bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2189: Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer
Authors: Tejaswi Tejaswi , Zhang Baozhen , Wang Qixuan , Hou Ye , Jin Qiushi , Xu Jie , Yang Hongbo , Liu Tingting , DeGraff David J. , Yue Feng 
Published: July 2021

Abstract
Urinary bladder cancers (BLCA) are commonly diagnosed urologic malignancy in the United States. Muscle invasive BLCA is a morbid and expensive disease to treat, thus increased molecular understanding is necessary. BLCA has recently been characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARg have been shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remains unknown. Here, we determined the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles (FOXA1 and GATA3) in luminal and basal subtypes of bladder cancers. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct TF binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identified a novel clinically relevant transcriptional factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. In summary, our work identifies a subtype-specific epigenomic and 3D genome structure in urinary bladder cancers and suggests a novel link between the circadian TF NPAS2 and a clinical bladder cancer subtype.
Citation Format: Tejaswi Tejaswi, Baozhen Zhang, Qixuan Wang, Ye Hou, Qiushi Jin, Jie Xu, Hongbo Yang, Tingting Liu, David J. DeGraff, Feng Yue. Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2189.
Abstract 2251: Gene expression analysis by RNA-sequencing highlights differential regulated pathways involved in cell cycle and inflammation in orbitofacial neurofibromas
Authors: Imada Eddie L. , Edward Deepak P. , Arnold Antje , Al-Hussain Hailah , Strianese Diego , Marchionni Luigi , Rodriguez Fausto J. 
Published: July 2021

Abstract
Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. Orbitofacial NFs in particular may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit, and anecdotal evidence suggest that they may have increased local aggressiveness compared to NFs developing at other sites. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We performed global RNA-sequencing in orbitofacial (n=10) and non-orbitofacial (n=9) NFs. A total of 880 mRNA transcripts were differentially expressed between the two groups (adjusted p&gt;0.05), The top 10 genes relatively overexpressed in orbitofacial NF included NEFL, TREM2, CST1, GAP43, ADORA3, MIA, SYT6, FCGR3A, SPP1, and FCGR1A. The top 10 genes relatively underexpressed in orbitofacial NF included XG, WISP2, MMP27, CXCL14, MFAP5, APLNR, MYOC, SLITRK6, STMN2, and TDRD1. Gene enrichment analyses demonstrated a variety of gene sets differentially affected including pathways involved in cell proliferation, interferon and immune related pathways. Comparisons with publicly available databases of various Schwann cell tumors and models using CAT plots demonstrated the highest overlap with differentially expressed genes in plexiform NF vs MPNST (&gt;10%). In summary, we identified gene expression differences between orbitofacial NF and NFs occurring at other anatomic locations. Further investigation may be warranted, given that orbitofacial NF are notoriously difficult to treat and associated with disproportionate morbidity.
Citation Format: Eddie L. Imada, Deepak P. Edward, Antje Arnold, Hailah Al-Hussain, Diego Strianese, Luigi Marchionni, Fausto J. Rodriguez. Gene expression analysis by RNA-sequencing highlights differential regulated pathways involved in cell cycle and inflammation in orbitofacial neurofibromas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2251.
Abstract 2358: miRNA-483-3p overexpression unleashes invasiveness of metastatic colorectal cancer by NDRG1 targeting and upregulation of the HER3-AKT axis
Authors: Candiello Ermes , Reato Gigliola , Verginelli Federica , D'Ambrosio Antonio , Gambardella Gennaro , Albano Raffaella , Luraghi Paolo , Comoglio Paolo M. , Bertotti Andrea , Trusolino Livio , Boccaccio Carla 
Published: July 2021

