bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 747: Characteristic molecular signature of pericardial effusion identifies malignant cancer in pericardial disorder patients
Authors: Nam Suk Woo , Kim Sang Yean , Kim Hyung Seok , Yang Hee Doo , Na Min Jeong 
Published: August 2019

Abstract
Pericardial effusion (PE) can develop in patients with virtually any condition that affects the pericardium, including acute pericarditis and a variety of systemic disorders. PE is also common in cancer patients, and that may develop by several different mechanisms by direct or metastatic spread of the primary process or as a complication of antineoplastic therapies. Thus, definite differentiation of malignant PE and rapid diagnosis are of particular therapeutic and prognostic importance. We aim to determine etiology-based characteristic molecular changes of PE in pericardial disorder patients, and to identify novel molecular signature for early detection of cancer patients with pericardial disorder. We obtained pericardial fluids from the pericardial disorders including cancer patients. Whole genomic transcriptome scan resulted in 1,639 outlier genes as cancer-specific PE molecular signature. Further analysis showed that a cancer-specific molecular signature exists and discerns cancer patients with non-cancer patients, and that also suggested 191 gene elements as stringent classifier between cancer vs non-cancer (Welch’s t test, p &lt; 0.05 and Ven diagrammatic analysis). Gene set enrichment analysis (GSEA) with additional computational analysis of 1,639 cancer-specific PE molecular signature identified CD24, SDC1, and ST14 as strong molecular markers for identifying cancer in PE patients. In conclusion, whole transcriptomic analysis of pericardial fluids of pericardial disorder patients suggest that etiology-specific molecular signatures can discriminate different patterns of PE, and that they provide useful information for mechanistic studies that may lead to a better understanding of the molecular basis of PE pathology.
Keywords: pericardial fluid, differential gene expression, diagnostic markers, CD24, SDC1, ST14
Citation Format: Suk Woo Nam, Sang Yean Kim, Hyung Seok Kim, Hee Doo Yang, Min Jeong Na. Characteristic molecular signature of pericardial effusion identifies malignant cancer in pericardial disorder patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 747.
Abstract 752: Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden
Authors: Ohashi Kadoaki , Makimoto Go , Tomida Shuta , Nishii Kazuya , Toyooka Shinichi , Kiura Katsuyuki 
Published: August 2019

Abstract
Background: Alectinib, a highly selective anaplastic lymphoma kinase (ALK) inhibitor, demonstrates an unprecedented effect in ALK-positive lung cancers. However, some tumors quickly develop resistance to alectinib. In this study, we aimed to investigate the mechanism of the rapidly acquired resistance to alectinib using clinical samples.
Methods: Autopsied specimens of lung, liver, and renal tumors were obtained from a 51-year-old male patient with advanced ALK-positive lung cancer, who had acquired resistance to alectinib in only three months. Two alectinib-resistant cell lines were established from pleural effusion (ABC-14) or liver tumors (ABC-17). A patient-derived xenograft (PDX) model was also developed from liver tumors. Next-generation sequencing (NGS), direct DNA sequencing, and quantitative real time reverse transcription-PCR were performed.
Results: ABC-14 harbored no ALK mutations and showed sensitivity to crizotinib, an ALK/MET inhibitor. It also showed mesenchymal-epithelial transition factor (MET) gene amplification and amphiregulin overexpression. The combination of crizotinib and erlotinib showed beneficial inhibitory effects on cell growth. ABC-17 and PDX tumors harbored ALK G1202R. PDX tumors metastasized to multiple organs in vivo, whereas lorlatinib, the third-generation ALK inhibitor, diminished tumor growth both in vitro and in vivo. NGS demonstrated high tumor mutation burden (TMB) and heterogeneous evolution of the patient tissues. The autopsied lung tumors harbored ALK G1202R (c. 3604 G&gt;A) and the right renal metastasis harbored ALK G1202R (c. 3604 G&gt;C); the mutation thus altered codon sequences.
Conclusions: High TMB and heterogeneous tumor evolution may have conferred the rapid resistance to alectinib. Timely administration of lorlatinib or combination therapies with an ALK inhibitor and other RTK inhibitors may constitute a potent therapeutic strategy.
Financial support: This research was supported by a Grant for Lung Cancer Research (K.O.), provided by the Japan Lung Cancer Society.
Citation Format: Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Kazuya Nishii, Shinichi Toyooka, Katsuyuki Kiura. Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 752.
Abstract 761: Up-regulation of miR-10a affect on prostate cancer racial disparity
Authors: Hashimoto Yutaka , Shiina Marisa , Tanaka Yuichiro , Dasgupta Pritha , Kulkarni Priyanka , Kato Taku , Wong Ryan K. , Shahryari Varahram , Maekawa Shigekatsu , Yamamura Soichiro , Bhagiratha Divya , Saini Sharanjot , Deng Guoren , Tabatabai Laura , Majid Shahana , Dahiya Rajvir , Dahiya Rajvir 
Published: August 2019

