bluuebunny/crossref_metadata_2025_split huggingface dataset:
DISP-10. A SYSTEMATIC REVIEW OF SEX DIFFERENCES OF INCIDENCE AND OVERALL SURVIVAL IN 15 NON-REPRODUCTIVE CANCERS
Authors: Dmukauskas Mantas , Waite Kristin , Livinski Alicia , Edelson Jacob , Cioffi Gino , Hunter Chyren , Brown Jalen , Jackson Sarah , Song Minkyo , Day Chi-Ping , Schaffer Alejandro , Barnholtz-Sloan Jill 
Published: November 2022

Abstract
Sex is an important factor that influences disease development, progression, and treatment. In multiple non-reproductive cancers, sex differences in incidence, progression, treatment response, survival, and other clinical outcomes are observed. Overall, males have a 20% higher chance of developing cancer over their lifetime, and experience worse clinical outcomes when compared with females. The NIH recognizes the importance of sex as a biologic variable and addressing sex as a biological variable is now required for all researchers submitting NIH grants. While more researchers are investigating the role of sex differences in cancer, a systematic review that examines the patterns of sex differences in incidence and survival across 15 non-reproductive cancers has not yet been published. We performed a systematic review by searching five databases using keywords and controlled vocabulary terms for each concept of interest and limited to English language. Records were included if it reported sex differences in human adults (18+), addressed incidence, mortality, or survival, at least one of the 15 cancers of interest, and were a cohort, cross-sectional, RCT, or case control study. Covidence was used for screening and two reviewers independently screened each record at title/abstract and then full text. Two reviewers independently completed data extraction using Microsoft Excel and the Cochrane RoB 2.0, and JBI tools were used for risk of bias assessment. The searches and pilot of the methods are underway. Understanding the role sex-differences play on incidence and survival are important for adding to our understanding of advances in diagnosis and treatment of individuals with cancer.
DISP-13. FEMALE MICE HAVE GREATER SUSTAINED ACTIVITY SUPPRESSION AND HYPERSOMNOLENCE AFTER RADIATION THERAPY: EXPLORATION OF SEX DIFFERENCES IN A MODEL OF CRANIAL-RADIATION-INDUCED HYPERSOMNOLENCE (C-RIH)
Authors: Adegbesan Kendra , Ardori Francesco Tomassoni , Yanpallewar Sudhirkumar , Bradley Sean , Chudasama Yogita , Briceno Nicole , King Amanda , Tessarollo Lino , Gilbert Mark , Smart DeeDee , Armstrong Terri , Shuboni-Mulligan Dorela 
Published: November 2022

Abstract
Female cancer patients have a better prognosis but more adverse events with chemotherapy; less is known with other cancer treatments like radiation therapy. Previous literature has demonstrated sex-dependent effects on the hippocampi and behavioral tasks within post-natal mice after radiotherapy. We explored the differences in activity and sleep in adult male and female mice within our previously established mouse model of cranial-irradiation-induced hypersomnolence (C-RIH). Ten mice of each sex (B6 x B6D2 backcrossed with C57/b6NCr) were observed for general activity and sleep continuously over 10 days before and after therapeutic irradiation (whole brain, 15Gy, single fraction). Behavioral assessments aimed at measuring anxiety (Light Dark Box, Elevated Zero Maze) and depression (Sucrose Preference Test) related behaviors, and working memory (Y Maze) were then used to assess any radiation-induced changes in mood or cognition. Independent samples t-tests compared male and female cohorts before and after radiation. At baseline, females had significantly higher peak activity (p &lt; 0.001), as well as day (p &lt; 0.001), and night (p = 0.004) activity. Females also showed less anxiety in the Elevated Zero Maze (p &lt; 0.001) and Light-Dark Box (p = 0.012). In the Y-Maze, females had significantly more alternations (entry into each arm without repeat) (p = 0.004). Males and females consumed the same proportion of sucrose solution in respect to water (p = 0.124). After radiation, males and females showed a significant decrease in activity, with females displaying a higher suppression of night activity both 1-3 days (t(18) = 2.162, p = 0.045) and 7-9 days (t(18) = 2.266, p = 0.037). Female mice also showed increased night hypersomnolence at 1-3 days (t(18) = 4.474, &lt; p = 0.001) and 7-9 days (t(18) = 2.920, p = 0.01). Further analysis is underway on post-radiation sex differences in sleep and activity. Here we used a mouse model of C-RIH to assess the behavioral outcomes between the sexes and found marked effects on sleep and activity.
DISP-14. DEFINING INTERVENTIONS AND METRICS TO IMPROVE DIVERSITY IN CNS CLINICAL TRIAL PARTICIPATION: A SNO AND RANO EFFORT
Authors: Budhu Joshua , Porter Alyx , Jackson Sadhana , Lee Eudocia , McFaline-Figueroa J Ricardo , Willmarth Nicole , Dalmage Mahalia , Kawachi Ichiro , Arons David , Chang Susan M , Wen Patrick Y , Hervey-Jumper Shawn L , Chukwueke Ugonma 
Published: November 2022

