bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3873: Profiling the tumor microenvironment within clear cell renal cell carcinoma by single-nuclei RNA-Seq
Authors: Liu Ruiyang , Strunilin Ilya , Wu Yige , Karpova Alla , Chen Siqi , Mo Chia-Kuei , Li Yize , Chen Feng , Ding Li 
Published: June 2022

Abstract
Clear cell renal carcinoma (ccRCC) appears as one of the most immune infiltrated tumors in pan-cancer comparisons. A systematic characterization of the immune microenvironment of ccRCC is important for understanding the disease progression and would be beneficial to predicting disease outcomes. To better understand the cellular components within the tumor microenvironment (TME), the interactions among different cell types, and the contribution to disease outcomes, we collected 34 ccRCC tumor samples for single-nuclei RNA-Seq (snRNASeq) profiling. We obtained 161312 cells in total, including 6791 stroma cells (endothelial cells, fibroblasts and myofibroblasts) and 38918 immune cells (lymphoid and myeloid populations).Analysis of cell-cell-interactions suggests tumor cells interact most frequently with stroma and immune cells. Of interest, we noticed some ligand-receptor pair interactions commonly found among all samples, such as VEGFA from tumor cells with VEGFR1/2 from endothelial cells, suggesting the presence of angiogenesis. Within endothelial populations, we found a common interaction between ANGPT2 and TEK, whose interaction scores are moderately correlated with lymphocyte percentages across samples, suggesting this interaction could contribute to endothelium leakage and lymphocytes recruitment. To better understand the immune cell subtype/states within each immune cell type, we further distinguished 14 different subpopulations within macrophages according to key marker expressions. The presence of the subpopulations suggest diverse states and heterogeneous functions within macrophages. Of note, the expression of iron uptake receptor TFRC is elevated in higher-grade tumors. Higher TFRC expression is associated with poorer prognosis, which is also validated by the CPTAC discovery cohort using bulk proteomics data. In summary, our study showcases the potential of using snRNA-Seq to profile the TME of ccRCC, in identifying important cell-cell interactions and predicting disease outcomes.
Citation Format: Ruiyang Liu, Ilya Strunilin, Yige Wu, Alla Karpova, Siqi Chen, Chia-Kuei Mo, Yize Li, Feng Chen, Li Ding. Profiling the tumor microenvironment within clear cell renal cell carcinoma by single-nuclei RNA-Seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3873.
Abstract 3875: De novo spatial proteomic profiling of immune synapses using machine learning-guided microscoop
Authors: Liu You-Pi , Chong Weng Man , Huang Harry , Chen Yi-De , Chung Chia-Wen , Chang Hsiao-Jen , Chang Chih-Wei , Liao Jung-Chi 
Published: June 2022

Abstract
The spatial proteome of the immune synapse (IS) between a target cell and a lymphocyte is fundamentally important to understand the mechanism of cell-mediated immunity for both immuno-oncology and therapeutic applications. In this research, we used Microscoop, a fully-automatic microscope system integrated with a machine learning-based algorithm, to best determine ISs for proteomic mapping. We used Raji B cells as antigen-presenting cells (APCs) and induced the formation of ISs by incubating with Jurkat T cells. Multiple IS images were applied to train our algorithm using convolution neural network-based deep learning. A sequential process including fluorescence imaging, deep learning-enabled pattern generation, and photochemical labeling was implemented to achieve spatial-specific biotinylation of the IS proteins. Moreover, Microscoop is capable to repeat the process automatically on thousands of fields of view to label sufficient immune-synaptic proteins with biotin-tag for further enrichment allowing protein identification with mass spectrometry. We have successfully labeled and isolated proteins from spatially reorganized interfaces between T cells and APCs. Following MS-based proteomic analysis, several hundreds of proteins were identified, including the proteins known to be specifically associated with T-cell receptor (TCR) activation such as LCK, one of the major factors involved in TCR signaling at ISs. More interestingly, we identified several proteins novel for ISs, including proteins involved in phosphatidylinositol signaling. Our data showcases the capability of subcellular de novo spatial proteomics of the Microscoop technology, revealing novel factors responsible for initiating the immune response of a lymphocyte and shedding light on immune checkpoint signaling and tumor immunotherapy.
Citation Format: You-Pi Liu, Weng Man Chong, Harry Huang, Yi-De Chen, Chia-Wen Chung, Hsiao-Jen Chang, Chih-Wei Chang, Jung-Chi Liao. De novo spatial proteomic profiling of immune synapses using machine learning-guided microscoop [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3875.
Abstract 3879: High dimensional analysis of tumor microenvironment and heterogeneity in FIGO IB endometrial carcinomas using imaging mass cytometry
Authors: Lien Hilde Eide , Berg Hege Fredriksen , Hoivik Erling Andre , Trovik Jone , Haldorsen Ingfrid Salvesen , Akslen Lars Andreas , Krakstad Camilla 
Published: June 2022

