobic exercise on lymphatic vessels and lymphatic endothelial cell junctions in melanoma in male C57BL/6J mice. BP melanoma cells derived from transgenic mice with BrafV600E/+ and Pten−/− mutations were injected subcutaneously. Mice were assigned to no exercise and exercise groups when tumors reached ~30 mm3. The exercise group completed treadmill running at 12 meters/minute for 45 minutes for 5 consecutive days with 2 days of rest per week for 2 weeks before tumor harvest. Tumor lymphatic endothelial cells were identified by LYVE-1, endothelial tight junctions by ZO-1, and nuclei were identified by DAPI using immunofluorescence staining on frozen tumors. The number of total lymphatic vessels, elongated vessels( &gt;100 µm), open lumens, and co-localization of ZO-1 with LYVE-1 was quantified on 6 random images per tumor using NIH Image J software. ANOVA and t-test were used to conduct statistical analysis (p &lt; 0.05). Tumors from exercised mice had higher lymphatic vessel density (p=0.002) and more open lumens (p=0.001). Surprisingly, tumors from exercised mice had fewer ZO-1 positive vessels (p=0.015) and lower co-localization of ZO-1 and LYVE-1 (p = 0.0185) than tumors from non-exercised mice, suggesting fewer stable endothelial cell junctions in lymphatic vessels. The higher lymphatic vessel density and higher number of open lumens present in tumors from exercised mice may contribute to an exercise-induced improved anti-tumor immune response, which has been previously reported. However, the lower ZO-1 expression on lymphatic endothelial cells in tumors from exercised mice may indicate lymphatic vasculature dysfunction and/or hyper-permeability. Further work is needed to assess the functional changes in tumor lymphatic vasculature by exercise, and how these changes impact the anti-tumor immune response and metastasis.
Citation Format: Priya Tirumala, Jonghae Lee, Keri L. Schadler. Understanding the role of exercise in lymphatic vessel regulation in melanoma [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 5402.