tbuckley/cabot-search huggingface dataset:
Metabolomic and Transcriptomic Analysis of MCF-7 Cells Exposed to 23 Chemicals at Human-Relevant Levels: Estimation of Individual Chemical Contribution to Effects
Authors: Min Liu, Shenglan Jia, Ting Dong, Fanrong Zhao, Tengfei Xu, Qin Yang, Jicheng Gong, Mingliang Fang
Journal: Environmental Health Perspectives (2020)

Humans are constantly being exposed to various xenobiotics at relatively low concentrations. To date, limited evidence is available to ascertain whether a complex xenobiotic mixture at human-relevant levels causes any health effect. Moreover, there is no effective method to pinpoint the contribution of each chemical toward such an effect.This study aims to understand the responses of cells to a mixture containing 23 xenobiotics at human-relevant levels and develop a feasible method to decipher the chemical(s) that contribute significantly to the observed effect.We characterized the metabolome and transcriptome of breast cancer cells (MCF-7) before and after exposure to the mixture at human-relevant levels; preexposure levels were derived from existing large-scale biomonitoring data. A high-throughput metabolomics-based "leave-one-out" method was proposed to understand the relative contribution of each component by comparing the metabolome with and without the particular chemical in the mixture.The metabolomic analysis suggested that the mixture altered metabolites associated with cell proliferation and oxidative stress. For the transcriptomes, gene ontology terms and pathways including "cell cycle," "cell proliferation," and "cell division" were significantly altered after mixture exposure. The mixture altered genes associated with pathways such as "genotoxicity" and "nuclear factor erythroid 2-related factor 2 (Nrf2)." Through joint pathways analysis, metabolites and genes were observed to be well-aligned in pyrimidine and purine metabolisms. The leave-one-out results showed that many chemicals made their contributions to specific metabolic pathways. The overall metabolome pattern of the absence of 2,4-dihyroxybenzophenone (DHB) or bisphenol A (BPA) showed great resemblance to controls, suggesting their higher relative contribution to the observed effect.The omics results showed that exposure to the mixture at human-relevant levels can induce significant in vitro cellular changes. Also, the leave one out method offers an effective approach for deconvoluting the effects of the mixture. https://doi.org/10.1289/EHP6641.
NFB-12. TRAMETINIB THERAPY FOR PEDIATRIC PATIENTS WITH REFRACTORY LOW GRADE GLIOMA OR EXTENSIVE SYMPTOMATIC PLEXIFORM NEUROFIBROMA
Authors: Celine D Hounjet, Rebecca Ronsley, Sylvia Cheng, S Rod Rassekh, Walter J Duncan, Christopher Dunham, Jane Gardiner, Arvindera Ghag, Jeffrey P, Ludemann, David Wensley, Wingfield Rehmus, Michael A Sargent, Naomi Evans, Vesna Popovska, Juliette Hukin
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Refractory symptomatic plexiform neurofibromas (PNF) and inoperable refractory low grade gliomas (LGG) pose a clinical challenge that may be life threatening. Phase 1 and 2 clinical trials of MEK inhibition with selumetinib in inoperable PNF and LGG have demonstrated promising results in pediatrics, however access has been limited to enrollment on clinical trial. Phase 1 clinical trial for trametinib a MEK 1 and 2 inhibitor has been completed, publication is pending. Thus we have treated a series of children on a compassionate basis with extensive PN or LGG refractory disease with trametinib, as this is available in Canada. METHODS We have treated children with trametinib on a compassionate basis in our province since 2017. Review of the clinical data regarding this therapy has been IRB approved. RESULTS Two young patients were treated for indication of life threatening extensive PNF and have had tumor shrinkage and improvement of clinical status. Treatment has been complicated by paronychiae, eczema exacerbation, chondrodermatitis nodularis helicis, RSV and influenza B infection and CTCAE grade 2 pneumonia. In spite of the side effects these two patients remain on treatment due to clear benefit from therapy including: improved respiratory compromise, hearing and dysphagia. We will present the data of additional patients treated with trametinib. CONCLUSION Trametinib is an effective therapy for life threatening PNF by changing the natural history of tumor growth in young children. Further data is required in terms of tolerance, efficacy and durability of response in such patients in the setting of clinical trials.
