bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 102: LMP1-mediated recruitment of ALIX directs exosomal PD-L1 sorting and contributes to immunosuppression in EBV+ nasopharyngeal carcinoma
Authors: He Fajian , Gong Yan , Zhou Yajuan , Xie Conghua 
Published: March 2024

Abstract
Epstein-Barr virus (EBV) is known to cause multiple cancers and plays a pivotal role in tumor immune evasion. Latent membrane protein 1 (LMP1) is a key viral oncoprotein expressed in most EBV-associated cancers and contributes to tumor microenvironment remodeling. However, the exact role of LMP1 in modulating tumor immunity remains unclear. In this study, we elucidate how LMP1 interacts with PD-L1 and ALIX to form a trimolecular complex, facilitating the selective sorting of PD-L1 into exosomes and consequently impairing CD8+ T cell function in nasopharyngeal carcinoma (NPC). Specifically, the transmembrane domain of LMP1 interacts with and stabilizes PD-L1, while the intracellular domain of LMP1 binds to ALIX, thus enabling access to the exosomal secretory pathway. This interaction leads to the formation of a trimolecular complex comprising LMP1, PD-L1, and ALIX, which is indispensable for the exosomal trafficking of PD-L1. Importantly, disrupting ALIX significantly diminishes LMP1-induced exosomal PD-L1 secretion, thereby restoring CD8+ T cell functionality. Furthermore, we found that elevated levels of LMP1/ALIX expression are positively associated with immunosuppressive characteristics and poorer outcomes in human NPC. Our findings highlight the crucial role of the LMP1/ALIX axis in exosomal PD-L1 sorting and EBV-mediated immune evasion, presenting a novel and promising target for cancer immunotherapy.
Citation Format: Fajian He, Yan Gong, Yajuan Zhou, Conghua Xie. LMP1-mediated recruitment of ALIX directs exosomal PD-L1 sorting and contributes to immunosuppression in EBV+ nasopharyngeal 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 102.
Abstract 1057: A blood-based multi-omics test for multicancer early detection: Combined retrospective and prospective studies
Authors: Mao Mao , Li Shiyong , Ren Qingqi , Luan Yi , Liang Weijie , Geng Shuaipeng , Huang Dao-Ling , Zhu Dandan , Chang Yinyin , Wu Wei , Zhang Yingying , Zhang Linfeng , Wang Yan , Feng Yumin , Wei Bing , Ma Jie , Duan Chaohui , Long Guanghui 
Published: March 2024

Abstract
Background: Recent studies have demonstrated that blood-based multi-cancer early detection (MCED) approaches may hold promise for identifying asymptomatic cancer patients from general population. However, most studies only exploit a single aspect of cancer hallmarks, which is challenging for the biological reasons as cancer is a heterogenous disease with a wide spectrum of pathological and clinical behaviors. Here we report a multi-omics MCED assay named SeekInCare, a CE-IVD Mark blood test, which incorporates genomic hallmarks: copy number aberrations, fragment size, end motifs and oncogenic viruses via shallow whole genome sequencing from cfDNA, and seven plasma protein tumor markers in 8 ml blood.
Methods: SeekInCare was developed using several retrospective cohorts and the method has been described in a publication (DOI: 10.1016/j.jmoldx.2021.06.003) IF: 4.1 Q2.
Results: We present the validation in a retrospective cohort consisting of 584 non-cancer individuals and 617 cancer patients covering 27 cancer types. SeekInCare achieved 65.5% sensitivity at 97.9% specificity, resulting in an AUC of 0.936. The sensitivities were 46.9%, 60.0%, 68.9%, 81.8% in stage I, II, III, IV patients. The sensitivities of 10 common cancer types are as the following: breast (46.2%), stomach (46.4%), colorectum (56.5%), gallbladder (60.0%), lung (62.8%), pancreas (64.7%), lymphoma (68.5%), esophagus (70.0%), liver (77.5%), and leukemia (86.7%). These cancer types account for 73.5% of cancer incidence and 81.8% of cancer-related mortality in China. We prospectively evaluated SeekInCare in a real-world cohort consisting of 1203 individuals who received the test as a laboratory developed test (median follow-up time: 753 days) in which it achieved 60.0% sensitivity, 96.1% specificity, 11.5% PPV and 99.7% NPV.
Conclusion: The performances of SeekInCare in both retrospective and prospective studies demonstrate that SeekInCare is an effective blood-based MCED test with similar performance as Grail’s Galleri test, which paves the way for clinical utility as a cancer screening test in average-risk populations.
Citation Format: Mao Mao, Shiyong Li, Qingqi Ren, Yi Luan, Weijie Liang, Shuaipeng Geng, Dao-Ling Huang, Dandan Zhu, Yinyin Chang, Wei Wu, Yingying Zhang, Linfeng Zhang, Yan Wang, Yumin Feng, Bing Wei, Jie Ma, Chaohui Duan, Guanghui Long. A blood-based multi-omics test for multicancer early detection: Combined retrospective and prospective studies [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 1057.
Abstract 1080: Using genome-wide CRISPR screening to develop novel combination therapies for high-risk Ewing’s sarcoma
Authors: Ravindrarajah Daenikka , Krishan Sukriti , Simpson Kayleen , Gulati Twishi , Cheung Belamy B. , Marshall Glenn M. 
Published: March 2024