Abstract
Purpose: Prostate cancer (PC) is the second most diagnosed cancer in men. African-American (AfA) men have higher incidence and twice the PC mortality rates compared to Caucasian-American (CaA) men. In this study, we investigated the biochemical role of miR-10a in prostate cancer racial disparity. Methods: We used PCa cell lines from CaA (DU145, LNCaP, PC3), AfA (MDA-PCa-2b, E006AA-hT) and a normal epithelial cell line (PWR1E) to examine miR-10a expression levels. Total RNA was extracted from total 138 human prostate cancer clinical samples (AfA: n=75, CaA: n=63) and cell lines. Gene expression levels were determined by quantitative real-time PCR (qPCR). A miRNA target database (miRWalk that integrates mainly three databases, miRDB, TargetScan and miRTarBase) was used for miR-10a target prediction. Cell proliferation and apoptosis were monitored after miR-10a knockdown by using anti-miR-10a. Results: miR-10a was significantly up-regulated in AfA prostate cancer cell line, E006AA-hT compared to CaA cells. Utilizing SFVAMC and NDRI patient cohorts, we confirmed that miR-10a expression was linked to a racial difference between AfA/CaA PCa patients. Knockdown of miR-10a showed decreased growth and apoptosis, though the effect was less in CaA compared to AfA cells. We found NCOR2 which is frequently deleted in castration- resistant prostate cancer patient specimens and tumor-suppressor PTEN as miR-10a targets that overlapped in multiple miRNA target prediction databases. Conclusion: These results demonstrate that miR-10a may be a central regulator of crucial events that contribute to racial differences in prostate cancer. Regulation of miR-10a expression may be a new therapeutic strategy for AfA prostate cancer patients.
Citation Format: Yutaka Hashimoto, Marisa Shiina, Yuichiro Tanaka, Pritha Dasgupta, Priyanka Kulkarni, Taku Kato, Ryan K. Wong, Varahram Shahryari, Shigekatsu Maekawa, Soichiro Yamamura, Divya Bhagiratha, Sharanjot Saini, Guoren Deng, Laura Tabatabai, Shahana Majid, Rajvir Dahiya, Rajvir Dahiya. Up-regulation of miR-10a affect on prostate cancer racial disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 761.
Abstract 772: MicroRNA regulatory networks: Concomitant in situ detection of microRNA, mRNA and protein in cancer samples
Authors: Nielsen Boye Schnack 
Published: August 2019

Abstract
The canonical mode of action of microRNAs involves the binding to the 3'UTR of mRNAs thereby mediating repression of protein synthesis. MicroRNAs comprise an interesting new group of cancer biomarkers and may also be therapeutic targets in cancer and other diseases using antisense oligos (ASO). The visualization of potential molecular dynamics between a microRNA, its target mRNA and the effect of protein expression can be facilitated by combined detection in tissue sections. MicroRNAs, as well as ASOs, can be detected in tissue sections or cultured cells by in situ hybridization (ISH) using LNA probes. We have developed a novel ISH assay for microRNA detection with improved sensitivity and signal-to-noise that can be used with any LNA probe on both FFPE and frozen sections. The assay is based on double-labeled LNA™ probes and detection can be either fluorescence or chromogenic staining. We have combined the fluorescence assay with immunofluorescence, for double and triple staining. We also combined the microRNA ISH assay with mRNA in situ hybridization using the highly specific RNAscope probes. We show a variety of combinations, including examples of combined staining of microRNA-17, IL-1beta mRNA or TNF-alpha mRNA, and cytokeratin proteins in automated triple staining procedures of colon cancer samples. The focal expression of IL-1beta mRNA or TNF-alpha mRNA and the loss of microRNA-17 at the invasive front involving inflammatory cells and budding cancer cells is discussed.
Citation Format: Boye Schnack Nielsen. MicroRNA regulatory networks: Concomitant in situ detection of microRNA, mRNA and protein in cancer samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 772.
Abstract 783: miR-375 downregulates VEGFA via YAP1-EBRR2 pathway in esophageal cancer
Authors: Ren Shuchang , Tan Xiaohui , Wu Xiaoling , Chen Tao , Latham Patricia , Fu Sidney W. 
Published: August 2019