QOL-58. ASSESSING FATIGUE EXPERIENCED BY PEDIATRIC PATIENTS WITH INTRACRANIAL NEOPLASMS
Authors: Eamon Eccles, Yan Han, Hao Liu, Jordan Holmes, Scott Coven
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Indiana University possessed one of the earliest clinical proton facilities in the United States. The purpose of this study was to assess fatigue and nausea/vomiting in children with central nervous system (CNS) tumors undergoing radiation therapy as part of their treatment regimen, and to understand what factors influence fatigue. DESIGN: The study was approved by the institutional review board at Indiana University and consent and/or assent from eligible participants was obtained prior to enrollment. The validated Fatigue Scale is scored on a 5-point Likert scale. Surveys were completed 1) prior to radiation therapy, 2) week three of radiation therapy, and 3) week six of radiation therapy. A score of 41 or higher for the Fatigue Scale-Parent (&amp;lt; 7 years), 12 or higher for the Fatigue Scale-Child (8–12 years), and 17 or higher for the Fatigue Scale-Adolescent (13–18 years), indicates significant cancer-related fatigue. RESULTS The study aimed to recruit a total of 50 patients during the eligible period; however, data on 31 individual participants were available for analysis. 25 patients underwent proton radiation therapy, while 6 patients underwent conventional photon therapy. The mean age of children was 8.8 years. Of the 31 patients, 22 recorded scores indicating significant cancer-related fatigue at some point during radiation therapy. CONCLUSIONS Cancer related fatigue continues to be a challenge, with limited understanding of factors that might predict clinically relevant fatigue This work demonstrates the feasibility of conducting symptom research for children undergoing radiation therapy; further research is needed to characterize predictors of fatigue.
EXTH-64. SMALL GTPASES IN MENINGIOMAS: PROLIFERATION, MIGRATION, SURVIVAL, POTENTIAL TREATMENT AND INTERACTIONS
Authors: Christoph Kesseler, Julian Kahr, Natalie Waldt, Nele Stroscher, Josephine Liebig, Frank Angenstein, Elmar Kirches, Christian Mawrin
Journal: Neuro-Oncology (2020)

Abstract PURPOSE To evaluate the role of the small GTPases RhoA, Rac1 and Cdc42 in meningiomas as therapeutic targets and their interactions in meningiomas. EXPERIMENTAL DESIGN We analyzed expression of GTPases in human meningioma samples and meningioma cell lines of various WHO grades. Malignant IOMM-Lee meningioma cells were used to generate shRNA mediated knockdowns of GTPases RhoA, Rac1 or Cdc42 and to study knockdown effects on proliferation and migration, as well as analysis of cell morphology by confocal microscopy. The same tests were used to investigate effects of the two inhibitors Fasudil and EHT-1864 of malignant IOMM-Lee, KT21 and benign Ben-Men cells and the effects of these drugs on IOMM-Lee knockdown cells. The effects of GTPase knockdowns and Fasudil treatment were studied in terms of overall survival by intracranial xenografts of mice. Potential interactions of GTPases regarding NF2, mTOR and FAK-Paxillin were examined. RESULTS Small GTPases were upregulated in meningiomas of higher tumor grades. Reduced proliferation and migration could be achieved by GTPase knockdown in IOMM-Lee cells. Additionally, the ROCK-inhibitor Fasudil and Rac1-inhibitor EHT-1864 reduced proliferation in different meningioma cell lines and reduced proliferation and migration independent of GTPase knockdowns/status. Moreover, overall survival in vivo could also be increased by knockdowns of RhoA and Rac1 as well as Fasudil treatment. GTPase expression was affected dependent on the NF2 status but effects were not very distinct, indicating that NF2 is not strongly involved in GTPase regulation in meningiomas. In terms of mTOR and FAK-Paxillin signaling, each GTPase changes those pathways in a different manner. CONCLUSION Small GTPases are important effectors in meningioma proliferation and migration in vitro as well as survival in vivo and their inhibition should be considered as potential treatment option.