Abstract
Despite major strides in cancer research, care, and therapy, these advances have not been equitable across race and ethnicity. Groups underrepresented in medicine (URM) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black and Latino Americans represent 29% of the population but only reflect 8% of oncology clinical trial participants. Recent studies have shown that this disparity is also present in neuro-oncology as women, Black, and Latino Americans remain under-accrued in clinical trials. Brain tumor patients already face unique barriers to clinical trial enrollment and completion due to disease-specific conditions–such as impaired motor function, cognition, language deficits, and caregiver dependency–which pose additional difficulties in clinical trial consent, enrollment, and adherence. As part of this collaborative initiative, we evaluated the impact of how a lack of diversity in cancer research is detrimental to scientific discovery and propose interventions focused on improving URM engagement with clinical research. Recommendations include the creation of inclusive trial design at the onset, decreasing barriers to care, expanding trial eligibility, and equitable access to tumor profiling for personalized medical trials. Additionally, setting reasonable metrics and goals for accrual and engagement with patient and community stakeholders will ultimately help to diversify trial participants. Lastly, diversification and inclusion practices within the neuro-oncology workforce, including all personnel involved in clinical research, will help to minimize bias, promote concordant care, and assist with developing sustainable solutions. The diversification of participation in neuro-oncology clinical trials is imperative. The lack of diversity in clinical trials can contribute to improper generalizability of treatment efficacy, resulting in potentially harmful practices. Equitable access and inclusion of URM brain tumor patients will not only enhance research discoveries but will also result in improved patient care for all cancer patients.
IMMU-04. SINGLE-CELL RNA-SEQUENCING IDENTIFIES FUNCTIONAL MACROPHAGE SUBSETS THAT ARE ENRICHED IN RESPONSE TO DIFFERENTIAL PHAGOCYTOSIS INDUCTION AGAINST GLIOMA
Authors: Chetty Senthil Lakshmana , Riemondy Kent , Donson Andrew , Balaakrishnan Ilango , Venkataraman Sujatha , Vibhakar Rajeev , Foreman Nicholas , Mitra Siddhartha 
Published: November 2022

Abstract
Pediatric diffuse midline gliomas (DMGs), are fatal brain tumors of childhood arising in the ventral pons. Currently, radiation therapy (RT) is the mainstay treatment for DIPG. However, RT is not a curative treatment and provides only temporary relief for most patients. Recent advances in immunotherapy have yielded some fantastic opportunities to effectively treat patients with high-grade pediatric brain tumors. In this study, we demonstrate that fractionated RT (4Gy X 3) induces immunogenic cell death and activates multiple damage-associated molecular patterns (DAMPs) on DMG/DIPG cells. Furthermore, combining 4Gy X 3 with anti-CD47 therapy enhances the in vitro phagocytosis of DIPG/DMG cells by peripheral blood mononuclear cell-derived macrophages. Next, using single-cell RNA sequencing (scRNA-seq), we investigated the transcriptomic profile of macrophages that were co-cultured with irradiated or non-irradiated DMG cells in the presence of either phosphate-buffered solution (PBS) or anti-CD47 monoclonal antibody for 24 hours. Our findings identified eleven distinct macrophage clusters displaying different gene expression patterns in all the treatment conditions. However, PBS treatment led to a marked increase in macrophages expressing antigen-presentation genes (HLA-DR and HLA-DQB1). 4Gy X 3 treatment led to the enrichment of macrophages expressing genes related to the oxidative phosphorylation pathway, whereas anti-CD47 treatment led to the enrichment of macrophages expressing genes related to interferon-gamma response and ERK-signaling pathway. Lastly, mice intracranially transplanted with DMG/DIPG that received 4Gy X 3 and anti-CD47 therapy showed a significant decrease in tumor growth and an increase in survival rate than those receiving either monotherapy alone. We are currently performing scRNA-seq validation studies on tumors obtained from orthotopic and syngeneic models of DMG. In summary, our results highlight the functional heterogeneity of macrophages and suggest that combining fractionated RT with anti-CD47 therapy has potent anti-tumor effects and may be used as a novel therapeutic approach for treating Glioma patients.
IMMU-05. THE INFLUENCE OF THE KETOGENIC DIET ON THE IMMUNE TOLERANT MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Kesarwani Pravin , Zhao Yi , Kant Shiva , Miller C Ryan , Chinnaiyan Prakash 
Published: November 2022

