Workshop report: Identifying opportunities for global integration of toxicogenomics databases, 26-27 June 2013, Research Triangle Park, NC, USA.

PubMed

Hendrickx, Diana M; Boyles, Rebecca R; Kleinjans, Jos C S; Dearry, Allen

2014-12-01

A joint US-EU workshop on enhancing data sharing and exchange in toxicogenomics was held at the National Institute for Environmental Health Sciences. Currently, efficient reuse of data is hampered by problems related to public data availability, data quality, database interoperability (the ability to exchange information), standardization and sustainability. At the workshop, experts from universities and research institutes presented databases, studies, organizations and tools that attempt to deal with these problems. Furthermore, a case study showing that combining toxicogenomics data from multiple resources leads to more accurate predictions in risk assessment was presented. All participants agreed that there is a need for a web portal describing the diverse, heterogeneous data resources relevant for toxicogenomics research. Furthermore, there was agreement that linking more data resources would improve toxicogenomics data analysis. To outline a roadmap to enhance interoperability between data resources, the participants recommend collecting user stories from the toxicogenomics research community on barriers in data sharing and exchange currently hampering answering to certain research questions. These user stories may guide the prioritization of steps to be taken for enhancing integration of toxicogenomics databases.

An Approach to Using Toxicogenomic Data in US EPA Human ...

EPA Pesticide Factsheets

EPA announced the availability of the final report, An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl Phthalate Case Study. This report outlines an approach to evaluate genomic data for use in risk assessment and a case study to illustrate the approach. The dibutyl phthalate (DBP) case study example focuses on male reproductive developmental effects and the qualitative application of genomic data because of the available data on DBP. The case study presented in this report is a separate activity from any of the ongoing IRIS human health assessments for the phthalates. The National Center for Environmental Assessment (NCEA) prepared this document for the purpose of describing and illustrating an approach for using toxicogenomic data in risk assessment.

Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilson, Vickie S., E-mail: wilson.vickie@epa.gov; Keshava, Nagalakshmi; Hester, Susan

2013-09-15

The predominant role of toxicogenomic data in risk assessment, thus far, has been one of augmentation of more traditional in vitro and in vivo toxicology data. This article focuses on the current available examples of instances where toxicogenomic data has been evaluated in human health risk assessment (e.g., acetochlor and arsenicals) which have been limited to the application of toxicogenomic data to inform mechanism of action. This article reviews the regulatory policy backdrop and highlights important efforts to ultimately achieve regulatory acceptance. A number of research efforts on specific chemicals that were designed for risk assessment purposes have employed mechanismmore » or mode of action hypothesis testing and generating strategies. The strides made by large scale efforts to utilize toxicogenomic data in screening, testing, and risk assessment are also discussed. These efforts include both the refinement of methodologies for performing toxicogenomics studies and analysis of the resultant data sets. The current issues limiting the application of toxicogenomics to define mode or mechanism of action in risk assessment are discussed together with interrelated research needs. In summary, as chemical risk assessment moves away from a single mechanism of action approach toward a toxicity pathway-based paradigm, we envision that toxicogenomic data from multiple technologies (e.g., proteomics, metabolomics, transcriptomics, supportive RT-PCR studies) can be used in conjunction with one another to understand the complexities of multiple, and possibly interacting, pathways affected by chemicals which will impact human health risk assessment.« less

Using binary classification to prioritize and curate articles for the Comparative Toxicogenomics Database.

PubMed

Vishnyakova, Dina; Pasche, Emilie; Ruch, Patrick

2012-01-01

We report on the original integration of an automatic text categorization pipeline, so-called ToxiCat (Toxicogenomic Categorizer), that we developed to perform biomedical documents classification and prioritization in order to speed up the curation of the Comparative Toxicogenomics Database (CTD). The task can be basically described as a binary classification task, where a scoring function is used to rank a selected set of articles. Then components of a question-answering system are used to extract CTD-specific annotations from the ranked list of articles. The ranking function is generated using a Support Vector Machine, which combines three main modules: an information retrieval engine for MEDLINE (EAGLi), a gene normalization service (NormaGene) developed for a previous BioCreative campaign and finally, a set of answering components and entity recognizer for diseases and chemicals. The main components of the pipeline are publicly available both as web application and web services. The specific integration performed for the BioCreative competition is available via a web user interface at http://pingu.unige.ch:8080/Toxicat.

Comparison of MeHg-induced toxicogenomic responses across in vivo and in vitro models used in developmental toxicology.

PubMed

Robinson, Joshua F; Theunissen, Peter T; van Dartel, Dorien A M; Pennings, Jeroen L; Faustman, Elaine M; Piersma, Aldert H

2011-09-01

Toxicogenomic evaluations may improve toxicity prediction of in vitro-based developmental models, such as whole embryo culture (WEC) and embryonic stem cells (ESC), by providing a robust mechanistic marker which can be linked with responses associated with developmental toxicity in vivo. While promising in theory, toxicogenomic comparisons between in vivo and in vitro models are complex due to inherent differences in model characteristics and experimental design. Determining factors which influence these global comparisons are critical in the identification of reliable mechanistic-based markers of developmental toxicity. In this study, we compared available toxicogenomic data assessing the impact of the known teratogen, methylmercury (MeHg) across a diverse set of in vitro and in vivo models to investigate the impact of experimental variables (i.e. model, dose, time) on our comparative assessments. We evaluated common and unique aspects at both the functional (Gene Ontology) and gene level of MeHg-induced response. At the functional level, we observed stronger similarity in MeHg-response between mouse embryos exposed in utero (2 studies), ESC, and WEC as compared to liver, brain and mouse embryonic fibroblast MeHg studies. These findings were strongly correlated to the presence of a MeHg-induced developmentally related gene signature. In addition, we identified specific MeHg-induced gene expression alterations associated with developmental signaling and heart development across WEC, ESC and in vivo systems. However, the significance of overlap between studies was highly dependent on traditional experimental variables (i.e. dose, time). In summary, we identify promising examples of unique gene expression responses which show in vitro-in vivo similarities supporting the relevance of in vitro developmental models for predicting in vivo developmental toxicity. Copyright © 2011 Elsevier Inc. All rights reserved.

Toxicogenomic analysis in the combined effect of tributyltin and benzo[a]pyrene on the development of zebrafish embryos.

PubMed

Huang, Lixing; Zuo, Zhenghong; Zhang, Youyu; Wang, Chonggang

2015-01-01

There is a growing recognition that the toxic effects of chemical mixtures are been an important issue in toxicological sciences. Tributyltin (TBT) and benzo[a]pyrene (BaP) are widespread pollutants that occur simultaneously in the aquatic environments. This study was designed to examine comprehensively the combined effects of TBT and BaP on zebrafish (Danio rerio) embryos using toxicogenomic approach combined with biochemical detection and morphological analysis, and tried to gain insight into the mechanisms underlying the combined effects of TBT and BaP. The results of toxicogenomic data indicated that: (1) TBT cotreatment rescued the embryos from decreased hatching ratio caused by BaP alone, while the alteration of gene expression (in this article the phrase gene expression is used as a synonym to gene transcription, although in is acknowledged that gene expression can also be regulated by, e.g., translation and mRNA or protein stability) relative to zebrafish hatching in the BaP groups was resumed by the cotreatment with TBT; (2) BaP cotreatment decreased TBT-mediated dorsal curvature, and alleviated the perturbation of Notch pathway caused by TBT alone; (3) cotreatment with TBT decreased BaP-mediated bradycardia, which might be due to that TBT cotreatment alleviated the perturbation in expression of genes related to cardiac muscle cell development and calcium handling caused by BaP alone; 4) TBT cotreatment brought an antagonistic effect on the BaP-mediated oxidative stress and DNA damage. These results suggested that toxicogenomic approach was available for analyzing combined toxicity with high sensitivity and accuracy, which might improve our understanding and predictability for the combined effects of chemicals. Copyright © 2014 Elsevier B.V. All rights reserved.

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

PubMed Central

Corvi, Raffaella; Ahr, Hans-Jürgen; Albertini, Silvio; Blakey, David H.; Clerici, Libero; Coecke, Sandra; Douglas, George R.; Gribaldo, Laura; Groten, John P.; Haase, Bernd; Hamernik, Karen; Hartung, Thomas; Inoue, Tohru; Indans, Ian; Maurici, Daniela; Orphanides, George; Rembges, Diana; Sansone, Susanna-Assunta; Snape, Jason R.; Toda, Eisaku; Tong, Weida; van Delft, Joost H.; Weis, Brenda; Schechtman, Leonard M.

2006-01-01

This is the report of the first workshop “Validation of Toxicogenomics-Based Test Systems” held 11–12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities. PMID:16507466

Meeting report: Validation of toxicogenomics-based test systems: ECVAM-ICCVAM/NICEATM considerations for regulatory use.

PubMed

Corvi, Raffaella; Ahr, Hans-Jürgen; Albertini, Silvio; Blakey, David H; Clerici, Libero; Coecke, Sandra; Douglas, George R; Gribaldo, Laura; Groten, John P; Haase, Bernd; Hamernik, Karen; Hartung, Thomas; Inoue, Tohru; Indans, Ian; Maurici, Daniela; Orphanides, George; Rembges, Diana; Sansone, Susanna-Assunta; Snape, Jason R; Toda, Eisaku; Tong, Weida; van Delft, Joost H; Weis, Brenda; Schechtman, Leonard M

2006-03-01

This is the report of the first workshop "Validation of Toxicogenomics-Based Test Systems" held 11-12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities.

Integrative data mining of high-throughput in vitro screens, in vivo data, and disease information to identify Adverse Outcome Pathway (AOP) signatures:ToxCast high-throughput screening data and Comparative Toxicogenomics Database (CTD) as a case study.

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework provides a systematic way to describe linkages between molecular and cellular processes and organism or population level effects. The current AOP assembly methods however, are inefficient. Our goal is to generate computationally-pr...

Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders.

PubMed

Robinson, Joshua F; Port, Jesse A; Yu, Xiaozhong; Faustman, Elaine M

2010-10-01

To understand the complex etiology of developmental disorders, an understanding of both genetic and environmental risk factors is needed. Human and rodent genetic studies have identified a multitude of gene candidates for specific developmental disorders such as neural tube defects (NTDs). With the emergence of toxicogenomic-based assessments, scientists now also have the ability to compare and understand the expression of thousands of genes simultaneously across strain, time, and exposure in developmental models. Using a systems-based approach in which we are able to evaluate information from various parts and levels of the developing organism, we propose a framework for integrating genetic information with toxicogenomic-based studies to better understand gene-environmental interactions critical for developmental disorders. This approach has allowed us to characterize candidate genes in the context of variables critical for determining susceptibility such as strain, time, and exposure. Using a combination of toxicogenomic studies and complementary bioinformatic tools, we characterize NTD candidate genes during normal development by function (gene ontology), linked phenotype (disease outcome), location, and expression (temporally and strain-dependent). In addition, we show how environmental exposures (cadmium, methylmercury) can influence expression of these genes in a strain-dependent manner. Using NTDs as an example of developmental disorder, we show how simple integration of genetic information from previous studies into the standard microarray design can enhance analysis of gene-environment interactions to better define environmental exposure-disease pathways in sensitive and resistant mouse strains. © Wiley-Liss, Inc.

Mixture toxicity revisited from a toxicogenomic perspective.

PubMed

Altenburger, Rolf; Scholz, Stefan; Schmitt-Jansen, Mechthild; Busch, Wibke; Escher, Beate I

2012-03-06

The advent of new genomic techniques has raised expectations that central questions of mixture toxicology such as for mechanisms of low dose interactions can now be answered. This review provides an overview on experimental studies from the past decade that address diagnostic and/or mechanistic questions regarding the combined effects of chemical mixtures using toxicogenomic techniques. From 2002 to 2011, 41 studies were published with a focus on mixture toxicity assessment. Primarily multiplexed quantification of gene transcripts was performed, though metabolomic and proteomic analysis of joint exposures have also been undertaken. It is now standard to explicitly state criteria for selecting concentrations and provide insight into data transformation and statistical treatment with respect to minimizing sources of undue variability. Bioinformatic analysis of toxicogenomic data, by contrast, is still a field with diverse and rapidly evolving tools. The reported combined effect assessments are discussed in the light of established toxicological dose-response and mixture toxicity models. Receptor-based assays seem to be the most advanced toward establishing quantitative relationships between exposure and biological responses. Often transcriptomic responses are discussed based on the presence or absence of signals, where the interpretation may remain ambiguous due to methodological problems. The majority of mixture studies design their studies to compare the recorded mixture outcome against responses for individual components only. This stands in stark contrast to our existing understanding of joint biological activity at the levels of chemical target interactions and apical combined effects. By joining established mixture effect models with toxicokinetic and -dynamic thinking, we suggest a conceptual framework that may help to overcome the current limitation of providing mainly anecdotal evidence on mixture effects. To achieve this we suggest (i) to design studies to establish quantitative relationships between dose and time dependency of responses and (ii) to adopt mixture toxicity models. Moreover, (iii) utilization of novel bioinformatic tools and (iv) stress response concepts could be productive to translate multiple responses into hypotheses on the relationships between general stress and specific toxicity reactions of organisms.

Intersection of toxicogenomics and high throughput screening in the Tox21 program: an NIEHS perspective.

PubMed

Merrick, B Alex; Paules, Richard S; Tice, Raymond R

Humans are exposed to thousands of chemicals with inadequate toxicological data. Advances in computational toxicology, robotic high throughput screening (HTS), and genome-wide expression have been integrated into the Tox21 program to better predict the toxicological effects of chemicals. Tox21 is a collaboration among US government agencies initiated in 2008 that aims to shift chemical hazard assessment from traditional animal toxicology to target-specific, mechanism-based, biological observations using in vitro assays and lower organism models. HTS uses biocomputational methods for probing thousands of chemicals in in vitro assays for gene-pathway response patterns predictive of adverse human health outcomes. In 1999, NIEHS began exploring the application of toxicogenomics to toxicology and recent advances in NextGen sequencing should greatly enhance the biological content obtained from HTS platforms. We foresee an intersection of new technologies in toxicogenomics and HTS as an innovative development in Tox21. Tox21 goals, priorities, progress, and challenges will be reviewed.

TOXICOGENOMIC STUDY OF TRIAZOLE FUNGICIDES AND PERFLUOROALKYL ACIDS

EPA Science Inventory

Toxicogenomic analysis of five environmental contaminants was performed to investigate the ability of genomics to categorize chemicals and elucidate mechanisms of toxicity. Three triazole antifungals (myclobutanil, propiconazole and triadimefon) and two perfluorinated compounds (...

Toxicogenomics and the Regulatory Framework

EPA Science Inventory

Toxicogenomics presents regulatory agencies with the opportunity to revolutionize their analyses by enabling the collection of information on a broader range of responses than currently considered in traditional regulatory decision making. Analyses of genomic responses are expec...

Predicting Drug-induced Hepatotoxicity Using QSAR and Toxicogenomics Approaches

PubMed Central

Low, Yen; Uehara, Takeki; Minowa, Yohsuke; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro; Sedykh, Alexander; Muratov, Eugene; Fourches, Denis; Zhu, Hao; Rusyn, Ivan; Tropsha, Alexander

2014-01-01

Quantitative Structure-Activity Relationship (QSAR) modeling and toxicogenomics are used independently as predictive tools in toxicology. In this study, we evaluated the power of several statistical models for predicting drug hepatotoxicity in rats using different descriptors of drug molecules, namely their chemical descriptors and toxicogenomic profiles. The records were taken from the Toxicogenomics Project rat liver microarray database containing information on 127 drugs (http://toxico.nibio.go.jp/datalist.html). The model endpoint was hepatotoxicity in the rat following 28 days of exposure, established by liver histopathology and serum chemistry. First, we developed multiple conventional QSAR classification models using a comprehensive set of chemical descriptors and several classification methods (k nearest neighbor, support vector machines, random forests, and distance weighted discrimination). With chemical descriptors alone, external predictivity (Correct Classification Rate, CCR) from 5-fold external cross-validation was 61%. Next, the same classification methods were employed to build models using only toxicogenomic data (24h after a single exposure) treated as biological descriptors. The optimized models used only 85 selected toxicogenomic descriptors and had CCR as high as 76%. Finally, hybrid models combining both chemical descriptors and transcripts were developed; their CCRs were between 68 and 77%. Although the accuracy of hybrid models did not exceed that of the models based on toxicogenomic data alone, the use of both chemical and biological descriptors enriched the interpretation of the models. In addition to finding 85 transcripts that were predictive and highly relevant to the mechanisms of drug-induced liver injury, chemical structural alerts for hepatotoxicity were also identified. These results suggest that concurrent exploration of the chemical features and acute treatment-induced changes in transcript levels will both enrich the mechanistic understanding of sub-chronic liver injury and afford models capable of accurate prediction of hepatotoxicity from chemical structure and short-term assay results. PMID:21699217

A DATABASE FOR TRACKING TOXICOGENOMIC SAMPLES AND PROCEDURES

EPA Science Inventory

Reproductive toxicogenomic studies generate large amounts of toxicological and genomic data. On the toxicology side, a substantial quantity of data accumulates from conventional endpoints such as histology, reproductive physiology and biochemistry. The largest source of genomics...

EPA'S TOXICOGENOMICS PARTNERSHIPS ACROSS GOVERNMENT, ACADEMIA AND INDUSTRY

EPA Science Inventory

Genomics, proteomics and metabonomics technologies are transforming the science of toxicology, and concurrent advances in computing and informatics are providing management and analysis solutions for this onslaught of toxicogenomic data. EPA has been actively developing an intra...

TOXICOGENOMICS AND HUMAN DISEASE RISK ASSESSMENT

EPA Science Inventory

Toxicogenomics and Human Disease Risk Assessment.

Complete sequencing of human and other genomes, availability of large-scale gene
expression arrays with ever-increasing numbers of genes displayed, and steady
improvements in protein expression technology can hav...

Integrating toxicogenomics data into cancer adverse outcome pathways

EPA Science Inventory

Integrating toxicogenomics data into adverse outcome pathways for cancer.J. Christopher CortonNHEERL/ORD, EPA, Research Triangle Park, NCAs the toxicology field continues to move towards a new paradigm in toxicity testing and safety assessment, there is the expectation that model...

EPA SCIENCE FORUM - EPA'S TOXICOGENOMICS PARTNERSHIPS ACROSS GOVERNMENT, ACADEMIA AND INDUSTRY

EPA Science Inventory

Over the past decade genomics, proteomics and metabonomics technologies have transformed the science of toxicology, and concurrent advances in computing and informatics have provided management and analysis solutions for this onslaught of toxicogenomic data. EPA has been actively...

Transcriptomic Dose-Response Analysis for Mode of Action ...

EPA Pesticide Factsheets

Microarray and RNA-seq technologies can play an important role in assessing the health risks associated with environmental exposures. The utility of gene expression data to predict hazard has been well documented. Early toxicogenomics studies used relatively high, single doses with minimal replication. Thus, they were not useful in understanding health risks at environmentally-relevant doses. Until the past decade, application of toxicogenomics in dose response assessment and determination of chemical mode of action has been limited. New transcriptomic biomarkers have evolved to detect chemical hazards in multiple tissues together with pathway methods to study biological effects across the full dose response range and critical time course. Comprehensive low dose datasets are now available and with the use of transcriptomic benchmark dose estimation techniques within a mode of action framework, the ability to incorporate informative genomic data into human health risk assessment has substantially improved. The key advantage to applying transcriptomic technology to risk assessment is both the sensitivity and comprehensive examination of direct and indirect molecular changes that lead to adverse outcomes. Book Chapter with topic on future application of toxicogenomics technologies for MoA and risk assessment

Developing Computational Tools for Application of Toxicogenomics to Environmental Regulations and Risk Assessment

EPA Science Inventory

Toxicogenomics is the study of changes in gene expression, protein, and metabolite profiles within cells and tissues, complementary to more traditional toxicological methods. Genomics tools provide detailed molecular data about the underlying biochemical mechanisms of toxicity, a...

TOXICOGENOMIC STUDY OF TRIAZOLE FUNGICIDES AND PERFLUOROALKYL ACIDS IN RAT LIVERS ACCURATELY CATEGORIZES CHEMICALS AND IDENTIFIES MECHANISMS OF TOXICITY

EPA Science Inventory

Toxicogenomic analysis of five environmental chemicals was performed to investigate the ability of genomics to predict toxicity, categorize chemicals, and elucidate mechanisms of toxicity. Three triazole antifungals (myclobutanil, propiconazole, and triadimefon) and two perfluori...

The fragility of omics risk and benefit perceptions.

PubMed

Börner, Franziska U; Schütz, Holger; Wiedemann, Peter

2011-03-25

How do individuals judge the risks and benefits of toxicogenomics, an emerging field of research which is completely unfamiliar to them? The hypothesis is that individuals' perceptions of the risks and benefits of toxicogenomics are fragile and can by influenced by different issues and context framings as a technology. The researchers expected that the effects on risk and benefit judgements would differ between lay individuals and experts in toxicogenomics. A 2×2×2 experiment that encompassed three factors was conducted. The first factor, issue framing incorporated the field of application for the technology (therapy vs. diagnosis setting). The second factor, context framing included organisations and institutions that would profit from the technology (companies vs. regulatory agencies) and the third factor encompasses the quality of individuals' level of knowledge, for example lay vs. expert knowledge. Research results suggest the differential power of framing effects. It seems that the clues provided by context frames - but not by issue frames - are able to influence the ways in which lay people and experts process information. The findings are interpreted in the line of the fuzzy trace theory that predicts reliance on fuzzy gist representations formed by stereotypes on a wide range of judgement problem including risk and benefit perceptions. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

SOURCES OF VARIATION IN BASELINE GENE EXPRESSION LEVELS FROM TOXICOGENOMIC STUDY CONTROL ANIMALS ACROSS MULTIPLE LABORATORIES

EPA Science Inventory

Variations in study design are typical for toxicogenomic studies, but their impact on gene expression in control animals has not been well characterized. A dataset of control animal microarray expression data was assembled by a working group of the Health and Environmental Scienc...

High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity

PubMed Central

Fabian, Gabriella; Farago, Nora; Feher, Liliana Z.; Nagy, Lajos I.; Kulin, Sandor; Kitajka, Klara; Bito, Tamas; Tubak, Vilmos; Katona, Robert L.; Tiszlavicz, Laszlo; Puskas, Laszlo G.

2011-01-01

Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present study our objective was to extend in vivo toxicogenomic screening from analyzing one or a few tissues to multiple organs, including heart, kidney, brain, liver and spleen. Nanocapillary quantitative real-time PCR (QRT-PCR) was used in the study, due to its higher throughput, sensitivity and reproducibility, and larger dynamic range compared to DNA microarray technologies. Based on previous data, 56 gene markers were selected coding for proteins with different functions, such as proteins for acute phase response, inflammation, oxidative stress, metabolic processes, heat-shock response, cell cycle/apoptosis regulation and enzymes which are involved in detoxification. Some of the marker genes are specific to certain organs, and some of them are general indicators of toxicity in multiple organs. Utility of the nanocapillary QRT-PCR platform was demonstrated by screening different references, as well as discovery of drug-like compounds for their gene expression profiles in different organs of treated mice in an acute experiment. For each compound, 896 QRT-PCR were done: four organs were used from each of the treated four animals to monitor the relative expression of 56 genes. Based on expression data of the discovery gene set of toxicology biomarkers the cardio- and nephrotoxicity of doxorubicin and sulfasalazin, the hepato- and nephrotoxicity of rotenone, dihydrocoumarin and aniline, and the liver toxicity of 2,4-diaminotoluene could be confirmed. The acute heart and kidney toxicity of the active metabolite SN-38 from its less toxic prodrug, irinotecan could be differentiated, and two novel gene markers for hormone replacement therapy were identified, namely fabp4 and pparg, which were down-regulated by estradiol treatment. PMID:22016648

Toward a Public Toxicogenomics Capability for Supporting Predictive Toxicology: Survey of Current Resources and Chemical Indexing of Experiments in GEO and ArrayExpress

EPA Science Inventory

A publicly available toxicogenomics capability for supporting predictive toxicology and meta-analysis depends on availability of gene expression data for chemical treatment scenarios, the ability to locate and aggregate such information by chemical, and broad data coverage within...

A DATABASE FOR TRACKING TOXICOGENOMIC SAMPLES AND PROCEDURES WITH GENOMIC, PROTEOMIC AND METABONOMIC COMPONENTS

EPA Science Inventory

A Database for Tracking Toxicogenomic Samples and Procedures with Genomic, Proteomic and Metabonomic Components
Wenjun Bao1, Jennifer Fostel2, Michael D. Waters2, B. Alex Merrick2, Drew Ekman3, Mitchell Kostich4, Judith Schmid1, David Dix1
Office of Research and Developmen...

US FDA and USA EPA Voluntary Submission of Genomic Data Guidance: Current and Future Use of Genomics in Decision Making

EPA Science Inventory

Appropriate utilization of data from toxicogenomic studies ins an ongoing concern of the regulated industries and the agencies charged with assessing safety or risk. An area of current interest is the possibility of toxicogenomics to enhance our ability to develop higher or high-...

Reconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions

PubMed Central

Blais, Edik M.; Rawls, Kristopher D.; Dougherty, Bonnie V.; Li, Zhuo I.; Kolling, Glynis L.; Ye, Ping; Wallqvist, Anders; Papin, Jason A.

2017-01-01

The laboratory rat has been used as a surrogate to study human biology for more than a century. Here we present the first genome-scale network reconstruction of Rattus norvegicus metabolism, iRno, and a significantly improved reconstruction of human metabolism, iHsa. These curated models comprehensively capture metabolic features known to distinguish rats from humans including vitamin C and bile acid synthesis pathways. After reconciling network differences between iRno and iHsa, we integrate toxicogenomics data from rat and human hepatocytes, to generate biomarker predictions in response to 76 drugs. We validate comparative predictions for xanthine derivatives with new experimental data and literature-based evidence delineating metabolite biomarkers unique to humans. Our results provide mechanistic insights into species-specific metabolism and facilitate the selection of biomarkers consistent with rat and human biology. These models can serve as powerful computational platforms for contextualizing experimental data and making functional predictions for clinical and basic science applications. PMID:28176778

USE OF TOXICOGENOMICS DATA IN RISK ASSESSMENT: CASE STUDY FOR A CHEMICAL IN THE ANDROGEN-MEDIATED MALE REPRODUCTIVE DEVELOPMENT TOXICITY PATHWAY

EPA Science Inventory

The goal of this project is to address the question, “Can existing toxicogenomics (TG) data improve Environmental Protection Agency (EPA) chemical health or risk assessments?” Although genomics data promises to impact multiple areas of science, medicine, law, and policy, there ar...

75 FR 1770 - An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-13

... qualitative aspects of the risk assessment because of the type of genomic data available for DBP. It is... Assessment (NCEA) within EPA's Office of Research and Development (ORD). Toxicogenomics is the application of... exploratory methods for analyzing genomic data for application to risk assessment and some preliminary results...

An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl Phthalate Case Study (Final Report, 2010)

EPA Science Inventory

EPA announced the availability of the final report, An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl Phthalate Case Study. This report outlines an approach to evaluate genomic data for use in risk assessment and a case study to ...

ARRAYS FOR BIOMONITORING ENVIRONMENTAL AND REPRODUCTIVE TOXICOLOGY

EPA Science Inventory

DNA arrays are receiving increasing interest as a tool for monitoring the developmental and reproductive impact of xenobiotics and other hazardous materials on human and wildlife populations. The primary tenet of toxicogenomics is that effects of environmental exposure on cellul...

Text Mining Effectively Scores and Ranks the Literature for Improving Chemical-Gene-Disease Curation at the Comparative Toxicogenomics Database

PubMed Central

Johnson, Robin J.; Lay, Jean M.; Lennon-Hopkins, Kelley; Saraceni-Richards, Cynthia; Sciaky, Daniela; Murphy, Cynthia Grondin; Mattingly, Carolyn J.

2013-01-01

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is a public resource that curates interactions between environmental chemicals and gene products, and their relationships to diseases, as a means of understanding the effects of environmental chemicals on human health. CTD provides a triad of core information in the form of chemical-gene, chemical-disease, and gene-disease interactions that are manually curated from scientific articles. To increase the efficiency, productivity, and data coverage of manual curation, we have leveraged text mining to help rank and prioritize the triaged literature. Here, we describe our text-mining process that computes and assigns each article a document relevancy score (DRS), wherein a high DRS suggests that an article is more likely to be relevant for curation at CTD. We evaluated our process by first text mining a corpus of 14,904 articles triaged for seven heavy metals (cadmium, cobalt, copper, lead, manganese, mercury, and nickel). Based upon initial analysis, a representative subset corpus of 3,583 articles was then selected from the 14,094 articles and sent to five CTD biocurators for review. The resulting curation of these 3,583 articles was analyzed for a variety of parameters, including article relevancy, novel data content, interaction yield rate, mean average precision, and biological and toxicological interpretability. We show that for all measured parameters, the DRS is an effective indicator for scoring and improving the ranking of literature for the curation of chemical-gene-disease information at CTD. Here, we demonstrate how fully incorporating text mining-based DRS scoring into our curation pipeline enhances manual curation by prioritizing more relevant articles, thereby increasing data content, productivity, and efficiency. PMID:23613709

Prediction model of potential hepatocarcinogenicity of rat hepatocarcinogens using a large-scale toxicogenomics database

DOE Office of Scientific and Technical Information (OSTI.GOV)

Uehara, Takeki, E-mail: takeki.uehara@shionogi.co.jp; Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, 7-6-8 Asagi, Ibaraki, Osaka 567-0085; Minowa, Yohsuke

2011-09-15

The present study was performed to develop a robust gene-based prediction model for early assessment of potential hepatocarcinogenicity of chemicals in rats by using our toxicogenomics database, TG-GATEs (Genomics-Assisted Toxicity Evaluation System developed by the Toxicogenomics Project in Japan). The positive training set consisted of high- or middle-dose groups that received 6 different non-genotoxic hepatocarcinogens during a 28-day period. The negative training set consisted of high- or middle-dose groups of 54 non-carcinogens. Support vector machine combined with wrapper-type gene selection algorithms was used for modeling. Consequently, our best classifier yielded prediction accuracies for hepatocarcinogenicity of 99% sensitivity and 97% specificitymore » in the training data set, and false positive prediction was almost completely eliminated. Pathway analysis of feature genes revealed that the mitogen-activated protein kinase p38- and phosphatidylinositol-3-kinase-centered interactome and the v-myc myelocytomatosis viral oncogene homolog-centered interactome were the 2 most significant networks. The usefulness and robustness of our predictor were further confirmed in an independent validation data set obtained from the public database. Interestingly, similar positive predictions were obtained in several genotoxic hepatocarcinogens as well as non-genotoxic hepatocarcinogens. These results indicate that the expression profiles of our newly selected candidate biomarker genes might be common characteristics in the early stage of carcinogenesis for both genotoxic and non-genotoxic carcinogens in the rat liver. Our toxicogenomic model might be useful for the prospective screening of hepatocarcinogenicity of compounds and prioritization of compounds for carcinogenicity testing. - Highlights: >We developed a toxicogenomic model to predict hepatocarcinogenicity of chemicals. >The optimized model consisting of 9 probes had 99% sensitivity and 97% specificity. >This model enables us to detect genotoxic as well as non-genotoxic hepatocarcinogens.« less

Prioritizing PubMed articles for the Comparative Toxicogenomic Database utilizing semantic information

PubMed Central

Wilbur, W. John

2012-01-01

The Comparative Toxicogenomics Database (CTD) contains manually curated literature that describes chemical–gene interactions, chemical–disease relationships and gene–disease relationships. Finding articles containing this information is the first and an important step to assist manual curation efficiency. However, the complex nature of named entities and their relationships make it challenging to choose relevant articles. In this article, we introduce a machine learning framework for prioritizing CTD-relevant articles based on our prior system for the protein–protein interaction article classification task in BioCreative III. To address new challenges in the CTD task, we explore a new entity identification method for genes, chemicals and diseases. In addition, latent topics are analyzed and used as a feature type to overcome the small size of the training set. Applied to the BioCreative 2012 Triage dataset, our method achieved 0.8030 mean average precision (MAP) in the official runs, resulting in the top MAP system among participants. Integrated with PubTator, a Web interface for annotating biomedical literature, the proposed system also received a positive review from the CTD curation team. PMID:23160415

Prioritizing PubMed articles for the Comparative Toxicogenomic Database utilizing semantic information.

PubMed

Kim, Sun; Kim, Won; Wei, Chih-Hsuan; Lu, Zhiyong; Wilbur, W John

2012-01-01

The Comparative Toxicogenomics Database (CTD) contains manually curated literature that describes chemical-gene interactions, chemical-disease relationships and gene-disease relationships. Finding articles containing this information is the first and an important step to assist manual curation efficiency. However, the complex nature of named entities and their relationships make it challenging to choose relevant articles. In this article, we introduce a machine learning framework for prioritizing CTD-relevant articles based on our prior system for the protein-protein interaction article classification task in BioCreative III. To address new challenges in the CTD task, we explore a new entity identification method for genes, chemicals and diseases. In addition, latent topics are analyzed and used as a feature type to overcome the small size of the training set. Applied to the BioCreative 2012 Triage dataset, our method achieved 0.8030 mean average precision (MAP) in the official runs, resulting in the top MAP system among participants. Integrated with PubTator, a Web interface for annotating biomedical literature, the proposed system also received a positive review from the CTD curation team.

Toxicogenomic Effects Common to Triazole Antifungals and Conserved Between Rats and Humans

EPA Science Inventory

The triazole antifungals myclobutanil, propiconazole and triadimefon cause varying degrees of hepatic toxicity and disrupt steroid hormone homeostasis in rodent in vivo models. To identify biological pathways consistently modulated across multiple time-points and various study d...

DEVELOPMENT OF MICROARRAYS AS A TOOL FOR DISCOVERING ENVIRONMENTAL EXPOSURE INDICATORS

EPA Science Inventory

Toxicogenomics includes research to identify differential gene expression in laboratory and field animals exposed to toxicants, and ultimately, to link the earliest indicators of exposure to adverse effects in organisms and populations. The USEPA National Exposure Research Labor...

Application of toxicogenomic profiling to evaluate effects of benzene and formaldehyde: from yeast to human

PubMed Central

McHale, Cliona M.; Smith, Martyn T.; Zhang, Luoping

2014-01-01

Genetic variation underlies a significant proportion of the individual variation in human susceptibility to toxicants. The primary current approaches to identify gene–environment (GxE) associations, genome-wide association studies (GWAS) and candidate gene association studies, require large exposed and control populations and an understanding of toxicity genes and pathways, respectively. This limits their application in the study of GxE associations for the leukemogens benzene and formaldehyde, whose toxicity has long been a focus of our research. As an alternative approach, we applied innovative in vitro functional genomics testing systems, including unbiased functional screening assays in yeast and a near-haploid human bone marrow cell line (KBM7). Through comparative genomic and computational analyses of the resulting data, we have identified human genes and pathways that may modulate susceptibility to benzene and formaldehyde. We have validated the roles of several genes in mammalian cell models. In populations occupationally exposed to low levels of benzene, we applied peripheral blood mononuclear cell transcriptomics and chromosome-wide aneuploidy studies (CWAS) in lymphocytes. In this review of the literature, we describe our comprehensive toxicogenomic approach and the potential mechanisms of toxicity and susceptibility genes identified for benzene and formaldehyde, as well as related studies conducted by other researchers. PMID:24571325

Toxicogenomic identification of biomarkers of acute respiratory exposure sensitizing agents

EPA Science Inventory

Allergy induction requires multiple exposures to an agent. Therefore the development of high-throughput or in vitro assays for effective screening of potential sensitizers will require the identification of biomarkers. The goal of this preliminary study was to identify potential ...

Toxicogenomic identification of biomarkers of acute respiratory expsoure to sensitizing agents

EPA Science Inventory

Allergy induction requires multiple exposures to an agent. Therefore the development of high-throughput or in vitro assays for effective screening of potential sensitizers will require the identification of biomarkers. The goal of this preliminary study was to identify potential ...

Customizing the Connectivity Map Approach for Functional Evaluation in Toxicogenomics Studies (SOT)

EPA Science Inventory

Evaluating effects on the transcriptome can provide insight on putative chemical-specific mechanisms of action (MOAs). With whole genome transcriptomics technologies becoming more amenable to high-throughput screening, libraries of chemicals can be evaluated in vitro to produce l...

Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPARα and CAR

EPA Science Inventory

A number of perfluorinated alkyl acids including perfluorooctanoic acid (PFOA) elicit effects similar to peroxisome proliferator chemicals (PPC) in mouse and rat liver. There is strong evidence that PPC cause many of their effects linked to liver cancer through the nuclear recep...

Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for Involvement of the Nuclear Receptors PPARα and CAR

EPA Science Inventory

A number of perfluorinated alkyl acids including perfluorooctanoic acid (PFOA) elicit effects similar to peroxisome proliferator chemicals (PPC) in mouse and rat liver. There is strong evidence that PPC cause many of their effects related to liver carcinogenesis through the nucle...

Genotoxicity Assessment of Drinking Water Disinfection Byproducts by DNA Damage and Repair Pathway Profiling Analysis.

PubMed

Lan, Jiaqi; Rahman, Sheikh Mokhlesur; Gou, Na; Jiang, Tao; Plewa, Micheal J; Alshawabkeh, Akram; Gu, April Z

2018-06-05

Genotoxicity is considered a major concern for drinking water disinfection byproducts (DBPs). Of over 700 DBPs identified to date, only a small number has been assessed with limited information for DBP genotoxicity mechanism(s). In this study, we evaluated genotoxicity of 20 regulated and unregulated DBPs applying a quantitative toxicogenomics approach. We used GFP-fused yeast strains that examine protein expression profiling of 38 proteins indicative of all known DNA damage and repair pathways. The toxicogenomics assay detected genotoxicity potential of these DBPs that is consistent with conventional genotoxicity assays end points. Furthermore, the high-resolution, real-time pathway activation and protein expression profiling, in combination with clustering analysis, revealed molecular level details in the genotoxicity mechanisms among different DBPs and enabled classification of DBPs based on their distinct DNA damage effects and repair mechanisms. Oxidative DNA damage and base alkylation were confirmed to be the main molecular mechanisms of DBP genotoxicity. Initial exploration of QSAR modeling using moleular genotoxicity end points (PELI) suggested that genotoxicity of DBPs in this study was correlated with topological and quantum chemical descriptors. This study presents a toxicogenomics-based assay for fast and efficient mechanistic genotoxicity screening and assessment of a large number of DBPs. The results help to fill in the knowledge gap in the understanding of the molecular mechanisms of DBP genotoxicity.

Toxicogenomic analysis of the hepatic effects of perfluorooctanoic acid on rare minnows (Gobiocypris rarus)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei Yanhong; Graduate School of the Chinese Academy of Sciences, Beijing, 100080; Liu Yang

2008-02-01

Perfluorooctanoic acid (PFOA) is a ubiquitous environmental contaminant that has been detected in a variety of terrestrial and aquatic organisms. To assess the effects of PFOA in fish and predict its potential mode of action, a toxicogenomic approach was applied to hepatic gene expression profile analysis in male and female rare minnows (Gobiocypris rarus) using a custom cDNA microarray containing 1773 unique genes. Rare minnows were treated with continuous flow-through exposure to PFOA at concentrations of 3, 10, and 30 mg/L for 28 days. Based on the observed histopathological changes, the livers from fish exposed to 10 mg/L PFOA weremore » selected for further hepatic gene expression analysis. While 124 and 171 genes were significantly altered by PFOA in males and females, respectively, of which 43 genes were commonly regulated in both sexes. The affected genes are involved in multiple biological processes, including lipid metabolism and transport, hormone action, immune responses, and mitochondrial functions. PFOA exposure significantly suppressed genes involved in fatty acid biosynthesis and transport but induced genes associated with intracellular trafficking of cholesterol. Alterations in expression of genes associated with mitochondrial fatty acid {beta}-oxidation were only observed in female rare minnows. In addition, PFOA inhibited genes responsible for thyroid hormone biosynthesis and significantly induced estrogen-responsive genes. These findings implicate PFOA in endocrine disruption. This work contributes not only to the elucidation of the potential mode of toxicity of PFOA to aquatic organisms but also to the use of toxicogenomic approaches to address issues in environmental toxicology.« less

Toxicogenomic responses of nanotoxicity in Daphnia magna exposed to silver nitrate and coated silver nanoparticles

EPA Science Inventory

Applications for silver nanomaterials in consumer products are rapidly expanding, creating an urgent need for toxicological examination of the exposure potential and ecological effects of silver nanoparticles (AgNPs). The integration of genomic techniques into environmental toxic...

Comparison of L1000 and Affymetrix Microarray for In Vitro Concentration-Response Gene Expression Profiling (SOT)

EPA Science Inventory

Advances in high-throughput screening technologies and in vitro systems have opened doors for cost-efficient evaluation of chemical effects on a diversity of biological endpoints. However, toxicogenomics platforms remain too costly to evaluate large libraries of chemicals in conc...

Signal transduction disturbance related to hepatocarcinogenesis in mouse by prolonged exposure to Nanjing drinking water.

PubMed

Zhang, Rui; Sun, Jie; Zhang, Yan; Cheng, Shupei; Zhang, Xiaowei

2013-09-01

Toxicogenomic approaches were used to investigate the potential hepatocarcinogenic effects on mice by oral exposure to Nanjing drinking water (NJDW). Changes in the hepatic transcriptome of 3 weeks male mice (Mus musculus) were monitored and dissected after oral exposure to NJDW for 90 days. No preneoplastic and neoplastic lesions were observed in the hepatic tissue by the end of NJDW exposure. However, total of 746 genes were changed transcriptionally. Thirty-one percent of differentially expressed genes (DEGs) were associated with the functional categories of cell cycle regulation, adhesion, growth, apoptosis, and signal transduction, which are closely implicated in tumorigenesis and progression. Interrogation of Kyoto Encyclopedia of Genes and Genomes revealed that 43 DEGs were mapped to several crucial signaling pathways implicated in the pathogenesis of hepatocellular carcinoma (HCC). In signal transduction network constructed via Genes2Networks software, Egfr, Akt1, Atf2, Ctnnb1, Hras, Mapk1, Smad2, and Ccnd1 were hubs. Direct gene-disease relationships obtained from Comparative Toxicogenomics Database and scientific literatures revealed that the hubs have direct mechanism or biomarker relationships with hepatocellular preneoplastic lesions or hepatocarcinogenesis. Therefore, prolonged intake of NJDW without employing any indoor water treatment strategy might predispose mouse to HCC. Furthermore, Egfr, Akt1, Ctnnb1, Hras, Mapk1, Smad2, and Ccnd1 were identified as promising biomarkers of the potential combined hepatocarcinogenicity.

The Metamorphosis of Amphibian Toxicogenomics

PubMed Central

Helbing, Caren C.

2012-01-01

Amphibians are important vertebrates in toxicology often representing both aquatic and terrestrial forms within the life history of the same species. Of the thousands of species, only two have substantial genomics resources: the recently published genome of the Pipid, Xenopus (Silurana) tropicalis, and transcript information (and ongoing genome sequencing project) of Xenopus laevis. However, many more species representative of regional ecological niches and life strategies are used in toxicology worldwide. Since Xenopus species diverged from the most populous frog family, the Ranidae, ~200 million years ago, there are notable differences between them and the even more distant Caudates (salamanders) and Caecilians. These differences include genome size, gene composition, and extent of polyploidization. Application of toxicogenomics to amphibians requires the mobilization of resources and expertise to develop de novo sequence assemblies and analysis strategies for a broader range of amphibian species. The present mini-review will present the advances in toxicogenomics as pertains to amphibians with particular emphasis upon the development and use of genomic techniques (inclusive of transcriptomics, proteomics, and metabolomics) and the challenges inherent therein. PMID:22435070

Yeast Toxicogenomics: Genome-Wide Responses to Chemical Stresses with Impact in Environmental Health, Pharmacology, and Biotechnology

PubMed Central

dos Santos, Sandra C.; Teixeira, Miguel Cacho; Cabrito, Tânia R.; Sá-Correia, Isabel

2012-01-01

The emerging transdisciplinary field of Toxicogenomics aims to study the cell response to a given toxicant at the genome, transcriptome, proteome, and metabolome levels. This approach is expected to provide earlier and more sensitive biomarkers of toxicological responses and help in the delineation of regulatory risk assessment. The use of model organisms to gather such genomic information, through the exploitation of Omics and Bioinformatics approaches and tools, together with more focused molecular and cellular biology studies are rapidly increasing our understanding and providing an integrative view on how cells interact with their environment. The use of the model eukaryote Saccharomyces cerevisiae in the field of Toxicogenomics is discussed in this review. Despite the limitations intrinsic to the use of such a simple single cell experimental model, S. cerevisiae appears to be very useful as a first screening tool, limiting the use of animal models. Moreover, it is also one of the most interesting systems to obtain a truly global understanding of the toxicological response and resistance mechanisms, being in the frontline of systems biology research and developments. The impact of the knowledge gathered in the yeast model, through the use of Toxicogenomics approaches, is highlighted here by its use in prediction of toxicological outcomes of exposure to pesticides and pharmaceutical drugs, but also by its impact in biotechnology, namely in the development of more robust crops and in the improvement of yeast strains as cell factories. PMID:22529852

CHEMICAL EFFECTS IN BIOLOGICAL SYSTEMS – DATA DICTIONARY (CEBS-DD): A COMPENDIUM OF TERMS FOR THE CAPTURE AND INTEGRATION OF BIOLOGICAL STUDY DESIGN DESCRIPTION, CONVENTIONAL PHENOTYPES AND ‘OMICS’ DATA

EPA Science Inventory

A critical component in the design of the Chemical Effects in Biological Systems (CEBS) Knowledgebase is a strategy to capture toxicogenomics study protocols and the toxicity endpoint data (clinical pathology and histopathology). A Study is generally an experiment carried out du...