Abstract
Esophageal cancer (EC), including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), is one of the deadliest cancers with extremely aggressive nature and poor survival rate. Diagnostic methods for EC mainly include endoscopy, barium swallow and ultrasound, which are either invasive or lack of sensitivity and specificity at early stages. Therefore, the development of a non-invasive and reliable diagnostic method with high sensitivity and specificity is crucial in improving early detection, diagnosis and treatment. microRNAs (miRNAs) are small RNA molecules that regulate the expression of protein-coding genes by directly binding to target mRNAs in a sequence-specific manner. The aim of this study is to identify novel miRNA biomarkers for EC diagnosis. By cross-referencing our data with others’ from NCBI, we identified a list of dysregulated miRNAs in EC, including miR-375. We assessed the expression of miR-375 in EC cell lines and tissues using real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). We found that miR-375 expression is significantly decreased in human EC cell lines (KEYS-70, KEYS-180, FLO-1 and JHU-ad1) compared to the normal esophageal squamous cell line, Het-1A. Using microdissection technique, we isolated normal epithelium, dysplasia, and invasive EC components from formalin-fixed, paraffin-embedded (FFPE) tissue followed by qRT-PCR analysis. Decreased expression of miR-375 was detected in 12 of 14 EC tissue samples (86%) compared to the matched normal tissues. MTT and Matrigel invasion assay demonstrated that forced expression of miR-375 suppressed the proliferation and invasion in EC cell lines. TargetScanS and miRanda were used to identify potential target genes of miR-375, which includes epidermal growth factor receptor 2 (HER2) and YES-associated protein (YAP1), both of them act as oncogenes in EC development. Interestingly, forced expression of miR-375 resulted in significantly reduced expression of human vascular endothelial growth factor-A (VEGF-A) gene, which is a downstream target gene of YAP1/ERBB2 pathway involving in tumor angiogenesis in EC cell lines. More functional analysis is under way. These findings suggest that miR-375 may act as a tumor suppressor, and could serve as a marker for EC diagnosis and management.
Citation Format: Shuchang Ren, Xiaohui Tan, Xiaoling Wu, Tao Chen, Patricia Latham, Sidney W. Fu. miR-375 downregulates VEGFA via YAP1-EBRR2 pathway in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 783.
Abstract 785: The inhibitory effect of compound ChlA-F onhuman bladder cancer cell invasion can be attributed to its blockage of SOX2 protein
Authors: Hua Xiaohui , Xu Jiheng , Huang Chuanshu , Li Jingxia , Tian Zhongxian , Huang Haishan 
Published: August 2019

Abstract
Sex-determining region Y-box 2 (SOX2), a well-known stemness biomarker, is highly expressed in a variety of cancers, including human highly invasive bladder cancer (BC). However, the role of SOX2 may vary in different kinds of malignancy. In the present study, we discovered that ChlA-F, a novel conformation derivative of isolate Cheliensisin A (Chel A), remarkably inhibits the invasive ability of human invasive BC cells through downregulation of SOX2 protein expression. We found that ChlA-F treatment dramatically decreases SOX2 protein expression in human high-grade invasive BC cells. Ectopic expression of SOX2 reversed ChlA-F inhibition of cell invasion ability in human bladder cancer cells, suggesting that SOX2 is a major target of ChlA-F during its inhibition of human BC invasion. Mechanistic studies revealed that SOX2 is downregulated by ChlA-F at both the protein degradation and protein translation levels. Further studies revealed that ChlA-F treatment induces HuR protein expression and that the increased HuR interacts with USP8 mRNA, resulting in elevation of USP8 mRNA stability and protein expression. Elevated USP8 subsequently acts as an E3 ligase to promote SOX2 ubiquitination and protein degradation. We also found that ChlA-F treatment substantially increases c-Jun phosphorylation at Ser63 and Ser73, initiating miR-200c transcription. The increased miR-200c directly binds to the 3’-UTR of SOX2 mRNA to suppress SOX2 protein translation. These results present novel mechanistic insight into understanding SOX2 inhibition upon ChlA-F treatment and provide important information for further exploration of ChlA-F as a new therapeutic compound for the treatment of highly invasive/metastatic human BC patients.
Citation Format: Xiaohui Hua, Jiheng Xu, Chuanshu Huang, Jingxia Li, Zhongxian Tian, Haishan Huang. The inhibitory effect of compound ChlA-F onhuman bladder cancer cell invasion can be attributed to its blockage of SOX2 protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 785.
Abstract 791: V-ATPase in glioma stem cells: V1G1 subunit expression correlates with metabolic behavior and mitochondria activity
Authors: Storaci Alessandra M. , Bertolini Irene , Caroli Manuela , Ferrero Stefano , Vaira Valentina 
Published: August 2019

