tbuckley/cabot-search huggingface dataset:
Abstract 1459: Selective killing of SMARCA4-deficient gynecologic cancers by mitochondria oxidative phosphorylation inhibitors
Authors: Yemin Wang, Dionzie Ong, Shary Yuting Chen, Eunice Li, Krystal Orlando, Elizabeth Raupach, Jennifer Ji, Bernard Weissman, Patrick Pirrotte, David Humtsman
Journal: Cancer Research (2020)

Abstract Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and dedifferentiated carcinoma of the ovary or endometrium are rare but highly aggressive types of gynecologic cancers. We and others have recently demonstrated that genetic inactivation of SMARCA4, one of the two ATPases of the SWI/SNF chromatin remodeling complex, along with protein loss is the only recurrent somatic mutation of SCCOHT. Furthermore, SMARCA4 loss appears as a key event in the development of a subset of dedifferentiated carcinoma of the ovary, endometrium or other organs. These SMARCA4-deficient dedifferentiated tumors and SCCOHT usually lose the expression of SMARCA2, the alternative ATPase of the SWI/SNF complex. Through mining the publicly available genome-wide CRISPR screen database from the Broad Institute DepMap Project for about 500 cell lines, we identified that SMARCA4/A2-dual deficient ovarian cell lines are selectively sensitive to the genetic ablation of multiple components of mitochondria electron transfer chain (ETC). Using seahorse metabolism assays, we revealed that SCCOHT cells have reduced glycolysis in comparison to other ovarian cancer cells and utilize mitochondria respiration for energy production regardless of the availability of glucose. Accordingly, both SCCOHT and SMARCA4-deficient dedifferentiated ovarian carcinoma cell lines are remarkably more sensitive to several inhibitors of ETC complex I, and tigecycline, a selective inhibitor of the mitochondria ribosomal translation, than other ovarian cancer cells, such as SMARCA4-intact ovarian high-grade serous carcinoma cells and clear cell ovarian carcinoma cells regardless of the expression level of ARID1A, a SWI/SNF complex subunit frequently lost in clear cell ovarian carcinoma. Re-expression of SMARCA4 increased the expression of SLC2A1, encoding the glucose transporter GLUT1, and decreased the sensitivity of SCCOHT cells to ETC complex I inhibitors, suggesting that SMARCA4 loss may reduce the transport of glucose leading to reduced glycolysis and increased reliance on mitochondria respiration, which is currently under investigation. Therefore, our data suggest that selective targeting mitochondria respiratory complex function can be an effective strategy for SCCOHT and other SMARCA4-deficient dedifferentiated cancers of gynecologic tract or other organs. Citation Format: Yemin Wang, Dionzie Ong, Shary Yuting Chen, Eunice Li, Krystal Orlando, Elizabeth Raupach, Jennifer Ji, Bernard Weissman, Patrick Pirrotte, David Humtsman. Selective killing of SMARCA4-deficient gynecologic cancers by mitochondria oxidative phosphorylation inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1459.
Characterization of a novel HDAC/RXR/HtrA1 signaling axis as a novel target to overcome cisplatin resistance in human non-small cell lung cancer
Authors: Wenjing Wang, Mengyue Zhao, Lijuan Cui, Yong Ren, Jingyuan Zhang, Junli Chen, Lina Jia, Jiayu Zhang, Jingyu Yang, Guoliang Chen, Charles R. Ashby, Chunfu Wu, Zhe-Sheng Chen, Lihui Wang
Journal: Molecular Cancer (2020)

Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome cisplatin resistance, it is important to understand the mechanisms underlying the resistance.A gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway.HtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXRα and HtrA1 in NSCLC patients' tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis.Our results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.
A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components
Authors: Monique B. Nilsson, Huiying Sun, Jacqulyne Robichaux, Matthias Pfeifer, Ultan McDermott, Jon Travers, Lixia Diao, Yuanxin Xi, Pan Tong, Li Shen, Mia Hofstad, Masanori Kawakami, Xiuning Le, Xi Liu, Youhong Fan, Alissa Poteete, Limei Hu, Marcelo V. Negrao, Hai Tran, Ethan Dmitrovsky, David Peng, Don L. Gibbons, Jing Wang, John V. Heymach
Journal: Science Translational Medicine (2020)