Functional toxicogenomic assessment of triclosan in human HepG2 cells using genome-wide CRISPR-Cas9 screen

EPA Science Inventory

Thousands of chemicals for which limited toxicological data are available are used and then detected in humans and the environment. Rapid and cost-effective approaches for assessing the toxicological properties of chemicals are needed. We used CRISPR-Cas9 functional genomic scree...

Discovery of Transcriptional Targets Regulated by Nuclear Receptors Using a Probabilistic Graphical Model

PubMed Central

Lee, Mikyung; Huang, Ruili; Tong, Weida

2016-01-01

Nuclear receptors (NRs) are ligand-activated transcriptional regulators that play vital roles in key biological processes such as growth, differentiation, metabolism, reproduction, and morphogenesis. Disruption of NRs can result in adverse health effects such as NR-mediated endocrine disruption. A comprehensive understanding of core transcriptional targets regulated by NRs helps to elucidate their key biological processes in both toxicological and therapeutic aspects. In this study, we applied a probabilistic graphical model to identify the transcriptional targets of NRs and the biological processes they govern. The Tox21 program profiled a collection of approximate 10 000 environmental chemicals and drugs against a panel of human NRs in a quantitative high-throughput screening format for their NR disruption potential. The Japanese Toxicogenomics Project, one of the most comprehensive efforts in the field of toxicogenomics, generated large-scale gene expression profiles on the effect of 131 compounds (in its first phase of study) at various doses, and different durations, and their combinations. We applied author-topic model to these 2 toxicological datasets, which consists of 11 NRs run in either agonist and/or antagonist mode (18 assays total) and 203 in vitro human gene expression profiles connected by 52 shared drugs. As a result, a set of clusters (topics), which consists of a set of NRs and their associated target genes were determined. Various transcriptional targets of the NRs were identified by assays run in either agonist or antagonist mode. Our results were validated by functional analysis and compared with TRANSFAC data. In summary, our approach resulted in effective identification of associated/affected NRs and their target genes, providing biologically meaningful hypothesis embedded in their relationships. PMID:26643261

Impact of Genomics Platform and Statistical Filtering on Transcriptional Benchmark Doses (BMD) and Multiple Approaches for Selection of Chemical Point of Departure (PoD)

PubMed Central

Webster, A. Francina; Chepelev, Nikolai; Gagné, Rémi; Kuo, Byron; Recio, Leslie; Williams, Andrew; Yauk, Carole L.

2015-01-01

Many regulatory agencies are exploring ways to integrate toxicogenomic data into their chemical risk assessments. The major challenge lies in determining how to distill the complex data produced by high-content, multi-dose gene expression studies into quantitative information. It has been proposed that benchmark dose (BMD) values derived from toxicogenomics data be used as point of departure (PoD) values in chemical risk assessments. However, there is limited information regarding which genomics platforms are most suitable and how to select appropriate PoD values. In this study, we compared BMD values modeled from RNA sequencing-, microarray-, and qPCR-derived gene expression data from a single study, and explored multiple approaches for selecting a single PoD from these data. The strategies evaluated include several that do not require prior mechanistic knowledge of the compound for selection of the PoD, thus providing approaches for assessing data-poor chemicals. We used RNA extracted from the livers of female mice exposed to non-carcinogenic (0, 2 mg/kg/day, mkd) and carcinogenic (4, 8 mkd) doses of furan for 21 days. We show that transcriptional BMD values were consistent across technologies and highly predictive of the two-year cancer bioassay-based PoD. We also demonstrate that filtering data based on statistically significant changes in gene expression prior to BMD modeling creates more conservative BMD values. Taken together, this case study on mice exposed to furan demonstrates that high-content toxicogenomics studies produce robust data for BMD modelling that are minimally affected by inter-technology variability and highly predictive of cancer-based PoD doses. PMID:26313361

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System weremore » used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. - Highlights: • Hypertrophy (H) and hypertrophic carcinogenesis (C) were studied by toxicogenomics. • Important genes for H and C were selected by logistic ridge regression analysis. • Amino acid biosynthesis and oxidative responses may be involved in C. • Predictive models for H and C provided 94.8% and 82.7% accuracy, respectively. • The identified genes could be useful for assessment of liver hypertrophy.« less

Human cell toxicogenomic analysis of bromoacetic acid: a regulated drinking water disinfection by-product.

PubMed

Muellner, Mark G; Attene-Ramos, Matias S; Hudson, Matthew E; Wagner, Elizabeth D; Plewa, Michael J

2010-04-01

The disinfection of drinking water is a major achievement in protecting the public health. However, current disinfection methods also generate disinfection by-products (DBPs). Many DBPs are cytotoxic, genotoxic, teratogenic, and carcinogenic and represent an important class of environmentally hazardous chemicals that may carry long-term human health implications. The objective of this research was to integrate in vitro toxicology with focused toxicogenomic analysis of the regulated DBP, bromoacetic acid (BAA) and to evaluate modulation of gene expression involved in DNA damage/repair and toxic responses, with nontransformed human cells. We generated transcriptome profiles for 168 genes with 30 min and 4 hr exposure times that did not induce acute cytotoxicity. Using qRT-PCR gene arrays, the levels of 25 transcripts were modulated to a statistically significant degree in response to a 30 min treatment with BAA (16 transcripts upregulated and nine downregulated). The largest changes were observed for RAD9A and BRCA1. The majority of the altered transcript profiles are genes involved in DNA repair, especially the repair of double strand DNA breaks, and in cell cycle regulation. With 4 hr of treatment the expression of 28 genes was modulated (12 upregulated and 16 downregulated); the largest fold changes were in HMOX1 and FMO1. This work represents the first nontransformed human cell toxicogenomic study with a regulated drinking water disinfection by-product. These data implicate double strand DNA breaks as a feature of BAA exposure. Future toxicogenomic studies of DBPs will further strengthen our limited knowledge in this growing area of drinking water research. Copyright 2009 Wiley-Liss, Inc.

An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl Phthalate (Dbp) Case Study (External Review Draft)

EPA Science Inventory

This draft report is a description of an approach to evaluate genomic data for use in risk assessment and a case study to illustrate the approach. The dibutyl phthalate (DBP) case study example focuses on male reproductive developmental effects and the qualitative application of...

Connection Map for Compounds (CMC): A Server for Combinatorial Drug Toxicity and Efficacy Analysis.

PubMed

Liu, Lei; Tsompana, Maria; Wang, Yong; Wu, Dingfeng; Zhu, Lixin; Zhu, Ruixin

2016-09-26

Drug discovery and development is a costly and time-consuming process with a high risk for failure resulting primarily from a drug's associated clinical safety and efficacy potential. Identifying and eliminating inapt candidate drugs as early as possible is an effective way for reducing unnecessary costs, but limited analytical tools are currently available for this purpose. Recent growth in the area of toxicogenomics and pharmacogenomics has provided with a vast amount of drug expression microarray data. Web servers such as CMap and LTMap have used this information to evaluate drug toxicity and mechanisms of action independently; however, their wider applicability has been limited by the lack of a combinatorial drug-safety type of analysis. Using available genome-wide drug transcriptional expression profiles, we developed the first web server for combinatorial evaluation of toxicity and efficacy of candidate drugs named "Connection Map for Compounds" (CMC). Using CMC, researchers can initially compare their query drug gene signatures with prebuilt gene profiles generated from two large-scale toxicogenomics databases, and subsequently perform a drug efficacy analysis for identification of known mechanisms of drug action or generation of new predictions. CMC provides a novel approach for drug repositioning and early evaluation in drug discovery with its unique combination of toxicity and efficacy analyses, expansibility of data and algorithms, and customization of reference gene profiles. CMC can be freely accessed at http://cadd.tongji.edu.cn/webserver/CMCbp.jsp .

Isoflurane is a suitable alternative to ether for anesthetizing rats prior to euthanasia for gene expression analysis.

PubMed

Nakatsu, Noriyuki; Igarashi, Yoshinobu; Aoshi, Taiki; Hamaguchi, Isao; Saito, Masumichi; Mizukami, Takuo; Momose, Haruka; Ishii, Ken J; Yamada, Hiroshi

2017-01-01

Diethyl ether (ether) had been widely used in Japan for anesthesia, despite its explosive properties and toxicity to both humans and animals. We also had used ether as an anesthetic for euthanizing rats for research in the Toxicogenomics Project (TGP). Because the use of ether for these purposes will likely cease, it is required to select an alternative anesthetic which is validated for consistency with existing TGP data acquired under ether anesthesia. We therefore compared two alternative anesthetic candidates, isoflurane and pentobarbital, with ether in terms of hematological findings, serum biochemical parameters, and gene expressions. As a result, few differences among the three agents were observed. In hematological and serum biochemistry analysis, no significant changes were found. In gene expression analysis, four known genes were extracted as differentially expressed genes in the liver of rats anesthetized with ether, isoflurane, or pentobarbital. However, no significant relationships were detected using gene ontology, pathway, or gene enrichment analyses by DAVID and TargetMine. Surprisingly, although it was expected that the lung would be affected by administration via inhalation, only one differentially expressed gene was extracted in the lung. Taken together, our data indicate that there are no significant differences among ether, isoflurane, and pentobarbital with respect to effects on hematological parameters, serum biochemistry parameters, and gene expression. Based on its smallest affect to existing data and its safety profile for humans and animals, we suggest isoflurane as a suitable alternative anesthetic for use in rat euthanasia in toxicogenomics analysis.

Similar compounds searching system by using the gene expression microarray database.

PubMed

Toyoshiba, Hiroyoshi; Sawada, Hiroshi; Naeshiro, Ichiro; Horinouchi, Akira

2009-04-10

Numbers of microarrays have been examined and several public and commercial databases have been developed. However, it is not easy to compare in-house microarray data with those in a database because of insufficient reproducibility due to differences in the experimental conditions. As one of the approach to use these databases, we developed the similar compounds searching system (SCSS) on a toxicogenomics database. The datasets of 55 compounds administered to rats in the Toxicogenomics Project (TGP) database in Japan were used in this study. Using the fold-change ranking method developed by Lamb et al. [Lamb, J., Crawford, E.D., Peck, D., Modell, J.W., Blat, I.C., Wrobel, M.J., Lerner, J., Brunet, J.P., Subramanian, A., Ross, K.N., Reich, M., Hieronymus, H., Wei, G., Armstrong, S.A., Haggarty, S.J., Clemons, P.A., Wei, R., Carr, S.A., Lander, E.S., Golub, T.R., 2006. The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929-1935] and criteria called hit ratio, the system let us compare in-house microarray data and those in the database. In-house generated data for clofibrate, phenobarbital, and a proprietary compound were tested to evaluate the performance of the SCSS method. Phenobarbital and clofibrate, which were included in the TGP database, scored highest by the SCSS method. Other high scoring compounds had effects similar to either phenobarbital (a cytochrome P450s inducer) or clofibrate (a peroxisome proliferator). Some of high scoring compounds identified using the proprietary compound-administered rats have been known to cause similar toxicological changes in different species. Our results suggest that the SCSS method could be used in drug discovery and development. Moreover, this method may be a powerful tool to understand the mechanisms by which biological systems respond to various chemical compounds and may also predict adverse effects of new compounds.

Transcriptional Responses Reveal Similarities Between Preclinical Rat Liver Testing Systems.

PubMed

Liu, Zhichao; Delavan, Brian; Roberts, Ruth; Tong, Weida

2018-01-01

Toxicogenomics (TGx) is an important tool to gain an enhanced understanding of toxicity at the molecular level. Previously, we developed a pair ranking (PRank) method to assess in vitro to in vivo extrapolation (IVIVE) using toxicogenomic datasets from the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) database. With this method, we investiagted three important questions that were not addressed in our previous study: (1) is a 1-day in vivo short-term assay able to replace the 28-day standard and expensive toxicological assay? (2) are some biological processes more conservative across different preclinical testing systems than others? and (3) do these preclinical testing systems have the similar resolution in differentiating drugs by their therapeutic uses? For question 1, a high similarity was noted (PRank score = 0.90), indicating the potential utility of shorter term in vivo studies to predict outcome in longer term and more expensive in vivo model systems. There was a moderate similarity between rat primary hepatocytes and in vivo repeat-dose studies (PRank score = 0.71) but a low similarity (PRank score = 0.56) between rat primary hepatocytes and in vivo single dose studies. To address question 2, we limited the analysis to gene sets relevant to specific toxicogenomic pathways and we found that pathways such as lipid metabolism were consistently over-represented in all three assay systems. For question 3, all three preclinical assay systems could distinguish compounds from different therapeutic categories. This suggests that any noted differences in assay systems was biological process-dependent and furthermore that all three systems have utility in assessing drug responses within a certain drug class. In conclusion, this comparison of three commonly used rat TGx systems provides useful information in utility and application of TGx assays.

Genomic Models of Short-Term Exposure Accurately Predict Long-Term Chemical Carcinogenicity and Identify Putative Mechanisms of Action

PubMed Central

Gusenleitner, Daniel; Auerbach, Scott S.; Melia, Tisha; Gómez, Harold F.; Sherr, David H.; Monti, Stefano

2014-01-01

Background Despite an overall decrease in incidence of and mortality from cancer, about 40% of Americans will be diagnosed with the disease in their lifetime, and around 20% will die of it. Current approaches to test carcinogenic chemicals adopt the 2-year rodent bioassay, which is costly and time-consuming. As a result, fewer than 2% of the chemicals on the market have actually been tested. However, evidence accumulated to date suggests that gene expression profiles from model organisms exposed to chemical compounds reflect underlying mechanisms of action, and that these toxicogenomic models could be used in the prediction of chemical carcinogenicity. Results In this study, we used a rat-based microarray dataset from the NTP DrugMatrix Database to test the ability of toxicogenomics to model carcinogenicity. We analyzed 1,221 gene-expression profiles obtained from rats treated with 127 well-characterized compounds, including genotoxic and non-genotoxic carcinogens. We built a classifier that predicts a chemical's carcinogenic potential with an AUC of 0.78, and validated it on an independent dataset from the Japanese Toxicogenomics Project consisting of 2,065 profiles from 72 compounds. Finally, we identified differentially expressed genes associated with chemical carcinogenesis, and developed novel data-driven approaches for the molecular characterization of the response to chemical stressors. Conclusion Here, we validate a toxicogenomic approach to predict carcinogenicity and provide strong evidence that, with a larger set of compounds, we should be able to improve the sensitivity and specificity of the predictions. We found that the prediction of carcinogenicity is tissue-dependent and that the results also confirm and expand upon previous studies implicating DNA damage, the peroxisome proliferator-activated receptor, the aryl hydrocarbon receptor, and regenerative pathology in the response to carcinogen exposure. PMID:25058030

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.

PubMed

Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

2017-03-01

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

Entitymetrics: Measuring the Impact of Entities

PubMed Central

Ding, Ying; Song, Min; Han, Jia; Yu, Qi; Yan, Erjia; Lin, Lili; Chambers, Tamy

2013-01-01

This paper proposes entitymetrics to measure the impact of knowledge units. Entitymetrics highlight the importance of entities embedded in scientific literature for further knowledge discovery. In this paper, we use Metformin, a drug for diabetes, as an example to form an entity-entity citation network based on literature related to Metformin. We then calculate the network features and compare the centrality ranks of biological entities with results from Comparative Toxicogenomics Database (CTD). The comparison demonstrates the usefulness of entitymetrics to detect most of the outstanding interactions manually curated in CTD. PMID:24009660

Editor's Highlight: Off-Target Effects of Neuroleptics and Antidepressants on Saccharomyces cerevisiae.

PubMed

Caldara, Marina; Graziano, Sara; Gullì, Mariolina; Cadonici, Stefania; Marmiroli, Nelson

2017-04-01

Over the past years, the use of antidepressants and neuroleptics has steadily increased. Although incredibly useful to treat disorders like depression, schizophrenia, epilepsy, or mental retardation, these drugs display many side effects. Toxicogenomic studies aim to limit this problem by trying to identify cellular targets and off-targets of medical compounds. The baker yeast Saccharomyces cerevisiae has been shown to be a key player in this approach, as it represents an incredible toolbox for the dissection of complex biological processes. Moreover, the evolutionary conservation of many pathways allows the translation of yeast data to the human system. In this paper, a better attention was paid to chlorpromazine, as it still is one of the most widely used drug in therapy. The results of a toxicogenomic screening performed on a yeast mutants collection treated with chlorpromazine were instrumental to identify a set of genes for further analyses. For this purpose, a multidisciplinary approach was used based on growth phenotypes identification, Gene Ontology search, and network analysis. Then, the impacts of three antidepressants (imipramine, doxepin, and nortriptyline) and three neuroleptics (promazine, chlorpromazine, and promethazine) on S. cerevisiae were compared through physiological analyses, microscopy characterization, and transcriptomic studies. Data highlight key differences between neuroleptics and antidepressants, but also between the individual molecules. By performing a network analysis on the human homologous genes, it emerged that genes and proteins involved in the Notch pathway are possible off-targets of these molecules, along with key regulatory proteins. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effect of the difference in vehicles on gene expression in the rat liver--analysis of the control data in the Toxicogenomics Project Database.

PubMed

Takashima, Kayoko; Mizukawa, Yumiko; Morishita, Katsumi; Okuyama, Manabu; Kasahara, Toshihiko; Toritsuka, Naoki; Miyagishima, Toshikazu; Nagao, Taku; Urushidani, Tetsuro

2006-05-08

The Toxicogenomics Project is a 5-year collaborative project by the Japanese government and pharmaceutical companies in 2002. Its aim is to construct a large-scale toxicology database of 150 compounds orally administered to rats. The test consists of a single administration test (3, 6, 9 and 24 h) and a repeated administration test (3, 7, 14 and 28 days), and the conventional toxicology data together with the gene expression data in liver as analyzed by using Affymetrix GeneChip are being accumulated. In the project, either methylcellulose or corn oil is employed as vehicle. We examined whether the vehicle itself affects the analysis of gene expression and found that corn oil alone affected the food consumption and biochemical parameters mainly related to lipid metabolism, and this accompanied typical changes in the gene expression. Most of the genes modulated by corn oil were related to cholesterol or fatty acid metabolism (e.g., CYP7A1, CYP8B1, 3-hydroxy-3-methylglutaryl-Coenzyme A reductase, squalene epoxidase, angiopoietin-like protein 4, fatty acid synthase, fatty acid binding proteins), suggesting that the response was physiologic to the oil intake. Many of the lipid-related genes showed circadian rhythm within a day, but the expression pattern of general clock genes (e.g., period 2, arylhydrocarbon nuclear receptor translocator-like, D site albumin promoter binding protein) were unaffected by corn oil, suggesting that the effects are specific for lipid metabolism. These results would be useful for usage of the database especially when drugs with different vehicle control are compared.

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; King, Benjamin L.; Wiegers, Jolene; Grondin, Cynthia J.; Sciaky, Daniela; Johnson, Robin J.; Mattingly, Carolyn J.

2016-01-01

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD’s gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects. PMID:27171405

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database.

PubMed

Davis, Allan Peter; Wiegers, Thomas C; King, Benjamin L; Wiegers, Jolene; Grondin, Cynthia J; Sciaky, Daniela; Johnson, Robin J; Mattingly, Carolyn J

2016-01-01

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD's gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects.

Toxicological responses of environmental mixtures: Environmental metal mixtures display synergistic induction of metal-responsive and oxidative stress genes in placental cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adebambo, Oluwadamilare A.; Ray, Paul D.; Shea, Damian

Exposure to elevated levels of the toxic metals inorganic arsenic (iAs) and cadmium (Cd) represents a major global health problem. These metals often occur as mixtures in the environment, creating the potential for interactive or synergistic biological effects different from those observed in single exposure conditions. In the present study, environmental mixtures collected from two waste sites in China and comparable mixtures prepared in the laboratory were tested for toxicogenomic response in placental JEG-3 cells. These cells serve as a model for evaluating cellular responses to exposures during pregnancy. One of the mixtures was predominated by iAs and one bymore » Cd. Six gene biomarkers were measured in order to evaluate the effects from the metal mixtures using dose and time-course experiments including: heme oxygenase 1 (HO-1) and metallothionein isoforms (MT1A, MT1F and MT1G) previously shown to be preferentially induced by exposure to either iAs or Cd, and metal transporter genes aquaporin-9 (AQP9) and ATPase, Cu{sup 2+} transporting, beta polypeptide (ATP7B). There was a significant increase in the mRNA expression levels of ATP7B, HO-1, MT1A, MT1F, and MT1G in mixture-treated cells compared to the iAs or Cd only-treated cells. Notably, the genomic responses were observed at concentrations significantly lower than levels found at the environmental collection sites. These data demonstrate that metal mixtures increase the expression of gene biomarkers in placental JEG-3 cells in a synergistic manner. Taken together, the data suggest that toxic metals that co-occur may induce detrimental health effects that are currently underestimated when analyzed as single metals. - Highlights: • Toxicogenomic responses of environmental metal mixtures assessed • Induction of ATP7B, HO-1, MT1A, MT1F and MT1G by metal mixtures observed in placental cells • Higher gene induction in response to metal mixtures versus single metal treatments.« less

Asymmetric author-topic model for knowledge discovering of big data in toxicogenomics.

PubMed

Chung, Ming-Hua; Wang, Yuping; Tang, Hailin; Zou, Wen; Basinger, John; Xu, Xiaowei; Tong, Weida

2015-01-01

The advancement of high-throughput screening technologies facilitates the generation of massive amount of biological data, a big data phenomena in biomedical science. Yet, researchers still heavily rely on keyword search and/or literature review to navigate the databases and analyses are often done in rather small-scale. As a result, the rich information of a database has not been fully utilized, particularly for the information embedded in the interactive nature between data points that are largely ignored and buried. For the past 10 years, probabilistic topic modeling has been recognized as an effective machine learning algorithm to annotate the hidden thematic structure of massive collection of documents. The analogy between text corpus and large-scale genomic data enables the application of text mining tools, like probabilistic topic models, to explore hidden patterns of genomic data and to the extension of altered biological functions. In this paper, we developed a generalized probabilistic topic model to analyze a toxicogenomics dataset that consists of a large number of gene expression data from the rat livers treated with drugs in multiple dose and time-points. We discovered the hidden patterns in gene expression associated with the effect of doses and time-points of treatment. Finally, we illustrated the ability of our model to identify the evidence of potential reduction of animal use.

Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin.

PubMed

Zhou, Mi; Feng, Mei; Fu, Ling-Ling; Ji, Lin-Dan; Zhao, Jin-Shun; Xu, Jin

2016-11-01

Tributyltin (TBT) is one of the most widely used organotin biocides, which has severe endocrine-disrupting effects on marine species and mammals. Given that TBT accumulates at higher levels in the liver than in any other organ, and it acts mainly as a hepatotoxic agent, it is important to clearly delineate the hepatotoxicity of TBT. However, most of the available studies on TBT have focused on observations at the cellular level, while studies at the level of genes and proteins are limited; therefore, the molecular mechanisms of TBT-induced hepatotoxicity remains largely unclear. In the present study, we applied a toxicogenomic approach to investigate the effects of TBT on gene expression in the human normal liver cell line HL7702. Gene expression profiling identified the apoptotic pathway as the major cause of hepatotoxicity induced by TBT. Flow cytometry assays confirmed that medium- and high-dose TBT treatments significantly increased the number of apoptotic cells, and more cells underwent late apoptosis in the high-dose TBT group. The genes encoding heat shock proteins (HSPs), kinases and tumor necrosis factor receptors mediated TBT-induced apoptosis. These findings revealed novel molecular mechanisms of TBT-induced hepatotoxicity, and the current microarray data may also provide clues for future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Toxicogenomics in regulatory ecotoxicology

USGS Publications Warehouse

Ankley, Gerald T.; Daston, George P.; Degitz, Sigmund J.; Denslow, Nancy D.; Hoke, Robert A.; Kennedy, Sean W.; Miracle, Ann L.; Perkins, Edward J.; Snape, Jason; Tillitt, Donald E.; Tyler, Charles R.; Versteeg, Donald

2006-01-01

Recently, we have witnessed an explosion of different genomic approaches that, through a combination of advanced biological, instrumental, and bioinformatic techniques, can yield a previously unparalleled amount of data concerning the molecular and biochemical status of organisms. Fueled partially by large, well-publicized efforts such as the Human Genome Project, genomic research has become a rapidly growing topical area in multiple biological disciplines. Since 1999, when the term “toxicogenomics” was coined to describe the application of genomics to toxicology (1), a rapid increase in publications on the topic has occurred (Figure 1). The potential utility of toxicogenomics in toxicological research and regulatory activities has been the subject of scientific discussions and, as with any new technology, has evoked a wide range of opinion (2–6).

Targeted journal curation as a method to improve data currency at the Comparative Toxicogenomics Database

PubMed Central

Davis, Allan Peter; Johnson, Robin J.; Lennon-Hopkins, Kelley; Sciaky, Daniela; Rosenstein, Michael C.; Wiegers, Thomas C.; Mattingly, Carolyn J.

2012-01-01

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators read the scientific literature and manually curate a triad of chemical–gene, chemical–disease and gene–disease interactions. Typically, articles for CTD are selected using a chemical-centric approach by querying PubMed to retrieve a corpus containing the chemical of interest. Although this technique ensures adequate coverage of knowledge about the chemical (i.e. data completeness), it does not necessarily reflect the most current state of all toxicological research in the community at large (i.e. data currency). Keeping databases current with the most recent scientific results, as well as providing a rich historical background from legacy articles, is a challenging process. To address this issue of data currency, CTD designed and tested a journal-centric approach of curation to complement our chemical-centric method. We first identified priority journals based on defined criteria. Next, over 7 weeks, three biocurators reviewed 2425 articles from three consecutive years (2009–2011) of three targeted journals. From this corpus, 1252 articles contained relevant data for CTD and 52 752 interactions were manually curated. Here, we describe our journal selection process, two methods of document delivery for the biocurators and the analysis of the resulting curation metrics, including data currency, and both intra-journal and inter-journal comparisons of research topics. Based on our results, we expect that curation by select journals can (i) be easily incorporated into the curation pipeline to complement our chemical-centric approach; (ii) build content more evenly for chemicals, genes and diseases in CTD (rather than biasing data by chemicals-of-interest); (iii) reflect developing areas in environmental health and (iv) improve overall data currency for chemicals, genes and diseases. Database URL: http://ctdbase.org/ PMID:23221299

The toxicological application of transcriptomics and epigenomics in zebrafish and other teleosts.

PubMed

Williams, Tim D; Mirbahai, Leda; Chipman, J Kevin

2014-03-01

Zebrafish (Danio rerio) is one of a number of teleost fish species frequently employed in toxicology. Toxico-genomics determines global transcriptomic responses to chemical exposures and can predict their effects. It has been applied successfully within aquatic toxicology to assist in chemical testing, determination of mechanisms and environmental monitoring. Moreover, the related field of toxico-epigenomics, that determines chemical-induced changes in DNA methylation, histone modifications and micro-RNA expression, is emerging as a valuable contribution to understanding mechanisms of both adaptive and adverse responses. Zebrafish has proven a useful and convenient model species for both transcriptomic and epigenetic toxicological studies. Despite zebrafish's dominance in other areas of fish biology, alternative fish species are used extensively in toxico-genomics. The main reason for this is that environmental monitoring generally focuses on species native to the region of interest. We are starting to see advances in the integration of high-throughput screening, omics techniques and bioinformatics together with more traditional indicator endpoints that are relevant to regulators. Integration of such approaches with high-throughput testing of zebrafish embryos, leading to the discovery of adverse outcome pathways, promises to make a major contribution to ensuring the safety of chemicals in the environment.

Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.

PubMed

Kawamoto, Taisuke; Ito, Yuichi; Morita, Osamu; Honda, Hiroshi

2017-01-01

Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

Using Domestic and Free-Ranging Arctic Canid Models for Environmental Molecular Toxicology Research.

PubMed

Harley, John R; Bammler, Theo K; Farin, Federico M; Beyer, Richard P; Kavanagh, Terrance J; Dunlap, Kriya L; Knott, Katrina K; Ylitalo, Gina M; O'Hara, Todd M

2016-02-16

The use of sentinel species for population and ecosystem health assessments has been advocated as part of a One Health perspective. The Arctic is experiencing rapid change, including climate and environmental shifts, as well as increased resource development, which will alter exposure of biota to environmental agents of disease. Arctic canid species have wide geographic ranges and feeding ecologies and are often exposed to high concentrations of both terrestrial and marine-based contaminants. The domestic dog (Canis lupus familiaris) has been used in biomedical research for a number of years and has been advocated as a sentinel for human health due to its proximity to humans and, in some instances, similar diet. Exploiting the potential of molecular tools for describing the toxicogenomics of Arctic canids is critical for their development as biomedical models as well as environmental sentinels. Here, we present three approaches analyzing toxicogenomics of Arctic contaminants in both domestic and free-ranging canids (Arctic fox, Vulpes lagopus). We describe a number of confounding variables that must be addressed when conducting toxicogenomics studies in canid and other mammalian models. The ability for canids to act as models for Arctic molecular toxicology research is unique and significant for advancing our understanding and expanding the tool box for assessing the changing landscape of environmental agents of disease in the Arctic.

Risk assessment of Soulatrolide and Mammea (A/BA+A/BB) coumarins from Calophyllum brasiliense by a toxicogenomic and toxicological approach.

PubMed

Gomez-Verjan, J C; Estrella-Parra, E; Vazquez-Martinez, E R; Gonzalez-Sanchez, I; Guerrero-Magos, G; Mendoza-Villanueva, D; Isus, L; Alfaro, A; Cerbón-Cervantes, M; Aloy, P; Reyes-Chilpa, R

2016-05-01

Calophyllum brasiliense (Calophyllaceae) is a tropical rain forest tree distributed in Central and South America. It is an important source of tetracyclic dipyrano coumarins (Soulatrolide) and Mammea type coumarins. Soulatrolide is a potent inhibitor of HIV-1 reverse transcriptase and displays activity against Mycobacterium tuberculosis. Meanwhile, Mammea A/BA and A/BB, pure or as a mixture, are highly active against several human leukemia cell lines, Trypanosoma cruzi and Leishmania amazonensis. Nevertheless, there are few studies evaluating their safety profile. In the present work we performed toxicogenomic and toxicological analysis for both type of compounds. Soulatrolide, and the Mammea A/BA + A/BB mixture (2.1) were slightly toxic accordingly to Lorke assay classification (DL50 > 3000 mg/kg). After a short-term administration (100 mg/kg/daily, orally, 1 week) liver toxicogenomic analysis revealed 46 up and 72 downregulated genes for Mammea coumarins, and 665 up and 1077 downregulated genes for Soulatrolide. Gene enrichment analysis identified transcripts involved in drug metabolism for both compounds. In addition, network analysis through protein-protein interactions, tissue evaluation by TUNEL assay, and histological examination revealed no tissue damage on liver, kidney and spleen after treatments. Our results indicate that both type of coumarins displayed a safety profile, supporting their use in further preclinical studies to determine its therapeutic potential. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biomarkers of Exposure to Toxic Substances. Volume 2: Genomics: Unique Patterns of Differential Gene Expression and Pathway Perturbation Resulting from Exposure to Nephrotoxins with Regional Specific Toxicity

DTIC Science & Technology

2009-05-01

of chemicals agents . Changes in gene expression are among the most sensitive indicators of chemical exposure. Toxicogenomics, which is based on DNA...assessing gene expression changes and subsequently the mechanism of renal injury following exposure to nephrotoxins selected for their regional...Serine Treatment on Selected Serum Chemistry Parameters ........................ 8 Table 4: Effect of PUR Treatment on Selected Serum Chemistry

Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jackson, Anna Francina, E-mail: Francina.Jackson@hc-sc.gc.ca; Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa K1S 5B6; Williams, Andrew, E-mail: Andrew.Williams@hc-sc.gc.ca

2014-01-01

Furan is a chemical hepatocarcinogen in mice and rats. Its previously postulated cancer mode of action (MOA) is chronic cytotoxicity followed by sustained regenerative proliferation; however, its molecular basis is unknown. To this end, we conducted toxicogenomic analysis of B3C6F1 mouse livers following three week exposures to non-carcinogenic (0, 1, 2 mg/kg bw) or carcinogenic (4 and 8 mg/kg bw) doses of furan. We saw enrichment for pathways responsible for cytotoxicity: stress-activated protein kinase (SAPK) and death receptor (DR5 and TNF-alpha) signaling, and proliferation: extracellular signal-regulated kinases (ERKs) and TNF-alpha. We also noted the involvement of NF-kappaB and c-Jun inmore » response to furan, which are genes that are known to be required for liver regeneration. Furan metabolism by CYP2E1 produces cis-2-butene-1,4-dial (BDA), which is required for ensuing cytotoxicity and oxidative stress. NRF2 is a master regulator of gene expression during oxidative stress and we suggest that chronic NFR2 activity and chronic inflammation may represent critical transition events between the adaptive (regeneration) and adverse (cancer) outcomes. Another objective of this study was to demonstrate the applicability of toxicogenomics data in quantitative risk assessment. We modeled benchmark doses for our transcriptional data and previously published cancer data, and observed consistency between the two. Margin of exposure values for both transcriptional and cancer endpoints were also similar. In conclusion, using furan as a case study we have demonstrated the value of toxicogenomics data in elucidating dose-dependent MOA transitions and in quantitative risk assessment. - Highlights: • Global gene expression changes in furan-exposed mouse livers were analyzed. • A molecular mode of action for furan-induced hepatocarcinogenesis is proposed. • Key pathways include NRF2, SAPK, ERK and death receptor signaling. • Important roles for TNF-alpha, c-Jun, and NF-κB in tumorigenesis are proposed. • BMD and MoE values from transcriptional and apical data are compared.« less

Toxicogenomic analysis of N-nitrosomorpholine induced changes in rat liver: Comparison of genomic and proteomic responses and anchoring to histopathological parameters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oberemm, A., E-mail: axel.oberemm@bfr.bund.d; Ahr, H.-J.; Bannasch, P.

2009-12-01

A common animal model of chemical hepatocarcinogenesis was used to examine the utility of transcriptomic and proteomic data to identify early biomarkers related to chemically induced carcinogenesis. N-nitrosomorpholine, a frequently used genotoxic model carcinogen, was applied via drinking water at 120 mg/L to male Wistar rats for 7 weeks followed by an exposure-free period of 43 weeks. Seven specimens of each treatment group (untreated control and 120 mg/L N-nitrosomorpholine in drinking water) were sacrificed at nine time points during and after N-nitrosomorpholine treatment. Individual samples from the liver were prepared for histological and toxicogenomic analyses. For histological detection of preneoplasticmore » and neoplastic tissue areas, sections were stained using antibodies against the placental form of glutathione-S-transferase (GST-P). Gene and protein expression profiles of liver tissue homogenates were analyzed using RG-U34A Affymetrix rat gene chips and two-dimensional gel electrophoresis-based proteomics, respectively. In order to compare results obtained by histopathology, transcriptomics and proteomics, GST-P-stained liver sections were evaluated morphometrically, which revealed a parallel time course of the area fraction of preneoplastic lesions and gene plus protein expression patterns. On the transcriptional level, an increase of hepatic GST-P expression was detectable as early as 3 weeks after study onset. Comparing deregulated genes and proteins, eight species were identified which showed a corresponding expression profile on both expression levels. Functional analysis suggests that these genes and corresponding proteins may be useful as biomarkers of early hepatocarcinogenesis.« less

Alternatives to animal testing: research, trends, validation, regulatory acceptance.

PubMed

Huggins, Jane

2003-01-01

Current trends and issues in the development of alternatives to the use of animals in biomedical experimentation are discussed in this position paper. Eight topics are considered and include refinement of acute toxicity assays; eye corrosion/irritation alternatives; skin corrosion/irritation alternatives; contact sensitization alternatives; developmental/reproductive testing alternatives; genetic engineering (transgenic) assays; toxicogenomics; and validation of alternative methods. The discussion of refinement of acute toxicity assays is focused primarily on developments with regard to reduction of the number of animals used in the LD(50) assay. However, the substitution of humane endpoints such as clinical signs of toxicity for lethality in these assays is also evaluated. Alternative assays for eye corrosion/irritation as well as those for skin corrosion/irritation are described with particular attention paid to the outcomes, both successful and unsuccessful, of several validation efforts. Alternative assays for contact sensitization and developmental/reproductive toxicity are presented as examples of methods designed for the examination of interactions between toxins and somewhat more complex physiological systems. Moreover, genetic engineering and toxicogenomics are discussed with an eye toward the future of biological experimentation in general. The implications of gene manipulation for research animals, specifically, are also examined. Finally, validation methods are investigated as to their effectiveness, or lack thereof, and suggestions for their standardization and improvement, as well as implementation are reviewed.

EPA CHEMICAL PRIORITIZATION COMMUNITY OF PRACTICE.

EPA Science Inventory

IN 2005 THE NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY (NCCT) ORGANIZED EPA CHEMICAL PRIORITIATION COMMUNITY OF PRACTICE (CPCP) TO PROVIDE A FORUM FOR DISCUSSING THE UTILITY OF COMPUTATIONAL CHEMISTRY, HIGH-THROUGHPUT SCREENIG (HTS) AND VARIOUS TOXICOGENOMIC TECHNOLOGIES FOR CH...

ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (S)

EPA Science Inventory

ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry, bioactivity profiling and toxicogenomic data to predict potential for toxicity and prioritize limited testing resour...

Leveraging toxicogenomics data to build predictive biomarkers supporting AOP assessment

EPA Science Inventory

Chemicals induce liver cancer in rodents through well characterized adverse outcome pathways (AOPs) that include molecular initiating events (MIEs). In addition to genotoxicity, these include nongenotoxic mechanisms of cytotoxicity and receptor activation (aryl hydrocarbon recept...

THE TOXCAST PROGRAM FOR PRIORITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS

EPA Science Inventory

The United States Environmental Protection Agency (EPA) is developing methods for utilizing computational chemistry, high-throughput screening (HTS) and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources towards chemicals...

APPROACHES IN PROTEOMICS AND GENOMICS FOR ECO-TOXICOLOGY

EPA Science Inventory

A new area of scientific investigation, coined toxicogenomics, enables researchers to understand and study the interaction between the environment and inherited genetic characteristics. This understanding will be critical to fully appreciate the response of organisms to environm...

Toward a public toxicogenomics capability for supporting predictive toxicology: survey of current resources and chemical indexing of experiments in GEO and ArrayExpress.

PubMed

Williams-Devane, ClarLynda R; Wolf, Maritja A; Richard, Ann M

2009-06-01

A publicly available toxicogenomics capability for supporting predictive toxicology and meta-analysis depends on availability of gene expression data for chemical treatment scenarios, the ability to locate and aggregate such information by chemical, and broad data coverage within chemical, genomics, and toxicological information domains. This capability also depends on common genomics standards, protocol description, and functional linkages of diverse public Internet data resources. We present a survey of public genomics resources from these vantage points and conclude that, despite progress in many areas, the current state of the majority of public microarray databases is inadequate for supporting these objectives, particularly with regard to chemical indexing. To begin to address these inadequacies, we focus chemical annotation efforts on experimental content contained in the two primary public genomic resources: ArrayExpress and Gene Expression Omnibus. Automated scripts and extensive manual review were employed to transform free-text experiment descriptions into a standardized, chemically indexed inventory of experiments in both resources. These files, which include top-level summary annotations, allow for identification of current chemical-associated experimental content, as well as chemical-exposure-related (or "Treatment") content of greatest potential value to toxicogenomics investigation. With these chemical-index files, it is possible for the first time to assess the breadth and overlap of chemical study space represented in these databases, and to begin to assess the sufficiency of data with shared protocols for chemical similarity inferences. Chemical indexing of public genomics databases is a first important step toward integrating chemical, toxicological and genomics data into predictive toxicology.

Cross-Platform Toxicogenomics for the Prediction of Non-Genotoxic Hepatocarcinogenesis in Rat

PubMed Central

Metzger, Ute; Templin, Markus F.; Plummer, Simon; Ellinger-Ziegelbauer, Heidrun; Zell, Andreas

2014-01-01

In the area of omics profiling in toxicology, i.e. toxicogenomics, characteristic molecular profiles have previously been incorporated into prediction models for early assessment of a carcinogenic potential and mechanism-based classification of compounds. Traditionally, the biomarker signatures used for model construction were derived from individual high-throughput techniques, such as microarrays designed for monitoring global mRNA expression. In this study, we built predictive models by integrating omics data across complementary microarray platforms and introduced new concepts for modeling of pathway alterations and molecular interactions between multiple biological layers. We trained and evaluated diverse machine learning-based models, differing in the incorporated features and learning algorithms on a cross-omics dataset encompassing mRNA, miRNA, and protein expression profiles obtained from rat liver samples treated with a heterogeneous set of substances. Most of these compounds could be unambiguously classified as genotoxic carcinogens, non-genotoxic carcinogens, or non-hepatocarcinogens based on evidence from published studies. Since mixed characteristics were reported for the compounds Cyproterone acetate, Thioacetamide, and Wy-14643, we reclassified these compounds as either genotoxic or non-genotoxic carcinogens based on their molecular profiles. Evaluating our toxicogenomics models in a repeated external cross-validation procedure, we demonstrated that the prediction accuracy of our models could be increased by joining the biomarker signatures across multiple biological layers and by adding complex features derived from cross-platform integration of the omics data. Furthermore, we found that adding these features resulted in a better separation of the compound classes and a more confident reclassification of the three undefined compounds as non-genotoxic carcinogens. PMID:24830643

DEVELOPMENTAL TOXICOGENOMIC STUDIES OF PFOA AND PFOS IN MICE.

EPA Science Inventory

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are developmentally toxic in rodents. To better understand the mechanism(s) associated with this toxicity, we have conducted transcript profiling in mice. In an initial study, pregnant animals were dosed througho...

Toxicogenomics Applied to Ecotoxicology

EPA Science Inventory

This chapter focuses on evaluation of the current practice of ecotoxicogenomics, less than a decade after the term was coined, as the field continues to evolve. We describe major applications of genomic approaches to define modes/mechanisms of action and derive biologically-base...

CELLULAR UPTAKE AND TOXICITY OF DENDRITIC NANOMATERIALS: AN INTEGRATED PHYSICOCHEMICAL AND TOXICOGENOMICS STUDY

EPA Science Inventory

The successful completion of this project is expected to provide industry with critical data and predictive tools needed to assess the health and environmental impact of dendritic nanomaterials such as EDA core PAMAM dendrimers.

EPA'S TOXCAST PROGRAM FOR PREDICTING HAZARD AND PRIORITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS

EPA Science Inventory

EPA is developing methods for utilizing computational chemistry, high-throughput screening (HTS) and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources towards chemicals that likely represent the greatest hazard to human ...

Pathway-Based Concentration Response Profiles from Toxicogenomics Data

EPA Science Inventory

Microarray analysis of gene expression of in vitro systems could be a powerful tool for assessing chemical hazard. Differentially expressed genes specific to cells, chemicals, and concentrations can be organized into molecular pathways that inform mode of action. An important par...

TOXICOGENOMIC DISSECTION OF RODENT LIVER TRANSCRIPT PROFILES AFTER EXPOSURE TO PERFLUOROALKYL ACIDS

EPA Science Inventory

Exposure to peroxisome proliferator chemicals (PPC) leads to alterations in the balance between hepatocyte growth and apoptosis, increases in liver to body weight ratios and liver tumors. The perfluoroalkyl acids including perfluorooctanoate (PFOA) and perfluorooctane sulfonate (...