Abstract
Ewing’s sarcoma (EWS) is an aggressive bone and soft-tissue cancer, characterized by a hallmark fusion oncoprotein comprising the amino terminus of a FET gene and the carboxy terminus of an ETS gene, most commonly (85%), the EWSR1-FLI1 t (11,22) fusion.TK-216 is a first-in-class EWSR1-FLI1 inhibitor currently in phase II clinical trials for EWS. Although TK-216 was designed to target the fusion protein interaction directly, it has demonstrated limited efficacy as a monotherapy. Thus, more effective TK-216 combination therapies are needed. We have used genome wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Knockout screening in EWS cells treated with TK-216 to identify novel synthetic lethality. We have identified 97 genes whose deletion potentially enhances the action of TK-216 in EWS cells. We have also identified several druggable targets, such as USP9X and the oxidative phosphorylation (OXPHOS) pathway as synthetic lethal interactions for TK-216. USP9X is known to deubiquitinate and stabilize the EWS-FLI1 fusion protein. USP9X and EWS-FLI1 protein expression levels were found to be positively correlated in EWS clinical specimens. USP9X siRNA-mediated gene silencing reduced EWS cell viability. Most importantly, USP9X siRNA-mediated gene silencing sensitized EWS cells to TK-216 treatment. In addition, inhibition of USP9X with a small-molecule inhibitor WP1130, led to significant cell death in EWS alone and in combination with TK-216 with wide therapeutic indices. The molecular mechanism of synergy and in vivo efficacy of the novel TK-216 combination will be determined in our study for future clinical translation.
Citation Format: Daenikka Ravindrarajah, Sukriti Krishan, Kayleen Simpson, Twishi Gulati, Belamy B. Cheung, Glenn M. Marshall. Using genome-wide CRISPR screening to develop novel combination therapies for high-risk Ewing’s 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 1080.
Abstract 1087: Synergistic mechanisms against pediatric bone sarcoma models: Trabectedin enhances oncolytic virotherapy intratumoral spread and antitumor immune activation
Authors: Ringwalt Emily , Currier Mark , Glaspell Andrea , Cannon Matthew V. , Chen Chun-Yu , Gross Amy C. , Cam Maren , Wang Pin-Yi , Roberts Ryan D. , Cripe Timothy P. 
Published: March 2024