Abstract
Glioblastoma (GBM) represents a particularly aggressive and immune-resistant cancer. Preclinical investigations have identified the anti-tumor activity of a ketogenic diet (KD) in GBM, potentially being used as a tool to target its glycolytic phenotype. Since immune cells in the tumor have a similar reliance upon nutrients to perform their individual functions, we sought to determine if the KD influenced the immune landscape of GBM. Utilizing genetically-engineered murine GBM tumor cells orthotopically implanted in immune-competent mice, we demonstrate that KD improved survival in GBM. Immunophenotyping of tumors identified a novel role KD plays in macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-macrophages and a decrease in pro-inflammatory M1-macrophages. We recapitulated KD in vitro using a modified cell culture based on comprehensive metabolomic profiling of serum in KD-fed mice. Consistent with in vivo studies, murine macrophages cultured in these conditions skewed polarization towards the M2-phenotype with immune-suppressive properties. We went on to mechanistically link these findings to the activation of transcription factor PPARg. Although anti-tumor activity was observed in mice fed a KD, we hypothesized this parallel increase in M2 macrophage polarization tempered its potential therapeutic benefit. Colony-stimulating factor 1 (CSF-1) plays a central role in macrophage differentiation, and CSF-1R inhibition is actively being investigated as a strategy to skew their polarization towards an M1-phenotype. Therefore, we tested a combination of KD with the brain-penetrant CSF-1R inhibitor BLZ945. Consistent with our hypothesis, this combination demonstrated a striking improvement in survival (p = 0.0004), with 50% of mice achieving long-term survival ( &gt; 50 days). Correlative studies confirmed the capacity of BLZ945 to normalize KD-induced increases in M2s, and the combination induced an increase of anti-tumor iNOS+M1s. Combinatorial strategies using agents designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM.
IMMU-08. RAGE ABLATION ATTENUATES GLIOMA PROGRESSION AND ENHANCES TUMOR IMMUNE RESPONSES BY SUPPRESSING GALECTIN-3 EXPRESSION
Authors: Dayyani Mojtaba , Zhang Ian , Liu Shunan , Zhang Leying , Liang Rongrui , Fang Qinxiao , Zhao Jie , Ren Lyuzhi , Medina Eric , Filippov Aleksandr , Bonjoc Kimberley-Jane , Chaudhry Ammar , Bild Andrea , Badie Behnam 
Published: November 2022

Abstract

INTRODUCTION
Malignant gliomas consist of heterogenous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment (TME). Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth, invasion, and immune escape.

OBJECTIVE
We aimed to demonstrate that blockade of RAGE expression may tackle resistance pathways by inhibiting GBM progression, invasion, and immune evasion.

METHODS
We evaluated genetic ablation of RAGE on the tumorigenicity of two syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by immunohistochemistry, qPCR, ELISA, western blotting, NanoString, flow cytometry, and in vivo survival analysis.

RESULTS
Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition also enhanced tumor inflammatory responses by downregulating the expression of galectin-3, rendered the immunotherapy resistant K-Luc gliomas responsive to immune checkpoint blockade therapy, and significantly increased survival.