Toxicogenomic profiling of perfluorononanoic acid in wild-type and PPARa-null mice

EPA Science Inventory

Perfluorononanoic acid (PFNA) is a ubiquitous environmental contaminant and a developmental toxicant in laboratory animals. Like other perfluoroalkyl acids (PFAAs) such as perfluorooctane sulfonate (PFOA) and perfluoroalkyl acid (PFOS), PFNA is a known activator ofperoxisome prol...

THE MAQC PROJECT: ESTABLISHING QC METRICS AND THRESHOLDS FOR MICROARRAY QUALITY CONTROL

EPA Science Inventory

Microarrays represent a core technology in pharmacogenomics and toxicogenomics; however, before this technology can successfully and reliably be applied in clinical practice and regulatory decision-making, standards and quality measures need to be developed. The Microarray Qualit...

Toxicogenomic effects common to triazole antifungals and conserved between rats and humans.

PubMed

Goetz, Amber K; Dix, David J

2009-07-01

The triazole antifungals myclobutanil, propiconazole and triadimefon cause varying degrees of hepatic toxicity and disrupt steroid hormone homeostasis in rodent in vivo models. To identify biological pathways consistently modulated across multiple timepoints and various study designs, gene expression profiling was conducted on rat livers from three separate studies with triazole treatment groups ranging from 6 h after a single oral gavage exposure, to prenatal to adult exposures via feed. To explore conservation of responses across species, gene expression from the rat liver studies were compared to in vitro data from rat and human primary hepatocytes exposed to the triazoles. Toxicogenomic data on triazoles from 33 different treatment groups and 135 samples (microarrays) identified thousands of probe sets and dozens of pathways differentially expressed across time, dose, and species--many of these were common to all three triazoles, or conserved between rodents and humans. Common and conserved pathways included androgen and estrogen metabolism, xenobiotic metabolism signaling through CAR and PXR, and CYP mediated metabolism. Differentially expressed genes included the Phase I xenobiotic, fatty acid, sterol and steroid metabolism genes Cyp2b2 and CYP2B6, Cyp3a1 and CYP3A4, and Cyp4a22 and CYP4A11; Phase II conjugation enzyme genes Ugt1a1 and UGT1A1; and Phase III ABC transporter genes Abcb1 and ABCB1. Gene expression changes caused by all three triazoles in liver and hepatocytes were concentrated in biological pathways regulating lipid, sterol and steroid homeostasis, identifying a potential common mode of action conserved between rodents and humans. Modulation of hepatic sterol and steroid metabolism is a plausible mode of action for changes in serum testosterone and adverse reproductive outcomes observed in rat studies, and may be relevant to human risk assessment.

APPLICATION OF GENOMICS TO REPRODUCTIVE TOXICOLOGY: WORKING FROM RESEARCH TOWARDS RISK ASSESSMENT

EPA Science Inventory

Genomic technologies are available to examine the expression of thousands of genes simultaneously. These technologies represent a paradigm shift from single-gene approaches fundamentally altering the practice of toxicology. The goal of toxicogenomic studies is to improve human ...

Temporal and Dose-response Pathway Analysis for Predicting Chronic Chemical Toxicity

EPA Science Inventory

Current challenges facing chemical risk assessment are the time and resources required to meet the data standards necessary for a published assessment and the incorporation of modern biological information. The integration of toxicogenomics into the risk assessment paradigm may ...

THE FUTURE OF TOXICOGENOMICS

EPA Science Inventory

Toxicology has classically been seen as the science of poisons. In the modern world, however, it has evolved into a composite of related, but distinct disciplines, which together seek to understand how chemicals of all kinds - both man-made and natural - affect human health and t...

THE MAQC (MICROARRAY QUALITY CONTROL) PROJECT: CALIBRATED RNA SAMPLES, REFERENCE DATASETS, AND QC METRICS AND THRESHOLDS

EPA Science Inventory

FDAs Critical Path Initiative identifies pharmacogenomics and toxicogenomics as key opportunities in advancing medical product development and personalized medicine, and the Guidance for Industry: Pharmacogenomic Data Submissions has been released. Microarrays represent a co...

ExpoCast: Exposure Science for Prioritization and Toxicity Testing (S)

EPA Science Inventory

The US EPA is completing the Phase I pilot for a chemical prioritization research program, called ToxCast. Here EPA is developing methods for using computational chemistry, high-throughput screening, and toxicogenomic technologies to predict potential toxicity and prioritize limi...

ExpoCast: Exposure Science for Prioritization and Toxicity Testing

EPA Science Inventory

The US EPA is completing the Phase I pilot for a chemical prioritization research program, called ToxCastTM. Here EPA is developing methods for using computational chemistry, high-throughput screening, and toxicogenomic technologies to predict potential toxicity and prioritize l...

Effects of lithium on growth, maturation, reproduction and gene expression in the nematode Caenorhabditis elegans.

PubMed

Inokuchi, Ayako; Yamamoto, Ryoko; Morita, Fumiyo; Takumi, Shota; Matsusaki, Hiromi; Ishibashi, Hiroshi; Tominaga, Nobuaki; Arizono, Koji

2015-09-01

Lithium (Li) has been widely used to treat bipolar disorder, and industrial use of Li has been increasing; thus, environmental pollution and ecological impacts of Li have become a concern. This study was conducted to clarify the potential biological effects of LiCl and Li(2)CO(3) on a nematode, Caenorhabditis elegans as a model system for evaluating soil contaminated with Li. Exposure of C. elegans to LiCl and Li(2)CO(3) decreased growth/maturation and reproduction. The lowest observed effect concentrations for growth, maturation and reproduction were 1250, 313 and 10 000 µm, respectively, for LiCl and 750, 750 and 3000 µm, respectively, for Li(2)CO(3). We also investigated the physiological function of LiCl and LiCO(3) in C. elegans using DNA microarray analysis as an eco-toxicogenomic approach. Among approximately 300 unique genes, including metabolic genes, the exposure to 78 µm LiCl downregulated the expression of 36 cytochrome P450, 16 ABC transporter, 10 glutathione S-transferase, 16 lipid metabolism and two vitellogenin genes. On the other hand, exposure to 375 µm Li(2)CO(3) downregulated the expression of 11 cytochrome P450, 13 ABC transporter, 13 lipid metabolism and one vitellogenin genes. No gene was upregulated by LiCl or Li(2)CO(3). These results suggest that LiCl and Li(2)CO(3) potentially affect the biological and physiological function in C. elegans associated with alteration of the gene expression such as metabolic genes. Our data also provide experimental support for the utility of toxicogenomics by integrating gene expression profiling into a toxicological study of an environmentally important organism such as C. elegans. Copyright © 2015 John Wiley & Sons, Ltd.

A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure

PubMed Central

Luoma, Sarah E.; St. Armour, Genevieve E.; Thakkar, Esha

2017-01-01

The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs) associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system. PMID:28732062

Application of Toxicogenomics in Decision Making in Ecological and Human Health Risk Assessment

EPA Science Inventory

Uncertainties in risk assessment arise from sparse or inadequate data including gaps in our understanding of mode of action, the exposure-dose-response pathway, cross-species toxicokinetic and toxicodynamic information, and/or exposure data. There is an expectation that toxicogen...

ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (Developing Predictive Bioactivity Signatures from ToxCasts HTS Data)

EPA Science Inventory

ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry, bioactivity profiling and toxicogenomic data to predict potential for toxicity and prioritize limited testing resour...

Toward a Checklist for Exchange and Interpretation of Data froma Toxicology Study

EPA Science Inventory

With the advent of toxicogenomics came the need to share data across interdisciplinary teams and to deposit data associated with publications into public data repositories. Within a single institution, many variables associated with a study are standardized, for instance diet, an...

Sources of variation in baseline gene expression levels from toxicogenomics study control animals

EPA Science Inventory

The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization ofvariance due to individual, environmental, and technical factors. Meta-analysis ofmicroarray data from untreated or vehicle-treated animals within the con...

Gene Expression Profiling in Liver and Testis of Rats to Characterize the Toxicity of Triazole Fungicides

EPA Science Inventory

Four triazole fungicides were studied using toxicogenomic techniques to identify potential mechanisms of action. Adult male Sprague-Dawley rats were dosed for 14 days by gavage with fluconazole, myclobutanil, propiconazole, or triadimefon. Following exposure, serum was collected ...

GENE EXPRESSION PROFILING IN LIVER AND TESTIS OF RATS TO CHARACTERIZE THE TOXICITY OF TRIAZOLE FUNGICIDES.

EPA Science Inventory

Four triazole fungicides were studied using toxicogenomic techniques to identify potential mechanisms of action. Adult male Sprague-Dawley rats were dosed for 14 days by gavage with fluconazole, myclobutanil, propiconazole, or triadimefon. Following exposure, serum was collected ...

Transcriptomic Dose-Response Analysis for Mode of Action and Risk Assessment

EPA Science Inventory

Microarray and RNA-seq technologies can play an important role in assessing the health risks associated with environmental exposures. The utility of gene expression data to predict hazard has been well documented. Early toxicogenomics studies used relatively high, single doses w...

TOXICOGENOMICS AS A TOOL TO ASSESS EXPOSURE OF FISH TO ENVIRONMENTAL POLLUTANTS

EPA Science Inventory

Molecular biological techniques such as gene arrays and quantitative real-time PCR are becoming important tools to study alterations in normal gene expression in fish and other wildlife exposed to such pollutants as endocrine disrupting chemicals (EDCs). An important function fo...

Integrating Omic Technologies into Aquatic Ecological Risk Assessment and Environmental Monitoring: Hurdles, Achievements and Future Outlook

EPA Science Inventory

In this commentary we present the findings from an international consortium on fish toxicogenomics sponsored by the UK Natural Environment Research Council (NERC) with an objective of moving omic technologies into chemical risk assessment and environmental monitoring. Objectiv...

Integrating Omic Technologies into Aquatic Ecological Risk Assessment and Environmental Monitoring: Hurdles, Achievements and Future Outlook

EPA Science Inventory

Background: In this commentary we present the findings from an international consortium on fish toxicogenomics sponsored by the UK Natural Environment Research Council (NERC) with a remit of moving omic technologies into chemical risk assessment and environmental monitoring. Obj...

Ecotoxicogenomics to Support Ecological Risk Assessment: A Case Study with Bisphenol A in Fish

EPA Science Inventory

Toxicogenomic approaches are being increasingly applied in the field of ecotoxicology. Given the growing availability of ecotoxicogenomic data, the Agency and the broader scientific community are actively engaged in considering how best to use those data to support ecological ris...

Utilizing Toxicogenomic Data to Understand Chemical Mechanism of Action in Risk Assessment

EPA Science Inventory

A recent National Academy of Sciences report pointed to the strong potential for genomic technologies to contribute to the risk assessment process. The report, however, also acknowledged that neither has the full impact of genomic technology been realized nor has it been broadly ...

SOURCES OF VARIABILITY IN BASELINE GENE EXPRESSION IN RAT LIVER AND KIDNEY

EPA Science Inventory

Toxicogenomic studies are typically variable in design, but the impact of variations in study design and conduct on control animal gene expression has not been well characterized. A working group of the Health and Environmental Sciences Institute (HESI) Technical Committee on the...

Wiki-based Data Management System for Toxicogenomics

EPA Science Inventory

We are developing a data management system to enable systems-based toxicology at the US EPA. This is built upon the WikiLIMS platform and is capabale of housing not just genomics data but also a wide variety of toxicology data and associated experimental design information. Thi...

An Approach for Integrating Toxicogenomic Data in Risk Assessment: The Dibutyl Phthalate Case Study

EPA Science Inventory

An approach for evaluating and integrating genomic data in chemical risk assessment was developed based on the lessons learned from performing a case study for the chemical dibutyl phthalate. A case study prototype approach was first developed in accordance with EPA guidance and ...

TOXICOGENOMIC ANALYSIS OF TOLUENE EXPOSURE AT 3 AGES IN BROWN NORWAY RATS.

EPA Science Inventory

A major concern in assessing toxicity to environmental exposures is differential

susceptibility in subsets of the population. Aging adults, who comprise the fastest

growing segment of the population, may possess a greater sensitivity due to changes in

metabol...

NEW TECHNOLOGIES TO SOLVE OLD PROBLEMS AND ADDRESS ISSUES IN RISK ASSESSMENT

EPA Science Inventory

Appropriate utilization of data is an ongoing concern of the regulated industries and the agencies charged with assessing safety or risk. An area of current interest is the possibility that toxicogenomics will enhance our ability to develop higher or high-throughput models for pr...

PRESENTATION TYPE: Round Table Discussion (80 minutes) TITLE: Unlocking the ‘Omics Archive: Enabling Toxicogenomic/Proteomic Investigation from Archival Samples

EPA Science Inventory

Formalin fixation and paraffin embedding (FFPE) is a cross-industry gold standard for preparing nonclinical and clinical samples for histopathological assessment which preserves tissue architecture and enables storage of tissue in archival banks. These archival banks are an untap...

BIOMONITORING THE TOXICOGENOMIC RESPONSE TO ENDOCRINE DISRUPTING CHEMICALS IN HUMANS, LABORATORY SPECIES AND WILDLIFE

EPA Science Inventory

With the advent of sequence information for entire eukaryotic genomes, it is now possible to analyze gene expression on a genomic scale. The primary tool for genomic analysis of gene expression is the gene microarray. We have used commercially available and custom cDNA microarray...

KIDNEY TOXICOGENOMICS OF CHRONIC POTASSIUM BROMATE EXPOSURE IN F344 MALE RAT

EPA Science Inventory

Potassium bromate (KBrO3), used in both the food and cosmetics industry, and a drinking water disinfection by-product, is a nephrotoxic compound and rodent carcinogen. To gain insight into the carcinogenic mechanism of action and provide possible biomarkers of KBrO3 exposure, the...

KIDNEY TOXICOGENOMICS OF ACUTE SODIUM AND POTASSIUM BROMATE EXPOSURE IN F344 MALE RAT

EPA Science Inventory

Bromate, used in both the food and cosmetics industry, is a drinking water disinfection by-product that is nephrotoxic and carcinogenic to rodents. To gain insight into the carcinogenic mechanism of action, identify possible biomarkers of exposure, and determine if the cation, po...

DIFFERENTIAL EXPRESSION OF RETINOIC ACID BIOSYNTHETIC AND METABOLISM GENES IN LIVERS FROM MICE TREATED WITH HEPATOTUMORIGENIC AND NON-HEPATOTUMORIGENIC CONAZOLES

EPA Science Inventory

Conazoles are fungicides used in crop protection and as pharmaceuticals. Triadimefon and propiconazole are hepatotumorigenic in mice, while myclobutanil is not. Previous toxicogenomic studies suggest that alteration of the retinoic acid metabolism pathway may play a key event in ...

Three Conazoles Increase Hepatic Microsomal Retinoic Acid Metabolism and Decrease Mouse Hepatic Retinoic Acid Levels In Vivo

EPA Science Inventory

Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with...

Recommended approaches in the application of toxicogenomics to derive points of departure for chemical risk assessment

EPA Science Inventory

ABSTRACT:Only a fraction of chemicals in commerce have been fully assessed for their potential hazards to human health due to difficulties involved in conventional regulatory tests. It has recently been proposed that quantitative transcriptomic data can be used to determine bench...

Use of Toxicogenomic Data at the US EPA to Inform the Cancer Asessment of the Fungicide Propiconazole

EPA Science Inventory

The Office of Pesticide Programs’ (OPP) routinely utilizes mode of action (MOA) data when available for pesticide cancer risk assessment. A MOA analysis incorporates data from required toxicology studies and supplemental mechanistic data. These data are evaluated to identify a ...

Application of Toxicogenomics to Develop a Mode of Action for a Carcinogenic Conazole Fungicide

EPA Science Inventory

Conazoles are a common class of fungicides used to control fungal growth in the environment and in humans. Some of these agents have adverse toxicological outcomes in mammals as carcinogens, reproductive toxins, and hepatotoxins. We coupled the results from genomic analyses with ...

CHARACTERIZATION OF CYPS IN THE METABOLISM OF ALL TRANS RETINOIC ACID BY LIVER MICROSOMES FROM MICE TREATED WITH CONAZOLES

EPA Science Inventory

Conazoles are fungicides used in crop protection and as pharmaceuticals. Triadimefon and propiconazole are hepatotumorigenic in mice, while myclobutanil is not. Previous toxicogenomic studies suggest that alteration of the retinoic acid metabolism pathway may involve in conazole-...

The ToxCast Pathway Database for Identifying Toxicity Signatures and Potential Modes of Action from Chemical Screening Data

EPA Science Inventory

The U.S. Environmental Protection Agency (EPA), through its ToxCast program, is developing predictive toxicity approaches that will use in vitro high-throughput screening (HTS), high-content screening (HCS) and toxicogenomic data to predict in vivo toxicity phenotypes. There are ...

Cord blood gene expression supports that prenatal exposure to perfluoroalkyl substances causes depressed immune functionality in early childhood.

PubMed

Pennings, Jeroen L A; Jennen, Danyel G J; Nygaard, Unni C; Namork, Ellen; Haug, Line S; van Loveren, Henk; Granum, Berit

2016-01-01

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a class of synthetic compounds that have widespread use in consumer and industrial applications. PFAS are considered environmental pollutants that have various toxic properties, including effects on the immune system. Recent human studies indicate that prenatal exposure to PFAS leads to suppressed immune responses in early childhood. In this study, data from the Norwegian BraMat cohort was used to investigate transcriptomics profiles in neonatal cord blood and their association with maternal PFAS exposure, anti-rubella antibody levels at 3 years of age and the number of common cold episodes until 3 years. Genes associated with PFAS exposure showed enrichment for immunological and developmental functions. The analyses identified a toxicogenomics profile of 52 PFAS exposure-associated genes that were in common with genes associated with rubella titers and/or common cold episodes. This gene set contains several immunomodulatory genes (CYTL1, IL27) as well as other immune-associated genes (e.g. EMR4P, SHC4, ADORA2A). In addition, this study identified PPARD as a PFAS toxicogenomics marker. These markers can serve as the basis for further mechanistic or epidemiological studies. This study provides a transcriptomics connection between prenatal PFAS exposure and impaired immune function in early childhood and supports current views on PPAR- and NF-κB-mediated modes of action. The findings add to the available evidence that PFAS exposure is immunotoxic in humans and support regulatory policies to phase out these substances.

Analysis of baseline gene expression levels from toxicogenomics study control animals to identify sources of variation and predict responses to chemicals

EPA Science Inventory

The use of gene expression profiling to predict chemical mode of action would be enhanced by better characterization of variance due to individual, environmental, and technical factors. Meta-analysis of microarray data from untreated or vehicle-treated animals within the control ...

Toxicogenomic assessment of 6-OH-BDE47 induced developmental toxicity in chicken embryo

EPA Science Inventory

Hydroxylated and methoxylated polybrominated diphenyl ethers (OH-/MeO-PBDEs) are analogs of PBDEs with hundreds of possible structures and many of them can activate aryl hydrocarbon receptor (AhR), however, the in vivo evidence on the toxicity of OH-/MeO-PBDEs are still very limi...

ALTERATIONS IN A11 TRANS RETINOIC ACID METABOLISM IN LIVER MICROSOMES FROM MICE TREATED WITH HEPATOTUMORIGENIC AND NON-HEPATOTUMORIGENIC CONAZOLES

EPA Science Inventory

Conazoles are fungicides used in crop protection and as pharmaceuticals. Triadimefon and propiconazole are hepatotumorigenic in mice, while myclobutanil is not. Previous toxicogenomic studies suggest that alteration of the retinoic acid metabolism pathway may be a key event in co...

TOXICOGENOMIC ANALYSIS INCORPORATING OPERON-TRANSCRIPTIONAL COUPLING AND TOXICANT CONCENTRATRION-EXPRESSION RESPONSE: Analysis of MX-Treated Salmonella

EPA Science Inventory

What is the study? This study is the first to use microarray analysis in the Ames strains of Salmonella. The microarray chips were custom-designed for this study and are not commercially available, and we evaluated the well-studied drinking water mutagen, MX. Because much inform...

Toward a Public Toxicogenomics Capability for Supporting ...

EPA Pesticide Factsheets

A publicly available toxicogenomics capability for supporting predictive toxicology and meta-analysis depends on availability of gene expression data for chemical treatment scenarios, the ability to locate and aggregate such information by chemical, and broad data coverage within chemical, genomics, and toxicological information domains. This capability also depends on common genomics standards, protocol description, and functional linkages of diverse public Internet data resources. We present a survey of public genomics resources from these vantage points and conclude that, despite progress in many areas, the current state of the majority of public microarray databases is inadequate for supporting these objectives, particularly with regard to chemical indexing. To begin to address these inadequacies, we focus chemical annotation efforts on experimental content contained in the two primary public genomic resources: ArrayExpress and Gene Expression Omnibus. Automated scripts and extensive manual review were employed to transform free-text experiment descriptions into a standardized, chemically indexed inventory of experiments in both resources. These files, which include top-level summary annotations, allow for identification of current chemical-associated experimental content, as well as chemical-exposure–related (or

An Approach to Using Toxicogenomic Data in US EPA Human ...

EPA Pesticide Factsheets

This draft report is a description of an approach to evaluate genomic data for use in risk assessment and a case study to illustrate the approach. The dibutyl phthalate (DBP) case study example focuses on male reproductive developmental effects and the qualitative application of the available genomic data. The case study presented in this draft document is a separate activity from any of the ongoing IRIS human health assessments for the phthalates. This draft report is a description of an approach to evaluate genomic data for use in risk assessment and a case study to illustrate the approach. The dibutyl phthalate (DBP) case study example focuses on male reproductive developmental effects and the qualitative application of the available genomic data.

A CTD–Pfizer collaboration: manual curation of 88 000 scientific articles text mined for drug–disease and drug–phenotype interactions

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; Roberts, Phoebe M.; King, Benjamin L.; Lay, Jean M.; Lennon-Hopkins, Kelley; Sciaky, Daniela; Johnson, Robin; Keating, Heather; Greene, Nigel; Hernandez, Robert; McConnell, Kevin J.; Enayetallah, Ahmed E.; Mattingly, Carolyn J.

2013-01-01

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88 629 articles relating over 1 200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 2 54 173 toxicogenomic interactions (1 52 173 chemical–disease, 58 572 chemical–gene, 5 345 gene–disease and 38 083 phenotype interactions). All chemical–gene–disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer’s text-mining process to collate the articles, and CTD’s curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug–disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades’ worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/ PMID:24288140

A CTD-Pfizer collaboration: manual curation of 88,000 scientific articles text mined for drug-disease and drug-phenotype interactions.

PubMed

Davis, Allan Peter; Wiegers, Thomas C; Roberts, Phoebe M; King, Benjamin L; Lay, Jean M; Lennon-Hopkins, Kelley; Sciaky, Daniela; Johnson, Robin; Keating, Heather; Greene, Nigel; Hernandez, Robert; McConnell, Kevin J; Enayetallah, Ahmed E; Mattingly, Carolyn J

2013-01-01

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88,629 articles relating over 1,200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 254,173 toxicogenomic interactions (152,173 chemical-disease, 58,572 chemical-gene, 5,345 gene-disease and 38,083 phenotype interactions). All chemical-gene-disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer's text-mining process to collate the articles, and CTD's curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug-disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades' worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/

An approach for integrating toxicogenomic data in risk assessment: The dibutyl phthalate case study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Euling, Susan Y., E-mail: euling.susan@epa.gov; Thompson, Chad M.; Chiu, Weihsueh A.

An approach for evaluating and integrating genomic data in chemical risk assessment was developed based on the lessons learned from performing a case study for the chemical dibutyl phthalate. A case study prototype approach was first developed in accordance with EPA guidance and recommendations of the scientific community. Dibutyl phthalate (DBP) was selected for the case study exercise. The scoping phase of the dibutyl phthalate case study was conducted by considering the available DBP genomic data, taken together with the entire data set, for whether they could inform various risk assessment aspects, such as toxicodynamics, toxicokinetics, and dose–response. A descriptionmore » of weighing the available dibutyl phthalate data set for utility in risk assessment provides an example for considering genomic data for future chemical assessments. As a result of conducting the scoping process, two questions—Do the DBP toxicogenomic data inform 1) the mechanisms or modes of action?, and 2) the interspecies differences in toxicodynamics?—were selected to focus the case study exercise. Principles of the general approach include considering the genomics data in conjunction with all other data to determine their ability to inform the various qualitative and/or quantitative aspects of risk assessment, and evaluating the relationship between the available genomic and toxicity outcome data with respect to study comparability and phenotypic anchoring. Based on experience from the DBP case study, recommendations and a general approach for integrating genomic data in chemical assessment were developed to advance the broader effort to utilize 21st century data in risk assessment. - Highlights: • Performed DBP case study for integrating genomic data in risk assessment • Present approach for considering genomic data in chemical risk assessment • Present recommendations for use of genomic data in chemical risk assessment.« less

Developing Toxicogenomics as a Research Tool by Applying Benchmark Dose-Response Modeling to inform Chemical Mode of Action and Tumorigenic Potency

EPA Science Inventory

ABSTRACT Results of global gene expression profiling after short-term exposures can be used to inform tumorigenic potency and chemical mode of action (MOA) and thus serve as a strategy to prioritize future or data-poor chemicals for further evaluation. This compilation of cas...

Evaluation of In Vitro Biotransformation Using HepaRG Cells to Improve High-Throughput Chemical Hazard Prediction: A Toxicogenomics Analysis (SOT)

EPA Science Inventory

The US EPA’s ToxCast program has generated a wealth of data in >600 in vitro assayson a library of 1060 environmentally relevant chemicals and failed pharmaceuticals to facilitate hazard identification. An inherent criticism of many in vitro-based strategies is the inability of a...

A review of toxicity and mechanisms of individual and mixtures of heavy metals in the environment.

PubMed

Wu, Xiangyang; Cobbina, Samuel J; Mao, Guanghua; Xu, Hai; Zhang, Zhen; Yang, Liuqing

2016-05-01

The rational for the study was to review the literature on the toxicity and corresponding mechanisms associated with lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As), individually and as mixtures, in the environment. Heavy metals are ubiquitous and generally persist in the environment, enabling them to biomagnify in the food chain. Living systems most often interact with a cocktail of heavy metals in the environment. Heavy metal exposure to biological systems may lead to oxidation stress which may induce DNA damage, protein modification, lipid peroxidation, and others. In this review, the major mechanism associated with toxicities of individual metals was the generation of reactive oxygen species (ROS). Additionally, toxicities were expressed through depletion of glutathione and bonding to sulfhydryl groups of proteins. Interestingly, a metal like Pb becomes toxic to organisms through the depletion of antioxidants while Cd indirectly generates ROS by its ability to replace iron and copper. ROS generated through exposure to arsenic were associated with many modes of action, and heavy metal mixtures were found to have varied effects on organisms. Many models based on concentration addition (CA) and independent action (IA) have been introduced to help predict toxicities and mechanisms associated with metal mixtures. An integrated model which combines CA and IA was further proposed for evaluating toxicities of non-interactive mixtures. In cases where there are molecular interactions, the toxicogenomic approach was used to predict toxicities. The high-throughput toxicogenomics combines studies in genetics, genome-scale expression, cell and tissue expression, metabolite profiling, and bioinformatics.

Morphological and cytohistochemical evaluation of renal effects of cadmium-doped silica nanoparticles given intratracheally to rat

NASA Astrophysics Data System (ADS)

Coccini, T.; Roda, E.; Barni, S.; Manzo, L.

2013-04-01

Renal morphological parameters were determined in rats intratracheally instilled with model cadmium-containing silica nanoparticles (Cd-SiNPs, 1mg/rat), also exploring whether their potential modifications would be associated with toxicogenomic changes. Cd-SiNP effects, evaluated 7 and 30 days post-exposure, were assessed by (i) histopathology (Haematoxylin/Eosin Staining), (ii) characterization of apoptotic features by TUNEL staining. Data were compared with those obtained by CdCl2 (400μg/rat), SiNPs (600μg/rat), 0.1 ml saline. Area-specific cell apoptosis was observed in all treatment groups: cortex and inner medulla were the most affected regions. Apoptotic changes were apparent at 7 days post-exposure in both areas, and were still observable in inner medulla 30 days after treatment. Increase in apoptotic frequency was more pronounced in Cd-SiNP-treated animals compared to either CdCl2 or SiNPs. Histological findings showed comparable alterations in the renal glomerular (cortex) architecture occurring in all treatment groups at both time-points considered. The glomeruli appeared often collapsed, showing condensed, packed mesangial and endothelial cells. Oedematous haemorrhagic glomeruli were also observed in Cd-SiNPs-treated animals. Bare SiNPs caused morphological and apoptotic changes without modifying the renal gene expression profile. These findings support the concept that multiple assays and an integrated testing strategy should be recommended to characterize toxicological responses to nanoparticles in mammalian systems.

Gene expression analysis in rat lungs after intratracheal exposure to nanoparticles doped with cadmium

NASA Astrophysics Data System (ADS)

Coccini, Teresa; Fabbri, Marco; Roda, Elisa; Grazia Sacco, Maria; Manzo, Luigi; Gribaldo, Laura

2011-07-01

Silica nanoparticles (NPs) incorporating cadmium (Cd) have been developed for a range of potential application including drug delivery devices. Occupational Cd inhalation has been associated with emphysema, pulmonary fibrosis and lung tumours. Mechanistically, Cd can induce oxidative stress and mediate cell-signalling pathways that are involved in inflammation.This in vivo study aimed at investigating pulmonary molecular effects of NPs doped with Cd (NP-Cd, 1 mg/animal) compared to soluble CdCl2 (400 μg/animal), in Sprague Dawley rats treated intra-tracheally, 7 and 30 days after administration. NPs of silica containing Cd salt were prepared starting from commercial nano-size silica powder (HiSil™ T700 Degussa) with average pore size of 20 nm and surface area of 240 m2/g. Toxicogenomic analysis was performed by the DNA microarray technology (using Agilent Whole Rat Genome Microarray 4×44K) to evaluate changes in gene expression of the entire genome. These findings indicate that the whole genome analysis may represent a valuable approach to assess the whole spectrum of biological responses to cadmium containing nanomaterials.

A Pipeline for High-Throughput Concentration Response Modeling of Gene Expression for Toxicogenomics

PubMed Central

House, John S.; Grimm, Fabian A.; Jima, Dereje D.; Zhou, Yi-Hui; Rusyn, Ivan; Wright, Fred A.

2017-01-01

Cell-based assays are an attractive option to measure gene expression response to exposure, but the cost of whole-transcriptome RNA sequencing has been a barrier to the use of gene expression profiling for in vitro toxicity screening. In addition, standard RNA sequencing adds variability due to variable transcript length and amplification. Targeted probe-sequencing technologies such as TempO-Seq, with transcriptomic representation that can vary from hundreds of genes to the entire transcriptome, may reduce some components of variation. Analyses of high-throughput toxicogenomics data require renewed attention to read-calling algorithms and simplified dose–response modeling for datasets with relatively few samples. Using data from induced pluripotent stem cell-derived cardiomyocytes treated with chemicals at varying concentrations, we describe here and make available a pipeline for handling expression data generated by TempO-Seq to align reads, clean and normalize raw count data, identify differentially expressed genes, and calculate transcriptomic concentration–response points of departure. The methods are extensible to other forms of concentration–response gene-expression data, and we discuss the utility of the methods for assessing variation in susceptibility and the diseased cellular state. PMID:29163636

Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

PubMed Central

Currie, Richard A.; Peffer, Richard C.; Goetz, Amber K.; Omiecinski, Curtis J.; Goodman, Jay I.

2014-01-01

Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA. PMID:24675475

Gene expression profiling in liver and testis of rats to characterize the toxicity of triazole fungicides.

PubMed

Tully, Douglas B; Bao, Wenjun; Goetz, Amber K; Blystone, Chad R; Ren, Hongzu; Schmid, Judith E; Strader, Lillian F; Wood, Carmen R; Best, Deborah S; Narotsky, Michael G; Wolf, Douglas C; Rockett, John C; Dix, David J

2006-09-15

Four triazole fungicides were studied using toxicogenomic techniques to identify potential mechanisms of action. Adult male Sprague-Dawley rats were dosed for 14 days by gavage with fluconazole, myclobutanil, propiconazole, or triadimefon. Following exposure, serum was collected for hormone measurements, and liver and testes were collected for histology, enzyme biochemistry, or gene expression profiling. Body and testis weights were unaffected, but liver weights were significantly increased by all four triazoles, and hepatocytes exhibited centrilobular hypertrophy. Myclobutanil exposure increased serum testosterone and decreased sperm motility, but no treatment-related testis histopathology was observed. We hypothesized that gene expression profiles would identify potential mechanisms of toxicity and used DNA microarrays and quantitative real-time PCR (qPCR) to generate profiles. Triazole fungicides are designed to inhibit fungal cytochrome P450 (CYP) 51 enzyme but can also modulate the expression and function of mammalian CYP genes and enzymes. Triazoles affected the expression of numerous CYP genes in rat liver and testis, including multiple Cyp2c and Cyp3a isoforms as well as other xenobiotic metabolizing enzyme (XME) and transporter genes. For some genes, such as Ces2 and Udpgtr2, all four triazoles had similar effects on expression, suggesting possible common mechanisms of action. Many of these CYP, XME and transporter genes are regulated by xeno-sensing nuclear receptors, and hierarchical clustering of CAR/PXR-regulated genes demonstrated the similarities of toxicogenomic responses in liver between all four triazoles and in testis between myclobutanil and triadimefon. Triazoles also affected expression of multiple genes involved in steroid hormone metabolism in the two tissues. Thus, gene expression profiles helped identify possible toxicological mechanisms of the triazole fungicides.

Analysis of baseline gene expression levels from ...

EPA Pesticide Factsheets

The use of gene expression profiling to predict chemical mode of action would be enhanced by better characterization of variance due to individual, environmental, and technical factors. Meta-analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in gene expression. A dataset of control animal microarray expression data was assembled by a working group of the Health and Environmental Sciences Institute's Technical Committee on the Application of Genomics in Mechanism Based Risk Assessment in order to provide a public resource for assessments of variability in baseline gene expression. Data from over 500 Affymetrix microarrays from control rat liver and kidney were collected from 16 different institutions. Thirty-five biological and technical factors were obtained for each animal, describing a wide range of study characteristics, and a subset were evaluated in detail for their contribution to total variability using multivariate statistical and graphical techniques. The study factors that emerged as key sources of variability included gender, organ section, strain, and fasting state. These and other study factors were identified as key descriptors that should be included in the minimal information about a toxicogenomics study needed for interpretation of results by an independent source. Genes that are the most and least variable, gender-selectiv

Toxicogenomics and Cancer Susceptibility: Advances with Next-Generation Sequencing

PubMed Central

Ning, Baitang; Su, Zhenqiang; Mei, Nan; Hong, Huixiao; Deng, Helen; Shi, Leming; Fuscoe, James C.; Tolleson, William H.

2017-01-01

The aim of this review is to comprehensively summarize the recent achievements in the field of toxicogenomics and cancer research regarding genetic-environmental interactions in carcinogenesis and detection of genetic aberrations in cancer genomes by next-generation sequencing technology. Cancer is primarily a genetic disease in which genetic factors and environmental stimuli interact to cause genetic and epigenetic aberrations in human cells. Mutations in the germline act as either high-penetrance alleles that strongly increase the risk of cancer development, or as low-penetrance alleles that mildly change an individual’s susceptibility to cancer. Somatic mutations, resulting from either DNA damage induced by exposure to environmental mutagens or from spontaneous errors in DNA replication or repair are involved in the development or progression of the cancer. Induced or spontaneous changes in the epigenome may also drive carcinogenesis. Advances in next-generation sequencing technology provide us opportunities to accurately, economically, and rapidly identify genetic variants, somatic mutations, gene expression profiles, and epigenetic alterations with single-base resolution. Whole genome sequencing, whole exome sequencing, and RNA sequencing of paired cancer and adjacent normal tissue present a comprehensive picture of the cancer genome. These new findings should benefit public health by providing insights in understanding cancer biology, and in improving cancer diagnosis and therapy. PMID:24875441

Application of dynamic topic models to toxicogenomics data.

PubMed

Lee, Mikyung; Liu, Zhichao; Huang, Ruili; Tong, Weida

2016-10-06

All biological processes are inherently dynamic. Biological systems evolve transiently or sustainably according to sequential time points after perturbation by environment insults, drugs and chemicals. Investigating the temporal behavior of molecular events has been an important subject to understand the underlying mechanisms governing the biological system in response to, such as, drug treatment. The intrinsic complexity of time series data requires appropriate computational algorithms for data interpretation. In this study, we propose, for the first time, the application of dynamic topic models (DTM) for analyzing time-series gene expression data. A large time-series toxicogenomics dataset was studied. It contains over 3144 microarrays of gene expression data corresponding to rat livers treated with 131 compounds (most are drugs) at two doses (control and high dose) in a repeated schedule containing four separate time points (4-, 8-, 15- and 29-day). We analyzed, with DTM, the topics (consisting of a set of genes) and their biological interpretations over these four time points. We identified hidden patterns embedded in this time-series gene expression profiles. From the topic distribution for compound-time condition, a number of drugs were successfully clustered by their shared mode-of-action such as PPARɑ agonists and COX inhibitors. The biological meaning underlying each topic was interpreted using diverse sources of information such as functional analysis of the pathways and therapeutic uses of the drugs. Additionally, we found that sample clusters produced by DTM are much more coherent in terms of functional categories when compared to traditional clustering algorithms. We demonstrated that DTM, a text mining technique, can be a powerful computational approach for clustering time-series gene expression profiles with the probabilistic representation of their dynamic features along sequential time frames. The method offers an alternative way for uncovering hidden patterns embedded in time series gene expression profiles to gain enhanced understanding of dynamic behavior of gene regulation in the biological system.

Pathway Analysis Revealed Potential Diverse Health Impacts of Flavonoids that Bind Estrogen Receptors

PubMed Central

Ye, Hao; Ng, Hui Wen; Sakkiah, Sugunadevi; Ge, Weigong; Perkins, Roger; Tong, Weida; Hong, Huixiao

2016-01-01

Flavonoids are frequently used as dietary supplements in the absence of research evidence regarding health benefits or toxicity. Furthermore, ingested doses could far exceed those received from diet in the course of normal living. Some flavonoids exhibit binding to estrogen receptors (ERs) with consequential vigilance by regulatory authorities at the U.S. EPA and FDA. Regulatory authorities must consider both beneficial claims and potential adverse effects, warranting the increases in research that has spanned almost two decades. Here, we report pathway enrichment of 14 targets from the Comparative Toxicogenomics Database (CTD) and the Herbal Ingredients’ Targets (HIT) database for 22 flavonoids that bind ERs. The selected flavonoids are confirmed ER binders from our earlier studies, and were here found in mainly involved in three types of biological processes, ER regulation, estrogen metabolism and synthesis, and apoptosis. Besides cancers, we conjecture that the flavonoids may affect several diseases via apoptosis pathways. Diseases such as amyotrophic lateral sclerosis, viral myocarditis and non-alcoholic fatty liver disease could be implicated. More generally, apoptosis processes may be importantly evolved biological functions of flavonoids that bind ERs and high dose ingestion of those flavonoids could adversely disrupt the cellular apoptosis process. PMID:27023590

The extraction of drug-disease correlations based on module distance in incomplete human interactome.

PubMed

Yu, Liang; Wang, Bingbo; Ma, Xiaoke; Gao, Lin

2016-12-23

Extracting drug-disease correlations is crucial in unveiling disease mechanisms, as well as discovering new indications of available drugs, or drug repositioning. Both the interactome and the knowledge of disease-associated and drug-associated genes remain incomplete. We present a new method to predict the associations between drugs and diseases. Our method is based on a module distance, which is originally proposed to calculate distances between modules in incomplete human interactome. We first map all the disease genes and drug genes to a combined protein interaction network. Then based on the module distance, we calculate the distances between drug gene sets and disease gene sets, and take the distances as the relationships of drug-disease pairs. We also filter possible false positive drug-disease correlations by p-value. Finally, we validate the top-100 drug-disease associations related to six drugs in the predicted results. The overlapping between our predicted correlations with those reported in Comparative Toxicogenomics Database (CTD) and literatures, and their enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways demonstrate our approach can not only effectively identify new drug indications, but also provide new insight into drug-disease discovery.

Genome-wide Gene Expression Profiling of Acute Metal Exposures in Male Zebrafish

DTIC Science & Technology

2014-10-23

Data in Brief Genome-wide gene expression profiling of acute metal exposures in male zebrafish Christine E. Baer a,⁎, Danielle L. Ippolito b, Naissan... Zebrafish Whole organism Nickel Chromium Cobalt Toxicogenomics To capture global responses to metal poisoning and mechanistic insights into metal...toxicity, gene expression changes were evaluated in whole adult male zebrafish following acute 24 h high dose exposure to three metals with known human

Bio Warfare and Terrorism: Toxins and Other Mid-Spectrum Agents

DTIC Science & Technology

2005-01-01

biotechnology, toxicogenomics, toxin, tetrodotoxin, and others. Once an agent has and proteomics may also help to open the door to the 276 Bio Warfare...also interferon gamma, interleukin-6, and tumor alsointrfern gmma intrlekin6, ad tmor by the mold Aspergillus flavus and commonly conta- necrosis factor...as bullets. No the new sciences of genomics and proteomics to alter toxoid or antitoxin is available, genetic code and to affect the expression of

Comparative toxicogenomic analysis of oral Cr(VI) exposure effects in rat and mouse small intestinal epithelia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kopec, Anna K.; Thompson, Chad M.; Kim, Suntae

2012-07-15

Continuous exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water results in intestinal tumors in mice but not rats. Concentration-dependent gene expression effects were evaluated in female F344 rat duodenal and jejunal epithelia following 7 and 90 days of exposure to 0.3–520 mg/L (as sodium dichromate dihydrate, SDD) in drinking water. Whole-genome microarrays identified 3269 and 1815 duodenal, and 4557 and 1534 jejunal differentially expressed genes at 8 and 91 days, respectively, with significant overlaps between the intestinal segments. Functional annotation identified gene expression changes associated with oxidative stress, cell cycle, cell death, and immune response that weremore » consistent with reported changes in redox status and histopathology. Comparative analysis with B6C3F1 mouse data from a similarly designed study identified 2790 differentially expressed rat orthologs in the duodenum compared to 5013 mouse orthologs at day 8, and only 1504 rat and 3484 mouse orthologs at day 91. Automated dose–response modeling resulted in similar median EC{sub 50}s in the rodent duodenal and jejunal mucosae. Comparative examination of differentially expressed genes also identified divergently regulated orthologs. Comparable numbers of differentially expressed genes were observed at equivalent Cr concentrations (μg Cr/g duodenum). However, mice accumulated higher Cr levels than rats at ≥ 170 mg/L SDD, resulting in a ∼ 2-fold increase in the number of differentially expressed genes. These qualitative and quantitative differences in differential gene expression, which correlate with differences in tissue dose, likely contribute to the disparate intestinal tumor outcomes. -- Highlights: ► Cr(VI) elicits dose-dependent changes in gene expression in rat intestine. ► Cr(VI) elicits less differential gene expression in rats compared to mice. ► Cr(VI) gene expression can be phenotypically anchored to intestinal changes. ► Species-specific and divergent changes are consistent with species-specific tumors.« less

Way forward in case of a false positive in vitro genotoxicity result for a cosmetic substance?

PubMed

Doktorova, Tatyana Y; Ates, Gamze; Vinken, Mathieu; Vanhaecke, Tamara; Rogiers, Vera

2014-02-01

The currently used regulatory in vitro mutagenicity/genotoxicity test battery has a high sensitivity for detecting genotoxicants, but it suffers from a large number of irrelevant positive results (i.e. low specificity) thereby imposing the need for additional follow-up by in vitro and/or in vivo genotoxicity tests. This could have a major impact on the cosmetic industry in Europe, seen the imposed animal testing and marketing bans on cosmetics and their ingredients. Afflicted, but safe substances could therefore be lost. Using the example of triclosan, a cosmetic preservative, we describe here the potential applicability of a human toxicogenomics-based in vitro assay as a potential mechanistically based follow-up test for positive in vitro genotoxicity results. Triclosan shows a positive in vitro chromosomal aberration test, but is negative during in vivo follow-up tests. Toxicogenomics analysis unequivocally shows that triclosan is identified as a compound acting through non-DNA reactive mechanisms. This proof-of-principle study illustrates the potential of genome-wide transcriptomics data in combination with in vitro experimentation as a possible weight-of-evidence follow-up approach for de-risking a positive outcome in a standard mutagenicity/genotoxicity battery. As such a substantial number of cosmetic compounds wrongly identified as genotoxicants could be saved for the future. Copyright © 2013 Elsevier Ltd. All rights reserved.