Abstract
Osteosarcoma and Ewing sarcoma are the most common pediatric bone malignancies and, despite decades of research, efforts to treat patients with advanced disease remain dismal. To address this inadequacy, we leverage oncolytic herpes simplex virotherapy as a double-edged attack against tumors through 1) tumor cell-specific lysis and 2) antitumor immune stimulation. However, previous trials of oncolytic herpes simplex virotherapy in pediatric sarcomas displayed limited responses, likely due to the observed presence of immunosuppressive monocytes and macrophages. To improve efficacy, we combined oncolytic herpes simplex virotherapy with trabectedin, an FDA-approved DNA-binding agent known to disrupt gene expression and deplete monocytes and macrophages. Surprisingly, we found that the efficacy of this combination far surpassed our predictions, inducing complete and partial regressions in multiple models of Ewing sarcoma and osteosarcoma. To explore potential mechanisms driving this high degree of synergy, we performed single cell RNA sequencing on tumors of mice treated with monotherapy or combination therapy. Interestingly, trabectedin synergized with the oncolytic virotherapy through two unexpected mechanisms. Our analysis revealed that trabectedin increased intratumoral oncolytic virus spread by disrupting expression of the intrinsic antiviral response in human Ewing sarcoma cells. Additionally, trabectedin not only reduced immunosuppressive macrophages but also stimulated cytotoxic granzyme expression in infiltrating T and NK cells in immunocompetent osteosarcoma models. These effector NK and T cells were necessary for the regressions of osteosarcoma allografts treated with trabectedin and oncolytic virotherapy. Thus, trabectedin enhanced both the oncolytic effect of herpes simplex virotherapy and the effector function of cytotoxic lymphocytes that become activated in response to the virus. The combination of trabectedin and oncolytic herpes simplex virotherapy offers the potential to unite these mechanisms against bone tumors to achieve better outcomes for children.
Citation Format: Emily Ringwalt, Mark Currier, Andrea Glaspell, Matthew V. Cannon, Chun-Yu Chen, Amy C. Gross, Maren Cam, Pin-Yi Wang, Ryan D. Roberts, Timothy P. Cripe. Synergistic mechanisms against pediatric bone sarcoma models: Trabectedin enhances oncolytic virotherapy intratumoral spread and antitumor immune activation [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 1087.
Abstract 1101: A patient-derived xenograft in vitro platform identifies panobinostat as the most efficient drug to treat high-risk hepatoblastoma patients
Authors: Demir Salih , Indersie Emilie , Branchereau Sophie , Hiyama Eiso , Cairo Stefano , Kappler Roland 
Published: March 2024

Abstract
Hepatoblastoma is the most common pediatric liver tumor, and the treatment of patients with preoperative chemotherapy and surgical resection of the tumor has led to survival rates of up to 83%. However, resistance of the primary tumor towards chemotherapy and the persistence of metastases still represents major challenges to achieve complete remission in high-risk patients, which is associated with poor prognosis. In order to identify new treatment options, we have used a newly developed in vitro drug-testing platform comprised of conventional cell lines and cultures from dissociated patient-derived xenografts of pediatric liver cancers to test standard-of-care medications used in the current PHITT trial as well as compounds targeting a wide range of different cellular pathways. We identified histone deacetylase (HDAC) inhibitors as a promising drug family to reduce tumor cell growth in a dose-dependent manner, with panobinostat being the most effective drug tested. Subsequent in vitro assays showed that panobinostat reduced short- and long-term proliferation, retarded three-dimensional spheroid growth and ultimately induced apoptosis of hepatoblastoma cells. RNA sequencing indicated that panobinostat results in downregulation of MYC target genes and upregulation of the dual specificity phosphatase 1. Of clinical relevance, the combination of panobinostat with doxorubicin revealed a strong synergistic effect, even stronger than the one of cisplatin and doxorubicin, which is currently given to high-risk hepatoblastoma patients. Moreover, increased expression of HDAC4 and HDAC11 in primary tumor tissues was significantly associated with metastatic disease. Our results strongly suggest panobinostat to be used in future therapeutic trials for high-risk hepatoblastoma patients, especially when combined with doxorubicin.
Citation Format: Salih Demir, Emilie Indersie, Sophie Branchereau, Eiso Hiyama, Stefano Cairo, Roland Kappler. A patient-derived xenograft in vitro platform identifies panobinostat as the most efficient drug to treat high-risk hepatoblastoma patients [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 1101.
Abstract 1113: USP18 impairs the sensitivity of radiotherapy for nasopharyngeal carcinoma by promoting the ubiquitination and nuclear translocation of TRIM29
Authors: Lin Jia-Yi , Zhang Wei-Wei , Li Qing-Jie , Fang Xue-Liang , Li Jun-Yan , He Shi-Wei , Li Ying-Qin , Ma Jun , Liu Na , Zhao Yin , Guo Rui 
Published: March 2024