Acquired resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) remains a clinical challenge. Especially challenging are cases in which resistance emerges through EGFR-independent mechanisms, such as through pathways that promote epithelial-to-mesenchymal transition (EMT). Through an integrated transcriptomic, proteomic, and drug screening approach, we identified activation of the yes-associated protein (YAP) and forkhead box protein M1 (FOXM1) axis as a driver of EMT-associated EGFR TKI resistance. EGFR inhibitor resistance was associated with broad multidrug resistance that extended across multiple chemotherapeutic and targeted agents, consistent with the difficulty of effectively treating resistant disease. EGFR TKI-resistant cells displayed increased abundance of spindle assembly checkpoint (SAC) proteins, including polo-like kinase 1 (PLK1), Aurora kinases, survivin, and kinesin spindle protein (KSP). Moreover, EGFR TKI-resistant cells exhibited vulnerability to SAC inhibitors. Increased activation of the YAP/FOXM1 axis mediated an increase in the abundance of SAC components in resistant cells. The clinical relevance of these finding was indicated by evaluation of specimens from patients with EGFR mutant lung cancer, which showed that high FOXM1 expression correlated with expression of genes encoding SAC proteins and was associated with a worse clinical outcome. These data revealed the YAP/FOXM1 axis as a central regulator of EMT-associated EGFR TKI resistance and that this pathway, along with SAC components, are therapeutic vulnerabilities for targeting this multidrug-resistant phenotype.
Circulating microRNA-1 and microRNA-133a : potential biomarkers of myocardial steatosis in type 2 diabetes mellitus
Authors: D.D.G. Calvo, R.W. van der Meer, L.J. Rijzewijk, J.W.A. Smit, E. Revuelta-Lopez, L. Nasarre, J.C. Escola-Gil, H.J. Lamb, V. Llorente-Cortes
Journal: Cardiovascular Research (2016)
Abstract 1344: Simultaneous mRNA, protein, and immune repertoire profiling of antigen-specific T cells by single cell sequencing
Authors: Imteaz Siddique, Xiaoshan Shi, Margaret Nakamoto, Stefanie Mortimer
Journal: Cancer Research (2020)

Abstract High-throughput single cell RNA-seq (scRNA-seq) has transformed our understanding of complex and heterogenous immune populations. New advances in scRNA-seq are expanding the molecules that can be profiled at the single cell level, such as oligo-conjugated antibody technologies that enable protein expression profiling alongside mRNA. Although the ability to sequence the immune repertoire can provide crucial insights into understanding the complexities of the adaptive immune system and advancing discoveries in immuno-oncology, the ability to extract this information from single cells requires new technology to profile regions of the mRNA that are missed by conventional 3' scRNA-seq. In this study we utilized an ex vivo antigen stimulation system to measure antigen-specific T-cell activation and clonal amplification. Stimulated T cells from two donors were loaded onto the BD Rhapsody™ Single-Cell Analysis System to extract immune repertoire information in addition to gene and protein expression information from the same cells. In a single workflow, we profiled a panel of 400 mRNA targets, 20 BD® AbSeq protein markers associated with different status of T-cell activation, and the hypervariable region of T-cell receptors at the single cell resolution. The study is a proof of concept of combining mRNA, protein and immune repertoire analysis at the single cell level to deconvolute the heterogeneity and different activation of stimulated T cells. For Research Use Only. Not for use in diagnostic or therapeutic procedures. BD, the BD Logo, and Rhapsody are trademarks of Becton, Dickinson and Company or its affiliates. © 2019 BD. All rights reserved. Citation Format: Imteaz Siddique, Xiaoshan Shi, Margaret Nakamoto, Stefanie Mortimer. Simultaneous mRNA, protein, and immune repertoire profiling of antigen-specific T cells by single cell sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1344.
Author Correction: A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
Authors: Andrea Lunardi, Ugo Ala, Mirjam T. Epping, Leonardo Salmena, John G. Clohessy, Kaitlyn A. Webster, Guocan Wang, Roberta Mazzucchelli, Maristella Bianconi, Edward C. Stack, Rosina Lis, Akash Patnaik, Lewis C. Cantley, Glenn Bubley, Carlos Cordon-Cardo, William L. Gerald, Rodolfo Montironi, Sabina Signoretti, Massimo Loda, Caterina Nardella, Pier Paolo Pandolfi
Journal: Nature Genetics (2020)
Abstract 3374: Development of novel and improved monoclonal antiMUC16 antibodies for the targeted therapy of ovarian cancer
Authors: Ian Laster, Oladapo Yeku, David Spriggs
Journal: Cancer Research (2020)