Response of human renal tubular cells to cyclosporine and sirolimus: A toxicogenomic study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pallet, Nicolas; Rabant, Marion; Xu-Dubois, Yi-Chun

The molecular mechanisms involved in the potentially nephrotoxic response of tubular cells to immunosuppressive drugs remain poorly understood. Transcriptional profiles of human proximal tubular cells exposed to cyclosporine A (CsA), sirolimus (SRL) or their combination, were established using oligonucleotide microarrays. Hierarchical clustering of genes implicated in fibrotic processes showed a clear distinction between expression profiles with CsA and CsA + SRL treatments on the one hand and SRL treatment on the other. Functional analysis found that CsA and CsA + SRL treatments preferentially alter biological processes located at the cell membrane, such as ion transport or signal transduction, whereas SRLmore » modifies biological processes within the nucleus and related to transcriptional activity. Genome wide expression analysis suggested that CsA may induce an endoplasmic reticulum (ER) stress in tubular cells in vitro. Moreover we found that CsA exposure in vivo is associated with the upregulation of the ER stress marker BIP in kidney transplant biopsies. In conclusion, this toxicogenomic study highlights the molecular interaction networks that may contribute to the tubular response to CsA and SRL. These results may also offer a new working hypothesis for future research in the field of CsA nephrotoxicity. Further studies are needed to evaluate if ER stress detection in tubular cells in human biopsies can predict CsA nephrotoxicity.« less

Comparative analysis of predictive models for nongenotoxic hepatocarcinogenicity using both toxicogenomics and quantitative structure-activity relationships.

PubMed

Liu, Zhichao; Kelly, Reagan; Fang, Hong; Ding, Don; Tong, Weida

2011-07-18

The primary testing strategy to identify nongenotoxic carcinogens largely relies on the 2-year rodent bioassay, which is time-consuming and labor-intensive. There is an increasing effort to develop alternative approaches to prioritize the chemicals for, supplement, or even replace the cancer bioassay. In silico approaches based on quantitative structure-activity relationships (QSAR) are rapid and inexpensive and thus have been investigated for such purposes. A slightly more expensive approach based on short-term animal studies with toxicogenomics (TGx) represents another attractive option for this application. Thus, the primary questions are how much better predictive performance using short-term TGx models can be achieved compared to that of QSAR models, and what length of exposure is sufficient for high quality prediction based on TGx. In this study, we developed predictive models for rodent liver carcinogenicity using gene expression data generated from short-term animal models at different time points and QSAR. The study was focused on the prediction of nongenotoxic carcinogenicity since the genotoxic chemicals can be inexpensively removed from further development using various in vitro assays individually or in combination. We identified 62 chemicals whose hepatocarcinogenic potential was available from the National Center for Toxicological Research liver cancer database (NCTRlcdb). The gene expression profiles of liver tissue obtained from rats treated with these chemicals at different time points (1 day, 3 days, and 5 days) are available from the Gene Expression Omnibus (GEO) database. Both TGx and QSAR models were developed on the basis of the same set of chemicals using the same modeling approach, a nearest-centroid method with a minimum redundancy and maximum relevancy-based feature selection with performance assessed using compound-based 5-fold cross-validation. We found that the TGx models outperformed QSAR in every aspect of modeling. For example, the TGx models' predictive accuracy (0.77, 0.77, and 0.82 for the 1-day, 3-day, and 5-day models, respectively) was much higher for an independent validation set than that of a QSAR model (0.55). Permutation tests confirmed the statistical significance of the model's prediction performance. The study concluded that a short-term 5-day TGx animal model holds the potential to predict nongenotoxic hepatocarcinogenicity. © 2011 American Chemical Society

Toxicological Responses of Environmental Mixtures: Environmental Metals Mixtures Display Synergistic Induction of Metal-Responsive and Oxidative Stress Genes in Placental Cells

PubMed Central

Adebambo, Oluwadamilare A.; Ray, Paul D.; Shea, Damian; Fry, Rebecca C.

2016-01-01

Exposure to elevated levels of the toxic metals inorganic arsenic (iAs) and cadmium (Cd) represents a major global health problem. These metals often occur as mixtures in the environment, creating the potential for interactive or synergistic biological effects different from those observed in single exposure conditions. In the present study, environmental mixtures collected from two waste sites in China and comparable mixtures prepared in the laboratory were tested for toxicogenomic response in placental JEG-3 cells. These cells serve as a model for evaluating cellular responses to exposures during pregnancy. One of the mixtures was predominated by iAs and one by Cd. Six gene biomarkers were measured in order to evaluate the effects from the metals mixtures using dose and time-course experiments including: heme oxygenase 1 (HO-1) and metallothionein isoforms (MT1A, MT1F and MT1G) previously shown to be preferentially induced by exposure to either iAs or Cd, and metal transporter genes aquaporin-9 (AQP9) and ATPase, Cu2+ transporting, beta polypeptide (ATP7B). There was a significant increase in the mRNA expression levels of ATP7B, HO-1, MT1A, MT1F, and MT1G in mixture-treated cells compared to the iAs or Cd only-treated cells. Notably, the genomic responses were observed at concentrations significantly lower than levels found at the environmental collection sites. These data demonstrate that metal mixtures increase the expression of gene biomarkers in placental JEG-3 cells in a synergistic manner. Taken together, the data suggest that toxic metals that co-occur may induce detrimental health effects that are currently underestimated when analyzed as single metals. PMID:26472158

Collaborative biocuration--text-mining development task for document prioritization for curation.

PubMed

Wiegers, Thomas C; Davis, Allan Peter; Mattingly, Carolyn J

2012-01-01

The Critical Assessment of Information Extraction systems in Biology (BioCreAtIvE) challenge evaluation is a community-wide effort for evaluating text mining and information extraction systems for the biological domain. The 'BioCreative Workshop 2012' subcommittee identified three areas, or tracks, that comprised independent, but complementary aspects of data curation in which they sought community input: literature triage (Track I); curation workflow (Track II) and text mining/natural language processing (NLP) systems (Track III). Track I participants were invited to develop tools or systems that would effectively triage and prioritize articles for curation and present results in a prototype web interface. Training and test datasets were derived from the Comparative Toxicogenomics Database (CTD; http://ctdbase.org) and consisted of manuscripts from which chemical-gene-disease data were manually curated. A total of seven groups participated in Track I. For the triage component, the effectiveness of participant systems was measured by aggregate gene, disease and chemical 'named-entity recognition' (NER) across articles; the effectiveness of 'information retrieval' (IR) was also measured based on 'mean average precision' (MAP). Top recall scores for gene, disease and chemical NER were 49, 65 and 82%, respectively; the top MAP score was 80%. Each participating group also developed a prototype web interface; these interfaces were evaluated based on functionality and ease-of-use by CTD's biocuration project manager. In this article, we present a detailed description of the challenge and a summary of the results.

[The prospect of application of toxicogenetics/pharmcogenetics theory and methods in forensic practice].

PubMed

Shen, Dan-na; Yi, Xu-fu; Chen, Xiao-gang; Xu, Tong-li; Cui, Li-juan

2007-10-01

Individual response to drugs, toxicants, environmental chemicals and allergens varies with genotype. Some respond well to these substances without significant consequences, while others may respond strongly with severe consequences and even death. Toxicogenetics and toxicogenomics as well as pharmacogenetics explain the genetic basis for the variations of individual response to toxicants by sequencing the human genome and large-scale identification of genome polymorphism. The new disciplines will provide a new route for forensic specialists to determine the cause of death.

The Disease Portals, disease-gene annotation and the RGD disease ontology at the Rat Genome Database.

PubMed

Hayman, G Thomas; Laulederkind, Stanley J F; Smith, Jennifer R; Wang, Shur-Jen; Petri, Victoria; Nigam, Rajni; Tutaj, Marek; De Pons, Jeff; Dwinell, Melinda R; Shimoyama, Mary

2016-01-01

The Rat Genome Database (RGD;http://rgd.mcw.edu/) provides critical datasets and software tools to a diverse community of rat and non-rat researchers worldwide. To meet the needs of the many users whose research is disease oriented, RGD has created a series of Disease Portals and has prioritized its curation efforts on the datasets important to understanding the mechanisms of various diseases. Gene-disease relationships for three species, rat, human and mouse, are annotated to capture biomarkers, genetic associations, molecular mechanisms and therapeutic targets. To generate gene-disease annotations more effectively and in greater detail, RGD initially adopted the MEDIC disease vocabulary from the Comparative Toxicogenomics Database and adapted it for use by expanding this framework with the addition of over 1000 terms to create the RGD Disease Ontology (RDO). The RDO provides the foundation for, at present, 10 comprehensive disease area-related dataset and analysis platforms at RGD, the Disease Portals. Two major disease areas are the focus of data acquisition and curation efforts each year, leading to the release of the related Disease Portals. Collaborative efforts to realize a more robust disease ontology are underway. Database URL:http://rgd.mcw.edu. © The Author(s) 2016. Published by Oxford University Press.

A test strategy for the assessment of additive attributed toxicity of tobacco products.

PubMed

Kienhuis, Anne S; Staal, Yvonne C M; Soeteman-Hernández, Lya G; van de Nobelen, Suzanne; Talhout, Reinskje

2016-08-01

The new EU Tobacco Product Directive (TPD) prohibits tobacco products containing additives that are toxic in unburnt form or that increase overall toxicity of the product. This paper proposes a strategy to assess additive attributed toxicity in the context of the TPD. Literature was searched on toxicity testing strategies for regulatory purposes from tobacco industry and governmental institutes. Although mainly traditional in vivo testing strategies have been applied to assess toxicity of unburnt additives and increases in overall toxicity of tobacco products due to additives, in vitro tests combined with toxicogenomics and validated using biomarkers of exposure and disease are most promising in this respect. As such, tests are needed that are sensitive enough to assess additive attributed toxicity above the overall toxicity of tobacco products, which can associate assay outcomes to human risk and exposure. In conclusion, new, sensitive in vitro assays are needed to conclude whether comparable testing allows for assessment of small changes in overall toxicity attributed to additives. A more pragmatic approach for implementation on a short-term is mandated lowering of toxic emission components. Combined with risk assessment, this approach allows assessment of effectiveness of harm reduction strategies, including banning or reducing of additives. Copyright © 2016 Elsevier Ltd. All rights reserved.

In Silico Computational Transcriptomics Reveals Novel Endocrine Disruptors in Largemouth Bass ( Micropterus salmoides).

PubMed

Basili, Danilo; Zhang, Ji-Liang; Herbert, John; Kroll, Kevin; Denslow, Nancy D; Martyniuk, Christopher J; Falciani, Francesco; Antczak, Philipp

2018-06-15

In recent years, decreases in fish populations have been attributed, in part, to the effect of environmental chemicals on ovarian development. To understand the underlying molecular events we developed a dynamic model of ovary development linking gene transcription to key physiological end points, such as gonadosomatic index (GSI), plasma levels of estradiol (E2) and vitellogenin (VTG), in largemouth bass ( Micropterus salmoides). We were able to identify specific clusters of genes, which are affected at different stages of ovarian development. A subnetwork was identified that closely linked gene expression and physiological end points and by interrogating the Comparative Toxicogenomic Database (CTD), quercetin and tretinoin (ATRA) were identified as two potential candidates that may perturb this system. Predictions were validated by investigation of reproductive associated transcripts using qPCR in ovary and in the liver of both male and female largemouth bass treated after a single injection of quercetin and tretinoin (10 and 100 μg/kg). Both compounds were found to significantly alter the expression of some of these genes. Our findings support the use of omics and online repositories for identification of novel, yet untested, compounds. This is the first study of a dynamic model that links gene expression patterns across stages of ovarian development.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poulsen, Sarah S., E-mail: spo@nrcwe.dk; Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde; Saber, Anne T., E-mail: ats@nrcwe.dk

Multi-walled carbon nanotubes (MWCNTs) are an inhomogeneous group of nanomaterials that vary in lengths, shapes and types of metal contamination, which makes hazard evaluation difficult. Here we present a toxicogenomic analysis of female C57BL/6 mouse lungs following a single intratracheal instillation of 0, 18, 54 or 162 μg/mouse of a small, curled (CNT{sub Small}, 0.8 ± 0.1 μm in length) or large, thick MWCNT (CNT{sub Large}, 4 ± 0.4 μm in length). The two MWCNTs were extensively characterized by SEM and TEM imaging, thermogravimetric analysis, and Brunauer–Emmett–Teller surface area analysis. Lung tissues were harvested 24 h, 3 days and 28more » days post-exposure. DNA microarrays were used to analyze gene expression, in parallel with analysis of bronchoalveolar lavage fluid, lung histology, DNA damage (comet assay) and the presence of reactive oxygen species (dichlorodihydrofluorescein assay), to profile and characterize related pulmonary endpoints. Overall changes in global transcription following exposure to CNT{sub Small} or CNT{sub Large} were similar. Both MWCNTs elicited strong acute phase and inflammatory responses that peaked at day 3, persisted up to 28 days, and were characterized by increased cellular influx in bronchoalveolar lavage fluid, interstitial pneumonia and gene expression changes. However, CNT{sub Large} elicited an earlier onset of inflammation and DNA damage, and induced more fibrosis and a unique fibrotic gene expression signature at day 28, compared to CNT{sub Small}. The results indicate that the extent of change at the molecular level during early response phases following an acute exposure is greater in mice exposed to CNT{sub Large}, which may eventually lead to the different responses observed at day 28. - Highlights: • We evaluate the toxicogenomic response in mice following MWCNT instillation. • Two MWCNTs of different properties were examined and thoroughly characterized. • MWCNT exposure leads to increased pulmonary inflammation and acute phase response. • The thick and straight MWCNT induced transcriptional and histological pulmonary fibrotic changes. • This was not observed following exposure to the thinner and curled MWCNT.« less

Toxicogenomic assessment of 6-OH-BDE47 induced ...

EPA Pesticide Factsheets

Hydroxylated and methoxylated polybrominated diphenyl ethers (OH-/MeO-PBDEs) are analogs of PBDEs with hundreds of possible structures and many of them can activate aryl hydrocarbon receptor (AhR), however, the in vivo evidence on the toxicity of OH-/MeO-PBDEs are still very limited. 6-OH-BDE47 is a relatively potent AhR activator and a predominant congener of OH-PBDEs detected in the environment. Here the developmental toxicity of 6-OH-BDE47 in chicken embryos was assessed using a toxicogenomic approach. Fertilized chicken eggs were dosed via in ovo administration of 0.006 to 0.474 nmol 6-OH-BDE47/g egg followed by 18-days incubation. Significant embryo mortality (LD50=0.294 pmol/g egg) and increased hepatic somatic index (HSI) were caused by 6-OH-BDE47 exposure. The functional enrichment of differentially expressed genes (DEGs) associated with oxidative phosphorylation, generation of precursor metabolites and energy, and electron transport chain suggest that 6-OH-BDE47 exposure may disrupt the embryo development by altering the function of energy production in mitochondrion. Moreover, AhR mediated responses including up-regulation of CYP1A4 was observed in the livers of embryos exposed to 6-OH-BDE47. Overall, this study confirmed the prediction of embryo lethality by 6-OH-BDE47 consistent with an adverse outcome pathway (AOP) linking AhR activation to embryo lethality. The results provide an example of application of AOP in the hazard and ecological risk asse

Human cell toxicogenomic analysis links reactive oxygen species to the toxicity of monohaloacetic acid drinking water disinfection byproducts

PubMed Central

Pals, Justin; Attene-Ramos, Matias S.; Xia, Menghang; Wagner, Elizabeth D.; Plewa, Michael J.

2014-01-01

Chronic exposure to drinking water disinfection byproducts has been linked to adverse health risks. The monohaloacetic acids (monoHAAs) are generated as byproducts during the disinfection of drinking water and are cytotoxic, genotoxic, mutagenic, and teratogenic. Iodoacetic acid toxicity was mitigated by antioxidants, suggesting the involvement of oxidative stress. Other monoHAAs may share a similar mode of action. Each monoHAA generated a significant concentration-response increase in the expression of a β-lactamase reporter under the control of the Antioxidant Response Element (ARE). The monoHAAs generated oxidative stress with a rank order of IAA > BAA >> CAA; this rank order was observed with other toxicological endpoints. Toxicogenomic analysis was conducted with a non-transformed human intestinal epithelial cell line (FHs 74 Int). Exposure to the monoHAAs altered the transcription levels of multiple oxidative stress responsive genes, indicating that each exposure generated oxidative stress. The transcriptome profiles showed an increase in TXNRD1 and SRXN1, suggesting peroxiredoxin proteins had been oxidized during monoHAA exposures. Three sources of reactive oxygen species were identified, the hypohalous acid generating peroxidase enzymes LPO and MPO, NADPH-dependent oxidase NOX5, and PTGS2 (COX-2) mediated arachidonic acid metabolism. Each monoHAA exposure caused an increase in COX-2 mRNA levels. These data provide a functional association between monoHAA exposure and adverse health outcomes such as oxidative stress, inflammation, and cancer. PMID:24050308

A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

PubMed Central

Kohonen, Pekka; Parkkinen, Juuso A.; Willighagen, Egon L.; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafström, Roland C.

2017-01-01

Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a ‘big data compacting and data fusion’—concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a ‘predictive toxicogenomics space’ (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 108 data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy. PMID:28671182

Comparative Toxicogenomic Responses to the Flame Retardant mITP in Developing Zebrafish.

PubMed

Haggard, Derik E; Das, Siba R; Tanguay, Robert L

2017-02-20

Monosubstituted isopropylated triaryl phosphate (mITP) is a major component of Firemaster 550, an additive flame retardant mixture commonly used in polyurethane foams. Developmental toxicity studies in zebrafish established mITP as the most toxic component of FM 550, which causes pericardial edema and heart looping failure. Mechanistic studies showed that mITP is an aryl hydrocarbon receptor (AhR) ligand; however, the cardiotoxic effects of mITP were independent of the AhR. We performed comparative whole genome transcriptomics in wild-type and ahr2 hu3335 zebrafish, which lack functional ahr2, to identify transcriptional signatures causally involved in the mechanism of mITP-induced cardiotoxicity. Regardless of ahr2 status, mITP exposure resulted in decreased expression of transcripts related to the synthesis of all-trans-retinoic acid and a host of Hox genes. Clustered gene ontology enrichment analysis showed unique enrichment in biological processes related to xenobiotic metabolism and response to external stimuli in wild-type samples. Transcript enrichments overlapping both genotypes involved the retinoid metabolic process and sensory/visual perception biological processes. Examination of the gene-gene interaction network of the differentially expressed transcripts in both genetic backgrounds demonstrated a strong AhR interaction network specific to wild-type samples, with overlapping genes regulated by retinoic acid receptors (RARs). A transcriptome analysis of control ahr2-null zebrafish identified potential cross-talk among AhR, Nrf2, and Hif1α. Collectively, we confirmed that mITP is an AhR ligand and present evidence in support of our hypothesis that mITP's developmental cardiotoxic effects are mediated by inhibition at the RAR level.

Toxicogenomics and clinical toxicology: an example of the connection between basic and applied sciences.

PubMed

Ferrer-Dufol, Ana; Menao-Guillen, Sebastian

2009-04-10

The relationship between basic research and its potential clinical applications is often a difficult subject. Clinical toxicology has always been very dependent on experimental research whose usefulness has been impaired by the existence of huge differences in the toxicity expression of different substances, inter- and intra-species which make it difficult to predict clinical effects in humans. The new methods in molecular biology developed in the last decades are furnishing very useful tools to study some of the more relevant molecules implied in toxicokinetic and toxicodynamic processes. We aim to show some meaningful examples of how recent research developments with genes and proteins have clear applications to understand significant clinical matters, such as inter-individual variations in susceptibility to chemicals, and other phenomena related to the way some substances act to induce variations in the expression and functionality of these targets.

Systems toxicology of chemically induced liver and kidney injuries: histopathology‐associated gene co‐expression modules

PubMed Central

Te, Jerez A.; AbdulHameed, Mohamed Diwan M.

2016-01-01

Abstract Organ injuries caused by environmental chemical exposures or use of pharmaceutical drugs pose a serious health risk that may be difficult to assess because of a lack of non‐invasive diagnostic tests. Mapping chemical injuries to organ‐specific histopathology outcomes via biomarkers will provide a foundation for designing precise and robust diagnostic tests. We identified co‐expressed genes (modules) specific to injury endpoints using the Open Toxicogenomics Project‐Genomics Assisted Toxicity Evaluation System (TG‐GATEs) – a toxicogenomics database containing organ‐specific gene expression data matched to dose‐ and time‐dependent chemical exposures and adverse histopathology assessments in Sprague–Dawley rats. We proposed a protocol for selecting gene modules associated with chemical‐induced injuries that classify 11 liver and eight kidney histopathology endpoints based on dose‐dependent activation of the identified modules. We showed that the activation of the modules for a particular chemical exposure condition, i.e., chemical‐time‐dose combination, correlated with the severity of histopathological damage in a dose‐dependent manner. Furthermore, the modules could distinguish different types of injuries caused by chemical exposures as well as determine whether the injury module activation was specific to the tissue of origin (liver and kidney). The generated modules provide a link between toxic chemical exposures, different molecular initiating events among underlying molecular pathways and resultant organ damage. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Journal of Applied Toxicology published by John Wiley & Sons, Ltd. PMID:26725466

Predictive Modeling of Chemical Hazard by Integrating Numerical Descriptors of Chemical Structures and Short-term Toxicity Assay Data

PubMed Central

Rusyn, Ivan; Sedykh, Alexander; Guyton, Kathryn Z.; Tropsha, Alexander

2012-01-01

Quantitative structure-activity relationship (QSAR) models are widely used for in silico prediction of in vivo toxicity of drug candidates or environmental chemicals, adding value to candidate selection in drug development or in a search for less hazardous and more sustainable alternatives for chemicals in commerce. The development of traditional QSAR models is enabled by numerical descriptors representing the inherent chemical properties that can be easily defined for any number of molecules; however, traditional QSAR models often have limited predictive power due to the lack of data and complexity of in vivo endpoints. Although it has been indeed difficult to obtain experimentally derived toxicity data on a large number of chemicals in the past, the results of quantitative in vitro screening of thousands of environmental chemicals in hundreds of experimental systems are now available and continue to accumulate. In addition, publicly accessible toxicogenomics data collected on hundreds of chemicals provide another dimension of molecular information that is potentially useful for predictive toxicity modeling. These new characteristics of molecular bioactivity arising from short-term biological assays, i.e., in vitro screening and/or in vivo toxicogenomics data can now be exploited in combination with chemical structural information to generate hybrid QSAR–like quantitative models to predict human toxicity and carcinogenicity. Using several case studies, we illustrate the benefits of a hybrid modeling approach, namely improvements in the accuracy of models, enhanced interpretation of the most predictive features, and expanded applicability domain for wider chemical space coverage. PMID:22387746

Human cell toxicogenomic analysis linking reactive oxygen species to the toxicity of monohaloacetic acid drinking water disinfection byproducts.

PubMed

Pals, Justin; Attene-Ramos, Matias S; Xia, Menghang; Wagner, Elizabeth D; Plewa, Michael J

2013-01-01

Chronic exposure to drinking water disinfection byproducts has been linked to adverse health risks. The monohaloacetic acids (monoHAAs) are generated as byproducts during the disinfection of drinking water and are cytotoxic, genotoxic, mutagenic, and teratogenic. Iodoacetic acid toxicity was mitigated by antioxidants, suggesting the involvement of oxidative stress. Other monoHAAs may share a similar mode of action. Each monoHAA generated a significant concentration-response increase in the expression of a β-lactamase reporter under the control of the antioxidant response element (ARE). The monoHAAs generated oxidative stress with a rank order of iodoacetic acid (IAA) > bromoacetic acid (BAA) ≫ chloroacetic acid (CAA); this rank order was observed with other toxicological end points. Toxicogenomic analysis was conducted with a nontransformed human intestinal epithelial cell line (FHs 74 Int). Exposure to the monoHAAs altered the transcription levels of multiple oxidative stress responsive genes, indicating that each exposure generated oxidative stress. The transcriptome profiles showed an increase in thioredoxin reductase 1 (TXNRD1) and sulfiredoxin (SRXN1), suggesting peroxiredoxin proteins had been oxidized during monoHAA exposures. Three possible sources of reactive oxygen species were identified, the hypohalous acid generating peroxidase enzymes lactoperoxidase (LPO) and myeloperoxidase (MPO), nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase 5 (NOX5), and PTGS2 (COX-2) mediated arachidonic acid metabolism. Each monoHAA exposure caused an increase in COX-2 mRNA levels. These data provide a functional association between monoHAA exposure and adverse health outcomes such as oxidative stress, inflammation, and cancer.

An Integrative data mining approach to identifying Adverse ...

EPA Pesticide Factsheets

The Adverse Outcome Pathway (AOP) framework is a tool for making biological connections and summarizing key information across different levels of biological organization to connect biological perturbations at the molecular level to adverse outcomes for an individual or population. Computational approaches to explore and determine these connections can accelerate the assembly of AOPs. By leveraging the wealth of publicly available data covering chemical effects on biological systems, computationally-predicted AOPs (cpAOPs) were assembled via data mining of high-throughput screening (HTS) in vitro data, in vivo data and other disease phenotype information. Frequent Itemset Mining (FIM) was used to find associations between the gene targets of ToxCast HTS assays and disease data from Comparative Toxicogenomics Database (CTD) by using the chemicals as the common aggregators between datasets. The method was also used to map gene expression data to disease data from CTD. A cpAOP network was defined by considering genes and diseases as nodes and FIM associations as edges. This network contained 18,283 gene to disease associations for the ToxCast data and 110,253 for CTD gene expression. Two case studies show the value of the cpAOP network by extracting subnetworks focused either on fatty liver disease or the Aryl Hydrocarbon Receptor (AHR). The subnetwork surrounding fatty liver disease included many genes known to play a role in this disease. When querying the cpAOP

Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses

PubMed Central

Rahman, Luna; Wu, Dongmei; Johnston, Michael; William, Andrew; Halappanavar, Sabina

2017-01-01

Titanium dioxide nanoparticles (TiO2NPs) induce lung inflammation in experimental animals. In this study, we conducted a comprehensive toxicogenomic analysis of lung responses in mice exposed to six individual TiO2NPs exhibiting different sizes (8, 20 and 300nm), crystalline structure (anatase, rutile or anatase/rutile) and surface modifications (hydrophobic or hydrophilic) to investigate whether the mechanisms leading to TiO2NP-induced lung inflammation are property specific. A detailed histopathological analysis was conducted to investigate the long-term disease implications of acute exposure to TiO2NPs. C57BL/6 mice were exposed to 18, 54, 162 or 486 µg of TiO2NPs/mouse via single intratracheal instillation. Controls were exposed to dispersion medium only. Bronchoalveolar lavage fluid (BALF) and lung tissue were sampled on 1, 28 and 90 days post-exposure. Although all TiO2NPs induced lung inflammation as measured by the neutrophil influx in BALF, rutile-type TiO2NPs induced higher inflammation with the hydrophilic rutile TiO2NP showing the maximum increase. Accordingly, the rutile TiO2NPs induced higher number of differentially expressed genes. Histopathological analysis of lung sections on Day 90 post-exposure showed increased collagen staining and fibrosis-like changes following exposure to the rutile TiO2NPs at the highest dose tested. Among the anatase, the smallest TiO2NP of 8nm showed the maximum response. The anatase TiO2NP of 300nm was the least responsive of all. The results suggest that the severity of lung inflammation is property specific; however, the underlying mechanisms (genes and pathways perturbed) leading to inflammation were the same for all particle types. While the particle size clearly influenced the overall acute lung responses, a combination of small size, crystalline structure and hydrophilic surface contributed to the long-term pathological effects observed at the highest dose (486 µg/mouse). Although the dose at which the pathological changes were observed is considered physiologically high, the study highlights the disease potential of certain TiO2NPs of specific properties. PMID:27760801

Enabling online studies of conceptual relationships between medical terms: developing an efficient web platform.

PubMed

Albin, Aaron; Ji, Xiaonan; Borlawsky, Tara B; Ye, Zhan; Lin, Simon; Payne, Philip Ro; Huang, Kun; Xiang, Yang

2014-10-07

The Unified Medical Language System (UMLS) contains many important ontologies in which terms are connected by semantic relations. For many studies on the relationships between biomedical concepts, the use of transitively associated information from ontologies and the UMLS has been shown to be effective. Although there are a few tools and methods available for extracting transitive relationships from the UMLS, they usually have major restrictions on the length of transitive relations or on the number of data sources. Our goal was to design an efficient online platform that enables efficient studies on the conceptual relationships between any medical terms. To overcome the restrictions of available methods and to facilitate studies on the conceptual relationships between medical terms, we developed a Web platform, onGrid, that supports efficient transitive queries and conceptual relationship studies using the UMLS. This framework uses the latest technique in converting natural language queries into UMLS concepts, performs efficient transitive queries, and visualizes the result paths. It also dynamically builds a relationship matrix for two sets of input biomedical terms. We are thus able to perform effective studies on conceptual relationships between medical terms based on their relationship matrix. The advantage of onGrid is that it can be applied to study any two sets of biomedical concept relations and the relations within one set of biomedical concepts. We use onGrid to study the disease-disease relationships in the Online Mendelian Inheritance in Man (OMIM). By crossvalidating our results with an external database, the Comparative Toxicogenomics Database (CTD), we demonstrated that onGrid is effective for the study of conceptual relationships between medical terms. onGrid is an efficient tool for querying the UMLS for transitive relations, studying the relationship between medical terms, and generating hypotheses.

Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity.

PubMed

Carchia, E; Porreca, I; Almeida, P J; D'Angelo, F; Cuomo, D; Ceccarelli, M; De Felice, M; Mallardo, M; Ambrosino, C

2015-10-29

Epidemiologic and experimental studies have associated changes of blood glucose homeostasis to Bisphenol A (BPA) exposure. We took a toxicogenomic approach to investigate the mechanisms of low-dose (1 × 10(-9 )M) BPA toxicity in ex vivo cultures of primary murine pancreatic islets and hepatocytes. Twenty-nine inhibited genes were identified in islets and none in exposed hepatocytes. Although their expression was slightly altered, their impaired cellular level, as a whole, resulted in specific phenotypic changes. Damage of mitochondrial function and metabolism, as predicted by bioinformatics analyses, was observed: BPA exposure led to a time-dependent decrease in mitochondrial membrane potential, to an increase of ROS cellular levels and, finally, to an induction of apoptosis, attributable to the bigger Bax/Bcl-2 ratio owing to activation of NF-κB pathway. Our data suggest a multifactorial mechanism for BPA toxicity in pancreatic islets with emphasis to mitochondria dysfunction and NF-κB activation. Finally, we assessed in vitro the viability of BPA-treated islets in stressing condition, as exposure to high glucose, evidencing a reduced ability of the exposed islets to respond to further damages. The result was confirmed in vivo evaluating the reduction of glycemia in hyperglycemic mice transplanted with control and BPA-treated pancreatic islets. The reported findings identify the pancreatic islet as the main target of BPA toxicity in impairing the glycemia. They suggest that the BPA exposure can weaken the response of the pancreatic islets to damages. The last observation could represent a broader concept whose consideration should lead to the development of experimental plans better reproducing the multiple exposure conditions.

A novel genotoxin-specific qPCR array based on the metabolically competent human HepaRG™ cell line as a rapid and reliable tool for improved in vitro hazard assessment.

PubMed

Ates, Gamze; Mertens, Birgit; Heymans, Anja; Verschaeve, Luc; Milushev, Dimiter; Vanparys, Philippe; Roosens, Nancy H C; De Keersmaecker, Sigrid C J; Rogiers, Vera; Doktorova, Tatyana Y

2018-04-01

Although the value of the regulatory accepted batteries for in vitro genotoxicity testing is recognized, they result in a high number of false positives. This has a major impact on society and industries developing novel compounds for pharmaceutical, chemical, and consumer products, as afflicted compounds have to be (prematurely) abandoned or further tested on animals. Using the metabolically competent human HepaRG ™ cell line and toxicogenomics approaches, we have developed an upgraded, innovative, and proprietary gene classifier. This gene classifier is based on transcriptomic changes induced by 12 genotoxic and 12 non-genotoxic reference compounds tested at sub-cytotoxic concentrations, i.e., IC10 concentrations as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The resulting gene classifier was translated into an easy-to-handle qPCR array that, as shown by pathway analysis, covers several different cellular processes related to genotoxicity. To further assess the predictivity of the tool, a set of 5 known positive and 5 known negative test compounds for genotoxicity was evaluated. In addition, 2 compounds with debatable genotoxicity data were tested to explore how the qPCR array would classify these. With an accuracy of 100%, when equivocal results were considered positive, the results showed that combining HepaRG ™ cells with a genotoxin-specific qPCR array can improve (geno)toxicological hazard assessment. In addition, the developed qPCR array was able to provide additional information on compounds for which so far debatable genotoxicity data are available. The results indicate that the new in vitro tool can improve human safety assessment of chemicals in general by basing predictions on mechanistic toxicogenomics information.

Discovering functional modules by topic modeling RNA-Seq based toxicogenomic data.

PubMed

Yu, Ke; Gong, Binsheng; Lee, Mikyung; Liu, Zhichao; Xu, Joshua; Perkins, Roger; Tong, Weida

2014-09-15

Toxicogenomics (TGx) endeavors to elucidate the underlying molecular mechanisms through exploring gene expression profiles in response to toxic substances. Recently, RNA-Seq is increasingly regarded as a more powerful alternative to microarrays in TGx studies. However, realizing RNA-Seq's full potential requires novel approaches to extracting information from the complex TGx data. Considering read counts as the number of times a word occurs in a document, gene expression profiles from RNA-Seq are analogous to a word by document matrix used in text mining. Topic modeling aiming at to discover the latent structures in text corpora would be helpful to explore RNA-Seq based TGx data. In this study, topic modeling was applied on a typical RNA-Seq based TGx data set to discover hidden functional modules. The RNA-Seq based gene expression profiles were transformed into "documents", on which latent Dirichlet allocation (LDA) was used to build a topic model. We found samples treated by the compounds with the same modes of actions (MoAs) could be clustered based on topic similarities. The topic most relevant to each cluster was identified as a "marker" topic, which was interpreted by gene enrichment analysis with MoAs then confirmed by compound and pathways associations mined from literature. To further validate the "marker" topics, we tested topic transferability from RNA-Seq to microarrays. The RNA-Seq based gene expression profile of a topic specifically associated with peroxisome proliferator-activated receptors (PPAR) signaling pathway was used to query samples with similar expression profiles in two different microarray data sets, yielding accuracy of about 85%. This proof-of-concept study demonstrates the applicability of topic modeling to discover functional modules in RNA-Seq data and suggests a valuable computational tool for leveraging information within TGx data in RNA-Seq era.

Next-generation text-mining mediated generation of chemical response-specific gene sets for interpretation of gene expression data.

PubMed

Hettne, Kristina M; Boorsma, André; van Dartel, Dorien A M; Goeman, Jelle J; de Jong, Esther; Piersma, Aldert H; Stierum, Rob H; Kleinjans, Jos C; Kors, Jan A

2013-01-29

Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles. We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD-derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals. Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals. Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect.

Next-generation text-mining mediated generation of chemical response-specific gene sets for interpretation of gene expression data

PubMed Central

2013-01-01

Background Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles. Methods We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD-derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals. Results Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals. Conclusions Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect. PMID:23356878

Alterations of gene expression indicating effects on estrogen signaling and lipid homeostasis in seabream hepatocytes exposed to extracts of seawater sampled from a coastal area of the central Adriatic Sea (Italy).

PubMed

Cocci, Paolo; Capriotti, Martina; Mosconi, Gilberto; Campanelli, Alessandra; Frapiccini, Emanuela; Marini, Mauro; Caprioli, Giovanni; Sagratini, Gianni; Aretusi, Graziano; Palermo, Francesco Alessandro

2017-02-01

Recent evidences suggest that the toxicological effects of endocrine disrupting chemicals (EDCs) involve multiple nuclear receptor-mediated pathways, including estrogen receptor (ER) and peroxisome proliferator-activated receptor (PPAR) signaling systems. Thus, our objective in this study was to detect the summated endocrine effects of EDCs with metabolic activity in coastal waters of the central Adriatic Sea by means of a toxicogenomic approach using seabream hepatocytes. Gene expression patterns were also correlated with seawater levels of polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs). We found that seawater extracts taken at certain areas induced gene expression profiles of ERα/vitellogenin, PPARα/Stearoyl-CoA desaturase 1A, cytochrome P4501A (CYP1A) and metallothionein. These increased levels of biomarkers responses correlated with spatial distribution of PAHs/PCBs concentrations observed by chemical analysis in the different study areas. Collectively, our data give a snapshot of the presence of complex EDC mixtures that are able to perturb metabolic signaling in coastal marine waters. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inferring drug-disease associations based on known protein complexes.

PubMed

Yu, Liang; Huang, Jianbin; Ma, Zhixin; Zhang, Jing; Zou, Yapeng; Gao, Lin

2015-01-01

Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html.

Disease model curation improvements at Mouse Genome Informatics

PubMed Central

Bello, Susan M.; Richardson, Joel E.; Davis, Allan P.; Wiegers, Thomas C.; Mattingly, Carolyn J.; Dolan, Mary E.; Smith, Cynthia L.; Blake, Judith A.; Eppig, Janan T.

2012-01-01

Optimal curation of human diseases requires an ontology or structured vocabulary that contains terms familiar to end users, is robust enough to support multiple levels of annotation granularity, is limited to disease terms and is stable enough to avoid extensive reannotation following updates. At Mouse Genome Informatics (MGI), we currently use disease terms from Online Mendelian Inheritance in Man (OMIM) to curate mouse models of human disease. While OMIM provides highly detailed disease records that are familiar to many in the medical community, it lacks structure to support multilevel annotation. To improve disease annotation at MGI, we evaluated the merged Medical Subject Headings (MeSH) and OMIM disease vocabulary created by the Comparative Toxicogenomics Database (CTD) project. Overlaying MeSH onto OMIM provides hierarchical access to broad disease terms, a feature missing from the OMIM. We created an extended version of the vocabulary to meet the genetic disease-specific curation needs at MGI. Here we describe our evaluation of the CTD application, the extensions made by MGI and discuss the strengths and weaknesses of this approach. Database URL: http://www.informatics.jax.org/ PMID:22434831

Inferring drug-disease associations based on known protein complexes

PubMed Central

2015-01-01

Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html. PMID:26044949

Contribution of new technologies to characterization and prediction of adverse effects.

PubMed

Rouquié, David; Heneweer, Marjoke; Botham, Jane; Ketelslegers, Hans; Markell, Lauren; Pfister, Thomas; Steiling, Winfried; Strauss, Volker; Hennes, Christa

2015-02-01

Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway concepts.

A Network Pharmacology Approach to Determine the Active Components and Potential Targets of Curculigo Orchioides in the Treatment of Osteoporosis.

PubMed

Wang, Nani; Zhao, Guizhi; Zhang, Yang; Wang, Xuping; Zhao, Lisha; Xu, Pingcui; Shou, Dan

2017-10-27

BACKGROUND Osteoporosis is a complex bone disorder with a genetic predisposition, and is a cause of health problems worldwide. In China, Curculigo orchioides (CO) has been widely used as a herbal medicine in the prevention and treatment of osteoporosis. However, research on the mechanism of action of CO is still lacking. The aim of this study was to identify the absorbable components, potential targets, and associated treatment pathways of CO using a network pharmacology approach. MATERIAL AND METHODS We explored the chemical components of CO and used the five main principles of drug absorption to identify absorbable components. Targets for the therapeutic actions of CO were obtained from the PharmMapper server database. Pathway enrichment analysis was performed using the Comparative Toxicogenomics Database (CTD). Cytoscape was used to visualize the multiple components-multiple target-multiple pathways-multiple disease network for CO. RESULTS We identified 77 chemical components of CO, of which 32 components could be absorbed in the blood. These potential active components of CO regulated 83 targets and affected 58 pathways. Data analysis showed that the genes for estrogen receptor alpha (ESR1) and beta (ESR2), and the gene for 11 beta-hydroxysteroid dehydrogenase type 1, or cortisone reductase (HSD11B1) were the main targets of CO. Endocrine regulatory factors and factors regulating calcium reabsorption, steroid hormone biosynthesis, and metabolic pathways were related to these main targets and to ten corresponding compounds. CONCLUSIONS The network pharmacology approach used in our study has attempted to explain the mechanisms for the effects of CO in the prevention and treatment of osteoporosis, and provides an alternative approach to the investigation of the effects of this complex compound.

Compound-specific effects of diverse neurodevelopmental toxicants on global gene expression in the neural embryonic stem cell test (ESTn)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Theunissen, P.T., E-mail: Peter.Theunissen@rivm.nl; Department of Toxicogenomics, Maastricht University, Maastricht; Robinson, J.F.

Alternative assays for developmental toxicity testing are needed to reduce animal use in regulatory toxicology. The in vitro murine neural embryonic stem cell test (ESTn) was designed as an alternative for neurodevelopmental toxicity testing. The integration of toxicogenomic-based approaches may further increase predictivity as well as provide insight into underlying mechanisms of developmental toxicity. In the present study, we investigated concentration-dependent effects of six mechanistically diverse compounds, acetaldehyde (ACE), carbamazepine (CBZ), flusilazole (FLU), monoethylhexyl phthalate (MEHP), penicillin G (PENG) and phenytoin (PHE), on the transcriptome and neural differentiation in the ESTn. All compounds with the exception of PENG altered ESTnmore » morphology (cytotoxicity and neural differentiation) in a concentration-dependent manner. Compound induced gene expression changes and corresponding enriched gene ontology biological processes (GO–BP) were identified after 24 h exposure at equipotent differentiation-inhibiting concentrations of the compounds. Both compound-specific and common gene expression changes were observed between subsets of tested compounds, in terms of significance, magnitude of regulation and functionality. For example, ACE, CBZ and FLU induced robust changes in number of significantly altered genes (≥ 687 genes) as well as a variety of GO–BP, as compared to MEHP, PHE and PENG (≤ 55 genes with no significant changes in GO–BP observed). Genes associated with developmentally related processes (embryonic morphogenesis, neuron differentiation, and Wnt signaling) showed diverse regulation after exposure to ACE, CBZ and FLU. In addition, gene expression and GO–BP enrichment showed concentration dependence, allowing discrimination of non-toxic versus toxic concentrations on the basis of transcriptomics. This information may be used to define adaptive versus toxic responses at the transcriptome level.« less

Toxicogenomic investigation of Tetrahymena thermophila exposed to dichlorodiphenyltrichloroethane (DDT), tributyltin (TBT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

PubMed

Chang, Yue; Feng, LiFang; Miao, Wei

2011-07-01

Dichlorodiphenyltrichloroethane (DDT), tributyltin (TBT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are persistent in the environment and cause continuous toxic effects in humans and aquatic life. Tetrahymena thermophila has the potential for use as a model for research regarding toxicants. In this study, this organism was used to analyze a genome-wide microarray generated from cells exposed to DDT, TBT and TCDD. To accomplish this, genes differentially expressed when treated with each toxicant were identified, after which their functions were categorized using GO enrichment analysis. The results suggested that the responses of T. thermophila were similar to those of multicellular organisms. Additionally, the context likelihood of relatedness method (CLR) was applied to construct a TCDD-relevant network. The T-shaped network obtained could be functionally divided into two subnetworks. The general functions of both subnetworks were related to the epigenetic mechanism of TCDD. Based on analysis of the networks, a model of the TCDD effect on T. thermophila was inferred. Thus, Tetrahymena has the potential to be a good unicellular eukaryotic model for toxic mechanism research at the genome level.

NPACT: Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database

PubMed Central

Mangal, Manu; Sagar, Parul; Singh, Harinder; Raghava, Gajendra P. S.; Agarwal, Subhash M.

2013-01-01

Plant-derived molecules have been highly valued by biomedical researchers and pharmaceutical companies for developing drugs, as they are thought to be optimized during evolution. Therefore, we have collected and compiled a central resource Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/) that gathers the information related to experimentally validated plant-derived natural compounds exhibiting anti-cancerous activity (in vitro and in vivo), to complement the other databases. It currently contains 1574 compound entries, and each record provides information on their structure, manually curated published data on in vitro and in vivo experiments along with reference for users referral, inhibitory values (IC50/ED50/EC50/GI50), properties (physical, elemental and topological), cancer types, cell lines, protein targets, commercial suppliers and drug likeness of compounds. NPACT can easily be browsed or queried using various options, and an online similarity tool has also been made available. Further, to facilitate retrieval of existing data, each record is hyperlinked to similar databases like SuperNatural, Herbal Ingredients’ Targets, Comparative Toxicogenomics Database, PubChem and NCI-60 GI50 data. PMID:23203877

COMPUTING THERAPY FOR PRECISION MEDICINE: COLLABORATIVE FILTERING INTEGRATES AND PREDICTS MULTI-ENTITY INTERACTIONS.

