bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6095: SMOC2 as a potential biomarker with diagnostic value in uterine leiomyosarcoma
Authors: Cai Chen , Falcao Raul , Kokaraki Georgia , Souza Jorge Estefano , de Souza Gustavo , Carlson Joseph Woodard , Petta Tirzah Braz 
Published: June 2022

Abstract
Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignant tumor with poor prognosis. In contrast, uterine leiomyoma (uLM) is the most common benign tumor of the uterus found in women of reproductive age. Extracellular matrix (ECM) accumulation and remodeling are thought to be crucial for the development of these two tumors. To better understand the differences of ECM dynamics in these tumors, we have collected samples from 67 uLMS, 66 uLM and 68 normal myometrium (MM) which were analyzed by RNAseq (Illumina) and a high-resolution isoelectric focusing (HiRIEF) liquid chromatography-mass spectrometry (LC-MS)-based method (Dionex UltiMate™ 3000 RSLCnano System coupled to a Q-Exactive mass spectrometer, Thermo Scientific). After meta-analysis between uLM and uLMS groups using DESeq2 and edgeR, 112 genes were defined as common shared differentiatly expressed genes (DEG). Specific uLMS DEG were analyzed by gene ontology, KEGG pathway, and Reactome pathway. In the top 10 ranking of most affected biological processes/molecular functions/cellular components, we identified the gene SMOC2, a secreted calcium-binding protein of the BM-40/SPARC family which is present in the ECM and has been shown to be involved in fibrosis by modulating TGF-β1. SMOC2 is upregulated in uLM and is downregulated in both RNA and protein expression level in uLMS, compared to MM samples. We also observed that the TGFB1 pathway is downregulated in uLMS and upregulated in uLM, suggesting that this may induce high production of ECM which is related to fibrosis. In conclusion, this preliminary data shows SMOC2 as a potential biomarker to differentiate uLM and uLMS at the protein level and we plan to further study the role of SMOC2 in cell lines to improve our understanding on uLMS malignancy.
Citation Format: Chen Cai, Raul Falcao, Georgia Kokaraki, Jorge Estefano Souza, Gustavo de Souza, Joseph Woodard Carlson, Tirzah Braz Petta. SMOC2 as a potential biomarker with diagnostic value in uterine leiomyosarcoma [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 6095.
Abstract 6106: The effect of neoadjuvant chemotherapy on tumor immune microenvironment in ovarian cancer
Authors: Cao Guangming , Hua Dingchao , Cui Lina , Zhao Xiaochen , Wang Shuzhen , Zhu Lei 
Published: June 2022

Abstract
Background: Ovarian cancer (OC) is a highly lethal gynecologic malignancy, neoadjuvant chemotherapy (NACT) with interval de-bulking surgery (IDS) is an established strategy for woman with advanced epithelial ovarian cancer (EOC). Tumor infiltrating lymphocytes (TILs) play an important role in the pathogenesis of OC. However, the effect of NACT on tumor immune microenvironment (TIME) has not been evaluated.
Methods: All patients underwent NACT with IDS. Formalin-fixed paraffin-embedded tissue samples were collected from biopsy specimens and the corresponding post-NACT surgical specimens. The densities and percentage of specific TILs [CD8+, CD3+, CD4+, CD20+, tumor associated macrophages (TAMs), dim CD56+NK, bright CD56+NK, PD-1+ etc.] within the TIME were analyzed by multiplex immunohistochemistry (3DMedcines Inc.). Serum CA 125 was measured 3-weekly per protocol and evaluated the response to NACT using GCIG CA125 response criteria.
Results: A total of 28 patients were enrolled in this study with planned IDS after NACT. Of 25 patients evaluated by GCIG CA125 response criteria, 76% (19/25) had a CA125 response. In CA125 response patients, we observed significant recruitments of the densities and percentage of CD8+ in tumor, percentage of PD-1+ cell in tumor after-NACT vs before-NACT (34.85/mm3 vs 110.54/mm3, p=0.0258; 0.50% vs 1.73%, p=0.0132; 0.53% vs 2.66%, p=0.0576, respectively), while no significant change was found in TAMs, NK cells and CD20+ cells. However, in CA125 non-response patients, the TILs in tumor did not change significantly.