Abstract
Patients with localized endometrial carcinomas (FIGO IA and IB) have a 5-year relative survival rate of &gt; 90%. Still, some patients with an expected good prognosis experience recurrence of disease which dramatically reduces survival rates. Currently, we lack the knowledge to predict which patients will get recurrence. We used Imaging Mass Cytometry to examine 27 proteins in tissue microarrays of 36 primary FIGO IB endometrial carcinomas, of which 17 later recurred. High dimensional images were segmented to extract single-cell information for each tumor. Distinct epithelial-, stromal- and immune cell types of the tumor microenvironment were identified and phenotyped, using protein expression intensities and unsupervised cell clustering. Neighboring cells of CD8+ cells were extracted and phenotyped. In non-recurrent tumors, more cytotoxic T cells were identified adjacent to two epithelial cell populations characterized by high vimentin and progesterone receptor expression (p &lt; 0.01 and p = 0.02). Tumors that were enriched for vimentin showed significantly better recurrence-free survival than tumors with low vimentin or high alpha-smooth muscle actin (a-SMA) signal (p = 0.026). This study reveals distinct characteristics in the microenvironment of low stage tumors that may aid in identifying high-risk patients. Further, the study provides new insight on the pathogenic processes involved in tumor progression of endometrial cancer.
Citation Format: Hilde Eide Lien, Hege Fredriksen Berg, Erling Andre Hoivik, Jone Trovik, Ingfrid Salvesen Haldorsen, Lars Andreas Akslen, Camilla Krakstad. High dimensional analysis of tumor microenvironment and heterogeneity in FIGO IB endometrial carcinomas using imaging mass cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3879.
Abstract 3881: Immune profiling of advanced prostate cancer harboring homologous recombination deficiency
Authors: Soleimani Maryam , Kung Sonia , Saxena Neetu , Fazli Ladan , Nappi Lucia 
Published: June 2022

Abstract
Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 6-8% of patients with localized PCa and up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumor microenvironment (TME) associated with HRD is poorly understood. We used PCa tumors of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumor immunology.
Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n=13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumor cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n=104), neoadjuvant hormone therapy treated (NHT) (n=16), neuroendocrine (NEPC) (n=41) and CRPC (n=22) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis.
Results: Among screened HRD alterations,BRCA1/2 were the most frequently identified (BRCA1/2n=6, FANCCn=1, FANCD2=2, PALB2=1, CDK12n=1, ATRn=2). CD8+ cells were primarily localized in the stroma of HRD cohort specimens and were more abundant compared to NEPC (p≤ 0.05) and untreated tumors (p≤0.01). The HRD cohort had higher levels of A2aR, in TC and SL (p≤0 .0001 for both) and higher levels of PD-L2 in TC (p≤0.0001) compared to all other cohorts and in the SL (p≤0.05) compared to untreated, CRPC and NEPC cohorts. Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort, and in HRD cohort SL compared to all cohorts (p≤0.0001 for both). There was no difference in TIM-3 or GAL9 expression.
Conclusions: Evaluation of stromal and tumor cell immune profiling indicates that compared to other subtypes, PCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable immunotherapeutic pathways which may render clinical benefit in this patient population.
Citation Format: Maryam Soleimani, Sonia Kung, Neetu Saxena, Ladan Fazli, Lucia Nappi. Immune profiling of advanced prostate cancer harboring homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3881.
Abstract 3889: Identification of ADRN-specific, MES-specific, and pan-subtype therapeutic targets in neuroblastoma
Authors: Kendsersky Nathan M. , Mabe Nathaniel W. , Farrel Alvin , Grossmann Liron D. , Odrobina Michal , Stegmaier Kimberly , Maris John M. 
Published: June 2022