Abstract There is a need for the development of better targeted therapies in the treatment of ovarian cancer. Monoclonal antibodies directed towards MUC16, a diagnostic and prognostic marker for ovarian cancer, with improved selectivity and specificity would be an instrumental component in the construction of novel methods of drug delivery and immunotherapies. C57BL/6 mice were immunized with various MUC16 peptides and truncated MUC16 constructs to extend the scope of MUC16 epitopes within the proximal COOH portion of the retained elements. Three rounds of hybridomas were made from harvested murine splenocytes, and subsequent rounds of peptide-based ELISA and cell-based flow cytometry were performed to select the most promising subclones from each of the fusions. Over 50 hybridomas producing antibodies against MUC16 have been identified and screened for reactivity with MUC16 peptide sequences and native, full-length MUC16 protein presented on the surface of ovarian cancer cell line cells. The antibodies were isotyped, and 10 have been selected for initial characterization. Non-overlapping epitopes were mapped via sequential and tandem peptide-based ELISA. With improved selectivity and specificity, these monoclonal antibodies will be used in the construction of antibody drug conjugates (ADCs) as potential targeted therapies in the treatment of ovarian cancer. Efficacy testing of the candidate antibodies in Matrigel invasion and direct growth inhibition assays is underway. Comparative effectiveness of the binding, internalization, and killing by ADCs in ovarian cancer cell lines will be presented. Antibodies against key MUC16 epitopes may have value in the development of antigen directed therapy. Citation Format: Ian Laster, Oladapo Yeku, David Spriggs. Development of novel and improved monoclonal antiMUC16 antibodies for the targeted therapy of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3374.
Poly(lactic-co-glycolic acid)-based composite bone-substitute materials
Authors: Duoyi Zhao, Tongtong Zhu, Jie Li, Liguo Cui, Zhiyu Zhang, Xiuli Zhuang, Jianxun Ding
Journal: Bioactive Materials (2020)

Research and development of the ideal artificial bone-substitute materials to replace autologous and allogeneic bones for repairing bone defects is still a challenge in clinical orthopedics. Recently, poly(lactic-co-glycolic acid) (PLGA)-based artificial bone-substitute materials are attracting increasing attention as the benefit of their suitable biocompatibility, degradability, mechanical properties, and capabilities to promote bone regeneration. In this article, we comprehensively review the artificial bone-substitute materials made from PLGA or the composites of PLGA and other organic and inorganic substances, elaborate on their applications for bone regeneration with or without bioactive factors, and prospect the challenges and opportunities in clinical bone regeneration.
Abstract 1148: Salivary auto-antibodies as diagnostic markers of oral cavity squamous cell carcinoma
Authors: Pei Chun Hsueh, Chih Ching Wu
Journal: Cancer Research (2020)