Conclusion: NACT could release the tumor associated antigen by killing tumor cells for uptake by tumor-infiltrating dendritic cells and promote the infiltration of CD8+ and PD-1+ T lymphocyte in CA125 response OC patients. Given the limited clinical prognostic information and the number of patients in this study, the results of this study will need confirmation in larger studies in the future.
Citation Format: Guangming Cao, Dingchao Hua, Lina Cui, Xiaochen Zhao, Shuzhen Wang, Lei Zhu. The effect of neoadjuvant chemotherapy on tumor immune microenvironment in ovarian cancer [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 6106.
Abstract 613: AL009 is a multi-Siglec inhibitor engineered to bind myeloid cells that enhances innate and adaptive immunity to cancer
Authors: Nalle Sam , Lam Helen , Barner Cheryl , Long Hua , Liang Spencer , Rosenthal Arnon , Maslyar Daniel 
Published: June 2022

Abstract
Background - Inhibitory sialic acid-binding immunoglobulin-type lectins (Siglecs) are a subset of the Siglec family of cell surface receptors that potentiate immune tolerance. A multitude of inhibitory Siglecs on myeloid cells become engaged in sialic acid-rich tumor microenvironments, suggesting that disrupting Siglec-sialic acid signaling could confer therapeutic benefit in cancer. To accomplish this, we designed AL009, an engineered Siglec-9 extracellular domain-Fc fusion molecule that acts as a sialic acid trap and a multi-Siglec inhibitor, repolarizing suppressive myeloid cells and activating an anti-cancer response.
Methods - Cooperative binding of AL009 was analyzed by flow cytometry using cultured human tumor cell lines and myeloid-derived suppressor cells (MDSCs) differentiated from primary human monocytes. Monocytes, MDSCs, and macrophages differentiated from primary human monocytes were assessed for AL009 binding by flow cytometry. AL009m (AL009 with a mouse Fc) was fluorophore-labeled and intravenously injected into B6 mice to analyze biodistribution via ex vivo tissue imaging over time. Initial toxicology screening was conducted in cynomolgus monkeys in a non-terminal study.
Results - AL009 displays cooperative binding with sialic acid and Fc gamma receptors on myeloid cells. When comparing binding among myeloid cell subsets, AL009 preferentially binds MDSCs. Analysis of the biodistribution of labeled AL009m in mice showed the greatest accumulation in the spleen, consistent with immune cell targeting in vivo. Further, Fc engineering of AL009 improved the pharmacodynamic profile compared to a non-engineered Fc. In cynomolgus monkeys, single doses of 80 mg/kg appeared safe and without clinically significant findings.
Conclusions - The engineered structure of AL009 leads to preferential binding to an immunosuppressive subset of myeloid cells. This targeting leads to repolarization of myeloid cells and activates an innate and adaptive anti-cancer response. Pharmacologically relevant doses of AL009 appear well-tolerated in initial studies in non-human primates, supporting further development for entry into clinical studies.
Citation Format: Sam Nalle, Helen Lam, Cheryl Barner, Hua Long, Spencer Liang, Arnon Rosenthal, Daniel Maslyar. AL009 is a multi-Siglec inhibitor engineered to bind myeloid cells that enhances innate and adaptive immunity to cancer [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 613.
Abstract 6183: A novel NQO1 bioactivatable drug induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill pancreatic cancer cells
Authors: Huang Xiumei , Jiang Lingxiang , Boudreau Matthew W. , Hergenrother Paul J. 