CONCLUSION
This study is the first to link RAGE expression with galactin-3 as an immune modulator in glioblastoma and revealed that the effect of glioma RAGE expression on TME was mediated through downregulation of Gal-3 and subsequent polarization of Tumor-associated macrophages. The therapeutic significance of RAGE downregulation was demonstrated by sensitizing a highly invasive and immune-resistant glioma model to immune checkpoint blockade and strongly supports the development of RAGE ablation as a complementary treatment strategy for malignant gliomas.
IMMU-12. ABERRANT EGFR SIGNALING IS ASSOCIATED WITH DIMINISHED CYTOTOXIC T-CELL INFILTRATION IN GLIOBLASTOMA PATIENTS
Authors: Pioso Marissa , Sun Lu , Bayley Nicholas , Anil Amanda , Lee Alexander , Nathanson David , Prins Robert 
Published: November 2022

Abstract
Glioblastoma (GBM) has not benefitted from recent advances in immunotherapy compared to other solid malignancies, which suggests that a deeper understanding of the immunobiology of GBM is necessary to develop better therapeutic options. Both oncogenic signaling and evasion of immune destruction are hallmarks of cancer, contributing to tumor growth and reduced survival, respectively. Despite recent evidence in non-CNS malignancies demonstrating the importance of aberrant oncogenic signaling on shaping the tumor immune microenvironment, the impact of aberrant epidermal growth factor (EGFR) signaling – genetically altered in 60% of GBM patients - on the tumor immune microenvironment is not well characterized in GBM. To evaluate the importance of altered EGFR signaling in GBM patient samples, we performed single-cell transcriptomic analysis of primary tumor infiltrating leukocytes (TILs) from twenty-five patients which revealed aberrant EGFR signaling is associated with a unique tumor immune microenvironment in both primary and recurrent disease. Specifically, in the primary disease setting, higher infiltration of macrophages and dendritic cells, and significantly lower infiltration of T-regulatory cells was observed in EGFR altered patients compared to non-altered patients. In recurrent disease, EGFR alterations were associated with significantly diminished infiltration of activated and activated exhausted cytotoxic T-cells compared to unaltered disease. Intriguingly, differential gene expression analysis revealed that EGFR altered patients display significantly increased expression of interferon stimulated genes (ISGs) in both myeloid and lymphoid lineages, while analysis of the tumor compartment unexpectedly revealed greater expression of MHCI genes. Collectively, these data emphasize the impact of aberrant EGFR signaling on the tumor immune microenvironment composition and suggest further characterization of EGFR-immune crosstalk and mechanism is warranted in GBM.
IMMU-17. LEVERAGING CORE EPIGENETIC PROGRAMMING OF IMMUNOSUPPRESSIVE MYELOID CELLS FOR THERAPEUTIC TARGETING OF GLIOBLASTOMA
Authors: Bayik Defne , Bartels Cynthia , Lovrenert Katreya , Zhang Duo , Watson Dionysios , Kay Kristen , Lee Juyeun , Vogelbaum Michael , Fan Yi , Scacheri Peter , Lathia Justin 
Published: November 2022

Abstract
Accumulation of various immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), facilitates progression and treatment resistance of glioblastoma (GBM). We previous demonstrated that monocytic MDSCs (mMDSCs) but not granulocytic MDSCs (gMDSCs) infiltrate tumors in mouse models and patients, and that nonspecific targeting of mMDSCs with chemotherapies provided therapeutic benefit in preclinical models of GBM. To investigate the differential role and trafficking of mMDSCs versus gMDSCs in GBM, we adoptively transferred these cells into tumor-bearing mice. Mice that received mMDSCs succumbed to disease at an earlier point compared to control mice or mice that received gMDSCs. To delineate the cellular basis of this distinct behavior of MDSC subsets, we performed assay for transposase-accessible chromatin using sequencing (ATAC-seq) and observed that cell adhesion-related genes were significantly enriched in open chromatin regions of mMDSCs as opposed to gMDSCs. Aligned with this epigenetic profile, mMDSCs from blood and tumors had significantly higher surface integrin β1 expression compared to gMDSCs in both mouse models and GBM patients. To evaluate the functional role of these integrins, we pre-treated mMDSCs with anti-integrin β1 prior to adoptive transfer. Blockade of surface integrin β1 interfered with the pro-tumorigenic role of mMDSCs, as the survival span of mice receiving these cells was similar to that of vehicle controls. Further analysis of the ATAC-Seq data revealed that dipeptidyl peptidase-4 (Dpp4), an interacting partner of integrin β1, was more accessible in mMDSCs compared to gMDSC. Consistently, bone marrow-derived mMDSCs in mouse and tumor-infiltrating mMDSCs in GBM patients expressed high levels of Dpp4. Pharmacological inhibition of Dpp4 reduced chemotaxis of mMDSCs in vitro and extended survival duration of mice with tumors. The findings from this study have broad implications across cancer types to modulate immunosuppressive myeloid cells by leveraging these novel insights into their adhesion mechanisms.
IMMU-19. IDENTIFICATION OF TARGET ANTIGENS FOR CHIMERIC ANTIGEN RECEPTOR T- CELL THERAPY AGAINST GLIOBLASTOMA USING A MONOCLONAL ANTIBODY LIBRARY RAISED AGAINST PATIENT-DERIVED TUMOR SPHERES
Authors: Kijima Noriyuki , Nakagawa Tomoyoshi , Hasegawa Kana , Ikeda Shunya , Yaga Moto , Wibowo Tansri , Kuroda Hideki , Hirayama Ryuichi , Okita Yoshiko , Tachi Tetsuro , Kagawa Naoki , Kanemura Yonehiro , Hosen Naoki , Kishima Haruhiko 
Published: November 2022