Abstract
In colorectal cancer, the genetic mechanisms underlying the metastatic switch are still poorly understood. Here we show that overexpression of miRNA-483-3p, encoded by a frequently amplified gene locus encompassing also insulin-like growth factor 2, confers an aggressive phenotype to stem-like cells derived from colorectal cancer metastases (m-colospheres). As result of miRNA-483-3p ectopic overexpression, m-colospheres displayed (i) increased proliferative response to exogenous EGFR family ligands EGF and NRG1; (ii) increased spontaneous and growth factor-induced in vitro invasiveness and epithelial-mesenchymal transition (EMT); (iii) enhanced stem-cell frequency and resistance to differentiation. By transcriptomic analyses and functional validation, we found that miRNA-483-3p targets NDRG1, a known ‘metastasis suppressor', which is responsible for degradation of EGFR family members, in particular HER3. As result, ectopic or native miRNA-483-3p overexpression was associated with hyper-activation of the signaling pathway triggered by HER3, including AKT and GSK3β, responsible for activation of EMT transcription factors. Consistently, treatment of miRNA-483-3p overexpressing m-colospheres with HER3 specific antibodies counteracted their proliferative and invasive phenotype. The pro-invasive role of miRNA-483-3p in patients was further confirmed by (i) analysis of colorectal tumors, where miRNA-483-3p expression levels directly correlated with expression of EMT transcription factors and poor-prognosis, and (ii) downregulation of naturally occurring miRNA-483-3p overexpression, which prevented invasion of tumors formed by m-colosphere transplantation. These results indicate that miRNA-483-3p can support colorectal cancer invasion through a signaling pathway amenable to targeting in human patients.
Citation Format: Ermes Candiello, Gigliola Reato, Federica Verginelli, Antonio D'Ambrosio, Gennaro Gambardella, Raffaella Albano, Paolo Luraghi, Paolo M. Comoglio, Andrea Bertotti, Livio Trusolino, Carla Boccaccio. miRNA-483-3p overexpression unleashes invasiveness of metastatic colorectal cancer by NDRG1 targeting and upregulation of the HER3-AKT axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2358.
Abstract 2486: Pleiotropic anti-cancer effects of STING in estrogen receptor positive breast cancer cells
Authors: Liu Chun-Yu , Chen Ji-Lin , Huang Chun-Teng , Chu Pei-Yi , Tseng Mei-Fang , Lee Yu-Hsuan , Wang Wan-Lun , Tseng Ling-Ming 
Published: July 2021

Abstract
Purpose: Stimulator of interferon genes (STING) is an upstream regulator of interferon and NF-κB, the key mediators of immune and inflammatory responses associated with cancer, triggered by cytosolic DNA. Downregulation of STING in breast tumor tissues has been reported. STING elicits caspase-8-dependent cell apoptosis via NF-κB in breast cancer cells. STING agonists are considered as potent anti-cancer agents. The current study aims to assess the biological functions of STING in breast cancer progression.
Experimental design: Data of mRNA expression levels and recurrence-free survival in patients with breast cancer from The Cancer Genome Atlas and Kaplan Meier-plotter databases were analyzed. Transwell assays were used to evaluate cell migrated and invaded abilities. Sphere formation was performed in stem cell-selective medium and ultra-low attachment plates. Two STING agonists, ADU-S100 and diABZI STING agonist-1 trihydrochloride, were used for in vitro studies. The molecular events were examined by Western blot analysis.
Results: Data from public database showed that lower transcripts levels of STING in Her2 and luminal B breast cancer tissues than normal breast tissues. Luminal-type breast cancer cell lines harbored low STING transcripts compared with other subtypes. Importantly, breast cancer patients with low expression levels of STING was associated with worse recurrence-free survival. Results of immunoblotting indicated that breast cancer cell lines have lower STING protein expressions than normal MCF10A cells. Knockdown of STING led to aggressive phenotypes of MCF10A and BT474 cells. In contrast, overexpression of STING suppressed the abilities of migration, invasion and sphere formation of MCF7 and BT474 cells. The markers of epithelial were increased while the markers of mesenchymal and stemness were decreased by STING overexpression. STING agonist slightly suppressed cell viability of breast cancer cells but not MCF10A cells. Treatment of STING agonists reduced cell migrated ability with upregulation of E-cadherin and γ-catenin.
Conclusion: These findings suggest that STING serves tumor-suppressive effects in breast cancer.
Citation Format: Chun-Yu Liu, Ji-Lin Chen, Chun-Teng Huang, Pei-Yi Chu, Mei-Fang Tseng, Yu-Hsuan Lee, Wan-Lun Wang, Ling-Ming Tseng. Pleiotropic anti-cancer effects of STING in estrogen receptor positive breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2486.
Abstract 259: Comparison of Illumina NovaSeq 6000 and MGISEQ-2000 in profiling xenograft models
Authors: Qian Wubin , Chen Xiaobo , Li Henry Q. , Guo Sheng 
Published: July 2021