Late preconditioning against myocardial stunning: Does aspirin close the “second window” of endogenous cardioprotection?**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Karin Przyklenk, Gerd Heusch
Journal: Journal of the American College of Cardiology (2003)
EXTH-65. USING METHYLATION PROFILES TO GUIDE THE REPURPOSING OF CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS
Authors: Anh Tran, Denise Scholtens, Lyndsee Zhang, Jenny Pokorny, Aneta Baran, Felix Sahm, Kenneth Aldape, Charles James, Craig Horbinski
Journal: Neuro-Oncology (2020)

Abstract Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas grow slowly, hence categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy for meningioma, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and identified associations of methylation at individual CpG sites as detected by the Illumina 450k platform with PFS. Subsequently, we searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter PFS (positive hazard ratios (HRs)) and with longer PFS (negative HRs) at FDR-adjusted p &amp;lt; 0.05. Using Cytoscape/Reactome FI app, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the sixteen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.
Treatment of Opioid Use Disorder Among Commercially Insured Patients in the Context of the COVID-19 Pandemic
Authors: Haiden A. Huskamp, Alisa B. Busch, Lori Uscher-Pines, Michael L. Barnett, Lauren Riedel, Ateev Mehrotra
Journal: JAMA (2020)

Thuy D. Nguyen, PhD; Sumedha Gupta, PhD; Engy Ziedan, PhD; Kosali I. Simon, PhD; G. Caleb Alexander, MD, MS; Brendan Saloner, PhD; Bradley D. Stein, MD, PhD
Magnetic multidirectional anchor-guided endoscopic submucosal tunnel dissection for large gastric lesions
Authors: Shengzhen Liu, Yichao Chai, Enqiang Linghu, Bo Zhang, Ningli Chai, Yi Lv
Journal: Endoscopy (2020)

Magnetic anchor-guided endoscopic submucosal dissection (MAG-ESD) using an extracorporeal electromagnet was developed to provide excellent visualization and to facilitate complicated ESD in patients with early gastric cancer (EGC), with its use being reported in several studies over recent years [1] [2] [3]. Endoscopic submucosal tunnel dissection (ESTD) has been reported as a treatment for the en bloc dissection of large early neoplastic lesions with higher dissection speed and better radical cure rates than standard ESD [4] [5]. This case report describes a new method, magnetic multidirectional anchor-guided ESTD (MMAG-ESTD), for the treatment of large EGCs in human subjects.
MBRS-59. SINGLE-CELL WHOLE-GENOME SEQUENCING DISSECTS INTRA-TUMOURAL GENOMIC HETEROGENEITY AND CLONAL EVOLUTION IN CHILDHOOD MEDULLOBLASTOMA
Authors: Marina Danilenko, Masood Zaka, Claire Keeling, Stephen Crosier, Rafiqul Hussain, Edward Schwalbe, Dan Williamson, Jonathan Coxhead, Vikki Rand, Simon Bailey, Steven Clifford
Journal: Neuro-Oncology (2020)

Abstract Medulloblastomas harbor clinically-significant intra-tumoral heterogeneity for key biomarkers (e.g. MYC/MYCN, β-catenin). Recent studies have characterized transcriptional heterogeneity at the single-cell level, however the underlying genomic copy number and mutational architecture remains to be resolved. We therefore sought to establish the intra-tumoural genomic heterogeneity of medulloblastoma at single-cell resolution. Copy number patterns were dissected by whole-genome sequencing in 1024 single cells isolated from multiple distinct tumour regions within 16 snap-frozen medulloblastomas, representing the major molecular subgroups (WNT, SHH, Group3, Group4) and genotypes (i.e. MYC amplification, TP53 mutation). Common copy number driver and subclonal events were identified, providing clear evidence of copy number evolution in medulloblastoma development. Moreover, subclonal whole-arm and focal copy number alterations covering important genomic loci (e.g. on chr10 of SHH patients) were detected in single tumour cells, yet undetectable at the bulk-tumor level. Spatial copy number heterogeneity was also common, with differences between clonal and subclonal events detected in distinct regions of individual tumours. Mutational analysis of the cells allowed dissection of spatial and clonal heterogeneity patterns for key medulloblastoma mutations (e.g. CTNNB1, TP53, SMARCA4, PTCH1) within our cohort. Integrated copy number and mutational analysis is underway to establish their inter-relationships and relative contributions to clonal evolution during tumourigenesis. In summary, single-cell analysis has enabled the resolution of common mutational and copy number drivers, alongside sub-clonal events and distinct patterns of clonal and spatial evolution, in medulloblastoma development. We anticipate these findings will provide a critical foundation for future improved biomarker selection, and the development of targeted therapies.