Abstract
Background The vacuolar H+-ATPase (V-ATPase) is a multisubunit proton pump with a role in the acidification of the extra- and intra-cellular environments. Recent evidence connected V-ATPase deregulation and human diseases, including cancer. We previously demonstrated that the overexpression of the catalytic subunit V1G1 is correlated with glioma stem cells (GSC) maintenance. According to V1G1 expression, we sorted glioblastoma patients-derived neurospheres cultures (NS) into two categories: V1G1HIGH and V1G1LOW NS. These NS differ in terms of stem cell genes expression, sphere formation, invasion ability, lysosomal acidity and bioenergetics.
Methods V1G1HIGH, V1G1LOW NS treated with 10nM of BafilomycinA1 (BafA1) or vehicle for 24h (n=3 per group) were used for the functional experiments. Lactate, glucose, ATP levels were measured by commercial kits. Metabolic proteins expression was assessed by western blot. ROS production and mitochondria function were measured by flow cytometry using MitoSox and TMRE assays, respectively.
Results At basal conditions, V1G1LOW NS produce higher levels of lactate (p=0.0379) whereas V1G1HIGH NS show higher levels of extracellular glucose and intracellular ATP. Accordingly, the two NS cultures show an opposite trend in LDH subunits expression with LDHA, which pushes lactate production, being more expressed in V1G1LOW (p=0.0027). Conversely, LDHB that facilities the production of pyruvate from lactate, and the transporter MCT1 are more expressed in V1G1HIGH NS. Interestingly, using the V-ATPase specific inhibitor BafA1, metabolic characteristics of V1G1HIGH are redirected to the V1G1LOW phenotype. Moreover, in V1G1HIGH NS BafA1 induces ROS production and affects mitochondria activity, increasing their depolarization.
Conclusions Taken together these data suggest two distinct metabolic behaviors of NS according to V-ATPase expression. Indeed for energy production V1G1LOW NS could rely on a glycolytic metabolism whereas V1G1HIGH NS on oxidative phosphorylation. Moreover, when overexpressed the proton pump could also have a role in preserving mitochondria polarity. Although preliminary, this is the first evidence reporting a role for V-ATPase in the regulation of cancer stem cell metabolism.
Citation Format: Alessandra M. Storaci, Irene Bertolini, Manuela Caroli, Stefano Ferrero, Valentina Vaira. V-ATPase in glioma stem cells: V1G1 subunit expression correlates with metabolic behavior and mitochondria activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 791.
Abstract 799: Aberrant mitochondrial protein involvement through early PDAC initiation and progression using multiplexed DNA-PAINT and correlative histology
Authors: Rames Matthew J. , Civitci Fehmi , Zheng Ting , Wagner Josiah , Link Jason , Nan Xiaolin 
Published: August 2019