Abstract
BACKGROUND: Comprehensive genomic profiling of tumor models, including patient-derived xenografts, cell lines and organoids, is an integral prerequisite for productive in vivo studies. There are now two leading sequencing platforms from Illumina and MGI Tech. In this study, we compared the performance of the two platforms in sequencing xenograft tumors, which contain both human tumor cells and mouse stromal cells.
METHODS: We performed genomic profiling on several xenograft tumors by both sequencers, including RNA-seq and whole-exome sequencing (WES) for 3 samples, and whole-genome sequencing (WGS) for 1 sample. We then performed a comprehensive assessment of sequencer performance using multiple criteria.
RESULTS: The mouse ratios from the two sequencers were very close in all RNA-seq/WES/WGS datasets, indicating no or similar species bias for both platforms. The RNA-seq datasets showed high gene expression concordance, with Pearson correlation coefficients of 0.993, 0.992 and 0.993. The WES datasets showed high mutation concordance, with the mutation overlapping rates of 98.9%, 99.3% and 99.1%, and the mutation ratio correlation coefficients of 0.971, 0.976 and 0.977. The WGS data showed overall overlapping rate of 95.5%, and mutation ratio correlation coefficient of 0.955, while for SNPs and INDELs, the overlapping rate was 97.1% and 86.1%.
CONCLUSIONS: Our study shows that the MGISEQ and Illumina sequencers have comparable performance in sequencing xenograft tumors.
Citation Format: Wubin Qian, Xiaobo Chen, Henry Q. Li, Sheng Guo. Comparison of Illumina NovaSeq 6000 and MGISEQ-2000 in profiling xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 259.
Abstract 2823: Exploring the role of neutrophil myeloperoxidase in lung cancer
Authors: Valadez-Cosmes Paulina , Cosic Nejra , Kienzl Melanie , Maitz Kathrin , Raftopoulou Sofia , Houghton A. McGarry , Heinemann Akos , Davies Michael J. , Kargl Julia 
Published: July 2021

Abstract
The aim of this study is to investigate whether myeloperoxidase, a neutrophil-derived molecule in the tumor microenvironment, can influence tumor growth in lung cancer. Lung cancer is the leading cause of cancer related deaths worldwide. Chronic inflammation plays a key role in lung cancer and some studies point out the role of neutrophils as critical mediators of lung carcinogenesis. In this context, some of the neutrophil granule components have been proposed to contribute to tumor development. One of these molecules is myeloperoxidase. Myeloperoxidase is a heme peroxidase enzyme that generates reactive oxygen/nitrogen species and is most abundantly expressed in neutrophils. Upon neutrophil activation, during acute inflammation or in the tumor microenvironment, MPO is secreted into the extracellular milieu during degranulation and utilizes H2O2 to hypochlorous acid that reacts with surrounding proteins and cell surface molecules and thereby can alter signaling pathways and cell functions. So far, we have found some evidence on myeloperoxidase acting in favor of tumor development. In vivo, LSL-K-ras/MPO-/- mice revealed prolonged survival and reduced tumor burden when compared to LSL-K-ras/MPO+/+ mice. Consistently, in a heterotopic syngeneic tumor mouse model, MPO knockout mice (C57/B6-J/MPO-/-) displayed smaller tumors in comparison to the WT littermates. In vitro, myeloperoxidase is able to bind, internalize and preserve its enzymatic activity in human lung adenocarcinoma A549 cells. Furthermore, A549 cells showed increased proliferation and reduced apoptosis after MPO treatment as well as an enhanced phosphorylation of Akt and Erk proteins. According to our current results, myeloperoxidase may play a role in the development of lung cancer by regulating cancer cell function. Moreover, this project sheds light on the role of neutrophil-derived molecules as key players in the context of tumor growth.
Citation Format: Paulina Valadez-Cosmes, Nejra Cosic, Melanie Kienzl, Kathrin Maitz, Sofia Raftopoulou, A. McGarry Houghton, Akos Heinemann, Michael J. Davies, Julia Kargl. Exploring the role of neutrophil myeloperoxidase in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2823.
Abstract 370: Smoking history as an independent predictor for immune checkpoint inhibitors (ICIs) in metastatic non-small cell lung cancer (NSCLC)
Authors: Wang Xinan , Ricciuti Biagio , Alessi Joao V. , Nguyen Tom , Awad Mark M. , Lin Xihong , Johnson Bruce E. , Christiani David C. 
Published: July 2021