Published: June 2022

Abstract
As a fatal disease with short overall survival, pancreatic cancer is among the top five leading cause of cancer-related deaths worldwide, current therapies against pancreatic cancer lack tumor specificity and generally cause toxic side effects on normal and healthy tissues. Thus, exploring and developing novel tumor-specific agents for treating pancreatic cancer is a critical need. NAD(P)H:quinone oxidoreductase 1 (NQO1) is elevated in the pancreatic cancers whereas it lacks in associated normal tissues. Therefore, NQO1 bioactivatable drugs are promising due to tumor-selective killing NQO1-positive cancer cells. Our previous studies have revealed that the novel NQO1 bioactivatable drug - deoxynyboquinone (DNQ) is ten-fold more potent than the prototypic NQO1 bioactivatable drug β-lapachone to efficiently kill NQO1-positive cancer cells. However, DNQ causes a severe side effect action - high-grade methemoglobinemia that limits its clinical usefulness. Here, we developed a novel DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively killed pancreatic ductal adenocarcinoma (PDA) cells in an NQO1-dependent way with an extremely low IC50 (0.1 µM). IP-DNQ evoked massive ROS production and oxidative DNA lesions, resulting in PARP1 hyperactivation and mitochondrial catastrophe. Furthermore, we also observed that IP-DNQ induced G2/M phase cell cycle arrest and promoted programmed necrosis and caspase-dependent apoptosis co-existing in IP-DNQ-treated NQO1-positive pancreatic cancer cells. In addition, IP-DNQ treatment caused extremely low side effect of methemoglobinemia, significantly suppressed tumor growth and extended mice lifespan in orthotopic pancreatic cancer xenograft model. In summary, our findings offer a novel potential therapy against NQO1-positive pancreatic cancers and enable mechanism-based synergy with other anticancer drugs.
Citation Format: Xiumei Huang, Lingxiang Jiang, Matthew W. Boudreau, Paul J. Hergenrother. A novel NQO1 bioactivatable drug induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill pancreatic cancer 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 6183.
Abstract 6221: Tandem use of multi-omics and artificial intelligence identified novel prognostic and therapeutic biomarkers for head and neck squamous cell carcinoma
Authors: Bhat Ajaz A. , Masoodi Tariq , Mishra Deepika , Singh Mayank , Nisar Sabah , Hashem Sheema , Baba Sana K. , Bagga Puneet , Reddy Ravinder , Bedognetti Davide , Uddin Shahab , El-Rifai Wael , Macha Muzafar A. , Haris Mohammad 
Published: June 2022

Abstract
Introduction: Head and neck squamous cell carcinoma (HNSCC) is categorized into Human Papilloma Virus positive (HPV+ve) and negative (HPV-ve) tumors, with the latter being more aggressive and displaying poor overall survival (OS). There is a need to identify aggressive biomarkers for patient stratification and improved patient care.
Materials and Methods: Using the multi-omics data, including somatic mutations, copy number alterations, RNA sequencing, miRNA sequencing, and methylation from 513 HNSCC patients, we performed an integrative clustering analysis to differentiate HPV+ve and HPV-ve tumors and identify novel prognostic biomarkers for survival and treatment response. Using artificial intelligence (AI) based machine learning approach by implementing scikit-learn, we developed a model to predict the patient's OS.
Results: Our clustering analysis robustly segregated HNSCC patients into HPV+ve and HPV-ve tumors. Artificial intelligence-based machine learning model identified a 30 gene signature panel specific to HPV-ve tumors precisely predicting poor OS with an accuracy of 90.5±0.8% (95% CI) and AUC of 80.2%. Furthermore, the multivariate Cox regression survival model identified 12 genes as independent prognostic biomarkers in HPV-ve tumors, including overexpression of novel genes NT5E and TRIML2. Interestingly, higher expression of NT5E and TRIML2 due to promoter hypomethylation predicted therapy resistance in 62.8% and 65.1% of HNSCC patients, respectively. The prognostic signature panel of 30 genes was further validated using three additional expression data sets (n = 450) of HNSCC.
Conclusion: Our multi-omics and AI analysis revealed a novel HPV-ve molecular cluster with implications for predicting disease aggressiveness, therapeutic response, and OS in HNSCC patients.