Abstract
Background: Neuroblastoma is an extracranial solid tumor of childhood that arises from the developing sympathetic nervous system. Half of patients with high-risk disease do not survive despite multimodal therapy, and survival after relapse is unlikely. Recent studies have characterized two distinct neuroblastoma cell subtypes: the adrenergic (ADRN) subtype of sympathetic noradrenergic-like identity and the mesenchymal (MES) subtype of neural crest-like identity. ADRN-like cells are more aggressive and proliferative, while the MES-like cells are chemotherapy resistant. Neuroblastoma tumors are heterogenous and comprised of both ADRN and MES cell subtypes, which likely leads to differential responses to therapy. Thus, to eliminate cells that may lead to tumor relapse, it is critical to develop therapies against both neuroblastoma subtypes.
Methods: To identify candidate subtype-specific therapeutic targets, we used ssGSEA to classify human neuroblastoma tumors into ADRN- or MES-dominant and performed differential expression. We validated subtype-specific targets in additional datasets and models, including transdifferentiated neuroblastoma cell lines (ADRN-to-MES) after inducible overexpression of the MES transcription factor PRRX1.
Results: We show ADRN-specific expression of known preclinical and clinical neuroblastoma targets with limited or no expression in MES-dominant tumors. We propose CD276 (B7-H3) and L1CAM as pan-subtype targets with similar expression in both subtypes and stable expression after ADRN-to-MES transdifferentiation. In MES-specific neuroblastoma patient samples and cell lines, we identify the receptor tyrosine kinase AXL as a candidate MES target. MES neuroblastoma cell lines are more sensitive to small molecule AXL inhibitors (Cabozantinib, NPS-1034, and ONO-7475) compared to ADRN cell lines. We also observe higher expression of PDL1 and immunosuppressive chemokines in MES-dominant tumors and cell lines. Finally, we detect AXL and Gas6 transcripts in tumor-resident macrophages and fibroblasts, which may further promote immune evasion.
Conclusion: Here we have identified and prioritized ADRN-specific, MES-specific, and pan-subtype neuroblastoma therapeutic targets and suggest AXL-targeted therapy may eliminate both MES-dominant neuroblastoma cells and immune cell populations that contribute to an immunosuppressive microenvironment.
Citation Format: Nathan M. Kendsersky, Nathaniel W. Mabe, Alvin Farrel, Liron D. Grossmann, Michal Odrobina, Kimberly Stegmaier, John M. Maris. Identification of ADRN-specific, MES-specific, and pan-subtype therapeutic targets in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3889.
Abstract 3895: Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of pediatric glioblastoma
Authors: Kaushik Itishree , Gaikwad Shreyas , Srivastava Sanjay K. 
Published: June 2022

Abstract
Pediatric glioblastoma multiforme (GBM) is considered to be the second most lethal childhood cancer type after leukemia. Recent preclinical, clinical and genomic studies have highlighted upon the role of Hippo-Yap pathway in the progression of pediatric GBM. In addition, recent studies have established the role of YAP in creating immune suppressive tumor microenvironment (TME) facilitating drug resistance, recurrence and metastasis of GBM tumors. Herein, we report that ‘moxidectin’ an anti-helminthic drug inhibits the proliferation of SF268, SF295, SF188 and CT-2A Luc GBM cells by inducing apoptosis. Immunoblotting and immunofluorescence microscopy studies show that moxidectin mediates its effects by inhibiting MEK-ERK pathway, a regulator of Hippo-YAP signaling. As a result, moxidectin suppressed the nuclear translocation and transcriptional activity of YAP/TAZ-TEAD complex. Oral administration of 3.5mg/kg moxidectin suppressed the growth of GBM tumors by 90% in intracranial tumor model. Ex-vivo analysis of excised tumors confirmed the observations made in in vitro studies. We further conducted immunophenotyping on the excised tumors from both control and moxidectin treated mice to evaluate the effect of moxidectin on immune cell markers in TME and Tumor Draining Lymph Nodes (TDLNs). Our analysis indicated that treatment with moxidectin suppressed the immune suppressive TME created by GBM tumor. Interestingly, moxidectin enhanced antigen presentation in the TDLN. Indicating that it might play a role in activating the peripheral immune response. Moxidectin is an FDA approved drug and any findings from our research will promote its further investigation as a potential therapeutic agent for GBM patients.
Citation Format: Itishree Kaushik, Shreyas Gaikwad, Sanjay K. Srivastava. Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of pediatric glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3895.
Abstract 3941: TNG908 is an MTAPnull-selective PRMT5 inhibitor that drives tumor regressions in MTAP-deleted xenograft models across multiple histologies
Authors: Briggs Kimberly J. , Cottrell Kevin M. , Tonini Matthew R. , Wilker Erik W. , Gu Lina , Davis Charles B. , Zhang Minjie , Whittington Doug , Gotur Deepali , Goldstein Matthew J. , DiBenedetto Heather , Rudoltz Marc S. , Huang Alan , Maxwell John P. 
Published: June 2022