CTNI-24. A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY. TRAM-01
Authors: Sébastien Perreault, Valérie larouche, Uri Tabori, Cynthia Hawkins, Sarah Lippe, Benjamin Ellezam, Jean-Claude Décarie, Yves Théoret, Marie-Élaine Metras, Serge Sultan, Édith Cantin, Marie-Ève Routhier, Maxime Caru, Geneviève Legault, Eric Bouffet, Lucie Lafay-Cousin, Juliette Hukin, Craig Erker, Nada Jabado
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This multicenter phase II included three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Primary objective is to evaluate overall response rate after daily oral trametinib administration for 18 cycles each 28 days duration. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. RESULTS As of June 1 2020, 37 patients have been enrolled (NF1: 7 patients, KIAA1549-BRAF fusion: 22, other: 8 (including 5 patients with FGFR1 alterations). Median age is 9.3 years (range 2.3–25.4). Median follow-up is 8.8 months (range 0–19.3). Twenty-eight patients are evaluable. Best response includes: 4 partial response (PR) (14%), 5 minor response (MR) (18%), 18 stable disease (64%), 1 progressive disease (3.5%). Median time to response is 2.8 months (range 2.4–11.3). Median duration of response is 8.0 months (range 0.6–16.8. Progression free survival at 12 months is 83.1% (95% CI 70.5–98.0%) and median progression free survival has not reached. Nine patients (24%) discontinued treatment: 3 for progressive disease, 4 adverse events (3 alanine aminotransferase increase, 1 paronychia), 2 for other reasons. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.
Genetic diversity and characteristics of high-level tigecycline resistance Tet(X) in Acinetobacter species
Authors: Chong Chen, Chao-Yue Cui, Jun-Jun Yu, Qian He, Xiao-Ting Wu, Yu-Zhang He, Ze-Hua Cui, Cang Li, Qiu-Lin Jia, Xiang-Guang Shen, Ruan-Yang Sun, Xi-Ran Wang, Min-Ge Wang, Tian Tang, Yan Zhang, Xiao-Ping Liao, Barry N. Kreiswirth, Shi-Dan Zhou, Bin Huang, Hong Du, Jian Sun, Liang Chen, Ya-Hong Liu
Journal: Genome Medicine (2020)

Abstract Background The recent emergence and dissemination of high-level mobile tigecycline resistance Tet(X) challenge the clinical effectiveness of tigecycline, one of the last-resort therapeutic options for complicated infections caused by multidrug-resistant Gram-negative and Gram-positive pathogens. Although tet (X) has been found in various bacterial species, less is known about phylogeographic distribution and phenotypic variance of different genetic variants. Methods Herein, we conducted a multiregional whole-genome sequencing study of tet (X)-positive Acinetobacter isolates from human, animal, and their surrounding environmental sources in China. The molecular and enzymatic features of tet (X) variants were characterized by clonal expression, microbial degradation, reverse transcription, and gene transfer experiments, while the tet (X) genetic diversity and molecular evolution were explored by comparative genomic and Bayesian evolutionary analyses. Results We identified 193 tet (X)-positive isolates from 3846 samples, with the prevalence ranging from 2.3 to 25.3% in nine provinces in China. The tet (X) was broadly distributed in 12 Acinetobacter species, including six novel species firstly described here. Besides tet (X3) ( n = 188) and tet (X4) ( n = 5), two tet (X5) variants, tet (X5.2) ( n = 36) and tet (X5.3) ( n = 4), were also found together with tet (X3) or tet (X4) but without additive