Citation Format: Ajaz A. Bhat, Tariq Masoodi, Deepika Mishra, Mayank Singh, Sabah Nisar, Sheema Hashem, Sana K. Baba, Puneet Bagga, Ravinder Reddy, Davide Bedognetti, Shahab Uddin, Wael El-Rifai, Muzafar A. Macha, Mohammad Haris. Tandem use of multi-omics and artificial intelligence identified novel prognostic and therapeutic biomarkers for head and neck squamous cell carcinoma [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 6221.
Abstract 6278: Per- polyfluoroalkyl substance (PFAS) modulates steatosis and fibrogenic signaling in hepatocellular carcinoma cells
Authors: Qi Qi , Niture Suryakant , Gadi Sashi , Kumar Deepak 
Published: June 2022

Abstract
Perfluorooctanoic acid (PFOA), heptafluorobutyric acid (HFBA), and perfluorotetradecanoic acid (PFTA) are the per- and polyfluoroalkyl substances (PFAS) and organic pollutants that predominantly exist in the environment. Exposure to PFAS affects immune, thyroid and kidney function, lipid and insulin dysregulation, liver disease, and cancer. Mechanisms underlying the impact of low and physiologically relevant concentration of PFAS in liver diseases remain elusive. In the current study, we investigated the effect of PFOA, HFBA, and PFTA on cell proliferation, steatosis, and fibrogenic signaling in hepatocytes and liver cancer cell models. Exposure of PFOA and PFBA (10 to 1000 nM) specifically promoted cell proliferation in non-tumor derived HepaRG liver cells and in hepatocellular carcinoma HepG2 cells. PFASs increased the expression of TNFα and IL6 inflammatory markers and produced endogenous reactive oxygen species (ROS) production. Further, PFAS enhanced cell steatosis in liver (HepaRG and HepG2) cells which was accompanied by upregulation of steatotic, and fibrogenic markers as well as activated Unfolded Protein Response (UPR) signaling. RNA-seq data suggested that chronic exposures of PFOA modulated the expression of fatty acid/lipid metabolic gene expression that is involved in the development of fatty liver disease. Collectively our data suggests that chronic exposure to low concentration of PFAS may modulate cell steatosis and fibrogenic signaling in hepatocytes and HCC cells by activation of UPR signaling.
Citation Format: Qi Qi, Suryakant Niture, Sashi Gadi, Deepak Kumar. Per- polyfluoroalkyl substance (PFAS) modulates steatosis and fibrogenic signaling in hepatocellular carcinoma 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 6278.
Abstract 6309: Activated neutrophils inhibit chemotactic migration of activated T lymphocytes to CXCL11 by multiple mechanisms
Authors: Tamura Kohei , Kaneko Yuki , Futoh Yurie , Takahashi Kazuya , Kimura Yuki , Saito Akira , Tojo Mineyuki , Miyato Hideyo , Ohzawa Hideyuki , Saga Yasushi , Takei Yuji , Fujiwara Hiroyuki , Kitayama Joji 
Published: June 2022

Abstract
Objective High density of tumor-infiltrating lymphocytes (TILs) in the tumor is associated with favorable prognosis of cancer patients, while that of tumor-associated neutrophils (TAN) shows inverse correlation with outcome. We examined the effects of activated neutrophils on chemotactic migration of activated T cells in vitro. Methods Neutrophils and mononuclear cells (PBMC) were collected from the blood of healthy donor. Neutrophils were stimulated with PMA (1uM) or LPS (10ug/ml) for 15 min, washed extensively, and incubated for another 4 hours. PBMC were cultured on anti-CD3 mAb-coated plate with recomnibant-IL-2 (10ng/ml) for 7-14days. The activated T cells were placed in culture inserts with 3μm pore and migration to CXCL-11 (1000ng/ml) placed in lower chamber with or without neutrophils was examined after 2 hours. Random migration of activated T cells on fibronectin coated plate was evaluated with timelapsed analysis using Biostudio system. Degradation of CXCL-11 was examined with western blotting. Results Neutrophils stimulated with PMA or LPS produced neutrophil extracellular traps (NETs). Migration of T cells to CXCL-11 was drastically inhibited in the presence of PMA-activated neutrophils. The inhibition was similarly detected when NETs was removed from PMA-activated neutrophils by ultracentrifugation. Timelapse analysis also showed the NET-depleted supernatant greatly inhibited random migration, which was totally canceled by the pretreatment with 800U/ml catalase. When neutrophils were activated by LPS, T cell migration was also significantly inhibited (p=0.02) but not by NET-depleted supernatant (p=0.99). In western blotting, CXCL11 was totally degraded by LPS-stimulated neutrophils, which was greatly reduced by the depletion of NET component. CXCL11 degraded by NETs was restored by protease inhibitor, 5mM phenylmethylsulfonyl fluoride (PMSF). The reduced migration induced by LPS-stimulated neutrophils was mostly restored with 2mM PMSF. Conclusion Activated neutrophils inhibit chemotactic migration of activated T cells through multiple mechanisms including ROS production and chemokine degradation. TAN may have suppressive effects on the accumulation of TILs.