Abstract
TNG908 is an investigational PRMT5 inhibitor with a novel MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10-15% of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. TNG908 selectively binds the PRMT5-MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, which is postulated to create a large therapeutic index relative to PRMT5 inhibitors currently in clinical development. TNG908 is 15X selective for MTAPnull cell lines over isogenic MTAPWT cell lines, and has marked selectivity for MTAP-deleted cancer cell lines independent of lineage in a large, diverse cell line panel. In vitro mechanistic studies confirm that MTAPnull-selective PRMT5 inhibitors can selectively target MTAPnull cancer cells in either an admixture of MTAPnull and MTAPWT cells, or with intracellular MTA accumulation 2-5X relative to basal levels in MTAPWT cells. Oral administration of TNG908 drives dose-dependent, MTAPnull-selective antitumor activity in multiple xenograft models, including tumor regressions in models representing non-small cell lung cancer (adenocarcinoma and squamous), cholangiocarcinoma, urothelial carcinoma, and others. Preclinical studies suggest clinical combinations that leverage PRMT5 biology and/or concurrent oncogenic driver mutations, such as KRASG12C. In summary, TNG908 is a novel, potent PRMT5 inhibitor with excellent drug-like properties and strong preclinical activity in multiple xenograft models that has the potential for histology-agnostic clinical development in MTAP-deleted solid tumors.
Citation Format: Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Erik W. Wilker, Lina Gu, Charles B. Davis, Minjie Zhang, Doug Whittington, Deepali Gotur, Matthew J. Goldstein, Heather DiBenedetto, Marc S. Rudoltz, Alan Huang, John P. Maxwell. TNG908 is an MTAPnull-selective PRMT5 inhibitor that drives tumor regressions in MTAP-deleted xenograft models across multiple histologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3941.
Abstract 3982: Molecular mechanism of cisplatin-induced p53 activation, cell cycle regulation, and apoptosis in acute leukemia cells
Authors: Tchounwou Paul B. , Kumar Sanjay 
Published: June 2022

Abstract
Cisplatin (CDDP) is an anticancer drug successfully used in the treatment of various human malignancies. Although it has been shown to enhance the potency of arsenic trioxide in chronic myelogenous leukemia (CML) cells and to induce cytotoxicity in acute promyelocytic leukemia (APL) cell lines, its molecular mechanism of action is mostly unknown. We investigated a novel mode of action of CDDP through modulation of stress signals, disruption of MDM2-DAXX-HAUSP complex, and activation of p53 in APL cell lines. We found that CDDP-induced stress signals were transmitted and reduced expression of complex molecules and also effected their association leading to p53 activation. CDDP-activated p53 led to cell cycle arrest and induced both early and late apoptosis in APL cells. Our findings also showed that CDDP stimulated more promyelocytes formation with dense granules, activated p53 expression, and reduced expression of MDM2 in both APL mice bone marrow cells and liver tissues. This novel mechanism of action of CDDP in APL cells may help in the design of new anti-leukemic drugs for treatment of APL patients.
Citation Format: Paul B. Tchounwou, Sanjay Kumar. Molecular mechanism of cisplatin-induced p53 activation, cell cycle regulation, and apoptosis in acute leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3982.
Abstract 4015: Primary sites affecting the prognosis of Ewing's sarcoma
Authors: Mao Jun-Qing , Zhao Dan 
Published: June 2022

Abstract
Introduction Ewing’s sarcoma (ES) is a small round blue cell malignancy arising from the bone or soft tissue, and most commonly impacts adolescents and young adults. It is difficult to identify those who will likely relapse, however, ES has a very high recurrence rate. Given these realities, the objective of this study was to determine factors influencing the prognosis of ES patients.
Methods Clinical and genomic data of 99 patients with ES, were obtained from the cBioPortal. Tumor mutational burden (TMB) and patient survival information were also obtained from the cBioPortal.
Results In the data examined, ES had multiple primary sites of disease, including 16 femur, 10 hipbone, 10 rib, 10 tibia, 6 ischium pubis, 5 scapula, 4 fibula, 3 dorsal vertebra, 3 intra-abdominal, 3 lumbar vertebra, and 3 skull. A comparison of survival relationships between different primary sites of ES indicated that overall survival (OS) was significantly different between femur and dorsal vertebra (p = 0.023) and intra-abdominal and hipbone (p = 0.049). However, no significant difference was determined for TMB between the different primary sites. The median value of TMB was 0.23. Data were divided into two groups: high TMB (TMB-H,≥ 0.23 muts/Mb) and low TMB (TMB-L, &lt; 0.23muts/Mb). Interestingly, the OS of patients with TMB-L was significantly higher than that of patients with TMB-H (p = 0.049; 59.45 versus 42.00 months). The presence of metastases at the time of diagnosis was associated with poor OS ( p = 0.023;) and was a clinical factor associated with outcomes having statistical significance.
Conclusions Given the heterogeneity in outcomes for patients with ES, additional prognostic factors are needed to optimize clinical decision making. Prognosis was different depending on primary site of ES. Patients with ES in hipbone displayed a better prognosis compared to that in abdomen. Similarly, patients with ES in dorsal vertebra had a significantly higher OS than that in femur. As such, the primary site should perhaps be considered during ES treatment, although there was no significant difference between TMB and primary site. Our results indicate that high TMB is associated with inferior survival for ES and may provide insights for clinical practice.
Citation Format: Jun-Qing Mao, Dan Zhao. Primary sites affecting the prognosis of Ewing's sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4015.