PubMed

Regenbogen, Sam; Wilkins, Angela D; Lichtarge, Olivier

2016-01-01

Biomedicine produces copious information it cannot fully exploit. Specifically, there is considerable need to integrate knowledge from disparate studies to discover connections across domains. Here, we used a Collaborative Filtering approach, inspired by online recommendation algorithms, in which non-negative matrix factorization (NMF) predicts interactions among chemicals, genes, and diseases only from pairwise information about their interactions. Our approach, applied to matrices derived from the Comparative Toxicogenomics Database, successfully recovered Chemical-Disease, Chemical-Gene, and Disease-Gene networks in 10-fold cross-validation experiments. Additionally, we could predict each of these interaction matrices from the other two. Integrating all three CTD interaction matrices with NMF led to good predictions of STRING, an independent, external network of protein-protein interactions. Finally, this approach could integrate the CTD and STRING interaction data to improve Chemical-Gene cross-validation performance significantly, and, in a time-stamped study, it predicted information added to CTD after a given date, using only data prior to that date. We conclude that collaborative filtering can integrate information across multiple types of biological entities, and that as a first step towards precision medicine it can compute drug repurposing hypotheses.

COMPUTING THERAPY FOR PRECISION MEDICINE: COLLABORATIVE FILTERING INTEGRATES AND PREDICTS MULTI-ENTITY INTERACTIONS

PubMed Central

REGENBOGEN, SAM; WILKINS, ANGELA D.; LICHTARGE, OLIVIER

2015-01-01

Biomedicine produces copious information it cannot fully exploit. Specifically, there is considerable need to integrate knowledge from disparate studies to discover connections across domains. Here, we used a Collaborative Filtering approach, inspired by online recommendation algorithms, in which non-negative matrix factorization (NMF) predicts interactions among chemicals, genes, and diseases only from pairwise information about their interactions. Our approach, applied to matrices derived from the Comparative Toxicogenomics Database, successfully recovered Chemical-Disease, Chemical-Gene, and Disease-Gene networks in 10-fold cross-validation experiments. Additionally, we could predict each of these interaction matrices from the other two. Integrating all three CTD interaction matrices with NMF led to good predictions of STRING, an independent, external network of protein-protein interactions. Finally, this approach could integrate the CTD and STRING interaction data to improve Chemical-Gene cross-validation performance significantly, and, in a time-stamped study, it predicted information added to CTD after a given date, using only data prior to that date. We conclude that collaborative filtering can integrate information across multiple types of biological entities, and that as a first step towards precision medicine it can compute drug repurposing hypotheses. PMID:26776170

Toxicogenomic outcomes predictive of forestomach carcinogenesis following exposure to benzo(a)pyrene: Relevance to human cancer risk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Labib, Sarah, E-mail: Sarah.Labib@hc-sc.gc.ca; Guo, Charles H., E-mail: Charles.Guo@hc-sc.gc.ca; Williams, Andrew, E-mail: Andrew.Williams@hc-sc.gc.ca

2013-12-01

Forestomach tumors are observed in mice exposed to environmental carcinogens. However, the relevance of this data to humans is controversial because humans lack a forestomach. We hypothesize that an understanding of early molecular changes after exposure to a carcinogen in the forestomach will provide mode-of-action information to evaluate the applicability of forestomach cancers to human cancer risk assessment. In the present study we exposed mice to benzo(a)pyrene (BaP), an environmental carcinogen commonly associated with tumors of the rodent forestomach. Toxicogenomic tools were used to profile gene expression response in the forestomach. Adult Muta™Mouse males were orally exposed to 25, 50,more » and 75 mg BaP/kg-body-weight/day for 28 consecutive days. The forestomach was collected three days post-exposure. DNA microarrays, real-time RT-qPCR arrays, and protein analyses were employed to characterize responses in the forestomach. Microarray results showed altered expression of 414 genes across all treatment groups (± 1.5 fold; false discovery rate adjusted P ≤ 0.05). Significant downregulation of genes associated with phase II xenobiotic metabolism and increased expression of genes implicated in antigen processing and presentation, immune response, chemotaxis, and keratinocyte differentiation were observed in treated groups in a dose-dependent manner. A systematic comparison of the differentially expressed genes in the forestomach from the present study to differentially expressed genes identified in human diseases including human gastrointestinal tract cancers using the NextBio Human Disease Atlas showed significant commonalities between the two models. Our results provide molecular evidence supporting the use of the mouse forestomach model to evaluate chemically-induced gastrointestinal carcinogenesis in humans. - Highlights: • Benzo(a)pyrene-mediated transcriptomic response in the forestomach was examined. • The immunoproteosome subunits and MHC class I pathway were the most affected. • Keratinocyte differentiation associated gene expression changes were dose-dependent. • Molecular similarities exist between cancers of the forestomach and human stomach.« less

Toxicogenomics: the challenges and opportunities to identify biomarkers, signatures and thresholds to support mode-of-action.

PubMed

Currie, Richard A

2012-08-15

Toxicogenomics (TGx) can be defined as the application of "omics" techniques to toxicology and risk assessment. By identifying molecular changes associated with toxicity, TGx data might assist hazard identification and investigate causes. Early technical challenges were evaluated and addressed by consortia (e.g. ISLI/HESI and the Microarray Quality Control consortium), which demonstrated that TGx gave reliable and reproducible information. The MAQC also produced "best practice on signature generation" after conducting an extensive evaluation of different methods on common datasets. Two findings of note were the need for methods that control batch variability, and that the predictive ability of a signature changes in concert with the variability of the endpoint. The key challenge remaining is data interpretation, because TGx can identify molecular changes that are causal, associated with or incidental to toxicity. Application of Bradford Hill's tests for causation, which are used to build mode of action (MOA) arguments, can produce reasonable hypotheses linking altered pathways to phenotypic changes. However, challenges in interpretation still remain: are all pathway changes equal, which are most important and plausibly linked to toxicity? Therefore the expert judgement of the toxicologist is still needed. There are theoretical reasons why consistent alterations across a metabolic pathway are important, but similar changes in signalling pathways may not alter information flow. At the molecular level thresholds may be due to the inherent properties of the regulatory network, for example switch-like behaviours from some network motifs (e.g. positive feedback) in the perturbed pathway leading to the toxicity. The application of systems biology methods to TGx data can generate hypotheses that explain why a threshold response exists. However, are we adequately trained to make these judgments? There is a need for collaborative efforts between regulators, industry and academia to properly define how these technologies can be applied using appropriate case-studies. Copyright © 2012 Elsevier B.V. All rights reserved.

Secondhand Smoke-Prevalent Polycyclic Aromatic Hydrocarbon Binary Mixture-Induced Specific Mitogenic and Pro-inflammatory Cell Signaling Events in Lung Epithelial Cells.

PubMed

Osgood, Ross S; Upham, Brad L; Bushel, Pierre R; Velmurugan, Kalpana; Xiong, Ka-Na; Bauer, Alison K

2017-05-01

Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Secondhand Smoke-Prevalent Polycyclic Aromatic Hydrocarbon Binary Mixture-Induced Specific Mitogenic and Pro-inflammatory Cell Signaling Events in Lung Epithelial Cells

PubMed Central

Osgood, Ross S.; Upham, Brad L.; Bushel, Pierre R.; Velmurugan, Kalpana; Xiong, Ka-Na

2017-01-01

Abstract Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation. PMID:28329830

Toxicogenomics in Environmental Science.

PubMed

Brinke, Alexandra; Buchinger, Sebastian

This chapter reviews the current knowledge and recent progress in the field of environmental, aquatic ecotoxicogenomics with a focus on transcriptomic methods. In ecotoxicogenomics the omics technologies are applied for the detection and assessment of adverse effects in the environment, and thus are to be distinguished from omics used in human toxicology [Snape et al., Aquat Toxicol 67:143-154, 2004]. Transcriptomic methods in ecotoxicology are applied to gain a mechanistic understanding of toxic effects on organisms or populations, and thus aim to bridge the gap between cause and effect. A worthwhile effect-based interpretation of stressor induced changes on the transcriptome is based on the principle of phenotypic-anchoring [Paules, Environ Health Perspect 111:A338-A339, 2003]. Thereby, changes on the transcriptomic level can only be identified as effects if they are clearly linked to a specific stressor-induced effect on the macroscopic level. By integrating those macroscopic and transcriptomic effects, conclusions on the effect-inducing type of the stressor can be drawn. Stressor-specific effects on the transcriptomic level can be identified as stressor-specific induced pathways, transcriptomic patterns, or stressors-specific genetic biomarkers. In this chapter, examples of the combined application of macroscopic and transcriptional effects for the identification of environmental stressors, such as aquatic pollutants, are given and discussed. By means of these examples, challenges on the way to a standardized application of transcriptomics in ecotoxicology are discussed. This is also done against the background of the application of transcriptomic methods in environmental regulation such as the EU regulation Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

Evaluation of a toxicogenomic approach to the local lymph node assay (LLNA).

PubMed

Boverhof, Darrell R; Gollapudi, B Bhaskar; Hotchkiss, Jon A; Osterloh-Quiroz, Mandy; Woolhiser, Michael R

2009-02-01

Genomic technologies have the potential to enhance and complement existing toxicology endpoints; however, assessment of these approaches requires a systematic evaluation including a robust experimental design with genomic endpoints anchored to traditional toxicology endpoints. The present study was conducted to assess the sensitivity of genomic responses when compared with the traditional local lymph node assay (LLNA) endpoint of lymph node cell proliferation and to evaluate the responses for their ability to provide insights into mode of action. Female BALB/c mice were treated with the sensitizer trimellitic anhydride (TMA), following the standard LLNA dosing regimen, at doses of 0.1, 1, or 10% and traditional tritiated thymidine ((3)HTdR) incorporation and gene expression responses were monitored in the auricular lymph nodes. Additional mice dosed with either vehicle or 10% TMA and sacrificed on day 4 or 10, were also included to examine temporal effects on gene expression. Analysis of (3)HTdR incorporation revealed TMA-induced stimulation indices of 2.8, 22.9, and 61.0 relative to vehicle with an EC(3) of 0.11%. Examination of the dose-response gene expression responses identified 9, 833, and 2122 differentially expressed genes relative to vehicle for the 0.1, 1, and 10% TMA dose groups, respectively. Calculation of EC(3) values for differentially expressed genes did not identify a response that was more sensitive than the (3)HTdR value, although a number of genes displayed comparable sensitivity. Examination of temporal responses revealed 1760, 1870, and 953 differentially expressed genes at the 4-, 6-, and 10-day time points respectively. Functional analysis revealed many responses displayed dose- and time-specific induction patterns within the functional categories of cellular proliferation and immune response, including numerous immunoglobin genes which were highly induced at the day 10 time point. Overall, these experiments have systematically illustrated the potential utility of genomic endpoints to enhance the LLNA and support further exploration of this approach through examination of a more diverse array of chemicals.

Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic retinoic acid levels in vivo.

PubMed

Chen, Pei-Jen; Padgett, William T; Moore, Tanya; Winnik, Witold; Lambert, Guy R; Thai, Sheau-Fung; Hester, Susan D; Nesnow, Stephen

2009-01-15

Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863-78). The goals of this study were to examine effects of propiconazole, triadimefon, and myclobutanil, three triazole-containing conazoles, on the microsomal metabolism of atRA, the associated hepatic cytochrome P450 (P450) enzyme(s) involved in atRA metabolism, and their effects on hepatic atRA levels in vivo. The in vitro metabolism of atRA was quantitatively measured in liver microsomes from male CD-1 mice following four daily intraperitoneal injections of propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d). The formation of both 4-hydroxy-atRA and 4-oxo-atRA were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed slightly greater metabolizing activities compared to myclobutanil-induced microsomes. Both propiconazole and triadimefon treatment induced greater formation of 4-hydroxy-atRA compared to myclobutanil treatment. Chemical and immuno-inhibition metabolism studies suggested that Cyp26a1, Cyp2b, and Cyp3a, but not Cyp1a1 proteins were involved in atRA metabolism. Cyp2b10/20 and Cyp3a11 genes were significantly over-expressed in the livers of both triadimefon- and propiconazole-treated mice while Cyp26a1, Cyp2c65 and Cyp1a2 genes were over-expressed in the livers of either triadimefon- or propiconazole-treated mice, and Cyp2b10/20 and Cyp3a13 genes were over-expressed in the livers of myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases in Cyp2b and Cyp3a proteins. All three conazoles decreased hepatic atRA tissue levels ranging from 45-67%. The possible implications of these changes in hepatic atRA levels on cell proliferation in the mouse tumorigenesis process are discussed.

MicroRNA regulatory networks reflective of polyhexamethylene guanidine phosphate-induced fibrosis in A549 human alveolar adenocarcinoma cells.

PubMed

Shin, Da Young; Jeong, Mi Ho; Bang, In Jae; Kim, Ha Ryong; Chung, Kyu Hyuck

2018-05-01

Polyhexamethylene guanidine phosphate (PHMG-phosphate), an active component of humidifier disinfectant, is suspected to be a major cause of pulmonary fibrosis. Fibrosis, induced by recurrent epithelial damage, is significantly affected by epigenetic regulation, including microRNAs (miRNAs). The aim of this study was to investigate the fibrogenic mechanisms of PHMG-phosphate through the profiling of miRNAs and their target genes. A549 cells were treated with 0.75 μg/mL PHMG-phosphate for 24 and 48 h and miRNA microarray expression analysis was conducted. The putative mRNA targets of the miRNAs were identified and subjected to Gene Ontology analysis. After exposure to PHMG-phosphate for 24 and 48 h, 46 and 33 miRNAs, respectively, showed a significant change in expression over 1.5-fold compared with the control. The integrated analysis of miRNA and mRNA microarray results revealed the putative targets that were prominently enriched were associated with the epithelial-mesenchymal transition (EMT), cell cycle changes, and apoptosis. The dose-dependent induction of EMT by PHMG-phosphate exposure was confirmed by western blot. We identified 13 putative EMT-related targets that may play a role in PHMG-phosphate-induced fibrosis according to the Comparative Toxicogenomic Database. Our findings contribute to the comprehension of the fibrogenic mechanism of PHMG-phosphate and will aid further study on PHMG-phosphate-induced toxicity. Copyright © 2018 Elsevier B.V. All rights reserved.

DNA content alterations in Tetrahymena pyriformis macronucleus after exposure to food preservatives sodium nitrate and sodium benzoate.

PubMed

Loutsidou, Ariadni C; Hatzi, Vasiliki I; Chasapis, C T; Terzoudi, Georgia I; Spiliopoulou, Chara A; Stefanidou, Maria E

2012-12-01

The toxicity, in terms of changes in the DNA content, of two food preservatives, sodium nitrate and sodium benzoate was studied on the protozoan Tetrahymena pyriformis using DNA image analysis technology. For this purpose, selected doses of both food additives were administered for 2 h to protozoa cultures and DNA image analysis of T. pyriformis nuclei was performed. The analysis was based on the measurement of the Mean Optical Density which represents the cellular DNA content. The results have shown that after exposure of the protozoan cultures to doses equivalent to ADI, a statistically significant increase in the macronuclear DNA content compared to the unexposed control samples was observed. The observed increase in the macronuclear DNA content is indicative of the stimulation of the mitotic process and the observed increase in MOD, accompanied by a stimulation of the protozoan proliferation activity is in consistence with this assumption. Since alterations at the DNA level such as DNA content and uncontrolled mitogenic stimulation have been linked with chemical carcinogenesis, the results of the present study add information on the toxicogenomic profile of the selected chemicals and may potentially lead to reconsideration of the excessive use of nitrates aiming to protect public health.

Interactive toxicity of usnic acid and lipopolysaccharides in human liver HepG2 cells.

PubMed

Sahu, Saura C; O'Donnell, Michael W; Sprando, Robert L

2012-09-01

Usnic acid (UA), a natural botanical product, is a constituent of some dietary supplements used for weight loss. It has been associated with clinical hepatotoxicity leading to liver failure in humans. The present study was undertaken to evaluate the interactive toxicity, if any, of UA with lipopolysaccarides (LPS), a potential contaminant of food, at low non-toxic concentrations. The human hepatoblastoma HepG2 cells were treated with the vehicle control and test agents, separately and in a binary mixture, for 24 h at 37°C in 5% CO2. After the treatment period, the cells were evaluated by the traditional biochemical endpoints of toxicity in combination with the toxicogenomic endpoints that included cytotoxicity, oxidative stress, mitochondrial injury and changes in pathway-focused gene expression profiles. Compared with the controls, low non-toxic concentrations of UA and LPS separately showed no effect on the cells as determined by the biochemical endpoints. However, the simultaneous mixed exposure of the cells to their binary mixture resulted in increased cytotoxicity, oxidative stress and mitochondrial injury. The pathway-focused gene expression analysis resulted in the altered expression of several genes out of 84 genes examined. Most altered gene expressions induced by the binary mixture of UA and LPS were different from those induced by the individual constituents. The genes affected by the mixture were not modulated by either UA or LPS. The results of the present study suggest that the interactions of low nontoxic concentrations of UA and LPS produce toxicity in HepG2 cells. Published 2012. This article is a US Government work and is in the public domain in the USA.

Bisphenol A-associated epigenomic changes in prepubescent girls: a cross-sectional study in Gharbiah, Egypt

PubMed Central

2013-01-01

Background There is now compelling evidence that epigenetic modifications link adult disease susceptibility to environmental exposures during specific life stages, including pre-pubertal development. Animal studies indicate that bisphenol A (BPA), the monomer used in epoxy resins and polycarbonate plastics, may impact health through epigenetic mechanisms, and epidemiological data associate BPA levels with metabolic disorders, behavior changes, and reproductive effects. Thus, we conducted an environmental epidemiology study of BPA exposure and CpG methylation in pre-adolescent girls from Gharbiah, Egypt hypothesizing that methylation profiles exhibit exposure-dependent trends. Methods Urinary concentrations of total (free plus conjugated) species of BPA in spot samples were quantified for 60 girls aged 10 to 13. Genome-wide CpG methylation was concurrently measured in bisulfite-converted saliva DNA using the Infinium HumanMethylation27 BeadChip (N = 46). CpG sites from four candidate genes were validated via quantitative bisulfite pyrosequencing. Results CpG methylation varied widely among girls, and higher urinary BPA concentrations were generally associated with less genomic methylation. Based on pathway analyses, genes exhibiting reduced methylation with increasing urinary BPA were involved in immune function, transport activity, metabolism, and caspase activity. In particular, hypomethylation of CpG targets on chromosome X was associated with higher urinary BPA. Using the Comparative Toxicogenomics Database, we identified a number of candidate genes in our sample that previously have been associated with BPA-related expression change. Conclusions These data indicate that BPA may affect human health through specific epigenomic modification of genes in relevant pathways. Thus, epigenetic epidemiology holds promise for the identification of biomarkers from previous exposures and the development of epigenetic-based diagnostic strategies. PMID:23590724

Predicting Rat and Human Pregnane X Receptor Activators Using Bayesian Classification Models.

PubMed

AbdulHameed, Mohamed Diwan M; Ippolito, Danielle L; Wallqvist, Anders

2016-10-17

The pregnane X receptor (PXR) is a ligand-activated transcription factor that acts as a master regulator of metabolizing enzymes and transporters. To avoid adverse drug-drug interactions and diseases such as steatosis and cancers associated with PXR activation, identifying drugs and chemicals that activate PXR is of crucial importance. In this work, we developed ligand-based predictive computational models for both rat and human PXR activation, which allowed us to identify potentially harmful chemicals and evaluate species-specific effects of a given compound. We utilized a large publicly available data set of nearly 2000 compounds screened in cell-based reporter gene assays to develop Bayesian quantitative structure-activity relationship models using physicochemical properties and structural descriptors. Our analysis showed that PXR activators tend to be hydrophobic and significantly different from nonactivators in terms of their physicochemical properties such as molecular weight, logP, number of rings, and solubility. Our Bayesian models, evaluated by using 5-fold cross-validation, displayed a sensitivity of 75% (76%), specificity of 76% (75%), and accuracy of 89% (89%) for human (rat) PXR activation. We identified structural features shared by rat and human PXR activators as well as those unique to each species. We compared rat in vitro PXR activation data to in vivo data by using DrugMatrix, a large toxicogenomics database with gene expression data obtained from rats after exposure to diverse chemicals. Although in vivo gene expression data pointed to cross-talk between nuclear receptor activators that is captured only by in vivo assays, overall we found broad agreement between in vitro and in vivo PXR activation. Thus, the models developed here serve primarily as efficient initial high-throughput in silico screens of in vitro activity.

Genotoxicity testing: progress and prospects for the next decade.

PubMed

Turkez, Hasan; Arslan, Mehmet E; Ozdemir, Ozlem

2017-10-01

Genotoxicity and mutagenicity analyses have a significant role in the identification of hazard effects of therapeutic drugs, cosmetics, agrochemicals, industrial compounds, food additives, natural toxins and nanomaterials for regulatory purposes. To evaluate mutagenicity or genotoxicity, different in vitro and in vivo methodologies exert various genotoxicological endpoints such as point mutations, changes in number and structure of chromosomes. Areas covered: This review covered the basics of genotoxicity and in vitro/in vivo methods for determining of genetic damages. The limitations that have arisen as a result of the common use of these methods were also discussed. Finally, the perspectives of further prospects on the use of genotoxicity testing and genotoxic mode of action were emphasized. Expert opinion: The solution of actual and practical problems of genetic toxicology is inarguably based on the understanding of DNA damage mechanisms at molecular, subcellular, cellular, organ, system and organism levels. Current strategies to investigate human health risks should be modified to increase their performance for more reliable results and also new techniques such as toxicogenomics, epigenomics and single cell approaches must be integrated into genetic safety evolutions. The explored new biomarkers by the omic techniques will provide forceful genotoxicity assessment to reduce the cancer risk.

Hydra as a model organism to decipher the toxic effects of copper oxide nanorod: Eco-toxicogenomics approach.

PubMed

Murugadas, Anbazhagan; Zeeshan, Mohammed; Thamaraiselvi, Kaliannan; Ghaskadbi, Surendra; Akbarsha, Mohammad Abdulkader

2016-07-15

Nanotechnology has emerged as a powerful field of applied research. However, the potential toxicity of nano-materials is a cause of concern. A thorough toxicological investigation is required before a nanomaterial is evaluated for application of any kind. In this context, there is concerted effort to find appropriate test systems to assess the toxicity of nanomaterials. Toxicity of a nanomaterial greatly depends on its physicochemical properties and the biological system with which it interacts. The present research was carried out with a view to generate data on eco-toxicological impacts of copper oxide nanorod (CuO NR) in Hydra magnipapillata 105 at organismal, cellular and molecular levels. Exposure of hydra to CuO NR resulted in severe morphological alterations in a concentration- as well as duration-dependent manner. Impairment of feeding, population growth, and regeneration was also observed. In vivo and in vitro analyses revealed induction of oxidative stress, genotoxicity, and molecular machinery of apoptotic cell death, accompanied by disruption of cell cycle progression. Taken together, CuO nanorod is potentially toxic to the biological systems. Also, hydra offers potential to be used as a convenient model organism for aquatic ecotoxicological risk assessment of nanomaterials.

Hydra as a model organism to decipher the toxic effects of copper oxide nanorod: Eco-toxicogenomics approach

PubMed Central

Murugadas, Anbazhagan; Zeeshan, Mohammed; Thamaraiselvi, Kaliannan; Ghaskadbi, Surendra; Akbarsha, Mohammad Abdulkader

2016-01-01

Nanotechnology has emerged as a powerful field of applied research. However, the potential toxicity of nano-materials is a cause of concern. A thorough toxicological investigation is required before a nanomaterial is evaluated for application of any kind. In this context, there is concerted effort to find appropriate test systems to assess the toxicity of nanomaterials. Toxicity of a nanomaterial greatly depends on its physicochemical properties and the biological system with which it interacts. The present research was carried out with a view to generate data on eco-toxicological impacts of copper oxide nanorod (CuO NR) in Hydra magnipapillata 105 at organismal, cellular and molecular levels. Exposure of hydra to CuO NR resulted in severe morphological alterations in a concentration- as well as duration-dependent manner. Impairment of feeding, population growth, and regeneration was also observed. In vivo and in vitro analyses revealed induction of oxidative stress, genotoxicity, and molecular machinery of apoptotic cell death, accompanied by disruption of cell cycle progression. Taken together, CuO nanorod is potentially toxic to the biological systems. Also, hydra offers potential to be used as a convenient model organism for aquatic ecotoxicological risk assessment of nanomaterials. PMID:27417574

Toxicogenomics in the 3T3-L1 cell line, a new approach for screening of obesogenic compounds.

PubMed

Pereira-Fernandes, Anna; Vanparys, Caroline; Vergauwen, Lucia; Knapen, Dries; Jorens, Philippe Germaines; Blust, Ronny

2014-08-01

The obesogen hypothesis states that together with an energy imbalance between calories consumed and calories expended, exposure to environmental compounds early in life or throughout lifetime might have an influence on obesity development. In this work, we propose a new approach for obesogen screening, i.e., the use of transcriptomics in the 3T3-L1 pre-adipocyte cell line. Based on the data from a previous study of our group using a lipid accumulation based adipocyte differentiation assay, several human-relevant obesogenic compounds were selected: reference obesogens (Rosiglitazone, Tributyltin), test obesogens (Butylbenzyl phthalate, butylparaben, propylparaben, Bisphenol A), and non-obesogens (Ethylene Brassylate, Bis (2-ethylhexyl)phthalate). The high stability and reproducibility of the 3T3-L1 gene transcription patterns over different experiments and cell batches is demonstrated by this study. Obesogens and non-obesogen gene transcription profiles were clearly distinguished using hierarchical clustering. Furthermore, a gradual distinction corresponding to differences in induction of lipid accumulation could be made between test and reference obesogens based on transcription patterns, indicating the potential use of this strategy for classification of obesogens. Marker genes that are able to distinguish between non, test, and reference obesogens were identified. Well-known genes involved in adipocyte differentiation as well as genes with unknown functions were selected, implying a potential adipocyte-related function of the latter. Cell-physiological lipid accumulation was well estimated based on transcription levels of the marker genes, indicating the biological relevance of omics data. In conclusion, this study shows the high relevance and reproducibility of this 3T3-L1 based in vitro toxicogenomics tool for classification of obesogens and biomarker discovery. Although the results presented here are promising, further confirmation of the predictive value of the set of candidate biomarkers identified as well as the validation of their clinical role will be needed. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cardiovascular Outcomes and the Physical and Chemical Properties of Metal Ions Found in Particulate Matter Air Pollution: A QICAR Study

PubMed Central

Meng, Qingyu; Lu, Shou-En; Buckley, Barbara; Welsh, William J.; Whitsel, Eric A.; Hanna, Adel; Yeatts, Karin B.; Warren, Joshua; Herring, Amy H.; Xiu, Aijun

2013-01-01

Background: This paper presents an application of quantitative ion character–activity relationships (QICAR) to estimate associations of human cardiovascular (CV) diseases (CVDs) with a set of metal ion properties commonly observed in ambient air pollutants. QICAR has previously been used to predict ecotoxicity of inorganic metal ions based on ion properties. Objectives: The objective of this work was to examine potential associations of biological end points with a set of physical and chemical properties describing inorganic metal ions present in exposures using QICAR. Methods: Chemical and physical properties of 17 metal ions were obtained from peer-reviewed publications. Associations of cardiac arrhythmia, myocardial ischemia, myocardial infarction, stroke, and thrombosis with exposures to metal ions (measured as inference scores) were obtained from the Comparative Toxicogenomics Database (CTD). Robust regressions were applied to estimate the associations of CVDs with ion properties. Results: CVD was statistically significantly associated (Bonferroni-adjusted significance level of 0.003) with many ion properties reflecting ion size, solubility, oxidation potential, and abilities to form covalent and ionic bonds. The properties are relevant for reactive oxygen species (ROS) generation, which has been identified as a possible mechanism leading to CVDs. Conclusion: QICAR has the potential to complement existing epidemiologic methods for estimating associations between CVDs and air pollutant exposures by providing clues about the underlying mechanisms that may explain these associations. PMID:23462649

Toxicogenomic response of Mycobacterium bovis BCG to peracetic acid and a comparative analysis of the M. bovis BCG response to three oxidative disinfectants.

PubMed

Nde, Chantal W; Toghrol, Freshteh; Jang, Hyeung-Jin; Bentley, William E

2011-04-01

Tuberculosis is a leading cause of death worldwide and infects thousands of Americans annually. Mycobacterium bovis causes tuberculosis in humans and several animal species. Peracetic acid is an approved tuberculocide in hospital and domestic environments. This study presents for the first time the transcriptomic changes in M. bovis BCG after treatment with 0.1 mM peracetic acid for 10 and 20 min. This study also presents for the first time a comparison among the transcriptomic responses of M. bovis BCG to three oxidative disinfectants: peracetic acid, sodium hypochlorite, and hydrogen peroxide after 10 min of treatment. Results indicate that arginine biosynthesis, virulence, and oxidative stress response genes were upregulated after both peracetic acid treatment times. Three DNA repair genes were downregulated after 10 and 20 min and cell wall component genes were upregulated after 20 min. The devR-devS signal transduction system was upregulated after 10 min, suggesting a role in the protection against peracetic acid treatment. Results also suggest that peracetic acid and sodium hypochlorite both induce the expression of the ctpF gene which is upregulated in hypoxic environments. Further, this study reveals that in M. bovis BCG, hydrogen peroxide and peracetic acid both induce the expression of katG involved in oxidative stress response and the mbtD and mbtI genes involved in iron regulation/virulence.

Integrating genome-wide association study summaries and element-gene interaction datasets identified multiple associations between elements and complex diseases.

PubMed

He, Awen; Wang, Wenyu; Prakash, N Tejo; Tinkov, Alexey A; Skalny, Anatoly V; Wen, Yan; Hao, Jingcan; Guo, Xiong; Zhang, Feng

2018-03-01

Chemical elements are closely related to human health. Extensive genomic profile data of complex diseases offer us a good opportunity to systemically investigate the relationships between elements and complex diseases/traits. In this study, we applied gene set enrichment analysis (GSEA) approach to detect the associations between elements and complex diseases/traits though integrating element-gene interaction datasets and genome-wide association study (GWAS) data of complex diseases/traits. To illustrate the performance of GSEA, the element-gene interaction datasets of 24 elements were extracted from the comparative toxicogenomics database (CTD). GWAS summary datasets of 24 complex diseases or traits were downloaded from the dbGaP or GEFOS websites. We observed significant associations between 7 elements and 13 complex diseases or traits (all false discovery rate (FDR) < 0.05), including reported relationships such as aluminum vs. Alzheimer's disease (FDR = 0.042), calcium vs. bone mineral density (FDR = 0.031), magnesium vs. systemic lupus erythematosus (FDR = 0.012) as well as novel associations, such as nickel vs. hypertriglyceridemia (FDR = 0.002) and bipolar disorder (FDR = 0.027). Our study results are consistent with previous biological studies, supporting the good performance of GSEA. Our analyzing results based on GSEA framework provide novel clues for discovering causal relationships between elements and complex diseases. © 2017 WILEY PERIODICALS, INC.

Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens

PubMed Central

Thomas, Reuben; Phuong, Jimmy; McHale, Cliona M.; Zhang, Luoping

2012-01-01

We have applied bioinformatic approaches to identify pathways common to chemical leukemogens and to determine whether leukemogens could be distinguished from non-leukemogenic carcinogens. From all known and probable carcinogens classified by IARC and NTP, we identified 35 carcinogens that were associated with leukemia risk in human studies and 16 non-leukemogenic carcinogens. Using data on gene/protein targets available in the Comparative Toxicogenomics Database (CTD) for 29 of the leukemogens and 11 of the non-leukemogenic carcinogens, we analyzed for enrichment of all 250 human biochemical pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The top pathways targeted by the leukemogens included metabolism of xenobiotics by cytochrome P450, glutathione metabolism, neurotrophin signaling pathway, apoptosis, MAPK signaling, Toll-like receptor signaling and various cancer pathways. The 29 leukemogens formed 18 distinct clusters comprising 1 to 3 chemicals that did not correlate with known mechanism of action or with structural similarity as determined by 2D Tanimoto coefficients in the PubChem database. Unsupervised clustering and one-class support vector machines, based on the pathway data, were unable to distinguish the 29 leukemogens from 11 non-leukemogenic known and probable IARC carcinogens. However, using two-class random forests to estimate leukemogen and non-leukemogen patterns, we estimated a 76% chance of distinguishing a random leukemogen/non-leukemogen pair from each other. PMID:22851955

Comparative Analysis of Toxic Responses of Organic Extracts from Diesel and Selected Alternative Fuels Engine Emissions in Human Lung BEAS-2B Cells.

PubMed

Libalova, Helena; Rossner, Pavel; Vrbova, Kristyna; Brzicova, Tana; Sikorova, Jitka; Vojtisek-Lom, Michal; Beranek, Vit; Klema, Jiri; Ciganek, Miroslav; Neca, Jiri; Pencikova, Katerina; Machala, Miroslav; Topinka, Jan

2016-11-03

This study used toxicogenomics to identify the complex biological response of human lung BEAS-2B cells treated with organic components of particulate matter in the exhaust of a diesel engine. First, we characterized particles from standard diesel (B0), biodiesel (methylesters of rapeseed oil) in its neat form (B100) and 30% by volume blend with diesel fuel (B30), and neat hydrotreated vegetable oil (NEXBTL100). The concentration of polycyclic aromatic hydrocarbons (PAHs) and their derivatives in organic extracts was the lowest for NEXBTL100 and higher for biodiesel. We further analyzed global gene expression changes in BEAS-2B cells following 4 h and 24 h treatment with extracts. The concentrations of 50 µg extract/mL induced a similar molecular response. The common processes induced after 4 h treatment included antioxidant defense, metabolism of xenobiotics and lipids, suppression of pro-apoptotic stimuli, or induction of plasminogen activating cascade; 24 h treatment affected fewer processes, particularly those involved in detoxification of xenobiotics, including PAHs. The majority of distinctively deregulated genes detected after both 4 h and 24 h treatment were induced by NEXBTL100; the deregulated genes included, e.g., those involved in antioxidant defense and cell cycle regulation and proliferation. B100 extract, with the highest PAH concentrations, additionally affected several cell cycle regulatory genes and p38 signaling.

Computational Approaches to Chemical Hazard Assessment

PubMed Central

Luechtefeld, Thomas; Hartung, Thomas

2018-01-01

Summary Computational prediction of toxicity has reached new heights as a result of decades of growth in the magnitude and diversity of biological data. Public packages for statistics and machine learning make model creation faster. New theory in machine learning and cheminformatics enables integration of chemical structure, toxicogenomics, simulated and physical data in the prediction of chemical health hazards, and other toxicological information. Our earlier publications have characterized a toxicological dataset of unprecedented scale resulting from the European REACH legislation (Registration Evaluation Authorisation and Restriction of Chemicals). These publications dove into potential use cases for regulatory data and some models for exploiting this data. This article analyzes the options for the identification and categorization of chemicals, moves on to the derivation of descriptive features for chemicals, discusses different kinds of targets modeled in computational toxicology, and ends with a high-level perspective of the algorithms used to create computational toxicology models. PMID:29101769

Lynx web services for annotations and systems analysis of multi-gene disorders.

PubMed

Sulakhe, Dinanath; Taylor, Andrew; Balasubramanian, Sandhya; Feng, Bo; Xie, Bingqing; Börnigen, Daniela; Dave, Utpal J; Foster, Ian T; Gilliam, T Conrad; Maltsev, Natalia

2014-07-01

Lynx is a web-based integrated systems biology platform that supports annotation and analysis of experimental data and generation of weighted hypotheses on molecular mechanisms contributing to human phenotypes and disorders of interest. Lynx has integrated multiple classes of biomedical data (genomic, proteomic, pathways, phenotypic, toxicogenomic, contextual and others) from various public databases as well as manually curated data from our group and collaborators (LynxKB). Lynx provides tools for gene list enrichment analysis using multiple functional annotations and network-based gene prioritization. Lynx provides access to the integrated database and the analytical tools via REST based Web Services (http://lynx.ci.uchicago.edu/webservices.html). This comprises data retrieval services for specific functional annotations, services to search across the complete LynxKB (powered by Lucene), and services to access the analytical tools built within the Lynx platform. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Functional toxicogenomic assessment of triclosan in human ...

EPA Pesticide Factsheets

Thousands of chemicals for which limited toxicological data are available are used and then detected in humans and the environment. Rapid and cost-effective approaches for assessing the toxicological properties of chemicals are needed. We used CRISPR-Cas9 functional genomic screening to identify potential molecular mechanism of a widely used antimicrobial triclosan (TCS) in HepG2 cells. Resistant genes (whose knockout gives potential resistance) at IC50 (50% Inhibition concentration of cell viability) were significantly enriched in adherens junction pathway, MAPK signaling pathway and PPAR signaling pathway, suggesting a potential molecular mechanism in TCS induced cytotoxicity. Evaluation of top-ranked resistant genes, FTO (encoding an mRNA demethylase) and MAP2K3 (a MAP kinase kinase family gene), revealed that their loss conferred resistance to TCS. In contrast, sensitive genes (whose knockout enhances potential sensitivity) at IC10 and IC20 were specifically enriched in pathways involved with immune responses, which was concordant with the transcriptomic profiling of TCS at concentrations

A New Approach in Applying Systems Engineering Tools and Analysis to Determine Hepatocyte Toxicogenomics Risk Levels to Human Health.

PubMed

Gigrich, James; Sarkani, Shahryar; Holzer, Thomas

2017-03-01

There is an increasing backlog of potentially toxic compounds that cannot be evaluated with current animal-based approaches in a cost-effective and expeditious manner, thus putting human health at risk. Extrapolation of animal-based test results for human risk assessment often leads to different physiological outcomes. This article introduces the use of quantitative tools and methods from systems engineering to evaluate the risk of toxic compounds by the analysis of the amount of stress that human hepatocytes undergo in vitro when metabolizing GW7647 1 over extended times and concentrations. Hepatocytes are exceedingly connected systems that make it challenging to understand the highly varied dimensional genomics data to determine risk of exposure. Gene expression data of peroxisome proliferator-activated receptor-α (PPARα) 2 binding was measured over multiple concentrations and varied times of GW7647 exposure and leveraging mahalanombis distance to establish toxicity threshold risk levels. The application of these novel systems engineering tools provides new insight into the intricate workings of human hepatocytes to determine risk threshold levels from exposure. This approach is beneficial to decision makers and scientists, and it can help reduce the backlog of untested chemical compounds due to the high cost and inefficiency of animal-based models.

Predictive Power Estimation Algorithm (PPEA) - A New Algorithm to Reduce Overfitting for Genomic Biomarker Discovery

PubMed Central

Liu, Jiangang; Jolly, Robert A.; Smith, Aaron T.; Searfoss, George H.; Goldstein, Keith M.; Uversky, Vladimir N.; Dunker, Keith; Li, Shuyu; Thomas, Craig E.; Wei, Tao

2011-01-01

Toxicogenomics promises to aid in predicting adverse effects, understanding the mechanisms of drug action or toxicity, and uncovering unexpected or secondary pharmacology. However, modeling adverse effects using high dimensional and high noise genomic data is prone to over-fitting. Models constructed from such data sets often consist of a large number of genes with no obvious functional relevance to the biological effect the model intends to predict that can make it challenging to interpret the modeling results. To address these issues, we developed a novel algorithm, Predictive Power Estimation Algorithm (PPEA), which estimates the predictive power of each individual transcript through an iterative two-way bootstrapping procedure. By repeatedly enforcing that the sample number is larger than the transcript number, in each iteration of modeling and testing, PPEA reduces the potential risk of overfitting. We show with three different cases studies that: (1) PPEA can quickly derive a reliable rank order of predictive power of individual transcripts in a relatively small number of iterations, (2) the top ranked transcripts tend to be functionally related to the phenotype they are intended to predict, (3) using only the most predictive top ranked transcripts greatly facilitates development of multiplex assay such as qRT-PCR as a biomarker, and (4) more importantly, we were able to demonstrate that a small number of genes identified from the top-ranked transcripts are highly predictive of phenotype as their expression changes distinguished adverse from nonadverse effects of compounds in completely independent tests. Thus, we believe that the PPEA model effectively addresses the over-fitting problem and can be used to facilitate genomic biomarker discovery for predictive toxicology and drug responses. PMID:21935387

Reproductive and Developmental Toxicity of Formaldehyde: A Systematic Review

PubMed Central

Duong, Anh; Steinmaus, Craig; McHale, Cliona M.; Vaughan, Charles P.; Zhang, Luoping

2011-01-01

Formaldehyde, the recently classified carcinogen and ubiquitous environmental contaminant, has long been suspected of causing adverse reproductive and developmental effects, but previous reviews were inconclusive, due in part, to limitations in the design of many of the human population studies. In the current review, we systematically evaluated evidence of an association between formaldehyde exposure and adverse reproductive and developmental effects, in human populations and in vivo animal studies, in the peer-reviewed literature. The mostly retrospective human studies provided evidence of an association of maternal exposure with adverse reproductive and developmental effects. Further assessment of this association by meta-analysis revealed an increased risk of spontaneous abortion (1.76, 95% CI 1.20–2.59, p=0.002) and of all adverse pregnancy outcomes combined (1.54, 95% CI 1.27–1.88, p<0.001), in formaldehyde-exposed women, although differential recall, selection bias, or confounding cannot be ruled out. Evaluation of the animal studies including all routes of exposure, doses and dosing regimens studied, suggested positive associations between formaldehyde exposure and reproductive toxicity, mostly in males. Potential mechanisms underlying formaldehyde-induced reproductive and developmental toxicities, including chromosome and DNA damage (genotoxicity), oxidative stress, altered level and/or function of enzymes, hormones and proteins, apoptosis, toxicogenomic and epigenomic effects (such as DNA methylation), were identified. To clarify these associations, well-designed molecular epidemiologic studies, that include quantitative exposure assessment and diminish confounding factors, should examine both reproductive and developmental outcomes associated with exposure in males and females. Together with mechanistic and animal studies, this will allow us to better understand the systemic effect of formaldehyde exposure. PMID:21787879

A transcriptomic analysis of turmeric: Curcumin represses the expression of cholesterol biosynthetic genes and synergizes with simvastatin.

PubMed

Einbond, Linda Saxe; Manservisi, Fabiana; Wu, Hsan-Au; Balick, Michael; Antonetti, Victoria; Vornoli, Andrea; Menghetti, Ilaria; Belpoggi, Fiorella; Redenti, Stephen; Roter, Alan

2018-06-01

The spice turmeric (Curcuma longa L.) has a long history of use as an anti-inflammatory agent. The active component curcumin induces a variety of diverse biological effects and forms a series of degradation and metabolic products in vivo. Our hypothesis is that the field of toxicogenomics provides tools that can be used to characterize the mode of action and toxicity of turmeric components and to predict turmeric-drug interactions. Male Sprague-Dawley rats were treated for 4 days with turmeric root containing about 3% curcumin (comparable to what people consume in the fresh or dried root) or a fraction of turmeric enriched for curcumin (∼74%) and liver tissue collected for gene expression analysis. Two doses of each agent were added to the diet, corresponding to 540 and 2700 mg/kg body weight/day of turmeric. The transcriptomic effects of turmeric on rat liver tissue were examined using 3 programs, ToxFx Analysis Suite, in the context of a large drug database, Ingenuity Pathway and NextBio analyses. ToxFx analysis indicates that turmeric containing about 3% or 74% curcumin represses the expression of cholesterol biosynthetic genes. The dose of 400 mg/kg b.w./day curcumin induced the Drug Signature associated with hepatic inflammatory infiltrate. Ingenuity analysis confirmed that all 4 turmeric treatments had a significant effect on cholesterol biosynthesis, specifically the Cholesterol biosynthesis superpathway and Cholesterol biosynthesis 1 and 2. Among the top 10 up or downregulated genes, all 4 treatments downregulated PDK4; while 3 treatments downregulated ANGPTL4 or FASN. These findings suggest curcumin may enhance the anticancer effects of certain classes of statins, which we confirmed with biological assays. Given this enhancement, lower levels of statins may be required, and even be desirable. Our findings also warn of possible safety issues, such as potential inflammatory liver effects, for patients who ingest a combination of certain classes of statins and curcumin. Transcriptomic analysis suggests that turmeric is worthwhile to study to prevent and treat cancer and lipid disorders. Our approach lays new groundwork for studies of the mode of action and safety of herbal medicines and can also be used to develop a methodology to standardize herbal medicines. Copyright © 2018 Elsevier Ltd. All rights reserved.