Citation Format: Kohei Tamura, Yuki Kaneko, Yurie Futoh, Kazuya Takahashi, Yuki Kimura, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Hideyuki Ohzawa, Yasushi Saga, Yuji Takei, Hiroyuki Fujiwara, Joji Kitayama. Activated neutrophils inhibit chemotactic migration of activated T lymphocytes to CXCL11 by multiple mechanisms [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 6309.
Abstract 6324: Development and characterization of Ewing Sarcoma lung metastasis model
Authors: Dasgupta Atreyi , Kurenbekova Lyazat , Patel Tajhal , Yustein Jason T. 
Published: June 2022

Abstract
Introduction: Ewing Sarcoma (EwS) is the second most common bone tumor in children. At diagnosis, approximately 20-25% of patients with EwS have metastatic disease. While systemic chemotherapy, along with surgery and/or radiotherapy, has significantly increased the survival rate of patients with localized disease, metastatic Ewing sarcoma (EwS) has an extremely poor overall survival with a 5-year survival rate of approximately 20-30%. This prognosis has not changed in the last several decades. Thus, there is an imperative need to focus particularly on mechanisms of metastatic growth and progression and to identify and target the underlying intrinsic and extrinsic molecular features. Unfortunately, presently there is no reliable engineered mouse model to functionally study EwS development and metastasis. Using two independent EwS cell lines, we have developed highly aggressive, lung-specific metastatic models that show mechanistic overlap with human patient tumor data and are valuable resources to further study and target metastatic EwS.
Approach: Using a serial transplantation approach, we generated lung specific metastatic lines by repeated intra-tibial injection of two commonly used EwS cell lines (A673 and TC71), allowing metastatic foci to form, followed by dissociation and subsequent re-injection into the tibia. We repeated this 5 times to generate highly aggressive lung-specific metastatic cell lines. As a proof of principle, when equal numbers of GFP+ parental cells and mCherry+ lung metastatic cells are injected into the tibia in NSG mice they form primary tumors with red and green cells, while the metastatic lesions in lungs are almost exclusively mCherry+. A multi-omics approach including glycoproteomics, secretome, and transcriptomic analysis were then used to characterize these cells and compare them with patient tumor samples.
Results: Integration of focused proteomics and glycoproteomics data revealed upregulation in AXL, MEK6, STAT1, and STAT3 proteins and phosphoproteins in metastatic lesions. Focused RNA profiling with Nanostring technologies using formalin-fixed paraffin-embedded (FFPE) slides of patient tumor samples revealed increased expression of several other upstream genes that signal through STAT1, including IL-6, IKK-β, TRAF-6, and Myd88. In addition, upregulation in factors involved in tumor invasive front such as Furin, TIMP-2, MMP-2, and MMP-14 were also noted. We are currently in the process of further validating some of the key regulators using larger set of patient derived tumors and by targeting them in orthotopic mouse models.
Citation Format: Atreyi Dasgupta, Lyazat Kurenbekova, Tajhal Patel, Jason T. Yustein. Development and characterization of Ewing Sarcoma lung metastasis model [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 6324.