Abstract
Prior to pancreatic ductal adenocarcinoma (PDAC), pancreatic acini cells change their morphology through pancreatic intraepithelial neoplasia (PanIN) stages, becoming increasingly dysplastic as stroma and tissue hypoxia increase. This increasing hypoxia forms a cancer promoting microenvironment, wherein we propose metabolic changes trigger aberrant mitochondrial networks form healthy tissue. We developed tissue superresolution imaging to directly quantify structural mitochondrial response through patient histology, whereby DNA-PAINT can provide super-resolution detail decoupled from photo bleaching to visualize mitochondria through tissue layers. Expanding from preliminary data, target mitochondrial dynamics proteins’ organization will also be correlated to PanIN stages.
Introduction: Early oncogene involvement in PDAC progression links to metabolic and mitochondrial regulatory changes. Typically nutrient deprivation and hypoxia trigger cell death from increased reactive oxygen species production and organelle damage which trigger apoptosis, yet these prolonged effects can be cancer promoting when less severe. Mitochondrial dynamics and proteins related to mitochondrial fission and fusion can reduce apoptotic signaling, enhance aerobic glycolysis, and increase ROS to allow cancer progression.
Materials and Methods: Adapting from previous proof of concept, mitochondria (TOM20) within formalin-fixed paraffin embedded (FFPE) tissue sections were imaged with stochastic optical reconstruction microscopy (STORM). In brief: cadaver healthy pancreas FFPE tissue samples underwent deparafinization, antigen retrieval, indirect immuno-labeling with AlexaFluor647, TIRF illumination with a 60x objective was used for data collection, whereby data processing was conducted using the open-source FIJI and custom MATLAB software.
Results and Discussion: Preliminary data shows proof of principle that both STORM and DNA-PAINT can be correlated to histological staining of human pancreas.
Conclusions: Superresolution imaging reveals ultrastructural details of mitochondria in FFPE patient samples not resolved via conventional fluorescence imaging. Through quantitative feature analysis, we would be able to correlate aberrant mitochondria structure and abundance to PDAC progression.
Acknowledgements: Funding provided by the Cancer Early Detection Advanced Research (CEDAR) Center of OHSU Knight Cancer Institute.
Citation Format: Matthew J. Rames, Fehmi Civitci, Ting Zheng, Josiah Wagner, Jason Link, Xiaolin Nan. Aberrant mitochondrial protein involvement through early PDAC initiation and progression using multiplexed DNA-PAINT and correlative histology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 799.
Abstract 811: Multi-targeted inhibitors of mitochondrial one-carbon metabolism and cytosolic de novo purine synthesis enzymes as anti-tumor agents
Authors: Nayeen Md Junayed , Shah Khushbu , Dekhne Aamod , Ning Changwon , O'Connor Carrie , Katinas Jade M. , Wong Jennifer , Hou Zhanjun , Dann Charles E. , Matherly Larry H. , Gangjee Aleem 
Published: August 2019

Abstract
Targeting cellular one-carbon (1C) metabolism in cancer cells with pyrrolo[3,2-d]pyrimidine analogs provides in vivo antitumor efficacy. We discovered a first-in-class series of 5-substituted pyrrolo[3,2-d]pyrimidine analogs (AGF291, AGF320, AGF347) with inhibition of serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in mitochondrial 1C metabolism and a reported oncodriver. In addition, AGF291, AGF320 and AGF347 inhibited de novo purine nucleotide biosynthesis at glycinamide ribonucleotide formyltransferase (GARFTase) and 5-aminoimidazole-4-carboxamide (AICA) ribonucleotide formyltransferase (AICARFTase), and serine hydroxymethyltransferase 1 (SHMT1). In vivo studies demonstrated excellent antitumor efficacy for AGF347 against MIA PaCa-2 pancreatic adenocarcinoma xenografts in SCID mice with a median tumor growth delay (T-C) of &gt;38 days for 4 mice, and 1 of 5 mice tumor-free 122 days post-treatment. AGF359, a new analog in this series, was a potent inhibitor of KB human tumor cell proliferation in vitro. AGF359 inhibition of KB human tumor cells was reversed with glycine and adenosine, establishing mitochondrial 1C metabolism and de novo purine biosynthesis as the targeted pathways; AICA plus glycine was incompletely protective, implicating AICARFTase as a direct cellular target. AGF359, like AGF291, AGF320, and AGF347, inhibited purified human SHMT2 (Ki = 0.399 ± 0.174 µM), SHMT1 (Ki = 0.70 ± 0.088 µM) and AICARFTase (Ki = 8.86 ± 2.83 µM). There was no inhibition of 5,10-methylene tetrahydrofolate dehydrogenase 2 (MTHFD2). Further structural modifications of these multi-targeted agents afforded pyrrolo[3,2-d]pyrimidine analogs AGF307 and AGF312. Cell-based glycine/nucleotide rescue experiments in KB tumor cells established that, as with AGF359, AGF307 and AGF312 were dual inhibitors of the mitochondrial 1C metabolism (AGF307) and de novo purine biosynthesis (AGF307, AGF312). These compounds are currently in further preclinical evaluation as a prelude to possible clinical development as antitumor agents.
Citation Format: Md Junayed Nayeen, Khushbu Shah, Aamod Dekhne, Changwon Ning, Carrie O'Connor, Jade M. Katinas, Jennifer Wong, Zhanjun Hou, Charles E. Dann III, Larry H. Matherly, Aleem Gangjee. Multi-targeted inhibitors of mitochondrial one-carbon metabolism and cytosolic de novo purine synthesis enzymes as anti-tumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 811.