Nano-risk Science: application of toxicogenomics in an adverse outcome pathway framework for risk assessment of multi-walled carbon nanotubes.

PubMed

Labib, Sarah; Williams, Andrew; Yauk, Carole L; Nikota, Jake K; Wallin, Håkan; Vogel, Ulla; Halappanavar, Sabina

2016-03-15

A diverse class of engineered nanomaterials (ENMs) exhibiting a wide array of physical-chemical properties that are associated with toxicological effects in experimental animals is in commercial use. However, an integrated framework for human health risk assessment (HHRA) of ENMs has yet to be established. Rodent 2-year cancer bioassays, clinical chemistry, and histopathological endpoints are still considered the 'gold standard' for detecting substance-induced toxicity in animal models. However, the use of data derived from alternative toxicological tools, such as genome-wide expression profiling and in vitro high-throughput assays, are gaining acceptance by the regulatory community for hazard identification and for understanding the underlying mode-of-action. Here, we conducted a case study to evaluate the application of global gene expression data in deriving pathway-based points of departure (PODs) for multi-walled carbon nanotube (MWCNT)-induced lung fibrosis, a non-cancer endpoint of regulatory importance. Gene expression profiles from the lungs of mice exposed to three individual MWCNTs with different physical-chemical properties were used within the framework of an adverse outcome pathway (AOP) for lung fibrosis to identify key biological events linking MWCNT exposure to lung fibrosis. Significantly perturbed pathways were categorized along the key events described in the AOP. Benchmark doses (BMDs) were calculated for each perturbed pathway and were used to derive transcriptional BMDs for each MWCNT. Similar biological pathways were perturbed by the different MWCNT types across the doses and post-exposure time points studied. The pathway BMD values showed a time-dependent trend, with lower BMDs for pathways perturbed at the earlier post-exposure time points (24 h, 3d). The transcriptional BMDs were compared to the apical BMDs derived by the National Institute for Occupational Safety and Health (NIOSH) using alveolar septal thickness and fibrotic lesions endpoints. We found that regardless of the type of MWCNT, the BMD values for pathways associated with fibrosis were 14.0-30.4 μg/mouse, which are comparable to the BMDs derived by NIOSH for MWCNT-induced lung fibrotic lesions (21.0-27.1 μg/mouse). The results demonstrate that transcriptomic data can be used to as an effective mechanism-based method to derive acceptable levels of exposure to nanomaterials in product development when epidemiological data are unavailable.

Spoilt for choice: A critical review on the chemical and biological assessment of current wastewater treatment technologies.

PubMed

Prasse, Carsten; Stalter, Daniel; Schulte-Oehlmann, Ulrike; Oehlmann, Jörg; Ternes, Thomas A

2015-12-15

The knowledge we have gained in recent years on the presence and effects of compounds discharged by wastewater treatment plants (WWTPs) brings us to a point where we must question the appropriateness of current water quality evaluation methodologies. An increasing number of anthropogenic chemicals is detected in treated wastewater and there is increasing evidence of adverse environmental effects related to WWTP discharges. It has thus become clear that new strategies are needed to assess overall quality of conventional and advanced treated wastewaters. There is an urgent need for multidisciplinary approaches combining expertise from engineering, analytical and environmental chemistry, (eco)toxicology, and microbiology. This review summarizes the current approaches used to assess treated wastewater quality from the chemical and ecotoxicological perspective. Discussed chemical approaches include target, non-target and suspect analysis, sum parameters, identification and monitoring of transformation products, computational modeling as well as effect directed analysis and toxicity identification evaluation. The discussed ecotoxicological methodologies encompass in vitro testing (cytotoxicity, genotoxicity, mutagenicity, endocrine disruption, adaptive stress response activation, toxicogenomics) and in vivo tests (single and multi species, biomonitoring). We critically discuss the benefits and limitations of the different methodologies reviewed. Additionally, we provide an overview of the current state of research regarding the chemical and ecotoxicological evaluation of conventional as well as the most widely used advanced wastewater treatment technologies, i.e., ozonation, advanced oxidation processes, chlorination, activated carbon, and membrane filtration. In particular, possible directions for future research activities in this area are provided. Copyright © 2015 Elsevier Ltd. All rights reserved.

Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment

PubMed Central

McHale, Cliona M.; Zhang, Luoping; Smith, Martyn T.

2012-01-01

Benzene causes acute myeloid leukemia and probably other hematological malignancies. As benzene also causes hematotoxicity even in workers exposed to levels below the US permissible occupational exposure limit of 1 part per million, further assessment of the health risks associated with its exposure, particularly at low levels, is needed. Here, we describe the probable mechanism by which benzene induces leukemia involving the targeting of critical genes and pathways through the induction of genetic, chromosomal or epigenetic abnormalities and genomic instability, in a hematopoietic stem cell (HSC); stromal cell dysregulation; apoptosis of HSCs and stromal cells and altered proliferation and differentiation of HSCs. These effects modulated by benzene-induced oxidative stress, aryl hydrocarbon receptor dysregulation and reduced immunosurveillance, lead to the generation of leukemic stem cells and subsequent clonal evolution to leukemia. A mode of action (MOA) approach to the risk assessment of benzene was recently proposed. This approach is limited, however, by the challenges of defining a simple stochastic MOA of benzene-induced leukemogenesis and of identifying relevant and quantifiable parameters associated with potential key events. An alternative risk assessment approach is the application of toxicogenomics and systems biology in human populations, animals and in vitro models of the HSC stem cell niche, exposed to a range of levels of benzene. These approaches will inform our understanding of the mechanisms of benzene toxicity and identify additional biomarkers of exposure, early effect and susceptibility useful for risk assessment. PMID:22166497

Diagnostic performance of traditional hepatobiliary biomarkers of drug-induced liver injury in the rat.

PubMed

Ennulat, Daniela; Magid-Slav, Michal; Rehm, Sabine; Tatsuoka, Kay S

2010-08-01

Nonclinical studies provide the opportunity to anchor biochemical with morphologic findings; however, liver injury is often complex and heterogeneous, confounding the ability to relate biochemical changes with specific patterns of injury. The aim of the current study was to compare diagnostic performance of hepatobiliary markers for specific manifestations of drug-induced liver injury in rat using data collected in a recent hepatic toxicogenomics initiative in which rats (n = 3205) were given 182 different treatments for 4 or 14 days. Diagnostic accuracy of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbili), serum bile acids (SBA), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total cholesterol (Chol), and triglycerides (Trig) was evaluated for specific types of liver histopathology by Receiver Operating Characteristic (ROC) analysis. To assess the relationship between biochemical and morphologic changes in the absence of hepatocellular necrosis, a second ROC analysis was performed on a subset of rats (n = 2504) given treatments (n = 152) that did not cause hepatocellular necrosis. In the initial analysis, ALT, AST, Tbili, and SBA had the greatest diagnostic utility for manifestations of hepatocellular necrosis and biliary injury, with comparable magnitude of area under the ROC curve and serum hepatobiliary marker changes for both. In the absence of hepatocellular necrosis, ALT increases were observed with biochemical or morphologic evidence of cholestasis. In both analyses, diagnostic utility of ALP and GGT for biliary injury was limited; however, ALP had modest diagnostic value for peroxisome proliferation, and ALT, AST, and total Chol had moderate diagnostic utility for phospholipidosis. None of the eight markers evaluated had diagnostic value for manifestations of hypertrophy, cytoplasmic rarefaction, inflammation, or lipidosis.

Characteristics of genomic signatures derived using univariate methods and mechanistically anchored functional descriptors for predicting drug- and xenobiotic-induced nephrotoxicity.

PubMed

Shi, Weiwei; Bugrim, Andrej; Nikolsky, Yuri; Nikolskya, Tatiana; Brennan, Richard J

2008-01-01

ABSTRACT The ideal toxicity biomarker is composed of the properties of prediction (is detected prior to traditional pathological signs of injury), accuracy (high sensitivity and specificity), and mechanistic relationships to the endpoint measured (biological relevance). Gene expression-based toxicity biomarkers ("signatures") have shown good predictive power and accuracy, but are difficult to interpret biologically. We have compared different statistical methods of feature selection with knowledge-based approaches, using GeneGo's database of canonical pathway maps, to generate gene sets for the classification of renal tubule toxicity. The gene set selection algorithms include four univariate analyses: t-statistics, fold-change, B-statistics, and RankProd, and their combination and overlap for the identification of differentially expressed probes. Enrichment analysis following the results of the four univariate analyses, Hotelling T-square test, and, finally out-of-bag selection, a variant of cross-validation, were used to identify canonical pathway maps-sets of genes coordinately involved in key biological processes-with classification power. Differentially expressed genes identified by the different statistical univariate analyses all generated reasonably performing classifiers of tubule toxicity. Maps identified by enrichment analysis or Hotelling T-square had lower classification power, but highlighted perturbed lipid homeostasis as a common discriminator of nephrotoxic treatments. The out-of-bag method yielded the best functionally integrated classifier. The map "ephrins signaling" performed comparably to a classifier derived using sparse linear programming, a machine learning algorithm, and represents a signaling network specifically involved in renal tubule development and integrity. Such functional descriptors of toxicity promise to better integrate predictive toxicogenomics with mechanistic analysis, facilitating the interpretation and risk assessment of predictive genomic investigations.

Dose–response analysis of phthalate effects on gene expression in rat whole embryo culture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robinson, Joshua F.; Department of Toxicogenomics, Maastricht University, Maastricht; Verhoef, Aart

2012-10-01

The rat postimplantation whole embryo culture (WEC) model serves as a potential screening tool for developmental toxicity. In this model, cultured rat embryos are exposed during early embryogenesis and evaluated for morphological effects. The integration of molecular-based markers may lead to improved objectivity, sensitivity and predictability of WEC in assessing developmental toxic properties of compounds. In this study, we investigated the concentration-dependent effects of two phthalates differing in potency, mono(2-ethylhexyl) phthalate (MEHP) and monomethyl phthalate (MMP, less toxic), on the transcriptome in WEC to examine gene expression in relation with dysmorphogenesis. MEHP was more potent than MMP in inducing genemore » expression changes as well as changes on morphology. MEHP induced significant enrichment of cholesterol/lipid/steroid (CLS) metabolism and apoptosis pathways which was associated with developmental toxicity. Regulation of genes within CLS metabolism pathways represented the most sensitive markers of MEHP exposure, more sensitive than classical morphological endpoints. As shown in direct comparisons with toxicogenomic in vivo studies, alterations in the regulation of CLS metabolism pathways has been previously identified to be associated with developmental toxicity due to phthalate exposure in utero. Our results support the application of WEC as a model to examine relative phthalate potency through gene expression and morphological responses. Additionally, our results further define the applicability domain of the WEC model for developmental toxicological investigations. -- Highlights: ► We examine the effect of two phthalates on gene expression and morphology in WEC. ► MEHP is more potent than MMP in inducing gene expression changes and dysmorphogenesis. ► MEHP significantly disrupts cholesterol metabolism pathways in a dose-dependent manner. ► Specific phthalate-related mechanisms in WEC are relevant to mechanisms in vivo.« less

An integrative data mining approach to identifying adverse outcome pathway signatures.

PubMed

Oki, Noffisat O; Edwards, Stephen W

2016-03-28

The Adverse Outcome Pathway (AOP) framework is a tool for making biological connections and summarizing key information across different levels of biological organization to connect biological perturbations at the molecular level to adverse outcomes for an individual or population. Computational approaches to explore and determine these connections can accelerate the assembly of AOPs. By leveraging the wealth of publicly available data covering chemical effects on biological systems, computationally-predicted AOPs (cpAOPs) were assembled via data mining of high-throughput screening (HTS) in vitro data, in vivo data and other disease phenotype information. Frequent Itemset Mining (FIM) was used to find associations between the gene targets of ToxCast HTS assays and disease data from Comparative Toxicogenomics Database (CTD) by using the chemicals as the common aggregators between datasets. The method was also used to map gene expression data to disease data from CTD. A cpAOP network was defined by considering genes and diseases as nodes and FIM associations as edges. This network contained 18,283 gene to disease associations for the ToxCast data and 110,253 for CTD gene expression. Two case studies show the value of the cpAOP network by extracting subnetworks focused either on fatty liver disease or the Aryl Hydrocarbon Receptor (AHR). The subnetwork surrounding fatty liver disease included many genes known to play a role in this disease. When querying the cpAOP network with the AHR gene, an interesting subnetwork including glaucoma was identified. While substantial literature exists to support the potential for AHR ligands to elicit glaucoma, it was not explicitly captured in the public annotation information in CTD. The subnetwork from this analysis suggests a cpAOP that includes changes in CYP1B1 expression, which has been previously established in the literature as a primary cause of glaucoma. These case studies highlight the value in integrating multiple data sources when defining cpAOPs for HTS data. Copyright © 2016. Published by Elsevier Ireland Ltd.

MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells.

PubMed

Marrone, April K; Tryndyak, Volodymyr; Beland, Frederick A; Pogribny, Igor P

2016-02-01

Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, particularly in a marked over-expression of miR-410. An additional novel finding is the dose- and time-dependent inhibition of miR-122 in AFB1-treated HepaRG cells. Mechanistically, the AFB1-induced down-regulation of miR-122 was attributed to inhibition of the HNF4A/miR-122 regulatory pathway. These results demonstrate that HepaRG cells can be used to investigate miRNA responses to xenobiotic exposure, and illustrate the existence of early non-genotoxic events, in addition to a well-established genotoxic mode of action changes, in the mechanism of AFB1 and B[a]P carcinogenicity. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

Comparative Analysis of Toxic Responses of Organic Extracts from Diesel and Selected Alternative Fuels Engine Emissions in Human Lung BEAS-2B Cells

PubMed Central

Libalova, Helena; Rossner,, Pavel; Vrbova, Kristyna; Brzicova, Tana; Sikorova, Jitka; Vojtisek-Lom, Michal; Beranek, Vit; Klema, Jiri; Ciganek, Miroslav; Neca, Jiri; Pencikova, Katerina; Machala, Miroslav; Topinka, Jan

2016-01-01

This study used toxicogenomics to identify the complex biological response of human lung BEAS-2B cells treated with organic components of particulate matter in the exhaust of a diesel engine. First, we characterized particles from standard diesel (B0), biodiesel (methylesters of rapeseed oil) in its neat form (B100) and 30% by volume blend with diesel fuel (B30), and neat hydrotreated vegetable oil (NEXBTL100). The concentration of polycyclic aromatic hydrocarbons (PAHs) and their derivatives in organic extracts was the lowest for NEXBTL100 and higher for biodiesel. We further analyzed global gene expression changes in BEAS-2B cells following 4 h and 24 h treatment with extracts. The concentrations of 50 µg extract/mL induced a similar molecular response. The common processes induced after 4 h treatment included antioxidant defense, metabolism of xenobiotics and lipids, suppression of pro-apoptotic stimuli, or induction of plasminogen activating cascade; 24 h treatment affected fewer processes, particularly those involved in detoxification of xenobiotics, including PAHs. The majority of distinctively deregulated genes detected after both 4 h and 24 h treatment were induced by NEXBTL100; the deregulated genes included, e.g., those involved in antioxidant defense and cell cycle regulation and proliferation. B100 extract, with the highest PAH concentrations, additionally affected several cell cycle regulatory genes and p38 signaling. PMID:27827897

Synergy and other ineffective mixture risk definitions.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hertzberg, R.; MacDonell, M.; Environmental Assessment

2002-04-08

A substantial effort has been spent over the past few decades to label toxicologic interaction outcomes as synergistic, antagonistic, or additive. Although useful in influencing the emotions of the public and the press, these labels have contributed fairly little to our understanding of joint toxic action. Part of the difficulty is that their underlying toxicological concepts are only defined for two chemical mixtures, while most environmental and occupational exposures are to mixtures of many more chemicals. Furthermore, the mathematical characterizations of synergism and antagonism are inextricably linked to the prevailing definition of 'no interaction,' instead of some intrinsic toxicological property.more » For example, the US EPA has selected dose addition as the no-interaction definition for mixture risk assessment, so that synergism would represent toxic effects that exceed those predicted from dose addition. For now, labels such as synergism are useful to regulatory agencies, both for qualitative indications of public health risk as well as numerical decision tools for mixture risk characterization. Efforts to quantify interaction designations for use in risk assessment formulas, however, are highly simplified and carry large uncertainties. Several research directions, such as pharmacokinetic measurements and models, and toxicogenomics, should promote significant improvements by providing multi-component data that will allow biologically based mathematical models of joint toxicity to replace these pairwise interaction labels in mixture risk assessment procedures.« less

Functional Toxicogenomic Assessment of Triclosan in Human HepG2 Cells Using Genome-Wide CRISPR-Cas9 Screening.

PubMed

Xia, Pu; Zhang, Xiaowei; Xie, Yuwei; Guan, Miao; Villeneuve, Daniel L; Yu, Hongxia

2016-10-04

There are thousands of chemicals used by humans and detected in the environment for which limited or no toxicological data are available. Rapid and cost-effective approaches for assessing the toxicological properties of chemicals are needed. We used CRISPR-Cas9 functional genomic screening to identify the potential molecular mechanism of a widely used antimicrobial triclosan (TCS) in HepG2 cells. Resistant genes at IC50 (the concentration causing a 50% reduction in cell viability) were significantly enriched in the adherens junction pathway, MAPK signaling pathway, and PPAR signaling pathway, suggesting a potential role in the molecular mechanism of TCS-induced cytotoxicity. Evaluation of the top-ranked resistant genes, FTO (encoding an mRNA demethylase) and MAP2K3 (a MAP kinase kinase family gene), revealed that their loss conferred resistance to TCS. In contrast, sensitive genes at IC10 and IC20 were specifically enriched in pathways involved with immune responses, which was concordant with transcriptomic profiling of TCS at concentrations of

Decision Variants for the Automatic Determination of Optimal Feature Subset in RF-RFE.

PubMed

Chen, Qi; Meng, Zhaopeng; Liu, Xinyi; Jin, Qianguo; Su, Ran

2018-06-15

Feature selection, which identifies a set of most informative features from the original feature space, has been widely used to simplify the predictor. Recursive feature elimination (RFE), as one of the most popular feature selection approaches, is effective in data dimension reduction and efficiency increase. A ranking of features, as well as candidate subsets with the corresponding accuracy, is produced through RFE. The subset with highest accuracy (HA) or a preset number of features (PreNum) are often used as the final subset. However, this may lead to a large number of features being selected, or if there is no prior knowledge about this preset number, it is often ambiguous and subjective regarding final subset selection. A proper decision variant is in high demand to automatically determine the optimal subset. In this study, we conduct pioneering work to explore the decision variant after obtaining a list of candidate subsets from RFE. We provide a detailed analysis and comparison of several decision variants to automatically select the optimal feature subset. Random forest (RF)-recursive feature elimination (RF-RFE) algorithm and a voting strategy are introduced. We validated the variants on two totally different molecular biology datasets, one for a toxicogenomic study and the other one for protein sequence analysis. The study provides an automated way to determine the optimal feature subset when using RF-RFE.

Multiple-endpoints gene alteration-based (MEGA) assay: A toxicogenomics approach for water quality assessment of wastewater effluents.

PubMed

Fukushima, Toshikazu; Hara-Yamamura, Hiroe; Nakashima, Koji; Tan, Lea Chua; Okabe, Satoshi

2017-12-01

Wastewater effluents contain a significant number of toxic contaminants, which, even at low concentrations, display a wide variety of toxic actions. In this study, we developed a multiple-endpoints gene alteration-based (MEGA) assay, a real-time PCR-based transcriptomic analysis, to assess the water quality of wastewater effluents for human health risk assessment and management. Twenty-one genes from the human hepatoblastoma cell line (HepG2), covering the basic health-relevant stress responses such as response to xenobiotics, genotoxicity, and cytotoxicity, were selected and incorporated into the MEGA assay. The genes related to the p53-mediated DNA damage response and cytochrome P450 were selected as markers for genotoxicity and response to xenobiotics, respectively. Additionally, the genes that were dose-dependently regulated by exposure to the wastewater effluents were chosen as markers for cytotoxicity. The alterations in the expression of an individual gene, induced by exposure to the wastewater effluents, were evaluated by real-time PCR and the results were validated by genotoxicity (e.g., comet assay) and cell-based cytotoxicity tests. In summary, the MEGA assay is a real-time PCR-based assay that targets cellular responses to contaminants present in wastewater effluents at the transcriptional level; it is rapid, cost-effective, and high-throughput and can thus complement any chemical analysis for water quality assessment and management. Copyright © 2017 Elsevier Ltd. All rights reserved.

Toxicogenomic analysis of the particle dose- and size-response relationship of silica particles-induced toxicity in mice

NASA Astrophysics Data System (ADS)

Lu, Xiaoyan; Jin, Tingting; Jin, Yachao; Wu, Leihong; Hu, Bin; Tian, Yu; Fan, Xiaohui

2013-01-01

This study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm, which is essential to the safe design and application of SP. Data obtained from histopathological examinations suggested that SP of these sizes can all induce acute inflammation in the liver. In vivo imaging showed that intravenously administrated SP are mainly present in the liver, spleen and intestinal tract. Interestingly, in gene expression analysis, the cellular response pathways activated in the liver are predominantly conserved independently of particle dose when the same size SP are administered or are conserved independently of particle size, surface area and particle number when nano- or submicro-sized SP are administered at their toxic doses. Meanwhile, integrated analysis of transcriptomics, previous metabonomics and conventional toxicological results support the view that SP can result in inflammatory and oxidative stress, generate mitochondrial dysfunction, and eventually cause hepatocyte necrosis by neutrophil-mediated liver injury.

The toxicogenomic multiverse: convergent recruitment of proteins into animal venoms.

PubMed

Fry, Bryan G; Roelants, Kim; Champagne, Donald E; Scheib, Holger; Tyndall, Joel D A; King, Glenn F; Nevalainen, Timo J; Norman, Janette A; Lewis, Richard J; Norton, Raymond S; Renjifo, Camila; de la Vega, Ricardo C Rodríguez

2009-01-01

Throughout evolution, numerous proteins have been convergently recruited into the venoms of various animals, including centipedes, cephalopods, cone snails, fish, insects (several independent venom systems), platypus, scorpions, shrews, spiders, toxicoferan reptiles (lizards and snakes), and sea anemones. The protein scaffolds utilized convergently have included AVIT/colipase/prokineticin, CAP, chitinase, cystatin, defensins, hyaluronidase, Kunitz, lectin, lipocalin, natriuretic peptide, peptidase S1, phospholipase A(2), sphingomyelinase D, and SPRY. Many of these same venom protein types have also been convergently recruited for use in the hematophagous gland secretions of invertebrates (e.g., fleas, leeches, kissing bugs, mosquitoes, and ticks) and vertebrates (e.g., vampire bats). Here, we discuss a number of overarching structural, functional, and evolutionary generalities of the protein families from which these toxins have been frequently recruited and propose a revised and expanded working definition for venom. Given the large number of striking similarities between the protein compositions of conventional venoms and hematophagous secretions, we argue that the latter should also fall under the same definition.

Transcriptomic resources for environmental risk assessment: a case study in the Venice lagoon.

PubMed

Milan, M; Pauletto, M; Boffo, L; Carrer, C; Sorrentino, F; Ferrari, G; Pavan, L; Patarnello, T; Bargelloni, L

2015-02-01

The development of new resources to evaluate the environmental status is becoming increasingly important representing a key challenge for ocean and coastal management. Recently, the employment of transcriptomics in aquatic toxicology has led to increasing initiatives proposing to integrate eco-toxicogenomics in the evaluation of marine ecosystem health. However, several technical issues need to be addressed before introducing genomics as a reliable tool in regulatory ecotoxicology. The Venice lagoon constitutes an excellent case, in which the assessment of environmental risks derived from the nearby industrial activities represents a crucial task. In this context, the potential role of genomics to assist environmental monitoring was investigated through the definition of reliable gene expression markers associated to chemical contamination in Manila clams, and their subsequent employment for the classification of Venice lagoon areas. Overall, the present study addresses key issues to evaluate the future outlooks of genomics in the environmental monitoring and risk assessment. Copyright © 2014 Elsevier Ltd. All rights reserved.

DNA microarray technology in nutraceutical and food safety.

PubMed

Liu-Stratton, Yiwen; Roy, Sashwati; Sen, Chandan K

2004-04-15

The quality and quantity of diet is a key determinant of health and disease. Molecular diagnostics may play a key role in food safety related to genetically modified foods, food-borne pathogens and novel nutraceuticals. Functional outcomes in biology are determined, for the most part, by net balance between sets of genes related to the specific outcome in question. The DNA microarray technology offers a new dimension of strength in molecular diagnostics by permitting the simultaneous analysis of large sets of genes. Automation of assay and novel bioinformatics tools make DNA microarrays a robust technology for diagnostics. Since its development a few years ago, this technology has been used for the applications of toxicogenomics, pharmacogenomics, cell biology, and clinical investigations addressing the prevention and intervention of diseases. Optimization of this technology to specifically address food safety is a vast resource that remains to be mined. Efforts to develop diagnostic custom arrays and simplified bioinformatics tools for field use are warranted.

Construction of a robust microarray from a non-model species (largemouth bass) using pyrosequencing technology

PubMed Central

Garcia-Reyero, Natàlia; Griffitt, Robert J.; Liu, Li; Kroll, Kevin J.; Farmerie, William G.; Barber, David S.; Denslow, Nancy D.

2009-01-01

A novel custom microarray for largemouth bass (Micropterus salmoides) was designed with sequences obtained from a normalized cDNA library using the 454 Life Sciences GS-20 pyrosequencer. This approach yielded in excess of 58 million bases of high-quality sequence. The sequence information was combined with 2,616 reads obtained by traditional suppressive subtractive hybridizations to derive a total of 31,391 unique sequences. Annotation and coding sequences were predicted for these transcripts where possible. 16,350 annotated transcripts were selected as target sequences for the design of the custom largemouth bass oligonucleotide microarray. The microarray was validated by examining the transcriptomic response in male largemouth bass exposed to 17β-œstradiol. Transcriptomic responses were assessed in liver and gonad, and indicated gene expression profiles typical of exposure to œstradiol. The results demonstrate the potential to rapidly create the tools necessary to assess large scale transcriptional responses in non-model species, paving the way for expanded impact of toxicogenomics in ecotoxicology. PMID:19936325

Identification of consensus biomarkers for predicting non-genotoxic hepatocarcinogens

PubMed Central

Huang, Shan-Han; Tung, Chun-Wei

2017-01-01

The assessment of non-genotoxic hepatocarcinogens (NGHCs) is currently relying on two-year rodent bioassays. Toxicogenomics biomarkers provide a potential alternative method for the prioritization of NGHCs that could be useful for risk assessment. However, previous studies using inconsistently classified chemicals as the training set and a single microarray dataset concluded no consensus biomarkers. In this study, 4 consensus biomarkers of A2m, Ca3, Cxcl1, and Cyp8b1 were identified from four large-scale microarray datasets of the one-day single maximum tolerated dose and a large set of chemicals without inconsistent classifications. Machine learning techniques were subsequently applied to develop prediction models for NGHCs. The final bagging decision tree models were constructed with an average AUC performance of 0.803 for an independent test. A set of 16 chemicals with controversial classifications were reclassified according to the consensus biomarkers. The developed prediction models and identified consensus biomarkers are expected to be potential alternative methods for prioritization of NGHCs for further experimental validation. PMID:28117354

Epigenetic Regulation in Particulate Matter-Mediated Cardiopulmonary Toxicities: A Systems Biology Perspective.

PubMed

Wang, Ting; Garcia, Joe Gn; Zhang, Wei

2012-12-01

Particulate matter (PM) air pollution exerts significant adverse health effects in global populations, particularly in developing countries with extensive air pollution. Understanding of the mechanisms of PM-induced health effects including the risk for cardiovascular diseases remains limited. In addition to the direct cellular physiological responses such as mitochondrial dysfunction and oxidative stress, PM mediates remarkable dysregulation of gene expression, especially in cardiovascular tissues. The PM-mediated gene dysregulation is likely to be a complex mechanism affected by various genetic and non-genetic factors. Notably, PM is known to alter epigenetic markers (e.g., DNA methylation and histone modifications), which may contribute to air pollution-mediated health consequences including the risk for cardiovascular diseases. Notably, epigenetic changes induced by ambient PM exposure have emerged to play a critical role in gene regulation. Though the underlying mechanism(s) are not completely clear, the available evidence suggests that the modulated activities of DNA methyltransferase (DNMT), histone acetylase (HAT) and histone deacetylase (HDAC) may contribute to the epigenetic changes induced by PM or PM-related chemicals. By employing genome-wide epigenomic and systems biology approaches, PM toxicogenomics could conceivably progress greatly with the potential identification of individual epigenetic loci associated with dysregulated gene expression after PM exposure, as well the interactions between epigenetic pathways and PM. Furthermore, novel therapeutic targets based on epigenetic markers could be identified through future epigenomic studies on PM-mediated cardiopulmonary toxicities. These considerations collectively inform the future population health applications of genomics in developing countries while benefiting global personalized medicine at the same time.

A network biology-based approach to evaluating the effect of environmental contaminants on human interactome and diseases.

PubMed

Iida, M; Takemoto, K

2018-09-30

Environmental contaminant exposure can pose significant risks to human health. Therefore, evaluating the impact of this exposure is of great importance; however, it is often difficult because both the molecular mechanism of disease and the mode of action of the contaminants are complex. We used network biology techniques to quantitatively assess the impact of environmental contaminants on the human interactome and diseases with a particular focus on seven major contaminant categories: persistent organic pollutants (POPs), dioxins, polycyclic aromatic hydrocarbons (PAHs), pesticides, perfluorochemicals (PFCs), metals, and pharmaceutical and personal care products (PPCPs). We integrated publicly available data on toxicogenomics, the diseasome, protein-protein interactions (PPIs), and gene essentiality and found that a few contaminants were targeted to many genes, and a few genes were targeted by many contaminants. The contaminant targets were hub proteins in the human PPI network, whereas the target proteins in most categories did not contain abundant essential proteins. Generally, contaminant targets and disease-associated proteins were closely associated with the PPI network, and the closeness of the associations depended on the disease type and chemical category. Network biology techniques were used to identify environmental contaminants with broad effects on the human interactome and contaminant-sensitive biomarkers. Moreover, this method enabled us to quantify the relationship between environmental contaminants and human diseases, which was supported by epidemiological and experimental evidence. These methods and findings have facilitated the elucidation of the complex relationship between environmental exposure and adverse health outcomes. Copyright © 2018 Elsevier Inc. All rights reserved.

High-throughput, quantitative assessment of the effects of low-dose silica nanoparticles on lung cells: grasping complex toxicity with a great depth of field.

PubMed

Pisani, Cédric; Gaillard, Jean-Charles; Nouvel, Virginie; Odorico, Michaël; Armengaud, Jean; Prat, Odette

2015-04-18

The toxicity of manufactured fumed silica nanoparticles (NPs) remains poorly investigated compared to that of crystalline silica NPs, which have been associated with lung diseases after inhalation. Amorphous silica NPs are a raw material for manufactured nanocomposites, such as cosmetics, foods, and drugs, raising concerns about their potential toxicity. The size of the NPs was determined by dynamic light scattering and their shape was visualized by atomic force microscopy (10 ± 4 nm). The pertinent toxicological concentration and dynamic ranges were determined using viability tests and cellular impedance. We combined transcriptomics and proteomics to assess the cellular and molecular effects of fumed silica in A549 human alveolar epithelial cells. The "no observed transcriptomic adverse effect level" (NOTEL) was set to 1.0 μg/cm(2), and the "lowest observed adverse transcriptional effect level" (LOTEL) was set at 1.5 μg/cm(2). We carried out genome-wide expression profiles with microarrays and identified, by shotgun proteomics, the exoproteome changes in lung cells after exposure to NP doses (0.1, 1.0, 1.5, 3.0, and 6.0 μg/cm(2)) at two time points (24 h and 72 h). The data revealed a hierarchical, dose-dependent cellular response to silica NPs. At 1.5 μg/cm(2), the Rho signaling cascade, actin cytoskeleton remodeling, and clathrin-mediated endocytosis were induced. At 3.0 μg/cm(2), many inflammatory mediators were upregulated and the coagulation system pathway was triggered. Lastly, at 6.0 μg/cm(2), oxidative stress was initiated. The proteins identified in the extracellular compartment were consistent with these findings. The alliance of two high-throughput technologies allowed the quantitative assessment of the cellular effects and molecular consequences of exposure of lung cells to low doses of NPs. These results were obtained using a pathway-driven analysis instead of isolated genes. As in photography, toxicogenomics allows, at the same time, the visualization of a wide spectrum of biological responses and a "zoom in" to the details with a great depth of field. This study illustrates how such an approach based on human cell culture models is a valuable predictive screening tool to evaluate the toxicity of many potentially harmful emerging substances, alone or in mixtures, in the framework of future regulatory reinforcements.

Evaluation of sequencing approaches for high-throughput ...

EPA Pesticide Factsheets

Whole-genome in vitro transcriptomics has shown the capability to identify mechanisms of action and estimates of potency for chemical-mediated effects in a toxicological framework, but with limited throughput and high cost. We present the evaluation of three toxicogenomics platforms for potential application to high-throughput screening: 1. TempO-Seq utilizing custom designed paired probes per gene; 2. Targeted sequencing (TSQ) utilizing Illumina’s TruSeq RNA Access Library Prep Kit containing tiled exon-specific probe sets; 3. Low coverage whole transcriptome sequencing (LSQ) using Illumina’s TruSeq Stranded mRNA Kit. Each platform was required to cover the ~20,000 genes of the full transcriptome, operate directly with cell lysates, and be automatable with 384-well plates. Technical reproducibility was assessed using MAQC control RNA samples A and B, while functional utility for chemical screening was evaluated using six treatments at a single concentration after 6 hr in MCF7 breast cancer cells: 10 µM chlorpromazine, 10 µM ciclopriox, 10 µM genistein, 100 nM sirolimus, 1 µM tanespimycin, and 1 µM trichostatin A. All RNA samples and chemical treatments were run with 5 technical replicates. The three platforms achieved different read depths, with the TempO-Seq having ~34M mapped reads per sample, while TSQ and LSQ averaged 20M and 11M aligned reads per sample, respectively. Inter-replicate correlation averaged ≥0.95 for raw log2 expression values i

Toxicogenomic evaluation of microcystin-LR treated with ultrasonic irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hudder, Alice; Song Weihua; O'Shea, Kevin E.

2007-05-01

Microcystins are a family of toxins produced by cyanobacteria found throughout the world in marine and freshwater environments. The most commonly encountered form of microcystin is microcystin-LR (MC-LR). Humans are exposed to MC-LR by drinking contaminated water. The toxin accumulates rapidly in the liver where it exerts most of its damage. Treatment of water containing MC-LR by ultrasonic irradiation leads to the breakdown of the toxin. Both the parent toxin and the treated toxin reaction products (TTRP) were evaluated for toxic effects in mice. Animals were exposed to purified MC-LR or an equivalent dose of the TTRP and sacrificed aftermore » 4 h or 24 h. Serum was collected and assayed for lactate dehydrogenase (LDH) activity as an indicator of hepatotoxicity. LDH activity was detected in the serum of MC-LR exposed mice indicative of liver damage, but not in control mice. Only a fraction of that activity was detectable in mice exposed to TTRP. Liver RNA was used for microarray analysis and real-time PCR. Individual animals varied in their overall genomic response to the toxin; however, only 20 genes showed consistent changes in expression. These include chaperones which may be part of a generalized stress response; cytochrome P450 which may be involved in metabolizing the toxin; and lipid dystrophy genes such as lipin-2, uridine phosphorylase and a homolog to tribbles, a stress-inducible gene involved in cell death. Of the genes that responded to the MC-LR, none showed significant changes in expression profile in response to TTRP. Taken together, the data indicate that ultrasonic irradiation of MC-LR effectively reduces hepatotoxicity in mice and therefore may be a useful method for detoxification of drinking water.« less

Toxicogenomic profiling in maternal and fetal rodent brains following gestational exposure to chlorpyrifos

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moreira, Estefania G.; Department of Physiological Sciences, State University of Londrina, Londrina, PR; Yu Xiaozhong

2010-06-15

Considering the wide variety of effects that have been reported to occur in the developmental neurotoxicity of chlorpyrifos (CP) and the lack of consensus on their dependence of brain acetylcholinesterase (AChE) activity inhibition, we applied microarray technology to explore dose-dependent alterations in transcriptional response in the fetal and maternal C57BL/6 mouse brain after daily gestational exposure (days 6 to 17) to CP (2, 4, 10, 12 or 15 mg/kg, sc). We identified significantly altered genes across doses and assessed for overrepresentation of Gene Ontology (GO) biological processes and KEGG pathways. We further clustered genes based on their expression profiles acrossmore » doses and repeated the GO/pathways analysis for each cluster. The dose-effect relationship of CP on gene expression, both at the gene and pathway levels was non-monotonic and not necessarily related to brain AChE inhibition. The largest impact was observed in the 10 mg/kg dose group which was also the LOAEL for brain AChE inhibition. In the maternal brain, lower doses (4 mg/kg) influenced GO categories and pathways such as cell adhesion, behavior, lipid metabolism, long-term potentiation, nervous system development, neurogenesis, synaptic transmission. In the fetal brain, lower doses (2 and/or 4 mg/kg) significantly altered cell division, translation, transmission of nerve impulse, chromatin modification, long-term potentiation. In addition, some genes involved in nervous system development and signaling were shown to be specifically influenced by these lower CP doses. Our approach was sensitive and reflected the diversity of responses known to be disrupted by CP and highlighted possible additional consequences of CP neurotoxicity, such as disturbance of the ubiquitin proteasome system.« less

Assessment of the DNA damaging potential of environmental chemicals using a quantitative high-throughput screening approach to measure p53 activation.

PubMed

Witt, Kristine L; Hsieh, Jui-Hua; Smith-Roe, Stephanie L; Xia, Menghang; Huang, Ruili; Zhao, Jinghua; Auerbach, Scott S; Hur, Junguk; Tice, Raymond R

2017-08-01

Genotoxicity potential is a critical component of any comprehensive toxicological profile. Compounds that induce DNA or chromosomal damage often activate p53, a transcription factor essential to cell cycle regulation. Thus, within the US Tox21 Program, we screened a library of ∼10,000 (∼8,300 unique) environmental compounds and drugs for activation of the p53-signaling pathway using a quantitative high-throughput screening assay employing HCT-116 cells (p53 +/+ ) containing a stably integrated β-lactamase reporter gene under control of the p53 response element (p53RE). Cells were exposed (-S9) for 16 hr at 15 concentrations (generally 1.2 nM to 92 μM) three times, independently. Excluding compounds that failed analytical chemistry analysis or were suspected of inducing assay interference, 365 (4.7%) of 7,849 unique compounds were concluded to activate p53. As part of an in-depth characterization of our results, we first compared them with results from traditional in vitro genotoxicity assays (bacterial mutation, chromosomal aberration); ∼15% of known, direct-acting genotoxicants in our library activated the p53RE. Mining the Comparative Toxicogenomics Database revealed that these p53 actives were significantly associated with increased expression of p53 downstream genes involved in DNA damage responses. Furthermore, 53 chemical substructures associated with genotoxicity were enriched in certain classes of p53 actives, for example, anthracyclines (antineoplastics) and vinca alkaloids (tubulin disruptors). Interestingly, the tubulin disruptors manifested unusual nonmonotonic concentration response curves suggesting activity through a unique p53 regulatory mechanism. Through the analysis of our results, we aim to define a role for this assay as one component of a comprehensive toxicological characterization of large compound libraries. Environ. Mol. Mutagen. 58:494-507, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity.

PubMed

Zhang, J D; Berntenis, N; Roth, A; Ebeling, M

2014-06-01

Gene signatures of drug-induced toxicity are of broad interest, but they are often identified from small-scale, single-time point experiments, and are therefore of limited applicability. To address this issue, we performed multivariate analysis of gene expression, cell-based assays, and histopathological data in the TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system) database. Data mining highlights four genes-EGR1, ATF3, GDF15 and FGF21-that are induced 2 h after drug administration in human and rat primary hepatocytes poised to eventually undergo cytotoxicity-induced cell death. Modelling and simulation reveals that these early stress-response genes form a functional network with evolutionarily conserved structure and intrinsic dynamics. This is underlined by the fact that early induction of this network in vivo predicts drug-induced liver and kidney pathology with high accuracy. Our findings demonstrate the value of early gene-expression signatures in predicting and understanding compound-induced toxicity. The identified network can empower first-line tests that reduce animal use and costs of safety evaluation.

The zebrafish embryo model in toxicology and teratology, September 2–3, 2010, Karlsruhe, Germany.

PubMed

Busch, Wibke; Duis, Karen; Fenske, Martina; Maack, Gerd; Legler, Juliette; Padilla, Stephanie; Strähle, Uwe; Witters, Hilda; Scholz, Stefan

2011-05-01

The use of fish embryos is gaining popularity for research in the area of toxicology and teratology. Particularly embryos of the zebrafish offer an array of different applications ranging from regulatory testing to mechanistic research. For this reason a consortium of two research centres and a company with the support of the COST Action EuFishBiomed has organised the Workshop “The zebrafish embryo model in toxicology and teratology”, in Karlsruhe, Germany, 2nd–3rd September 2010. The workshop aimed at bringing together experts from different areas of toxicology using the (zebra)fish embryo and stimulating networking between scientists and representatives from regulatory bodies, research institutions and industry. Recent findings, presented in various platform presentations in the area of regulatory toxicity, high throughput screening, toxicogenomics, as well as environmental and human risk assessment are highlighted in this meeting report. Furthermore, the constraints and possibilities of the model as discussed at the workshop are described. A follow up-meeting was appreciated by the about 120 participants and is planned for 2012.

Novel approaches to improving the chemical safety of the meat chain towards toxicants.

PubMed

Engel, E; Ratel, J; Bouhlel, J; Planche, C; Meurillon, M

2015-11-01

In addition to microbiological issues, meat chemical safety is a growing concern for the public authorities, chain stakeholders and consumers. Meat may be contaminated by various chemical toxicants originating from the environment, treatments of agricultural production or food processing. Generally found at trace levels in meat, these toxicants may harm human health during chronic exposure. This paper overviews the key issues to be considered to ensure better control of their occurrence in meat and assessment of the related health risk. We first describe potential contaminants of meat products. Strategies to move towards a more efficient and systematic control of meat chemical safety are then presented in a second part, with a focus on emerging approaches based on toxicogenomics. The third part presents mitigation strategies to limit the impact of process-induced toxicants in meat. Finally, the last part introduces methodological advances to refine chemical risk assessment related to the occurrence of toxicants in meat by quantifying the influence of digestion on the fraction of food contaminants that may be assimilated by the human body. Copyright © 2015 Elsevier Ltd. All rights reserved.

A genome-wide nanotoxicology screen of Saccharomyces cerevisiae mutants reveals the basis for cadmium sulphide quantum dot tolerance and sensitivity.

PubMed

Marmiroli, M; Pagano, L; Pasquali, F; Zappettini, A; Tosato, V; Bruschi, C V; Marmiroli, N

2016-01-01

The use of cadmium sulphide quantum dots (CdS QDs) is increasing, particularly in the electronics industry. Their size (1-10 nm in diameter) is, however, such that they can be taken up by living cells. Here, a bakers' yeast (Saccharomyces cerevisiae) deletion mutant collection has been exploited to provide a high-throughput means of revealing the genetic basis for tolerance/susceptibility to CdS QD exposure. The deletion of 112 genes, some associated with the abiotic stress response, some with various metabolic processes, some with mitochondrial organization, some with transport and some with DNA repair, reduced the level of tolerance to CdS QDs. A gene ontology analysis highlighted the role of oxidative stress in determining the cellular response. The transformation of sensitive mutants with centromeric plasmids harbouring DNA from a wild type strain restored the wild type growth phenotype when the complemented genes encoded either HSC82, DSK2 or ALD3. The use of these simple eukaryote knock-out mutants for functional toxicogenomic analysis will inform studies focusing on higher organisms.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hirode, Mitsuhiro; Ono, Atsushi; Miyagishima, Toshikazu

We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for diagnosis of hepatic phospholipidosis, we extracted 78 probe sets of rat hepatic genes from data of 5 drugs, amiodarone, amitriptyline, clomipramine, imipramine, and ketoconazole, which actually induced this phenotype. Principal component analysis (PCA) using these probes clearly separated dose- and time-dependent clusters of treated groups from their controls. Moreover, 6 drugs (chloramphenicol, chlorpromazine, gentamicin, perhexiline, promethazine, and tamoxifen), which were reported to cause phospholipidosis but judged as negative by histopathological examination, were designated as positive by PCA usingmore » these probe sets. Eight drugs (carbon tetrachloride, coumarin, tetracycline, metformin, hydroxyzine, diltiazem, 2-bromoethylamine, and ethionamide), which showed phospholipidosis-like vacuolar formation in the histopathology, could be distinguished from the typical drugs causing phospholipidosis. Moreover, the possible induction of phospholipidosis was predictable by the expression of these genes 24 h after single administration in some of the drugs. We conclude that these identified 78 probe sets could be useful for diagnosis of phospholipidosis, and that toxicogenomics would be a promising approach for prediction of this type of toxicity.« less

Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?