Abstract Oral cavity squamous cell carcinoma (OSCC) is a destructive disease with its increasing new cases annually. OSCC is usually diagnosed at advanced clinical stage which leads to the poor outcomes of patients. Currently, no biomarkers provide capability for sufficient early detection of OSCC. Cancer-associated auto-antibody (auto-Ab) holds potentials as promising biomarkers for cancer detection because auto-Ab is easily detected with well-established secondary reagents. To ameliorate the detection of OSCC, we evaluated the capability of auto-Ab to 9 proteins as the OSCC biomarkers with multiplexed bead-based immunoassay, as the salivary levels of the 9 proteins are elevated in OSCC patients. The multiplexed bead-based assay has been established to simultaneously detect the salivary levels of the 9 auto-Abs and anti-p53, a well-characterized OSCC biomarker. Compared to the healthy individuals, the salivary levels for 8 of 9 auto-Abs as well as anti-p53 were significantly elevated in OSCC patients. The salivary levels of the 7 of 9 auto-Abs were significantly increased in individuals with oral potentially malignant disorder compared to the control group. In addition, the salivary levels of 8 of 9 auto-Abs as well as anti-p53 were statistically significant in early-stage OSCC patients. Moreover, the marker panel of the 9 auto-Abs can improve the detection of OSCC. Collectively, we have established the platform for detection of maker panels and the salivary auto-Abs are potential biomarkers for OSCC screening. Citation Format: Pei Chun Hsueh, Chih Ching Wu. Salivary auto-antibodies as diagnostic markers of oral cavity squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1148.
THU0043 The expression of cyclooxygenase, lipooxygenase and neuropeptides in muscle tissue of patients with polymyositis and dermatomyositis
Authors: J Tomasova Studynkova, S Kuchen, E Jeisy, J Schedel, F Charvat, K Jarosova, R Gay, H Sprott, J Vencovsky, S Gay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To investigate pathogenesis of inflammation in muscles of patients with idiopathic inflammatory myopathies (IIM) – dermatomyositis (DM), polymyositis (PM) by studying expression of cox, lox and neuropeptides, using <i>in situ</i> hybridization and immunohistochemistry. <h3>Methods</h3> Muscle tissue samples were obtained by needle biopsy from affected and non-affected sites distinguished by MRI-STIR technique. The second biopsy was performed after treatment. For studying cox, lox we used <i>in situ</i> hybridization with mRNA probes – antisense cox1, 2 and lox 5. Neuropeptides, such as substance P (SP), calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), were evaluated by using immunohistochemistry. <h3>Results</h3> 11 patients with DM or PM (9 female, 2 male) were examined. The expression of all investigated molecules (cox1, cox2, lox5, CGRP, SP, VIP, NPY) was detected on all muscle tissue. mRNA expression of cox and lox was increased in affected tissue (detectable expression was on 47 sections of 53–89%) in comparison with non-affected (40 sections of 64 ? 63%) and tissue after treatment. Expressing cells were muscle cells, inflammatory cells and vessels. Cox1 expression was found mainly on inflammatory cells and vessels, cox2 on muscle cells, inflammatory cells and vessels, lox5 mainly on muscle cells. Expression of neuropeptides was detected mainly on vessels, not on nerve cells. SP and CGRP were expressed in all tissues, VIP and NPY mainly in affected tissue. CGRP was expressed on smaller and thicker vessels in non-affected tissue and on bigger and thinner vessels in affected tissue, SP on smaller and thicker vessels in affected tissue. VIP and NPY staining was weak. <h3>Conclusion</h3> Expression of all investigated molecules was observed in all muscle tissue samples from IIM patients. This expression was increased in affected tissues compared with non-affected and tissue after treatment, which indicates the role of cox, lox and neuropeptides in pathogenesis of IIM. Expression of neuropeptides was detected on vessels, not on nerve cells that suggests activation of vascular system in inflamed tissue. This work was supported by grant IGA MZ CR NI/5369–3.
Abstract 5130: Proteomic characterization of cytoplasmic lipid droplets in human metastatic breast cancer cells
Authors: Alyssa S. Zembroski, Chaylen Andolino, Kimberly K. Buhman, Dorothy Teegarden
Journal: Cancer Research (2020)

Abstract One of the characteristic features of metastatic breast cancer is altered lipid metabolism, including increased cellular storage of neutral lipid in cytoplasmic lipid droplets (CLDs). CLD accumulation is associated with increased cancer aggressiveness, suggesting CLDs contribute to metastasis. Although multiple hypotheses exist for how CLDs may promote cancer progression, how exactly CLDs contribute to breast cancer metastasis is not clear. CLDs are composed of a neutral lipid core, a phospholipid monolayer, and associated proteins. Proteins that associate with CLDs are thought to regulate CLD metabolism; however, the proteome of CLDs in metastatic breast cancer and how these proteins may contribute to altered lipid metabolism and breast cancer progression is unknown. Therefore, we utilized untargeted shotgun proteomics and transmission electron microscopy to identify the proteome and assess the characteristics of CLDs in the MCF10CA1a human metastatic breast cancer cell line. We identified a total number of 1537 proteins in the CLD fraction isolated from MCF10CA1a cells, and these proteins were associated with a variety of cellular processes. Interestingly, unlike other cell lines such as adipocytes or enterocytes, the most enriched protein categories were involved in cellular processes outside of lipid metabolism. For example, proteins involved in cell-cell adhesion were the most enriched in the CLD fraction, and some of these proteins had associated terms in cell migration and signaling. In addition, we characterized CLD size and area in MCF10CA1a cells using transmission electron microscopy. Our results provide a hypothesis-generating list of potential players in breast cancer progression and aggressiveness, making them possible therapeutic targets for prevention or treatment of this disease. Citation Format: Alyssa S. Zembroski, Chaylen Andolino, Kimberly K. Buhman, Dorothy Teegarden. Proteomic characterization of cytoplasmic lipid droplets in human metastatic breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5130.