Abstract
Importance: Immune Checkpoint Inhibitors (ICIs) induce durable response in a subset of non-small cell lung cancer (NSCLC) patients. There is an unmet need to develop effective predictors for ICIs in metastatic NSCLC.
Objective: Define the predictive impact of smoking history (pack-years) on the clinical outcomes of ICI monotherapy and further to validate the potential clinical utility in metastatic NSCLC.
Design, setting, and participants: This study was conducted on 680 metastatic NSCLC patients treated with ICIs between April 2013 and September 2020 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. Patient TMB and programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS) were determined by clinical targeted Next Generation Sequencing (NGS) and immunohistochemistry (IHC) and detailed smoking history and clinicopathological characteristics were prospectively collected.
Main outcomes and measures: Evaluation of the association of smoking pack-years with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in metastatic NSCLC patients treated with ICI monotherapy. Assessment of time-dependent area under the curve (AUC) for predictive models of clinical outcomes.
Results: Among 680 metastatic NSCLC patients who received ICI monotherapy: 109 (16.0%) never smokers, 397 (58.4%) former smokers [median 30 pack-years], and 174 (25.6%) current smokers [median 40 pack-years]. Multivariable analysis suggested that doubling of smoking pack-years is significantly associated with better clinical outcomes of ICIs. (ORR OR = 1.20, P &lt; 0.001; PFS HR = 0.92, P &lt; 0.001; OS HR = 0.94, P = 0.01) Predictive models incorporating smoking pack-years yielded additional information and achieved similar model performance compared to the one using TMB.
Conclusions and Relevance: This finding suggests that detailed smoking information has a significant predictive value on clinical outcomes of ICI monotherapy independent of PD-L1 TPS. Smoking pack-years could serve as a non-invasive and consistent surrogate for TMB when it is not readily available for treatment-decision in metastatic NSCLC.
Citation Format: Xinan Wang, Biagio Ricciuti, Joao V. Alessi, Tom Nguyen, Mark M. Awad, Xihong Lin, Bruce E. Johnson, David C. Christiani. Smoking history as an independent predictor for immune checkpoint inhibitors (ICIs) in metastatic non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 370.
Abstract 382: Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort
Authors: Zhou Jian-Guo , Ma Hu , Gaipl Udo , Frey Benjamin , Hecht Markus , Fietkau Rainer 
Published: July 2021