PubMed Central

Doktorova, T. Y.; Yildirimman, Reha; Ceelen, Liesbeth; Vilardell, Mireia; Vanhaecke, Tamara; Vinken, Mathieu; Ates, Gamze; Heymans, Anja; Gmuender, Hans; Bort, Roque; Corvi, Raffaella; Phrakonkham, Pascal; Li, Ruoya; Mouchet, Nicolas; Chesne, Christophe; van Delft, Joost; Kleinjans, Jos; Castell, Jose; Herwig, Ralf; Rogiers, Vera

2014-01-01

The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen-specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88 % correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances. PMID:26417288

Web services-based text-mining demonstrates broad impacts for interoperability and process simplification.

PubMed

Wiegers, Thomas C; Davis, Allan Peter; Mattingly, Carolyn J

2014-01-01

The Critical Assessment of Information Extraction systems in Biology (BioCreAtIvE) challenge evaluation tasks collectively represent a community-wide effort to evaluate a variety of text-mining and information extraction systems applied to the biological domain. The BioCreative IV Workshop included five independent subject areas, including Track 3, which focused on named-entity recognition (NER) for the Comparative Toxicogenomics Database (CTD; http://ctdbase.org). Previously, CTD had organized document ranking and NER-related tasks for the BioCreative Workshop 2012; a key finding of that effort was that interoperability and integration complexity were major impediments to the direct application of the systems to CTD's text-mining pipeline. This underscored a prevailing problem with software integration efforts. Major interoperability-related issues included lack of process modularity, operating system incompatibility, tool configuration complexity and lack of standardization of high-level inter-process communications. One approach to potentially mitigate interoperability and general integration issues is the use of Web services to abstract implementation details; rather than integrating NER tools directly, HTTP-based calls from CTD's asynchronous, batch-oriented text-mining pipeline could be made to remote NER Web services for recognition of specific biological terms using BioC (an emerging family of XML formats) for inter-process communications. To test this concept, participating groups developed Representational State Transfer /BioC-compliant Web services tailored to CTD's NER requirements. Participants were provided with a comprehensive set of training materials. CTD evaluated results obtained from the remote Web service-based URLs against a test data set of 510 manually curated scientific articles. Twelve groups participated in the challenge. Recall, precision, balanced F-scores and response times were calculated. Top balanced F-scores for gene, chemical and disease NER were 61, 74 and 51%, respectively. Response times ranged from fractions-of-a-second to over a minute per article. We present a description of the challenge and summary of results, demonstrating how curation groups can effectively use interoperable NER technologies to simplify text-mining pipeline implementation. Database URL: http://ctdbase.org/ © The Author(s) 2014. Published by Oxford University Press.

Petri net-based prediction of therapeutic targets that recover abnormally phosphorylated proteins in muscle atrophy.

PubMed

Jung, Jinmyung; Kwon, Mijin; Bae, Sunghwa; Yim, Soorin; Lee, Doheon

2018-03-05

Muscle atrophy, an involuntary loss of muscle mass, is involved in various diseases and sometimes leads to mortality. However, therapeutics for muscle atrophy thus far have had limited effects. Here, we present a new approach for therapeutic target prediction using Petri net simulation of the status of phosphorylation, with a reasonable assumption that the recovery of abnormally phosphorylated proteins can be a treatment for muscle atrophy. The Petri net model was employed to simulate phosphorylation status in three states, i.e. reference, atrophic and each gene-inhibited state based on the myocyte-specific phosphorylation network. Here, we newly devised a phosphorylation specific Petri net that involves two types of transitions (phosphorylation or de-phosphorylation) and two types of places (activation with or without phosphorylation). Before predicting therapeutic targets, the simulation results in reference and atrophic states were validated by Western blotting experiments detecting five marker proteins, i.e. RELA, SMAD2, SMAD3, FOXO1 and FOXO3. Finally, we determined 37 potential therapeutic targets whose inhibition recovers the phosphorylation status from an atrophic state as indicated by the five validated marker proteins. In the evaluation, we confirmed that the 37 potential targets were enriched for muscle atrophy-related terms such as actin and muscle contraction processes, and they were also significantly overlapping with the genes associated with muscle atrophy reported in the Comparative Toxicogenomics Database (p-value < 0.05). Furthermore, we noticed that they included several proteins that could not be characterized by the shortest path analysis. The three potential targets, i.e. BMPR1B, ROCK, and LEPR, were manually validated with the literature. In this study, we suggest a new approach to predict potential therapeutic targets of muscle atrophy with an analysis of phosphorylation status simulated by Petri net. We generated a list of the potential therapeutic targets whose inhibition recovers abnormally phosphorylated proteins in an atrophic state. They were evaluated by various approaches, such as Western blotting, GO terms, literature, known muscle atrophy-related genes and shortest path analysis. We expect the new proposed strategy to provide an understanding of phosphorylation status in muscle atrophy and to provide assistance towards identifying new therapies.

Web services-based text-mining demonstrates broad impacts for interoperability and process simplification

PubMed Central

Wiegers, Thomas C.; Davis, Allan Peter; Mattingly, Carolyn J.

2014-01-01

The Critical Assessment of Information Extraction systems in Biology (BioCreAtIvE) challenge evaluation tasks collectively represent a community-wide effort to evaluate a variety of text-mining and information extraction systems applied to the biological domain. The BioCreative IV Workshop included five independent subject areas, including Track 3, which focused on named-entity recognition (NER) for the Comparative Toxicogenomics Database (CTD; http://ctdbase.org). Previously, CTD had organized document ranking and NER-related tasks for the BioCreative Workshop 2012; a key finding of that effort was that interoperability and integration complexity were major impediments to the direct application of the systems to CTD's text-mining pipeline. This underscored a prevailing problem with software integration efforts. Major interoperability-related issues included lack of process modularity, operating system incompatibility, tool configuration complexity and lack of standardization of high-level inter-process communications. One approach to potentially mitigate interoperability and general integration issues is the use of Web services to abstract implementation details; rather than integrating NER tools directly, HTTP-based calls from CTD's asynchronous, batch-oriented text-mining pipeline could be made to remote NER Web services for recognition of specific biological terms using BioC (an emerging family of XML formats) for inter-process communications. To test this concept, participating groups developed Representational State Transfer /BioC-compliant Web services tailored to CTD's NER requirements. Participants were provided with a comprehensive set of training materials. CTD evaluated results obtained from the remote Web service-based URLs against a test data set of 510 manually curated scientific articles. Twelve groups participated in the challenge. Recall, precision, balanced F-scores and response times were calculated. Top balanced F-scores for gene, chemical and disease NER were 61, 74 and 51%, respectively. Response times ranged from fractions-of-a-second to over a minute per article. We present a description of the challenge and summary of results, demonstrating how curation groups can effectively use interoperable NER technologies to simplify text-mining pipeline implementation. Database URL: http://ctdbase.org/ PMID:24919658

BioCreative V CDR task corpus: a resource for chemical disease relation extraction.

PubMed

Li, Jiao; Sun, Yueping; Johnson, Robin J; Sciaky, Daniela; Wei, Chih-Hsuan; Leaman, Robert; Davis, Allan Peter; Mattingly, Carolyn J; Wiegers, Thomas C; Lu, Zhiyong

2016-01-01

Community-run, formal evaluations and manually annotated text corpora are critically important for advancing biomedical text-mining research. Recently in BioCreative V, a new challenge was organized for the tasks of disease named entity recognition (DNER) and chemical-induced disease (CID) relation extraction. Given the nature of both tasks, a test collection is required to contain both disease/chemical annotations and relation annotations in the same set of articles. Despite previous efforts in biomedical corpus construction, none was found to be sufficient for the task. Thus, we developed our own corpus called BC5CDR during the challenge by inviting a team of Medical Subject Headings (MeSH) indexers for disease/chemical entity annotation and Comparative Toxicogenomics Database (CTD) curators for CID relation annotation. To ensure high annotation quality and productivity, detailed annotation guidelines and automatic annotation tools were provided. The resulting BC5CDR corpus consists of 1500 PubMed articles with 4409 annotated chemicals, 5818 diseases and 3116 chemical-disease interactions. Each entity annotation includes both the mention text spans and normalized concept identifiers, using MeSH as the controlled vocabulary. To ensure accuracy, the entities were first captured independently by two annotators followed by a consensus annotation: The average inter-annotator agreement (IAA) scores were 87.49% and 96.05% for the disease and chemicals, respectively, in the test set according to the Jaccard similarity coefficient. Our corpus was successfully used for the BioCreative V challenge tasks and should serve as a valuable resource for the text-mining research community.Database URL: http://www.biocreative.org/tasks/biocreative-v/track-3-cdr/. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products.

PubMed

Carter, C J; Blizard, R A

2016-10-27

The increasing incidence of autism suggests a major environmental influence. Epidemiology has implicated many candidates and genetics many susceptibility genes. Gene/environment interactions in autism were analysed using 206 autism susceptibility genes (ASG's) from the Autworks database to interrogate ∼1 million chemical/gene interactions in the comparative toxicogenomics database. Any bias towards ASG's was statistically determined for each chemical. Many suspect compounds identified in epidemiology, including tetrachlorodibenzodioxin, pesticides, particulate matter, benzo(a)pyrene, heavy metals, valproate, acetaminophen, SSRI's, cocaine, bisphenol A, phthalates, polyhalogenated biphenyls, flame retardants, diesel constituents, terbutaline and oxytocin, inter alia showed a significant degree of bias towards ASG's, as did relevant endogenous agents (retinoids, sex steroids, thyroxine, melatonin, folate, dopamine, serotonin). Numerous other suspected endocrine disruptors (over 100) selectively targeted ASG's including paraquat, atrazine and other pesticides not yet studied in autism and many compounds used in food, cosmetics or household products, including tretinoin, soy phytoestrogens, aspartame, titanium dioxide and sodium fluoride. Autism polymorphisms influence the sensitivity to some of these chemicals and these same genes play an important role in barrier function and control of respiratory cilia sweeping particulate matter from the airways. Pesticides, heavy metals and pollutants also disrupt barrier and/or ciliary function, which is regulated by sex steroids and by bitter/sweet taste receptors. Further epidemiological studies and neurodevelopmental and behavioural research is warranted to determine the relevance of large number of suspect candidates whose addition to the environment, household, food and cosmetics might be fuelling the autism epidemic in a gene-dependent manner. Copyright © 2016. Published by Elsevier Ltd.

Sieve-based coreference resolution enhances semi-supervised learning model for chemical-induced disease relation extraction.

PubMed

Le, Hoang-Quynh; Tran, Mai-Vu; Dang, Thanh Hai; Ha, Quang-Thuy; Collier, Nigel

2016-07-01

The BioCreative V chemical-disease relation (CDR) track was proposed to accelerate the progress of text mining in facilitating integrative understanding of chemicals, diseases and their relations. In this article, we describe an extension of our system (namely UET-CAM) that participated in the BioCreative V CDR. The original UET-CAM system's performance was ranked fourth among 18 participating systems by the BioCreative CDR track committee. In the Disease Named Entity Recognition and Normalization (DNER) phase, our system employed joint inference (decoding) with a perceptron-based named entity recognizer (NER) and a back-off model with Semantic Supervised Indexing and Skip-gram for named entity normalization. In the chemical-induced disease (CID) relation extraction phase, we proposed a pipeline that includes a coreference resolution module and a Support Vector Machine relation extraction model. The former module utilized a multi-pass sieve to extend entity recall. In this article, the UET-CAM system was improved by adding a 'silver' CID corpus to train the prediction model. This silver standard corpus of more than 50 thousand sentences was automatically built based on the Comparative Toxicogenomics Database (CTD) database. We evaluated our method on the CDR test set. Results showed that our system could reach the state of the art performance with F1 of 82.44 for the DNER task and 58.90 for the CID task. Analysis demonstrated substantial benefits of both the multi-pass sieve coreference resolution method (F1 + 4.13%) and the silver CID corpus (F1 +7.3%).Database URL: SilverCID-The silver-standard corpus for CID relation extraction is freely online available at: https://zenodo.org/record/34530 (doi:10.5281/zenodo.34530). © The Author(s) 2016. Published by Oxford University Press.

Smoke-induced microRNA and related proteome alterations. Modulation by chemopreventive agents.

PubMed

De Flora, Silvio; Balansky, Roumen; D'Agostini, Francesco; Cartiglia, Cristina; Longobardi, Mariagrazia; Steele, Vernon E; Izzotti, Alberto

2012-12-15

Dysregulation of microRNAs (miRNAs) has important consequences on gene and protein expression since a single miRNA targets a number of genes simultaneously. This article provides a review of published data and ongoing studies regarding the effects of cigarette smoke (CS), either mainstream (MCS) or environmental (ECS), on the expression of miRNAs and related proteins. The results generated in mice, rats, and humans provided evidence that exposure to CS results in an intense dysregulation of miRNA expression in the respiratory tract, which is mainly oriented in the sense of downregulation. In parallel, there was an upregulation of proteins targeted by the downregulated miRNAs. These trends reflect an attempt to defend the respiratory tract by means of antioxidant mechanisms, detoxification of carcinogens, DNA repair, anti-inflammatory pathways, apoptosis, etc. However, a long-lasting exposure to CS causes irreversible miRNA alterations that activate carcinogenic mechanisms, such as modulation of oncogenes and oncosuppressor genes, cell proliferation, recruitment of undifferentiated stem cells, inflammation, inhibition of intercellular communications, angiogenesis, invasion, and metastasis. The miRNA alterations induced by CS in the lung of mice and rats are similar to those observed in the human respiratory tract. Since a number of miRNAs that are modulated by CS and/or chemopreventive agents are subjected to single nucleotide polymorphisms in humans, they can be evaluated according to toxicogenomic/pharmacogenomics approaches. A variety of cancer chemopreventive agents tested in our laboratory modulated both baseline and CS-related miRNA and proteome alterations, thus contributing to evaluate both safety and efficacy of dietary and pharmacological agents. Copyright © 2012 UICC.

Use of toxicogenomics for identifying genetic markers of pulmonary oedema

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balharry, Dominique; Oreffo, Victor; Richards, Roy

2005-04-15

This study was undertaken primarily to identify genetic markers of oedema and inflammation. Mild pulmonary injury was induced following the instillation of the oedema-producing agent, bleomycin (0.5 units). Oedema was then confirmed by conventional toxicology (lavage protein levels, free cell counts and lung/body weight ratios) and histology 3 days post-bleomycin instillation.The expression profile of 1176 mRNA species was determined for bleomycin-exposed lung (Clontech Atlas macroarray, n = 9). To obtain pertinent results from these data, it was necessary to develop a simple, effective method for bioinformatic analysis of altered gene expression. Data were log{sub 10} transformed followed by global normalisation.more » Differential gene expression was accepted if: (a) genes were statistically significant (P {<=} 0.05) from a two-tailed t test; (b) genes were consistently outside a two standard deviation (SD) range from control levels. A combination of these techniques identified 31 mRNA transcripts (approximately 3%) which were significantly altered in bleomycin treated tissue. Of these genes, 26 were down-regulated whilst only five were up-regulated. Two distinct clusters were identified, with 17 genes classified as encoding hormone receptors, and nine as encoding ion channels. Both these clusters were consistently down-regulated.The magnitude of the changes in gene expression were quantified and confirmed by Q-PCR (n = 6), validating the macroarray data and the bioinformatic analysis employed.In conclusion, this study has developed a suitable macroarray analysis procedure and provides the basis for a better understanding of the gene expression changes occurring during the early phase of drug-induced pulmonary oedema.« less

Comparison of in vitro bioactivation of flutamide and its cyano analogue: evidence for reductive activation by human NADPH:cytochrome P450 reductase.

PubMed

Wen, Bo; Coe, Kevin J; Rademacher, Peter; Fitch, William L; Monshouwer, Mario; Nelson, Sidney D

2008-12-01

Flutamide (FLU), a nonsteroidal antiandrogen drug widely used in the treatment of prostate cancer, has been associated with idiosyncratic hepatotoxicity in patients. It is proposed that bioactivation of FLU and subsequent binding of reactive metabolite(s) to cellular proteins play a causative role. A toxicogenomic study comparing FLU and its nitro to cyano analogue (CYA) showed that the nitroaromatic group of FLU enhanced cytotoxicity to hepatocytes, indicating that reduction of the nitroaromatic group may represent a potential route of FLU-induced hepatotoxicity [Coe et al. (2007) Chem. Res. Toxicol. 20, 1277-1290]. In the current study, we compared in vitro bioactivation of FLU and CYA in human liver microsomes and cryopreserved human hepatocytes. A nitroreduction metabolite FLU-6 was formed in liver microsomal incubations of FLU under atmospheric oxygen levels and, to a greater extent, under anaerobic conditions. Seven glutathione (GSH) adducts of FLU, FLU-G1-7, were tentatively identified in human liver microsomal incubations using liquid chromatography-tandem mass spectrometry (LC/ MS/MS), while CYA formed only four corresponding GSH adducts, CYA-G1-4, under the same conditions. Of particular interest was the formation of FLU-G5-7 from FLU, where the nitroaromatic group of FLU was reduced to an amino group. A tentative pathway is that upon nitroreduction, the para-diamines undergo cytochrome P450 (P450)-catalyzed two-electron oxidations to form corresponding para-diimine intermediates that react with GSH to form GSH adducts FLU-G5-7, respectively. The identities of FLU-G5-7 were further confirmed by LC/MS/MS analyses of microsomal incubations of a synthesized standard FLU-6. In an attempt to identify enzymes involved in the nitroreduction of FLU, NADPH:cytochrome P450 reductase (CPR) was shown to reduce FLU to FLU-6 under both aerobic and anaerobic conditions. Furthermore, the formation of FLU-G5-7 was completely blocked by the addition of a reversible CPR inhibitor, alpha-lipoic acid, to the incubations of FLU under aerobic conditions. In summary, these results clearly demonstrate that nitroreduction of FLU by CPR contributes to bioactivation and potentially to hepatotoxicity of FLU.

Toxicogenomic analysis reveals profibrogenic effects of trichloroethylene in autoimmune-mediated cholangitis in mice.

PubMed

Kopec, Anna K; Sullivan, Bradley P; Kassel, Karen M; Joshi, Nikita; Luyendyk, James P

2014-10-01

Epidemiological studies suggest that exposure to environmental chemicals increases the risk of developing autoimmune liver disease. However, the identity of specific chemical perpetrators and the mechanisms whereby environmental chemicals modify liver disease is unclear. Previous studies link exposure to trichloroethylene (TCE) with the development of autoimmune liver disease and exacerbation of autoimmunity in lupus-prone MRL mice. In this study, we utilized NOD.c3c4 mice, which spontaneously develop autoimmune cholangitis bearing resemblance to some features of primary biliary cirrhosis. Nine-week-old female NOD.c3c4 mice were given TCE (0.5 mg/ml) or its vehicle (1% Cremophor-EL) in drinking water for 4 weeks. TCE had little effect on clinical chemistry, biliary cyst formation, or hepatic CD3+ T-cell accumulation. Hepatic microarray profiling revealed a dramatic suppression of early growth response 1 (EGR1) mRNA in livers of TCE-treated mice, which was verified by qPCR and immunohistochemical staining. Consistent with a reported link between reduced EGR1 expression and liver fibrosis, TCE increased hepatic type I collagen (COL1A1) mRNA and protein levels in livers of NOD.c3c4 mice. In contrast, TCE did not increase COL1A1 expression in NOD.ShiLtJ mice, which do not develop autoimmune cholangitis. These results suggest that in the context of concurrent autoimmune liver disease with a genetic basis, modification of hepatic gene expression by TCE may increase profibrogenic signaling in the liver. Moreover, these studies suggest that NOD.c3c4 mice may be a novel model to study gene-environment interactions critical for the development of autoimmune liver disease. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Literature-based compound profiling: application to toxicogenomics.

PubMed

Frijters, Raoul; Verhoeven, Stefan; Alkema, Wynand; van Schaik, René; Polman, Jan

2007-11-01

To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action.

Genetical Toxicogenomics in Drosophila Identifies Master Modulatory Loci that are Regulated by Developmental Exposure to Lead

PubMed Central

Ruden, Douglas M.; Chen, Lang; Possidente, Debra; Possidente, Bernard; Rasouli, Parsa; Wang, Luan; Lu, Xiangyi; Garfinkel, Mark D.; Hirsch, Helmut V. B.; Page, Grier P.

2009-01-01

The genetics of gene expression in recombinant inbred lines (RILs) can be mapped as expression quantitative trait loci (eQTLs). So-called “genetical genomics” studies have identified locally-acting eQTLs (cis-eQTLs) for genes that show differences in steady state RNA levels. These studies have also identified distantly-acting master-modulatory trans-eQTLs that regulate tens or hundreds of transcripts (hotspots or transbands). We expand on these studies by performing genetical genomics experiments in two environments in order to identify trans-eQTL that might be regulated by developmental exposure to the neurotoxin lead. Flies from each of 75 RIL were raised from eggs to adults on either control food (made with 250 µM sodium acetate), or lead-treated food (made with 250 µM lead acetate, PbAc). RNA expression analyses of whole adult male flies (5–10 days old) were performed with Affymetrix DrosII whole genome arrays (18,952 probesets). Among the 1,389 genes with cis-eQTL, there were 405 genes unique to control flies and 544 genes unique to lead-treated ones (440 genes had the same cis-eQTLs in both samples). There are 2,396 genes with trans-eQTL which mapped to 12 major transbands with greater than 95 genes. Permutation analyses of the strain labels but not the expression data suggests that the total number of eQTL and the number of transbands are more important criteria for validation than the size of the transband. Two transbands, one located on the 2nd chromosome and one on the 3rd chromosome, co-regulate 33 lead-induced genes, many of which are involved in neurodevelopmental processes. For these 33 genes, rather than allelic variation at one locus exerting differential effects in two environments, we found that variation at two different loci are required for optimal effects on lead-induced expression. PMID:19737576

The Transcriptome of the Zebrafish Embryo After Chemical Exposure: A Meta-Analysis.

PubMed

Schüttler, Andreas; Reiche, Kristin; Altenburger, Rolf; Busch, Wibke

2017-06-01

Numerous studies have been published in the past years investigating the transcriptome of the zebrafish embryo (ZFE) upon being subjected to chemical stress. Aiming at a more mechanistic understanding of the results of such studies, knowledge about commonalities of transcript regulation in response to chemical stress is needed. Thus, our goal in this study was to identify and interpret genes and gene sets constituting a general response to chemical exposure. Therefore, we aggregated and reanalyzed published toxicogenomics data obtained with the ZFE. We found that overlap of differentially transcribed genes in response to chemical stress across independent studies is generally low and the most commonly differentially transcribed genes appear in less than 50% of all treatments across studies. However, effect size analysis revealed several genes showing a common trend of differential expression, among which genes related to calcium homeostasis emerged as key, especially in exposure settings up to 24 h post-fertilization. Additionally, we found that these and other downregulated genes are often linked to anatomical regions developing during the respective exposure period. Genes showing a trend of increased expression were, among others, linked to signaling pathways (e.g., Wnt, Fgf) as well as lysosomal structures and apoptosis. The findings of this study help to increase the understanding of chemical stress responses in the developing zebrafish embryo and provide a starting point to improve experimental designs for this model system. In future, improved time- and concentration-resolved experiments should offer better understanding of stress response patterns and access to mechanistic information. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.

Food safety knowledge on the Bt mutant protein Cry8Ka5 employed in the development of coleopteran-resistant transgenic cotton plants.

PubMed

Farias, Davi F; Peijnenburg, Ad A C M; Grossi-de-Sá, Maria F; Carvalho, Ana F U

2015-01-01

Insecticidal Cry proteins from Bacillus thuringiensis (Bt) have been exploited in the development of genetically modified (GM) crops for pest control. However, several pests are still difficult to control such as the coleopteran boll weevil Anthonomus grandis. By applying in vitro molecular evolution to the cry8Ka1 gene sequence, variants were generated with improved activity against A. grandis. Among them, Cry8Ka5 mutant protein showed coleoptericidal activity 3-fold higher (LC50 2.83 μg/mL) than that of the original protein (Cry8Ka1). Cry8Ka5 has been used in breeding programs in order to obtain coleopteran-resistant cotton plants. Nevertheless, there is some concern in relation to the food safety of transgenic crops, especially to the heterologously expressed proteins. In this context, our research group has performed risk assessment studies on Cry8Ka5, using the tests recommended by Codex as well as tests that we proposed as alternative and/or complementary approaches. Our results on the risk analysis of Cry8Ka5 taken together with those of other Cry proteins, point out that there is a high degree of certainty on their food safety. It is reasonable to emphasize that most safety studies on Cry proteins have essentially used the Codex approach. However, other methodologies would potentially provide additional information such as studies on the effects of Cry proteins and derived peptides on the indigenous gastrointestinal microbiota and on intestinal epithelial cells of humans. Additionally, emerging technologies such as toxicogenomics potentially will offer sensitive alternatives for some current approaches or methods.

De novo transcriptome assembly and differential gene expression analysis of the calanoid copepod Acartia tonsa exposed to nickel nanoparticles.

PubMed

Zhou, Chao; Carotenuto, Ylenia; Vitiello, Valentina; Wu, Changwen; Zhang, Jianshe; Buttino, Isabella

2018-06-14

The calanoid copepod Acartia tonsa is a reference species in standardized ecotoxicology bioassay. Despite this interest, there is a lack of knowledge on molecular responses of A. tonsa to contaminants. We generated a de novo assembled transcriptome of A. tonsa exposed 4 days to 8.5 and 17 mg/L nickel nanoparticles (NiNPs), which have been shown to reduce egg hatching success and larval survival but had no effects on the adults. Aims of our study were to 1) improve the knowledge on the molecular responses of A. tonsa copepod and 2) increase the genomic resources of this copepod for further identification of potential biomarkers of NP exposure. The de novo assembled transcriptome of A. tonsa consisted of 53,619 unigenes, which were further annotated to nr, GO, KOG and KEGG databases. In particular, most unigenes were assigned to Metabolic and Cellular processes (34-45%) GO terms, and to Human disease (28%) and Organismal systems (23%) KEGG categories. Comparison among treatments showed that 373 unigenes were differentially expressed in A. tonsa exposed to NiNPs at 8.5 and 17 mg/L, with respect to control. Most of these genes were downregulated and took part in ribosome biogenesis, translation and protein turnover, thus suggesting that NiNPs could affect the copepod ribosome synthesis machinery and functioning. Overall, our study highlights the potential of toxicogenomic approach in gaining more mechanistic and functional information about the mode of action of emerging compounds on marine organisms, for biomarker discovering in crustaceans. Copyright © 2018 Elsevier Ltd. All rights reserved.

Food safety knowledge on the Bt mutant protein Cry8Ka5 employed in the development of coleopteran-resistant transgenic cotton plants

PubMed Central

Farias, Davi F; Peijnenburg, Ad A C M; Grossi-de-Sá, Maria F; Carvalho, Ana F U

2015-01-01

Insecticidal Cry proteins from Bacillus thuringiensis (Bt) have been exploited in the development of genetically modified (GM) crops for pest control. However, several pests are still difficult to control such as the coleopteran boll weevil Anthonomus grandis. By applying in vitro molecular evolution to the cry8Ka1 gene sequence, variants were generated with improved activity against A. grandis. Among them, Cry8Ka5 mutant protein showed coleoptericidal activity 3-fold higher (LC50 2.83 μg/mL) than that of the original protein (Cry8Ka1). Cry8Ka5 has been used in breeding programs in order to obtain coleopteran-resistant cotton plants. Nevertheless, there is some concern in relation to the food safety of transgenic crops, especially to the heterologously expressed proteins. In this context, our research group has performed risk assessment studies on Cry8Ka5, using the tests recommended by Codex as well as tests that we proposed as alternative and/or complementary approaches. Our results on the risk analysis of Cry8Ka5 taken together with those of other Cry proteins, point out that there is a high degree of certainty on their food safety. It is reasonable to emphasize that most safety studies on Cry proteins have essentially used the Codex approach. However, other methodologies would potentially provide additional information such as studies on the effects of Cry proteins and derived peptides on the indigenous gastrointestinal microbiota and on intestinal epithelial cells of humans. Additionally, emerging technologies such as toxicogenomics potentially will offer sensitive alternatives for some current approaches or methods. PMID:26513483

Effect of chemical mutagens and carcinogens on gene expression profiles in human TK6 cells.

PubMed

Godderis, Lode; Thomas, Reuben; Hubbard, Alan E; Tabish, Ali M; Hoet, Peter; Zhang, Luoping; Smith, Martyn T; Veulemans, Hendrik; McHale, Cliona M

2012-01-01

Characterization of toxicogenomic signatures of carcinogen exposure holds significant promise for mechanistic and predictive toxicology. In vitro transcriptomic studies allow the comparison of the response to chemicals with diverse mode of actions under controlled experimental conditions. We conducted an in vitro study in TK6 cells to characterize gene expression signatures of exposure to 15 genotoxic carcinogens frequently used in European industries. We also examined the dose-responsive changes in gene expression, and perturbation of biochemical pathways in response to these carcinogens. TK6 cells were exposed at 3 dose levels for 24 h with and without S9 human metabolic mix. Since S9 had an impact on gene expression (885 genes), we analyzed the gene expression data from cells cultures incubated with S9 and without S9 independently. The ribosome pathway was affected by all chemical-dose combinations. However in general, no similar gene expression was observed among carcinogens. Further, pathways, i.e. cell cycle, DNA repair mechanisms, RNA degradation, that were common within sets of chemical-dose combination were suggested by clustergram. Linear trends in dose-response of gene expression were observed for Trichloroethylene, Benz[a]anthracene, Epichlorohydrin, Benzene, and Hydroquinone. The significantly altered genes were involved in the regulation of (anti-) apoptosis, maintenance of cell survival, tumor necrosis factor-related pathways and immune response, in agreement with several other studies. Similarly in S9+ cultures, Benz[a]pyrene, Styrene and Trichloroethylene each modified over 1000 genes at high concentrations. Our findings expand our understanding of the transcriptomic response to genotoxic carcinogens, revealing the alteration of diverse sets of genes and pathways involved in cellular homeostasis and cell cycle control.

Effect of Chemical Mutagens and Carcinogens on Gene Expression Profiles in Human TK6 Cells

PubMed Central

Godderis, Lode; Thomas, Reuben; Hubbard, Alan E.; Tabish, Ali M.; Hoet, Peter; Zhang, Luoping; Smith, Martyn T.; Veulemans, Hendrik; McHale, Cliona M.

2012-01-01

Characterization of toxicogenomic signatures of carcinogen exposure holds significant promise for mechanistic and predictive toxicology. In vitro transcriptomic studies allow the comparison of the response to chemicals with diverse mode of actions under controlled experimental conditions. We conducted an in vitro study in TK6 cells to characterize gene expression signatures of exposure to 15 genotoxic carcinogens frequently used in European industries. We also examined the dose-responsive changes in gene expression, and perturbation of biochemical pathways in response to these carcinogens. TK6 cells were exposed at 3 dose levels for 24 h with and without S9 human metabolic mix. Since S9 had an impact on gene expression (885 genes), we analyzed the gene expression data from cells cultures incubated with S9 and without S9 independently. The ribosome pathway was affected by all chemical-dose combinations. However in general, no similar gene expression was observed among carcinogens. Further, pathways, i.e. cell cycle, DNA repair mechanisms, RNA degradation, that were common within sets of chemical-dose combination were suggested by clustergram. Linear trends in dose–response of gene expression were observed for Trichloroethylene, Benz[a]anthracene, Epichlorohydrin, Benzene, and Hydroquinone. The significantly altered genes were involved in the regulation of (anti-) apoptosis, maintenance of cell survival, tumor necrosis factor-related pathways and immune response, in agreement with several other studies. Similarly in S9+ cultures, Benz[a]pyrene, Styrene and Trichloroethylene each modified over 1000 genes at high concentrations. Our findings expand our understanding of the transcriptomic response to genotoxic carcinogens, revealing the alteration of diverse sets of genes and pathways involved in cellular homeostasis and cell cycle control. PMID:22723965

Comprehensive Assessments of RNA-seq by the SEQC Consortium: FDA-Led Efforts Advance Precision Medicine.

PubMed

Xu, Joshua; Gong, Binsheng; Wu, Leihong; Thakkar, Shraddha; Hong, Huixiao; Tong, Weida

2016-03-15

Studies on gene expression in response to therapy have led to the discovery of pharmacogenomics biomarkers and advances in precision medicine. Whole transcriptome sequencing (RNA-seq) is an emerging tool for profiling gene expression and has received wide adoption in the biomedical research community. However, its value in regulatory decision making requires rigorous assessment and consensus between various stakeholders, including the research community, regulatory agencies, and industry. The FDA-led SEquencing Quality Control (SEQC) consortium has made considerable progress in this direction, and is the subject of this review. Specifically, three RNA-seq platforms (Illumina HiSeq, Life Technologies SOLiD, and Roche 454) were extensively evaluated at multiple sites to assess cross-site and cross-platform reproducibility. The results demonstrated that relative gene expression measurements were consistently comparable across labs and platforms, but not so for the measurement of absolute expression levels. As part of the quality evaluation several studies were included to evaluate the utility of RNA-seq in clinical settings and safety assessment. The neuroblastoma study profiled tumor samples from 498 pediatric neuroblastoma patients by both microarray and RNA-seq. RNA-seq offers more utilities than microarray in determining the transcriptomic characteristics of cancer. However, RNA-seq and microarray-based models were comparable in clinical endpoint prediction, even when including additional features unique to RNA-seq beyond gene expression. The toxicogenomics study compared microarray and RNA-seq profiles of the liver samples from rats exposed to 27 different chemicals representing multiple toxicity modes of action. Cross-platform concordance was dependent on chemical treatment and transcript abundance. Though both RNA-seq and microarray are suitable for developing gene expression based predictive models with comparable prediction performance, RNA-seq offers advantages over microarray in profiling genes with low expression. The rat BodyMap study provided a comprehensive rat transcriptomic body map by performing RNA-Seq on 320 samples from 11 organs in either sex of juvenile, adolescent, adult and aged Fischer 344 rats. Lastly, the transferability study demonstrated that signature genes of predictive models are reciprocally transferable between microarray and RNA-seq data for model development using a comprehensive approach with two large clinical data sets. This result suggests continued usefulness of legacy microarray data in the coming RNA-seq era. In conclusion, the SEQC project enhances our understanding of RNA-seq and provides valuable guidelines for RNA-seq based clinical application and safety evaluation to advance precision medicine.

Adverse outcome pathway (AOP) development and evaluation ...

EPA Pesticide Factsheets

The Adverse Outcome Pathway provides a construct for assembling mechanistic information at different levels of biological organization in a form designed to support regulatory decision making. In particular, it frames the link between molecular and cellular events that can be measured in high throughput toxicity testing and the organism or population-level events that are commonly relevant in defining risk. Recognizing the importance of this emerging framework, the Organisation for Economic Co-operation and Development (OECD) launched a program to support the development, documentation and consideration of AOPs by the international community in 2012 (http://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm). In 2014, a handbook (https://aopkb.org/common/AOP_Handbook.pdf) was developed to guide users in the documentation and evaluation of AOPs and their entry into an official knowledgebase. The handbook draws on longstanding experience in consideration of mechanistic data (e.g., mode of action analysis) to inform risk assessment. To further assist users, a training program was developed by members of the OECD Extended Advisory Group to teach users the basic principles of AOP development and the best practices as outlined in the OECD AOP handbook. Training sessions began in early 2015, and this course will provide training for interested SOT scientists. Following this course, all participants will be familiar w

Advances in Toxico-Cheminformatics: Supporting a New ...

EPA Pesticide Factsheets

EPA’s National Center for Computational Toxicology is building capabilities to support a new paradigm for toxicity screening and prediction through the harnessing of legacy toxicity data, creation of data linkages, and generation of new high-throughput screening (HTS) data. The DSSTox project is working to improve public access to quality structure-annotated chemical toxicity information in less summarized forms than traditionally employed in SAR modeling, and in ways that facilitate both data-mining and read-across. Both DSSTox Structure-Files and the dedicated on-line DSSTox Structure-Browser are enabling seamless structure-based searching and linkages to and from previously isolated, chemically indexed public toxicity data resources (e.g., NTP, EPA IRIS, CPDB). Most recently, structure-enabled search capabilities have been extended to chemical exposure-related microarray experiments in the public EBI Array Express database, additionally linking this resource to the NIEHS CEBS toxicogenomics database. The public DSSTox chemical and bioassay inventory has been recently integrated into PubChem, allowing a user to take full advantage of PubChem structure-activity and bioassay clustering features. The DSSTox project is providing cheminformatics support for EPA’s ToxCastTM project, as well as supporting collaborations with the National Toxicology Program (NTP) HTS and the NIH Chemical Genomics Center (NCGC). Phase I of the ToxCastTM project is generating HT

Personalized Exposure Assessment: Promising Approaches for Human Environmental Health Research

PubMed Central

Weis, Brenda K.; Balshaw, David; Barr, John R.; Brown, David; Ellisman, Mark; Lioy, Paul; Omenn, Gilbert; Potter, John D.; Smith, Martyn T.; Sohn, Lydia; Suk, William A.; Sumner, Susan; Swenberg, James; Walt, David R.; Watkins, Simon; Thompson, Claudia; Wilson, Samuel H.

2005-01-01

New technologies and methods for assessing human exposure to chemicals, dietary and lifestyle factors, infectious agents, and other stressors provide an opportunity to extend the range of human health investigations and advance our understanding of the relationship between environmental exposure and disease. An ad hoc Committee on Environmental Exposure Technology Development was convened to identify new technologies and methods for deriving personalized exposure measurements for application to environmental health studies. The committee identified a “toolbox” of methods for measuring external (environmental) and internal (biologic) exposure and assessing human behaviors that influence the likelihood of exposure to environmental agents. The methods use environmental sensors, geographic information systems, biologic sensors, toxicogenomics, and body burden (biologic) measurements. We discuss each of the methods in relation to current use in human health research; specific gaps in the development, validation, and application of the methods are highlighted. We also present a conceptual framework for moving these technologies into use and acceptance by the scientific community. The framework focuses on understanding complex human diseases using an integrated approach to exposure assessment to define particular exposure–disease relationships and the interaction of genetic and environmental factors in disease occurrence. Improved methods for exposure assessment will result in better means of monitoring and targeting intervention and prevention programs. PMID:16002370

Technical guide for applications of gene expression profiling in human health risk assessment of environmental chemicals.

PubMed

Bourdon-Lacombe, Julie A; Moffat, Ivy D; Deveau, Michelle; Husain, Mainul; Auerbach, Scott; Krewski, Daniel; Thomas, Russell S; Bushel, Pierre R; Williams, Andrew; Yauk, Carole L

2015-07-01

Toxicogenomics promises to be an important part of future human health risk assessment of environmental chemicals. The application of gene expression profiles (e.g., for hazard identification, chemical prioritization, chemical grouping, mode of action discovery, and quantitative analysis of response) is growing in the literature, but their use in formal risk assessment by regulatory agencies is relatively infrequent. Although additional validations for specific applications are required, gene expression data can be of immediate use for increasing confidence in chemical evaluations. We believe that a primary reason for the current lack of integration is the limited practical guidance available for risk assessment specialists with limited experience in genomics. The present manuscript provides basic information on gene expression profiling, along with guidance on evaluating the quality of genomic experiments and data, and interpretation of results presented in the form of heat maps, pathway analyses and other common approaches. Moreover, potential ways to integrate information from gene expression experiments into current risk assessment are presented using published studies as examples. The primary objective of this work is to facilitate integration of gene expression data into human health risk assessments of environmental chemicals. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Integrating publicly-available data to generate computationally ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) framework provides a way of organizing knowledge related to the key biological events that result in a particular health outcome. For the majority of environmental chemicals, the availability of curated pathways characterizing potential toxicity is limited. Methods are needed to assimilate large amounts of available molecular data and quickly generate putative AOPs for further testing and use in hazard assessment. A graph-based workflow was used to facilitate the integration of multiple data types to generate computationally-predicted (cp) AOPs. Edges between graph entities were identified through direct experimental or literature information or computationally inferred using frequent itemset mining. Data from the TG-GATEs and ToxCast programs were used to channel large-scale toxicogenomics information into a cpAOP network (cpAOPnet) of over 20,000 relationships describing connections between chemical treatments, phenotypes, and perturbed pathways measured by differential gene expression and high-throughput screening targets. Sub-networks of cpAOPs for a reference chemical (carbon tetrachloride, CCl4) and outcome (hepatic steatosis) were extracted using the network topology. Comparison of the cpAOP subnetworks to published mechanistic descriptions for both CCl4 toxicity and hepatic steatosis demonstrate that computational approaches can be used to replicate manually curated AOPs and identify pathway targets that lack genomic mar

Genetic toxicology in the 21st century: Reflections and future ...

EPA Pesticide Factsheets

A symposium at the 40th anniversary of the Environmental Mutagen Society, held from October 24–28, 2009 in St. Louis, MO, surveyed the current status and future directions of genetic toxicology. This article summarizes the presentations and provides a perspective on the future. An abbreviated history is presented, highlighting the current standard battery of genotoxicity assays and persistent challenges. Application of computational toxicology to safety testing within a regulatory setting is discussed as a means for reducing the need for animal testing and human clinical trials, and current approaches and applications of in silico genotoxicity screening approaches across the pharmaceutical industry were surveyed and are reported here. The expanded use of toxicogenomics to illuminate mechanisms and bridge genotoxicity and carcinogenicity, and new public efforts to use high-throughput screening technologies to address lack of toxicity evaluation for the backlog of thousands of industrial chemicals in the environment are detailed. The Tox21 project involves coordinated efforts of four U.S. Government regulatory/research entities to use new and innovative assays to characterize key steps in toxicity pathways, including genotoxic and nongenotoxic mechanisms for carcinogenesis. Progress to date, highlighting preliminary test results from the National Toxicology Program is summarized. Finally, an overview is presented of ToxCast™, a related research program of the

Comparison of in Vitro Bioactivation of Flutamide and Its Cyano Analogue: Evidence for Reductive Activation by Human NADPH:Cytochrome P450 Reductase

PubMed Central

Wen, Bo; Coe, Kevin J.; Rademacher, Peter; Fitch, William L.; Monshouwer, Mario; Nelson, Sidney D.