Abstract
New therapies for GBM are urgently needed due to its poor prognosis and chimeric antigen receptor T (CAR-T) cell therapy is thought to be a promising strategy. To develop CAR-T cell therapy, cell surface targets that is highly specific for GBM cells are needed.Although extensive transcriptome analyses of GBM cells were performed, few transcripts highly specific for GBM cells have been identified. However, GBM cell-specific antigen epitopes formed by post-translational modifications of proteins may have been missed, and could still be discovered by thoroughly searching for cancer-specific monoclonal antibodies and characterizing the antigens they recognize. In this study, we applied this strategy to search for GBM-specific cell surface targets using patient derived tumor spheres. We identified two monoclonal antibodies E61 and A13 as those reacting with GBM cells but not with normal brain parenchymal cells. CAR-T cells derived from both monoclonal antibodies produced IL-2 and IFNɤ and exerted cytotoxicity to GBM cells by chromium 51 release assay. In addition, we identified B7-H3, which is frequently used for a CAR-T cell target against GBM, as the antigen recognized by B7-H3 by the expression cloning method. These results indicate that the strategy shown in this study is useful for identifying antigens that are expressed on patient-derived GBM cells and potentially useful as targets for CAR T cells.
IMMU-22. REPROGRAMMING OF MICROGLIA/MACROPHAGES IN GLIOBLASTOMA IMPROVES ANTI-TUMOR T CELL RESPONSES
Authors: Fermi Valentina , Warta Rolf , Rapp Carmen , Trong Philip Dao , Jungwirth Gerhard , Andreas Unterberg , Herold-Mende Christel 
Published: November 2022

Abstract
Glioma-infiltrating myeloid cells such microglia and macrophages (GAM) are a major component of the immunosuppressive tumor microenvironment in glioblastoma (GBM). Especially their anti-inflammatory M2-like activation state might counteract efficacy of immunotherapeutic interventions by impairing effector T cell infiltration and function. Therefore, we studied the ability of the small molecule inhibitors (SMI) PLX3397, BLZ945, and GW2580 that target the M2-associated colony stimulating factor-1 receptor (CSF1R) to shape GAM phenotype towards a pro-inflammatory M1-like phenotype and how this affects the T cell compartment.Upon treatment of freshly isolated CD11b-sorted GBM patient-derived GAMs (n = 15) a decreased expression of CD163 (M2-like) and an increased expression of HLA-DR (M1-like) as well as an increased nitrite production as an indirect measure for iNOS activation (M1-like) was observed which was most pronounced for BLZ945, and GW2580. Transcriptome analysis of treated vs. untreated GAMs supported a reprogramming towards a pro-inflammatory phenotype. In addition, treatment of GAMs in a GBM patient-derived tumor organoid model confirmed a substantial decrease of CD163+ M2-polarized GAM together with a reduced number of proliferating tumor cells. Finally, treatment of patient-derived GAMs led to an increased T cell transmigration through a dense barrier of autologous tumor-derived endothelial cells and increased the ability of T cells to kill autologous tumor cells. Our results support CSF1R blockade is able to reduce the immunosuppressive and pro-tumorigenic functions of GAM substantially and thereby could enhance the effectiveness of T cell-based immunotherapy.