Abstract
Background: Numerus studies already proved C-reactive protein (CRP) in pre-treat is a predictive biomarkers to for cancer patients treated with anti-PD(L)-1 antibodies. However, there aren't any study has evaluated CRP levels longitudinally in patients with immune checkpoint inhibitors (ICIs). This study provides a comprehensive investigation of CRP levels as well as its longitudinal trajectories as a dynamic predictor of treatment response and survival outcome in metastatic cancer patients undergoing immunotherapy with anti PD-1 or anti PD-L1 agents.
Methods: A total number of 104 patients were prospectively enrolled. First, multivariate survival analysis for clinical factors, which including cancer types, line of treatment, PD-L1 expression, brain metastases (BM), etc. Then, used multivariate joint modelling of longitudinal and time to event data to establish the relationship between longitudinal CRP and the overall survival (OS).
Results: 92/102 patients with more than 2 times CRP results in all of treatment timepoints. Longitudinal CRP levels combine with clinical factors emerged as independent predictors of worse OS (HR of jointed model= 1.82, 95% CI: 1.45-2.32, p &lt; 0.001), and this dynamic biomarker achieved a high accuracy (C-index 0.81) for predicting OS. However, those clinical factors didn't impact the dynamic CRP in this jointed model (HR of PD-L1= 1.68(0.79-3.65), HR of BM= 0.82(0.42-1.64), HR of PD-L1: BM=0.76(0.30-1.89)).
Conclusion: Our study highlights longitudinal CRP serves as potential personalized dynamic predictions for immunotherapeutic benefit of metastatic cancer patients.
Keywords: metastatic cancers, immune checkpoint inhibitors, C-reactive protein, dynamic predictor
Trial registration: Prospectively registered in ClinicalTrials.gov (NCT03453892) on January 24, 2018.
Citation Format: Jian-Guo Zhou, Hu Ma, Udo Gaipl, Benjamin Frey, Markus Hecht, Rainer Fietkau. Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 382.
Abstract 414: Efficacy of Balixafortide (POL6326) and Paclitaxel alone and in combination in humanized breast cancer PDX
Authors: Obrecht Daniel , Zimmermann Johann 
Published: July 2021

Abstract
Despite availability of new therapies, outcomes for patients with relapsed metastatic breast cancer is poor with moderate median overall survival. High CXCR4 levels correlate with aggressive metastatic phenotypes and poor prognosis in breast cancer (BC). Anti-cancer mechanisms of CXCR4 antagonists include inhibition of angiogenesis and metastasis, activation of immunosurveillance and chemo sensitization. Balixafortide (POL6326) is a potent, selective inhibitor of the chemokine receptor CXCR4 in PhIII for metastatic HER2-negative breast cancer (BC) in combination with tubulin-binding eribulin (NCT03786094). Clinical proof-of-concept in combination with eribulin was demonstrated in a PhI single arm dose-escalation trial in patients with metastatic HER2-negative BC (NCT01837095). The objective response rate for a dose of 5.5mg/kg balixafortide and 1.4mg/m2 eribulin) was 38% (median duration 4.4 months), and the clinical benefit rate was 63% (median duration 8.1 months). Tolerability and safety of eribulin in combination with balixafortide was comparable to that of eribulin monotherapy. Balixafortide was combined with paclitaxel in a humanized BC patient-derived xenograft (PDX) model to explore the efficacy in combination with another tubulin-binding drugs. Human immunophenotyping confirmed successful human CD34+ cell engraftment and expansion of human immune cells prior implantation of an invasive ductal carcinoma (ypT1a ypN1a R0 G3 L1 V1), ER/PR/Her-2 negative tumor. 10mg/kg paclitaxel was given 2x weekly iv. Dosing of balixafortide was 20mg/kg bid sc for 5 days with 2 days break. Total treatment duration was 28 days. Partial remission was achieved in the combination arm balixafortide+paclitaxel (T/C 13%, 87% inhibition of tumor volume vs vehicle control) which was stat. significantly better than paclitaxel monotherapy (T/C 42%). There was no decrease in tolerability in balixafortide combination vs paclitaxel alone. This data suggests combination with balixafortide is more efficacious and equally tolerated to paclitaxel single agent treatment.
Citation Format: Daniel Obrecht, Johann Zimmermann. Efficacy of Balixafortide (POL6326) and Paclitaxel alone and in combination in humanized breast cancer PDX [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 414.