effects on tetracyclines. These tet (X)-positive Acinetobacter spp. isolates exhibited 100% resistance rates to tigecycline and tetracycline, as well as high minimum inhibitory concentrations to eravacycline (2–8 μg/mL) and omadacycline (8–16 μg/mL). Genetic analysis revealed that different tet (X) variants shared an analogous IS CR2 -mediated transposon structure. The molecular evolutionary analysis indicated that Tet(X) variants likely shared the same common ancestor with the chromosomal monooxygenases that are found in environmental Flavobacteriaceae bacteria, but sequence divergence suggested separation ~ 9900 years ago (7887 BC), presumably associated with the mobilization of tet (X)-like genes through horizontal transfer. Conclusions Four tet (X) variants were identified in this study, and they were widely distributed in multiple Acinetobacter spp. strains from various ecological niches across China. Our research also highlighted the crucial role of IS CR2 in mobilizing tet (X)-like genes between different Acinetobacter species and explored the evolutionary history of Tet(X)-like monooxygenases. Further studies are needed to evaluate the clinical impact of these mobile tigecycline resistance genes.
EPCO-32. AN EPIGENETIC SINGLE-CELL ATLAS OF IDH-MUTANT GLIOMA REVEALS THE ROLE OF ATRX IN SHAPING TUMOR COMPOSITION
Authors: Husam Babikir, Lin Wang, Karin Shamardani, Sweta Sudhir, Gary Kohanbash, Manish Aghi, Joanna Philips, Aaron Diaz
Journal: Neuro-Oncology (2020)

Abstract Recent single-cell RNA-sequencing studies have identified a hierarchy of cell types that is common to all isocitrate dehydrogenase (IDH) -mutant gliomas. This finding is somewhat paradoxical since the genetic differences between IDH-mutant astrocytomas and IDH-mutant oligodendrogliomas are prognostic, predictive of therapeutic response, and correlated with differences in immune infiltrates. To integrate these disparate findings, we constructed a single-cell atlas of 28 human IDH-mutant primary untreated grade-II/III gliomas. All specimens were profiled by single-cell assay for transposase-accessible chromatin, with additional cohorts profiled via single-cell RNA-sequencing and single-cell spatial proteomics. We determined the cell-type specific differences between IDH-mutant gliomas in transcription-factor utilization, associated targeting and cis-regulatory grammars. To elucidate the role of the chromatin remodeler ATRX (inactivated in over 86% of IDH-mutant astrocytomas) in shaping observed differences in open chromatin, we knocked out ATRX in an immunocompetent model of IDH-mutant glioma and subjected murine tumors to single-cell profiling. We found: 1. ATRX-deficient, IDH-mutant human and murine gliomas both upregulate an astrocytic regulatory program driven by Nuclear Factor I genes and downregulate an oligodendrocytic program driven by basic helix-loop-helix transcription factors. 2. Both human and mouse ATRX-deficient, IDH-mutant gliomas up-regulate genes that promote myeloid-cell chemotaxis and both have significantly higher percentages of myeloid-derived immune-suppressive cells than controls; 3. A transcription-factor program is conserved between human and murine ATRX-deficient tumors that shapes glial identity and promotes local immunosuppression. These studies elucidate how IDH-mutant gliomas from different subtypes can have distinct cellular morphologies and tumor micronenvironments despite a common lineage hierarchy.