Abstract
Radiotherapy is the main and preferred treatment for nasopharyngeal carcinoma (NPC), owing to its high sensitivity to radiation. However, there are ~20% patients suffering from tumor recurrence. Accumulating evidences show that protein ubiquitination plays a vital role in radiation caused DNA damage response. Here, we identified that the deubiquitinase USP18 is highly expressed in NPC tissues, and inversely associated with radiosensitivity of NPC cells. USP18 interacts with TRIM29 and promotes its K27-linked ubiquitination independent of its deubiquitinase activity. Further investigation reveals that USP18 acts as a scaffold to recruit the E3 ubiquitin ligase TRIM21 to directly ubiquitinate TRIM29 at Lys307, thus promoting its oligomerization and nuclear translocation, and thereby facilitates the DNA damage repair of NPC cells after irradiation. Clinically, higher expression of USP18 indicates poor response to radiotherapy and worse prognosis in NPC patients. Our findings reveal the critical role of USP18 in regulating radiosensitivity, and targeting USP18-TRIM21-TRIM29 axis maybe a novel strategy to synergize with radiotherapy for NPC patients.
Citation Format: Jia-Yi Lin, Wei-Wei Zhang, Qing-Jie Li, Xue-Liang Fang, Jun-Yan Li, Shi-Wei He, Ying-Qin Li, Jun Ma, Na Liu, Yin Zhao, Rui Guo. USP18 impairs the sensitivity of radiotherapy for nasopharyngeal carcinoma by promoting the ubiquitination and nuclear translocation of TRIM29 [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 1113.
Abstract 1129: A multifaceted study of X-Ray radiation therapy across diverse mouse tumor models
Authors: Huang Jingqi , Li Wentao , He Xiaoyan , Cheng Weiwei , Zhang Lingyun , Li Guannan , Li Qiuliang , Wang Yongfei , Ren Xuesong , Wei Zhi , Shi Long , Wei Yiran , Jin Jing , Li Linfeng , Yun Wei 
Published: March 2024

Abstract
In this study, we showcase the application of X-ray radiation therapy of tumor-bearing mice across 13 syngeneic tumors, one intracranial tumor, and in combination with radiosensitizing drugs, aiming to develop potent cancer treatment strategies. 1.We examined the effects of different radiation levels on multiple tumor models using a therapeutic device delivering targeted radiation to the tumor site. 2.We investigated the combined benefits of radiation with the radiosensitizer Gemcitabine on the H22 liver tumor model. 3.We assessed the impact of radiation sensitization on the HCC1975-luc intracranial tumor model in combination with AZD0156, a drug that cannot cross the blood-brain barrier. The integrity of the blood-brain barrier and the presence of the pharmacodynamic marker pRAD50 of AZD0156 were evaluated. The results show that X-ray radiation has anti-tumor effects across diverse models, with combination drug treatment with both Gemcitabine and AZD0156 showing enhanced therapeutic effects. Furthermore, pRAD50 showed decreasing trend in the single dose PD study in HCC1975-luc intracranial model. We conclude that our platform provides robust methods for evaluating the therapeutic effects of X-Ray radiation, offering invaluable insights for the creation of new cancer therapies.
Citation Format: Jingqi Huang, Wentao Li, Xiaoyan He, Weiwei Cheng, Lingyun Zhang, Guannan Li, Qiuliang Li, Yongfei Wang, Xuesong Ren, Zhi Wei, Long Shi, Yiran Wei, Jing Jin, Linfeng Li, Wei Yun. A multifaceted study of X-Ray radiation therapy across diverse mouse tumor models [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 1129.
Abstract 113: Generation and validation of a novel humanized IL-31/IL-31RA/OSM/OSMR mouse model
Authors: Wang Linlin , Zhao Lei , Zhang Meiqi , Zhang Zhi , Chen Zhen , Kuraguchi Mari , Lian Jingjing , Zhang Jiansu 
Published: March 2024

Abstract
Oncostatin M (OSM) and interleukin-31 (IL-31) are two pleiotropic cytokines that share a common signaling receptor subunit, the OSM receptor beta (OSMR). Both cytokines are released by monocytes, macrophages, dendritic cells and T lymphocytes in inflammatory situations, and upon binding to their respective receptors, induce the production of inflammatory cytokines (such as IL-6), chemokines, and other cellular growth factors during tissue repair, mainly via the JAK/STAT signal pathway. As OSM and IL-31 are reported to be involved in a variety of physiological and pathological processes, targeting IL-31 or OSM signaling is of therapeutic interest. To provide a novel preclinical platform for testing novel modulators of these signaling axes, a humanized IL-31/IL-31RA/OSM/OSMR mouse model was generated. First, single gene knock-in mice were constructed by gene editing technology; multigenic knock-in mice were then obtained by breeding, yielding a quadruple humanized model in which the murine cytokine sequences were replaced by full-length human cytokine sequences in situ, while the murine receptor sequences were replaced by chimeric sequences comprised of the human extracellular region and murine intracellular regions in situ. mRNA expression confirmed expression of IL-31, IL-31RA, and OSMR in this model, while ELISA confirmed expression of human OSM protein in the model without evidence of murine OSM expression. Next, the signaling capacity of the humanized OSMR receptor was confirmed: mouse embryonic fibroblasts (MEFs) isolated from humanized B-hOSM/hOSMR mice were capable of responding to human OSM to release IL-6, while wild-type MEFs could only respond to murine OSM. Subsequently, the ability of IL-31RA antibodies to alleviate scratching was tested in a chemically induced model of atopic dermatitis. Compared to mice receiving control antibodies, scratching frequency in humanized B-hIL31/hIL31RA/hOSMR mice treated with nemolizumab was attenuated (analog antibody was generated in-house). Finally, blood counts and flow cytometric profiling indicates that the humanized mice have a normal frequency of leukocytes and lymphocytes. Taken together, this quadruple humanized IL-31/IL-31RA/OSM/OSMR mouse model is a promising preclinical tool that can be used to evaluate novel modulators of this signaling pathway prior to clinical development.
Citation Format: Linlin Wang, Lei Zhao, Meiqi Zhang, Zhi Zhang, Zhen Chen, Mari Kuraguchi, Jingjing Lian, Jiansu Zhang. Generation and validation of a novel humanized IL-31/IL-31RA/OSM/OSMR mouse model [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 113.
Abstract 1161: Deep spatial proteomics: A new approach for obtaining insight into the glioblastoma microenvironment
Authors: Saxena Kartikey , Daucke Rune , Pedersen Vilde , Klausen Pia Helene , Schoof Erwin , Kristensen Bjarne Winther 
Published: March 2024

Abstract
Glioblastoma is the most frequent and malignant brain tumor, with a median survival of approximately 14 months. The tumor microenvironment is composed of different cell types and is known to support the glioblastoma cells and contribute to poor patient prognosis. Since accumulating studies report discordance between mRNA and protein abundances both on population and single-cell levels, and since proteins are the effector molecules of the cells and the actual target molecules of most drugs, our aim is to dissect the tumor microenvironment by spatial LC-MS based proteomics. Glioblastoma formalin-fixed paraffin-embedded (FFPE) tissue was sectioned and placed on membrane glass slides suitable for laser capture microdissection (LCM), followed by precise isolation of single cells from the heterogeneous tumor microenvironment. We used the Zeiss Palm MicroBeam laser microdissection instrument, combined with an Orbitrap Eclipse Tribrid Mass Spectrometer running our in-house sensitivity tailored Data Independent Acquisition method (WISH-DIA) to analyze and quantify the proteomes. We obtained up to 3000 proteins out of only 100 cells and were able to demonstrate the feasibility of collecting and analyzing various cell types at the single-cell level. The proteins identified belonged to many different classes/families of proteins and were able to distinguish the different cell types. In conclusion, this on-going study demonstrates our ability to isolate single cells from the highly heterogeneous tumor microenvironment of glioblastoma with ultra-high sensitivity, thereby allowing the characterization of the proteome of the glioblastoma microenvironment followed by identification of potential therapeutic and/or diagnostic targets.
Citation Format: Kartikey Saxena, Rune Daucke, Vilde Pedersen, Pia Helene Klausen, Erwin Schoof, Bjarne Winther Kristensen. Deep spatial proteomics: A new approach for obtaining insight into the glioblastoma microenvironment [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 1161.