2009-01-01

Flutamide (FLU), a nonsteroidal antiandrogen drug widely used in the treatment of prostate cancer, has been associated with idiosyncratic hepatotoxicity in patients. It is proposed that bioactivation of FLU and subsequent binding of reactive metabolite(s) to cellular proteins play a causative role. A toxicogenomic study comparing FLU and its nitro to cyano analogue (CYA) showed that the nitroaromatic group of FLU enhanced cytotoxicity to hepatocytes, indicating that reduction of the nitroaromatic group may represent a potential route of FLU-induced hepatotoxicity [Coe et al. (2007) Chem. Res. Toxicol. 20, 1277–1290]. In the current study, we compared in vitro bioactivation of FLU and CYA in human liver microsomes and cryopreserved human hepatocytes. A nitroreduction metabolite FLU-6 was formed in liver microsomal incubations of FLU under atmospheric oxygen levels and, to a greater extent, under anaerobic conditions. Seven glutathione (GSH) adducts of FLU, FLU-G1–7, were tentatively identified in human liver microsomal incubations using liquid chromatography–tandem mass spectrometry (LC/MS/MS), while CYA formed only four corresponding GSH adducts, CYA-G1–4, under the same conditions. Of particular interest was the formation of FLU-G5–7 from FLU, where the nitroaromatic group of FLU was reduced to an amino group. A tentative pathway is that upon nitroreduction, the para-diamines undergo cytochrome P450 (P450)-catalyzed two-electron oxidations to form corresponding para-diimine intermediates that react with GSH to form GSH adducts FLU-G5–7, respectively. The identities of FLU-G5–7 were further confirmed by LC/MS/MS analyses of microsomal incubations of a synthesized standard FLU-6. In an attempt to identify enzymes involved in the nitroreduction of FLU, NADPH:cytochrome P450 reductase (CPR) was shown to reduce FLU to FLU-6 under both aerobic and anaerobic conditions. Furthermore, the formation of FLU-G5–7 was completely blocked by the addition of a reversible CPR inhibitor, α-lipoic acid, to the incubations of FLU under aerobic conditions. In summary, these results clearly demonstrate that nitroreduction of FLU by CPR contributes to bioactivation and potentially to hepatotoxicity of FLU. PMID:19548358

Toxicogenomic response of Pseudomonas aeruginosa to ortho-phenylphenol

PubMed Central

Nde, Chantal W; Jang, Hyeung-Jin; Toghrol, Freshteh; Bentley, William E

2008-01-01

Background Pseudomonas aeruginosa (P. aeruginosa) is the most common opportunistic pathogen implicated in nosocomial infections and in chronic lung infections in cystic fibrosis patients. Ortho-phenylphenol (OPP) is an antimicrobial agent used as an active ingredient in several EPA registered disinfectants. Despite its widespread use, there is a paucity of information on its target molecular pathways and the cellular responses that it elucidates in bacteria in general and in P. aeruginosa in particular. An understanding of the OPP-driven gene regulation and cellular response it elicits will facilitate more effective utilization of this antimicrobial and possibly lead to the development of more effective disinfectant treatments. Results Herein, we performed a genome-wide transcriptome analysis of the cellular responses of P. aeruginosa exposed to 0.82 mM OPP for 20 and 60 minutes. Our data indicated that OPP upregulated the transcription of genes encoding ribosomal, virulence and membrane transport proteins after both treatment times. After 20 minutes of exposure to 0.82 mM OPP, genes involved in the exhibition of swarming motility and anaerobic respiration were upregulated. After 60 minutes of OPP treatment, the transcription of genes involved in amino acid and lipopolysaccharide biosynthesis were upregulated. Further, the transcription of the ribosome modulation factor (rmf) and an alternative sigma factor (rpoS) of RNA polymerase were downregulated after both treatment times. Conclusion Results from this study indicate that after 20 minutes of exposure to OPP, genes that have been linked to the exhibition of anaerobic respiration and swarming motility were upregulated. This study also suggests that the downregulation of the rmf and rpoS genes may be indicative of the mechanism by which OPP causes decreases in cell viability in P. aeruginosa. Consequently, a protective response involving the upregulation of translation leading to the increased synthesis of membrane related proteins and virulence proteins is possibly induced after both treatment times. In addition, cell wall modification may occur due to the increased synthesis of lipopolysaccharide after 60 minutes exposure to OPP. This gene expression profile can now be utilized for a better understanding of the target cellular pathways of OPP in P. aeruginosa and how this organism develops resistance to OPP. PMID:18847467

Pulmonary Response to Surface-Coated Nanotitanium Dioxide Particles Includes Induction of Acute Phase Response Genes, Inflammatory Cascades, and Changes in MicroRNAs: A Toxicogenomic Study

PubMed Central

Halappanavar, Sabina; Jackson, Petra; Williams, Andrew; Jensen, Keld A; Hougaard, Karin S; Vogel, Ulla; Yauk, Carole L; Wallin, Håkan

2011-01-01

Titanium dioxide nanoparticles (nanoTiO2) are used in various applications including in paints. NanoTiO2 inhalation may induce pulmonary toxicity and systemic effects. However, the underlying molecular mechanisms are poorly understood. In this study, the effects of inhaled surface-coated nanoTiO2 on pulmonary global messenger RNA (mRNA) and microRNA (miRNA) expression in mouse were characterized to provide insight into the molecular response. Female C57BL/6BomTac mice were exposed for 1 hr daily to 42.4 ± 2.9 (SEM) mg surface-coated nanoTiO2/m3 for 11 consecutive days by inhalation and were sacrificed 5 days following the last exposure. Physicochemical properties of the particles were determined. Pulmonary response to nanoTiO2 was characterized using DNA microarrays and pathway-specific PCR arrays and related to data on pulmonary inflammation from bronchial lavages. NanoTiO2 exposure resulted in increased levels of mRNA for acute phase markers serum amyloid A-1 (Saa1) and serum amyloid A-3 (Saa3), several C-X-C and C-C motif chemokines, and cytokine tumor necrosis factor genes. Protein analysis of Saa1 and 3 showed selective upregulation of Saa3 in lung tissues. Sixteen miRNAs were induced by more than 1.2-fold (adjusted P-value < 0.05) following exposure. Real time polymerase chain reaction confirmed the upregulation of miR-1, miR-449a and revealed dramatic induction of miR-135b (60-fold). Thus, inhalation of surface-coated nanoTiO2 results in changes in the expression of genes associated with acute phase, inflammation and immune response 5 days post exposure with concomitant changes in several miRNAs. The role of these miRNAs in pulmonary response to inhaled particles is unknown and warrants further research. Environ. Mol. Mutagen., 2011. © 2011 Wiley-Liss, Inc.† PMID:21259345

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

PubMed Central

Proctor, Deborah M.; Suh, Mina; Haws, Laurie C.; Kirman, Christopher R.; Harris, Mark A.

2013-01-01

Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors. PMID:23445218

Transcriptomic study of the toxic mechanism triggered by beauvericin in Jurkat cells.

PubMed

Escrivá, L; Jennen, D; Caiment, F; Manyes, L

2018-03-01

Beauvericin (BEA), an ionophoric cyclic hexadepsipeptide mycotoxin, is able to increase oxidative stress by altering membrane ion permeability and uncoupling oxidative phosphorylation. A toxicogenomic study was performed to investigate gene expression changes triggered by BEA exposure (1.5, 3 and 5 μM; 24 h) in Jurkat cells through RNA-sequencing and differential gene expression analysis. Perturbed gene expression was observed in a concentration dependent manner, with 43 differentially expressed genes (DEGs) overlapped in the three studied concentrations. Gene ontology (GO) analysis showed several biological processes related to electron transport chain, oxidative phosphorylation, and cellular respiration significantly altered. Molecular functions linked to mitochondrial respiratory chain and oxidoreductase activity were over-represented (q-value < 0.01). Pathway analysis revealed oxidative phosphorylation and electron transport chain as the most significantly altered pathways in all studied doses (z-score > 1.96; adj p-value < 0.05). 77 genes involved in the respiratory chain were significantly down-regulated at least at one dose. Moreover, 21 genes related to apoptosis and programmed cell death, and 12 genes related to caspase activity were significantly altered, mainly affecting initiator caspases 8, 9 and 10. The results demonstrated BEA-induced mitochondrial damage affecting the respiratory chain, and pointing to apoptosis through the caspase cascade in human lymphoblastic T cells. Copyright © 2017 Elsevier B.V. All rights reserved.

RNA-Seq-based toxicogenomic assessment of fresh frozen and formalin-fixed tissues yields similar mechanistic insights.

PubMed

Auerbach, Scott S; Phadke, Dhiral P; Mav, Deepak; Holmgren, Stephanie; Gao, Yuan; Xie, Bin; Shin, Joo Heon; Shah, Ruchir R; Merrick, B Alex; Tice, Raymond R

2015-07-01

Formalin-fixed, paraffin-embedded (FFPE) pathology specimens represent a potentially vast resource for transcriptomic-based biomarker discovery. We present here a comparison of results from a whole transcriptome RNA-Seq analysis of RNA extracted from fresh frozen and FFPE livers. The samples were derived from rats exposed to aflatoxin B1 (AFB1 ) and a corresponding set of control animals. Principal components analysis indicated that samples were separated in the two groups representing presence or absence of chemical exposure, both in fresh frozen and FFPE sample types. Sixty-five percent of the differentially expressed transcripts (AFB1 vs. controls) in fresh frozen samples were also differentially expressed in FFPE samples (overlap significance: P < 0.0001). Genomic signature and gene set analysis of AFB1 differentially expressed transcript lists indicated highly similar results between fresh frozen and FFPE at the level of chemogenomic signatures (i.e., single chemical/dose/duration elicited transcriptomic signatures), mechanistic and pathology signatures, biological processes, canonical pathways and transcription factor networks. Overall, our results suggest that similar hypotheses about the biological mechanism of toxicity would be formulated from fresh frozen and FFPE samples. These results indicate that phenotypically anchored archival specimens represent a potentially informative resource for signature-based biomarker discovery and mechanistic characterization of toxicity. Copyright © 2014 John Wiley & Sons, Ltd.

A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens.

PubMed

Schaap, Mirjam M; Wackers, Paul F K; Zwart, Edwin P; Huijskens, Ilse; Jonker, Martijs J; Hendriks, Giel; Breit, Timo M; van Steeg, Harry; van de Water, Bob; Luijten, Mirjam

2015-12-01

Alternative methods to detect non-genotoxic carcinogens are urgently needed, as this class of carcinogens goes undetected in the current testing strategy for carcinogenicity under REACH. A complicating factor is that non-genotoxic carcinogens act through several distinctive modes of action, which makes prediction of their carcinogenic property difficult. We have recently demonstrated that gene expression profiling in primary mouse hepatocytes is a useful approach to categorize non-genotoxic carcinogens according to their modes of action. In the current study, we improved the methods used for analysis and added mouse embryonic stem cells as a second in vitro test system, because of their features complementary to hepatocytes. Our approach involved an unsupervised analysis based on the 30 most significantly up- and down-regulated genes per chemical. Mouse embryonic stem cells and primary mouse hepatocytes were exposed to a selected set of chemicals and subsequently subjected to gene expression profiling. We focused on non-genotoxic carcinogens, but also included genotoxic carcinogens and non-carcinogens to test the robustness of this approach. Application of the optimized comparison approach resulted in improved categorization of non-genotoxic carcinogens. Mouse embryonic stem cells were a useful addition, especially for genotoxic substances, but also for detection of non-genotoxic carcinogens that went undetected by primary hepatocytes. The approach presented here is an important step forward to categorize chemicals, especially those that are carcinogenic.

Practical aspects of mutagenicity testing strategy: an industrial perspective.

PubMed

Gollapudi, B B; Krishna, G

2000-11-20

Genetic toxicology studies play a central role in the development and marketing of new chemicals for pharmaceutical, agricultural, industrial, and consumer use. During the discovery phase of product development, rapid screening tests that require minimal amounts of test materials are used to assist in the design and prioritization of new molecules. At this stage, a modified Salmonella reverse mutation assay and an in vitro micronucleus test with mammalian cell culture are frequently used for screening. Regulatory genetic toxicology studies are conducted with a short list of compounds using protocols that conform to various international guidelines. A set of four assays usually constitutes the minimum test battery that satisfies global requirements. This set includes a bacterial reverse mutation assay, an in vitro cytogenetic test with mammalian cell culture, an in vitro gene mutation assay in mammalian cell cultures, and an in vivo rodent bone marrow micronucleus test. Supplementary studies are conducted in certain instances either as a follow-up to the findings from this initial testing battery and/or to satisfy a regulatory requirement. Currently available genetic toxicology assays have helped the scientific and industrial community over the past several decades in evaluating the mutagenic potential of chemical agents. The emerging field of toxicogenomics has the potential to redefine our ability to study the response of cells to genetic damage and hence our ability to study threshold phenomenon.

The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

PubMed

Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

2013-01-01

The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Microarray analysis of toxicogenomic effects of Ortho-phenylphenol in Staphylococcus aureus

PubMed Central

Jang, Hyeung-Jin; Nde, Chantal; Toghrol, Freshteh; Bentley, William E

2008-01-01

Background Staphylococcus aureus (S. aureus), is responsible for many infectious diseases, ranging from benign skin infections to life-threatening endocarditis and toxic shock syndrome. Ortho-phenylphenol (OPP) is an antimicrobial agent and an active ingredient of EPA-registered disinfectants with wide human exposure in various agricultural, hospital and veterinary disinfectant products. Despite many uses, an understanding of a cellular response to OPP and it's mechanism of action, targeted genes, and the connectivity between targeted genes and the rest of cell metabolism remains obscure. Results Herein, we performed a genome-wide transcriptome analysis of the cellular responses of S. aureus when exposed to 0.82 mM of OPP for 20 and 60 min. Our data indicated that OPP downregulated the biosynthesis of many amino acids, which are required for protein synthesis. In particular, the genes encoding the enzymes of the diaminopimelate (DAP) pathway which results in lysine biosynthesis were significantly downregualted. Intriguingly, we revealed that the transcription of genes encoding ribosomal proteins was upregulated by OPP and at the same time, the genes encoding iron acquisition and transport were downregulated. The genes encoding virulence factors were upregulated and genes encoding phospholipids were downregulated upon 20 min exposure to OPP. Conclusion By using microarray analysis that enables us to simultaneously and globally examine the complete transcriptome during cellular responses, we have revealed novel information regarding the mode of action of OPP on Staphylococcus: OPP inhibits anabolism of many amino acids and highly downregulates the genes that encode the enzymes involved in the DAP pathway. Lysine and DAP are essential for building up the peptidoglycan cell wall. It was concluded that the mode of action of OPP is similar to the mechanism of action of some antibiotics. The discovery of this phenomenon provides useful information that will benefit further antimicrobial research on S. aureus. PMID:18793396

PPARα siRNA–Treated Expression Profiles Uncover the Causal Sufficiency Network for Compound-Induced Liver Hypertrophy

PubMed Central

Dai, Xudong; Souza, Angus T. De; Dai, Hongyue; Lewis, David L; Lee, Chang-kyu; Spencer, Andy G; Herweijer, Hans; Hagstrom, Jim E; Linsley, Peter S; Bassett, Douglas E; Ulrich, Roger G; He, Yudong D

2007-01-01

Uncovering pathways underlying drug-induced toxicity is a fundamental objective in the field of toxicogenomics. Developing mechanism-based toxicity biomarkers requires the identification of such novel pathways and the order of their sufficiency in causing a phenotypic response. Genome-wide RNA interference (RNAi) phenotypic screening has emerged as an effective tool in unveiling the genes essential for specific cellular functions and biological activities. However, eliciting the relative contribution of and sufficiency relationships among the genes identified remains challenging. In the rodent, the most widely used animal model in preclinical studies, it is unrealistic to exhaustively examine all potential interactions by RNAi screening. Application of existing computational approaches to infer regulatory networks with biological outcomes in the rodent is limited by the requirements for a large number of targeted permutations. Therefore, we developed a two-step relay method that requires only one targeted perturbation for genome-wide de novo pathway discovery. Using expression profiles in response to small interfering RNAs (siRNAs) against the gene for peroxisome proliferator-activated receptor α (Ppara), our method unveiled the potential causal sufficiency order network for liver hypertrophy in the rodent. The validity of the inferred 16 causal transcripts or 15 known genes for PPARα-induced liver hypertrophy is supported by their ability to predict non-PPARα–induced liver hypertrophy with 84% sensitivity and 76% specificity. Simulation shows that the probability of achieving such predictive accuracy without the inferred causal relationship is exceedingly small (p < 0.005). Five of the most sufficient causal genes have been previously disrupted in mouse models; the resulting phenotypic changes in the liver support the inferred causal roles in liver hypertrophy. Our results demonstrate the feasibility of defining pathways mediating drug-induced toxicity from siRNA-treated expression profiles. When combined with phenotypic evaluation, our approach should help to unleash the full potential of siRNAs in systematically unveiling the molecular mechanism of biological events. PMID:17335344

Mode of action for reproductive and hepatic toxicity inferred from a genomic study of triazole antifungals.

PubMed

Goetz, Amber K; Dix, David J

2009-08-01

The mode of action for the reproductive toxicity of some triazole antifungals has been characterized as an increase in serum testosterone and hepatic response, and reduced insemination and fertility indices. In order to refine our mechanistic understanding of these potential modes of action, gene expression profiling was conducted on liver and testis from male Wistar Han IGS rats exposed to myclobutanil (500, 2000 ppm), propiconazole (500, 2500 ppm), or triadimefon (500, 1800 ppm) from gestation day six to postnatal day 92. Gene expression profiles indicated that all three triazoles significantly perturbed the fatty acid, steroid, and xenobiotic metabolism pathways in the male rat liver. In addition, triadimefon modulated expression of genes in the liver from the sterol biosynthesis pathway. Although expression of individual genes were affected, there were no common pathways modulated by all three triazoles in the testis. The pathways identified in the liver included numerous genes involved in phase I-III metabolism (Aldh1a1, Cyp1a1, Cyp2b2, Cyp3a1, Cyp3a2, Slco1a4, Udpgtr2), fatty acid metabolism (Cyp4a10, Pcx, Ppap2b), and steroid metabolism (Ugt1a1, Ugt2a1) for which expression was altered by the triazoles. These differentially expressed genes form part of a network involving lipid, sterol, and steroid homeostatic pathways regulated by the constitutive androstane (CAR), pregnane X (PXR), peroxisome proliferator-activated alpha, and other nuclear receptors in liver. These relatively high dose and long-term exposures to triazole antifungals appeared to perturb fatty acid and steroid metabolism in the male rat liver predominantly through the CAR and PXR signaling pathways. These toxicogenomic effects describe a plausible series of key events contributing to the disruption in steroid homeostasis and reproductive toxicity of select triazole antifungals.

An integrated approach with the zebrafish model for biomonitoring of municipal wastewater effluent and receiving waters.

PubMed

Li, Caixia; Chen, Qiyu; Zhang, Xiaoyan; Snyder, Shane A; Gong, Zhiyuan; Lam, Siew Hong

2017-12-11

Comprehensive monitoring of water pollution is challenging. With the increasing amount and types of anthropogenic compounds being released into water, there are rising concerns of undetected toxicity. This is especially true for municipal wastewater effluents that are discharged to surface waters. This study was designed to integrate zebrafish toxicogenomics, targeted gene expression, and morphological analyses, for toxicity evaluation of effluent discharged from two previously characterized wastewater treatment plants (WWTPs) in Pima County, Arizona, and their receiving surface water. Zebrafish embryos were exposed to organic extracts from the WWTP1 effluent that were reconstituted to represent 1× and 0.5× of the original concentration. Microarray analyses identified deregulated gene probes that mapped to 1666, 779, and 631 unique human homologs in the 1×, 0.5×, and the intersection of both groups, respectively. These were associated with 18 cellular and molecular functions ranging from cell cycle to metabolism and are involved in the development and function of 10 organ systems including nervous, cardiovascular, haematological, reproductive, and hepatic systems. Superpathway of cholesterol biosynthesis, retinoic acid receptor activation, glucocorticoid receptor and prolactin signaling were among the top 11 perturbed canonical pathways. Real-time quantitative PCR validated the expression changes of 12 selected genes. These genes were then tested on zebrafish embryos exposed to the reconstituted extract of water sampled downstream of WWTP1 and another nearby WWTP2. The expression of several targeted genes were significantly affected by the WWTP effluents and some of the downstream receiving waters. Morphological analyses using four transgenic zebrafish lines revealed potential toxicity associated with nervous, hepatic, endothelial-vascular and myeloid systems. This study demonstrated how information can be obtained using adverse outcome pathway framework to derive biological effect-based monitoring tools. This integrated approach using zebrafish can supplement analytical chemistry to provide more comprehensive monitoring of discharged effluents and their receiving waters. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sources of Variance in Baseline Gene Expression in the Rodent Liver

PubMed Central

Corton, J. Christopher; Bushel, Pierre R.; Fostel, Jennifer; O'Lone, Raegan B.

2012-01-01

The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in liver gene expression in the rodent. Here, studies which highlight contributions of different factors to gene expression variability in the rodent liver are discussed including a large meta-analysis of rat liver, which identified genes that vary in control animals in the absence of chemical treatment. Genes and their pathways that are the most and least variable were identified in a number of these studies. Life stage, fasting, sex, diet, circadian rhythm and liver lobe source can profoundly influence gene expression in the liver. Recognition of biological and technical factors that contribute to variability of background gene expression can help the investigator in the design of an experiment that maximizes sensitivity and reduces the influence of confounders that may lead to misinterpretation of genomic changes. The factors that contribute to variability in liver gene expression in rodents are likely analogous to those contributing to human interindividual variability in drug response and chemical toxicity. Identification of batteries of genes that are altered in a variety of background conditions could be used to predict responses to drugs and chemicals in appropriate models of the human liver. PMID:22230429

Identification of potential genomic biomarkers of hepatotoxicity caused by reactive metabolites of N-methylformamide: Application of stable isotope labeled compounds in toxicogenomic studies.

PubMed

Mutlib, Abdul; Jiang, Ping; Atherton, Jim; Obert, Leslie; Kostrubsky, Seva; Madore, Steven; Nelson, Sidney

2006-10-01

The inability to predict if a metabolically bioactivated compound will cause toxicity in later stages of drug development or post-marketing is of serious concern. One approach for improving the predictive success of compound toxicity has been to compare the gene expression profile in preclinical models dosed with novel compounds to a gene expression database generated from compounds with known toxicity. While this guilt-by-association approach can be useful, it is often difficult to elucidate gene expression changes that may be related to the generation of reactive metabolites. In an effort to address this issue, we compared the gene expression profiles obtained from animals treated with a soft-electrophile-producing hepatotoxic compound against corresponding deuterium labeled analogues resistant to metabolic processing. Our aim was to identify a subset of potential biomarker genes for hepatotoxicity caused by soft-electrophile-producing compounds. The current study utilized a known hepatotoxic compound N-methylformamide (NMF) and its two analogues labeled with deuterium at different positions to block metabolic oxidation at the formyl (d(1)) and methyl (d(3)) moieties. Groups of mice were dosed with each compound, and their livers were harvested at different time intervals. RNA was prepared and analyzed on Affymetrix GeneChip arrays. RNA transcripts showing statistically significant changes were identified, and selected changes were confirmed using TaqMan RT-PCR. Serum clinical chemistry and histopathologic evaluations were performed on selected samples as well. The data set generated from the different groups of animals enabled us to determine which gene expression changes were attributed to the bioactivating pathway. We were able to selectively modulate the metabolism of NMF by labeling various positions of the molecule with a stable isotope, allowing us to monitor gene changes specifically due to a particular metabolic pathway. Two groups of genes were identified, which were associated with the metabolism of a certain part of the NMF molecule. The metabolic pathway leading to the production of reactive methyl isocyanate resulted in distinct expression patterns that correlated with histopathologic findings. There was a clear correlation between the expression of certain genes involved in the cell cycle/apoptosis and inflammatory pathways and the presence of reactive metabolite. These genes may serve as potential genomic biomarkers of hepatotoxicity induced by soft-electrophile-producing compounds. However, the robustness of these potential genomic biomarkers will need to be validated using other hepatotoxicants (both soft- and hard-electrophile-producing agents) and compounds known to cause idiosyncratic liver toxicity before being adopted into the drug discovery screening process.

Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Auerbach, Scott S.; Shah, Ruchir R.; Mav, Deepak

Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 or 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan). Seven models were generated based on individual exposure durations (2, 14 or 90 days) or a combination ofmore » exposures (2 + 14, 2 + 90, 14 + 90 and 2 + 14 + 90 days). All sets of data, with the exception of one yielded models with 0% cross-validation error. Independent validation of the models was performed using expression data from the liver of rats exposed at 2 dose levels to a collection of alkenylbenzene flavoring agents. Depending on the model used and the exposure duration of the test data, independent validation error rates ranged from 47% to 10%. The variable with the most notable effect on independent validation accuracy was exposure duration of the alkenylbenzene test data. All models generally exhibited improved performance as the exposure duration of the alkenylbenzene data increased. The models differentiated between hepatocarcinogenic (estragole and safrole) and non-hepatocarcinogenic (anethole, eugenol and isoeugenol) alkenylbenzenes previously studied in a carcinogenicity bioassay. In the case of safrole the models correctly differentiated between carcinogenic and non-carcinogenic dose levels. The models predict that two alkenylbenzenes not previously assessed in a carcinogenicity bioassay, myristicin and isosafrole, would be weakly hepatocarcinogenic if studied at a dose level of 2 mmol/kg bw/day for 2 years in male F344 rats; therefore suggesting that these chemicals should be a higher priority relative to other untested alkenylbenzenes for evaluation in the carcinogenicity bioassay. The results of the study indicate that gene expression-based predictive models are an effective tool for identifying hepatocarcinogens. Furthermore, we find that exposure duration is a critical variable in the success or failure of such an approach, particularly when evaluating chemicals with unknown carcinogenic potency.« less

Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning.

PubMed

Auerbach, Scott S; Shah, Ruchir R; Mav, Deepak; Smith, Cynthia S; Walker, Nigel J; Vallant, Molly K; Boorman, Gary A; Irwin, Richard D

2010-03-15

Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 or 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan). Seven models were generated based on individual exposure durations (2, 14 or 90 days) or a combination of exposures (2+14, 2+90, 14+90 and 2+14+90 days). All sets of data, with the exception of one yielded models with 0% cross-validation error. Independent validation of the models was performed using expression data from the liver of rats exposed at 2 dose levels to a collection of alkenylbenzene flavoring agents. Depending on the model used and the exposure duration of the test data, independent validation error rates ranged from 47% to 10%. The variable with the most notable effect on independent validation accuracy was exposure duration of the alkenylbenzene test data. All models generally exhibited improved performance as the exposure duration of the alkenylbenzene data increased. The models differentiated between hepatocarcinogenic (estragole and safrole) and non-hepatocarcinogenic (anethole, eugenol and isoeugenol) alkenylbenzenes previously studied in a carcinogenicity bioassay. In the case of safrole the models correctly differentiated between carcinogenic and non-carcinogenic dose levels. The models predict that two alkenylbenzenes not previously assessed in a carcinogenicity bioassay, myristicin and isosafrole, would be weakly hepatocarcinogenic if studied at a dose level of 2 mmol/kg bw/day for 2 years in male F344 rats; therefore suggesting that these chemicals should be a higher priority relative to other untested alkenylbenzenes for evaluation in the carcinogenicity bioassay. The results of the study indicate that gene expression-based predictive models are an effective tool for identifying hepatocarcinogens. Furthermore, we find that exposure duration is a critical variable in the success or failure of such an approach, particularly when evaluating chemicals with unknown carcinogenic potency. Published by Elsevier Inc.

A systems approach for analysis of high content screening assay data with topic modeling.

PubMed

Bisgin, Halil; Chen, Minjun; Wang, Yuping; Kelly, Reagan; Fang, Hong; Xu, Xiaowei; Tong, Weida

2013-01-01

High Content Screening (HCS) has become an important tool for toxicity assessment, partly due to its advantage of handling multiple measurements simultaneously. This approach has provided insight and contributed to the understanding of systems biology at cellular level. To fully realize this potential, the simultaneously measured multiple endpoints from a live cell should be considered in a probabilistic relationship to assess the cell's condition to response stress from a treatment, which poses a great challenge to extract hidden knowledge and relationships from these measurements. In this work, we applied a text mining method of Latent Dirichlet Allocation (LDA) to analyze cellular endpoints from in vitro HCS assays and related to the findings to in vivo histopathological observations. We measured multiple HCS assay endpoints for 122 drugs. Since LDA requires the data to be represented in document-term format, we first converted the continuous value of the measurements to the word frequency that can processed by the text mining tool. For each of the drugs, we generated a document for each of the 4 time points. Thus, we ended with 488 documents (drug-hour) each having different values for the 10 endpoints which are treated as words. We extracted three topics using LDA and examined these to identify diagnostic topics for 45 common drugs located in vivo experiments from the Japanese Toxicogenomics Project (TGP) observing their necrosis findings at 6 and 24 hours after treatment. We found that assay endpoints assigned to particular topics were in concordance with the histopathology observed. Drugs showing necrosis at 6 hour were linked to severe damage events such as Steatosis, DNA Fragmentation, Mitochondrial Potential, and Lysosome Mass. DNA Damage and Apoptosis were associated with drugs causing necrosis at 24 hours, suggesting an interplay of the two pathways in these drugs. Drugs with no sign of necrosis we related to the Cell Loss and Nuclear Size assays, which is suggestive of hepatocyte regeneration. The evidence from this study suggests that topic modeling with LDA can enable us to interpret relationships of endpoints of in vitro assays along with an in vivo histological finding, necrosis. Effectiveness of this approach may add substantially to our understanding of systems biology.

An overview of transcriptional regulation in response to toxicological insult.

PubMed

Jennings, Paul; Limonciel, Alice; Felice, Luca; Leonard, Martin O

2013-01-01

The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-κB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology.

Exposure to low-dose bisphenol A impairs meiosis in the rat seminiferous tubule culture model: a physiotoxicogenomic approach.

PubMed

Ali, Sazan; Steinmetz, Gérard; Montillet, Guillaume; Perrard, Marie-Hélène; Loundou, Anderson; Durand, Philippe; Guichaoua, Marie-Roberte; Prat, Odette

2014-01-01

Bisphenol A (BPA) is one of the most widespread chemicals in the world and is suspected of being responsible for male reproductive impairments. Nevertheless, its molecular mode of action on spermatogenesis is unclear. This work combines physiology and toxicogenomics to identify mechanisms by which BPA affects the timing of meiosis and induces germ-cell abnormalities. We used a rat seminiferous tubule culture model mimicking the in vivo adult rat situation. BPA (1 nM and 10 nM) was added to the culture medium. Transcriptomic and meiotic studies were performed on the same cultures at the same exposure times (days 8, 14, and 21). Transcriptomics was performed using pangenomic rat microarrays. Immunocytochemistry was conducted with an anti-SCP3 antibody. The gene expression analysis showed that the total number of differentially expressed transcripts was time but not dose dependent. We focused on 120 genes directly involved in the first meiotic prophase, sustaining immunocytochemistry. Sixty-two genes were directly involved in pairing and recombination, some of them with high fold changes. Immunocytochemistry indicated alteration of meiotic progression in the presence of BPA, with increased leptotene and decreased diplotene spermatocyte percentages and partial meiotic arrest at the pachytene checkpoint. Morphological abnormalities were observed at all stages of the meiotic prophase. The prevalent abnormalities were total asynapsis and apoptosis. Transcriptomic analysis sustained immunocytological observations. We showed that low doses of BPA alter numerous genes expression, especially those involved in the reproductive system, and severely impair crucial events of the meiotic prophase leading to partial arrest of meiosis in rat seminiferous tubule cultures.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Xiugong, E-mail: xiugong.gao@fda.hhs.gov; Sprando, Robert L.; Yourick, Jeffrey J.

Developmental toxicity testing has traditionally relied on animal models which are costly, time consuming, and require the sacrifice of large numbers of animals. In addition, there are significant disparities between human beings and animals in their responses to chemicals. Thalidomide is a species-specific developmental toxicant that causes severe limb malformations in humans but not in mice. Here, we used microarrays to study transcriptomic changes induced by thalidomide in an in vitro model based on differentiation of mouse embryonic stem cells (mESCs). C57BL/6 mESCs were allowed to differentiate spontaneously and RNA was collected at 24, 48, and 72 h after exposuremore » to 0.25 mM thalidomide. Global gene expression analysis using microarrays revealed hundreds of differentially expressed genes upon thalidomide exposure that were enriched in gene ontology (GO) terms and canonical pathways associated with embryonic development and differentiation. In addition, many genes were found to be involved in small GTPases-mediated signal transduction, heart development, and inflammatory responses, which coincide with clinical evidences and may represent critical embryotoxicities of thalidomide. These results demonstrate that transcriptomics in combination with mouse embryonic stem cell differentiation is a promising alternative model for developmental toxicity assessment. - Highlights: • Studied genomic changes in mouse embryonic stem cells upon thalidomide exposure • Identified gene expression changes that may represent thalidomide embryotoxicity • The toxicogenomic changes coincide well with known thalidomide clinical outcomes. • The mouse embryonic stem cell model is suitable for developmental toxicity testing. • The model has the potential for high-throughput screening of a multitude of compounds.« less

Genetic Toxicology in the 21st Century: Reflections and Future Directions

PubMed Central

Mahadevan, Brinda; Snyder, Ronald D.; Waters, Michael D.; Benz, R. Daniel; Kemper, Raymond A.; Tice, Raymond R.; Richard, Ann M.

2011-01-01

A symposium at the 40th anniversary of the Environmental Mutagen Society, held from October 24–28, 2009 in St. Louis, MO, surveyed the current status and future directions of genetic toxicology. This article summarizes the presentations and provides a perspective on the future. An abbreviated history is presented, highlighting the current standard battery of genotoxicity assays and persistent challenges. Application of computational toxicology to safety testing within a regulatory setting is discussed as a means for reducing the need for animal testing and human clinical trials, and current approaches and applications of in silico genotoxicity screening approaches across the pharmaceutical industry were surveyed and are reported here. The expanded use of toxicogenomics to illuminate mechanisms and bridge genotoxicity and carcinogenicity, and new public efforts to use high-throughput screening technologies to address lack of toxicity evaluation for the backlog of thousands of industrial chemicals in the environment are detailed. The Tox21 project involves coordinated efforts of four U.S. Government regulatory/research entities to use new and innovative assays to characterize key steps in toxicity pathways, including genotoxic and nongenotoxic mechanisms for carcinogenesis. Progress to date, highlighting preliminary test results from the National Toxicology Program is summarized. Finally, an overview is presented of ToxCast™, a related research program of the U.S. Environmental Protection Agency, using a broad array of high throughput and high content technologies for toxicity profiling of environmental chemicals, and computational toxicology modeling. Progress and challenges, including the pressing need to incorporate metabolic activation capability, are summarized. PMID:21538556

Investigation of the Mode of Action Underlying the Tumorigenic Response Induced in B6C3F1 Mice Exposed Orally to Hexavalent Chromium

PubMed Central

Thompson, Chad M.; Proctor, Deborah M.; Haws, Laurie C.; Hébert, Charles D.; Grimes, Sheila D.; Shertzer, Howard G.; Kopec, Anna K.; Hixon, J.Gregory; Zacharewski, Timothy R.; Harris, Mark A.

2011-01-01

Chronic ingestion of high concentrations of hexavalent chromium [Cr(VI)] in drinking water induces intestinal tumors in mice. To investigate the mode of action (MOA) underlying these tumors, a 90-day drinking water study was conducted using similar exposure conditions as in a previous cancer bioassay, as well as lower (heretofore unexamined) drinking water concentrations. Tissue samples were collected in mice exposed for 7 or 90 days and subjected to histopathological, biochemical, toxicogenomic, and toxicokinetic analyses. Described herein are the results of toxicokinetic, biochemical, and pathological findings. Following 90 days of exposure to 0.3–520 mg/l of sodium dichromate dihydrate (SDD), total chromium concentrations in the duodenum were significantly elevated at ≥ 14 mg/l. At these concentrations, significant decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed. Beginning at 60 mg/l, intestinal lesions were observed including villous cytoplasmic vacuolization. Atrophy, apoptosis, and crypt hyperplasia were evident at ≥ 170 mg/l. Protein carbonyls were elevated at concentrations ≥ 4 mg/l SDD, whereas oxidative DNA damage, as assessed by 8-hydroxydeoxyguanosine, was not increased in any treatment group. Significant decreases in the GSH/GSSG ratio and similar histopathological lesions as observed in the duodenum were also observed in the jejunum following 90 days of exposure. Cytokine levels (e.g., interleukin-1β) were generally depressed or unaltered at the termination of the study. Overall, the data suggest that Cr(VI) in drinking water can induce oxidative stress, villous cytotoxicity, and crypt hyperplasia in the mouse intestine and may underlie the MOA of intestinal carcinogenesis in mice. PMID:21712504

Genetic toxicology and toxicogenomic analysis of three cigarette smoke condensates in vitro reveals few differences among full-flavor, blonde, and light products

PubMed Central

Yauk, Carole L; Williams, Andrew; Buick, Julie K; Chen, Guosheng; Maertens, Rebecca M; Halappanavar, Sabina; White, Paul A

2012-01-01

Cigarette smoking leads to various detrimental health outcomes. Tobacco companies produce different brands of cigarettes that are marketed as reduced harm tobacco products. Early examples included “light” cigarettes, which differ from regular cigarettes due to filter ventilation and/or differences in chemical constituents. In order to establish baseline similarities and differences among different tobacco brands available in Canada, the present study examined the cytotoxicity, mutagenicity, clastogenicity, and gene expression profiles of cigarette smoke condensate (CSC) from three tobacco products, encompassing a full-flavor, blonde, and “light” variety. Using the Salmonella mutagenicity assay, we confirmed that the three CSCs are mutagenic, and that the potency is related to the presence of aromatic amines. Using the Muta™Mouse FE1 cell line we determined that the CSCs were clastogenic and cytotoxic, but nonmutagenic, and the results showed few differences in potencies among the three brands. There were no clear brand-specific changes in gene expression; each brand yielded highly similar expression profiles within a time point and concentration. The molecular pathways and biological functions affected by exposure included xenobiotic metabolism, oxidative stress, DNA damage response, cell cycle arrest and apoptosis, as well as inflammation. Thus, there was no appreciable difference in toxicity or gene expression profiles between regular brands and products marketed as “light,” and hence no evidence of reduced harm. The work establishes baseline CSC cytotoxicity, mutagenicity, and expression profiles that can be used as a point of reference for comparison with data generated for products marketed as reduced harm and/or modified risk tobacco products. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc.† PMID:22431010

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases.

PubMed

Preciados, Mark; Yoo, Changwon; Roy, Deodutta

2016-12-13

During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer's Disease (AD), Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD- APOE , APP , ATP5A1 , CALM1 , CASP3 , GSK3B , IL1B , MAPT , PSEN2 and TNF- underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2 , DPYSL2 , EIF2S1 , ENO1 , MAPT , and PAXIP1 . These genes are also responsive to the following EEDs: ethinyl estradiol ( APBB2 , DPYSL2 , EIF2S1 , ENO1 , MAPT , and PAXIP1 ), BPA ( APBB2 , EIF2S1 , ENO1 , MAPT , and PAXIP1 ), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate ( DPYSL2 and MAPT ). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes- APLP1 , APP , GRIN1 , GRIN2B , MAPT , PSEN2 , PEN2 , and IDE -are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in addition to estrogen signaling, EEDs influencing NRF1 regulated communities of genes across genomic and epigenomic multiple networks may contribute in the development of complex chronic human brain health disorders.

Gene Expression Analysis of CL-20-induced Reversible Neurotoxicity Reveals GABAA Receptors as Potential Target in the Earthworm Eisenia fetida

PubMed Central

Gong, Ping; Guan, Xin; Pirooznia, Mehdi; Liang, Chun; Perkins, Edward J.

2012-01-01

The earthworm Eisenia fetida is one of the most used species in standardized soil ecotoxicity tests. Endpoints such as survival, growth and reproduction are eco-toxicologically relevant but provide little mechanistic insight into toxicity pathways, especially at the molecular level. Here we applied a toxicogenomic approach to investigate the mode of action underlying the reversible neurotoxicity of hexanitrohexaazaisowurtzitane (CL-20), a cyclic nitroamine explosives compound. We developed an E. fetida-specific shotgun microarray targeting 15119 unique E. fetida transcripts. Using this array we profiled gene expression in E. fetida in response to exposure to CL-20. Eighteen earthworms were exposed for 6 days to 0.2 μg/cm2 of CL-20 on filter paper, half of which were allowed to recover in a clean environment for 7 days. Nine vehicle control earthworms were sacrificed at day 6 and 13, separately. Electrophysiological measurements indicated that the conduction velocity of earthworm medial giant nerve fiber decreased significantly after 6-day exposure to CL-20, but was restored after 7 days of recovery. Total RNA was isolated from the four treatment groups including 6-day control, 6-day exposed, 13-day control and 13-day exposed (i.e. 6-day exposure followed by 7-day recovery), and was hybridized to the 15K shot-gun oligo array. Statistical and bioinformatic analyses suggest that CL-20 initiated neurotoxicity by non-competitively blocking the ligand-gated GABAA receptor ion channel, leading to altered expression of genes involved in GABAergic, cholinergic, and Agrin-MuSK pathways. In the recovery phase, expression of affected genes returned to normality, possibly as a result of autophagy and CL-20 dissociation/metabolism. This study provides significant insights into potential mechanisms of CL-20-induced neurotoxicity and the recovery of earthworms from transient neurotoxicity stress. PMID:22191394

The eNanoMapper database for nanomaterial safety information

PubMed Central

Chomenidis, Charalampos; Doganis, Philip; Fadeel, Bengt; Grafström, Roland; Hardy, Barry; Hastings, Janna; Hegi, Markus; Jeliazkov, Vedrin; Kochev, Nikolay; Kohonen, Pekka; Munteanu, Cristian R; Sarimveis, Haralambos; Smeets, Bart; Sopasakis, Pantelis; Tsiliki, Georgia; Vorgrimmler, David; Willighagen, Egon

2015-01-01

Summary Background: The NanoSafety Cluster, a cluster of projects funded by the European Commision, identified the need for a computational infrastructure for toxicological data management of engineered nanomaterials (ENMs). Ontologies, open standards, and interoperable designs were envisioned to empower a harmonized approach to European research in nanotechnology. This setting provides a number of opportunities and challenges in the representation of nanomaterials data and the integration of ENM information originating from diverse systems. Within this cluster, eNanoMapper works towards supporting the collaborative safety assessment for ENMs by creating a modular and extensible infrastructure for data sharing, data analysis, and building computational toxicology models for ENMs. Results: The eNanoMapper database solution builds on the previous experience of the consortium partners in supporting diverse data through flexible data storage, open source components and web services. We have recently described the design of the eNanoMapper prototype database along with a summary of challenges in the representation of ENM data and an extensive review of existing nano-related data models, databases, and nanomaterials-related entries in chemical and toxicogenomic databases. This paper continues with a focus on the database functionality exposed through its application programming interface (API), and its use in visualisation and modelling. Considering the preferred community practice of using spreadsheet templates, we developed a configurable spreadsheet parser facilitating user friendly data preparation and data upload. We further present a web application able to retrieve the experimental data via the API and analyze it with multiple data preprocessing and machine learning algorithms. Conclusion: We demonstrate how the eNanoMapper database is used to import and publish online ENM and assay data from several data sources, how the “representational state transfer” (REST) API enables building user friendly interfaces and graphical summaries of the data, and how these resources facilitate the modelling of reproducible quantitative structure–activity relationships for nanomaterials (NanoQSAR). PMID:26425413

Differential display in rat livers treated for 13 weeks with phenobarbital implicates a role for metabolic and oxidative stress in nongenotoxic carcinogenicity.

PubMed

Elrick, Mollisa M; Kramer, Jeffrey A; Alden, Carl L; Blomme, Eric A G; Bunch, Roderick T; Cabonce, Marc A; Curtiss, Sandra W; Kier, Larry D; Kolaja, Kyle L; Rodi, Charles P; Morris, Dale L

2005-01-01

Hepatic enzyme inducers such as phenobarbital are often nongenotoxic rodent hepatocarcinogens. Currently, nongenotoxic hepatocarcinogens can only be definitively identified through costly and extensive long-term, repeat-dose studies (e.g., 2-year rodent carcinogenicity assays). Although liver tumors caused by these compounds are often not found to be relevant to human health, the mechanism(s) by which they cause carcinogenesis are not well understood. Toxicogenomic technologies represent a new approach to understanding the molecular bases of toxicological liabilities such asnongenotoxic carcinogenicity early in the drug discovery/development process. Microarrays have been used to identify mechanistic molecular markers of nongenotoxic rodent hepatocarcinogenesis in short-term, repeat-dose preclinical safety studies. However, the initial "noise" of early adaptive changes may confound mechanistic interpretation of transcription profiling data from short-term studies, and the molecular processes triggered by treatment with a xenobiotic agent are likely to change over the course of long-term treatment. Here, we describe the use of a differential display technology to understand the molecular mechanisms related to 13 weeks of dosing with the prototype rodent nongenotoxic hepatocarcinogen, phenobarbital. These findings implicate a continuing role for oxidative stress in nongenotoxic carcinogenicity.An Excel data file containing raw data is available in full at http://taylorandfrancis.metapress.com/openurl.asp?genre=journal&issn=0192-6233. Click on the issue link for 33(1), then select this article. A download option appears at the bottom of this abstract. The file contains raw data for all gene changes detected by AFLP, including novel genes and genes of unknown function; sequences of detected genes; and animal body and liver weight ratios. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.

Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent

PubMed Central

Yuan, Jing; Guo, Sheng; Hall, David; Cammett, Anna M.; Jayadev, Supriya; Distel, Manuel; Storfer, Stephen; Huang, Zimei; Mootsikapun, Piroon; Ruxrungtham, Kiat; Podzamczer, Daniel; Haas, David W.

2012-01-01

Objective Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. Design We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. Methods Cases and controls were matched 1 : 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. Results We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. Conclusion Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening. PMID:21505298

Integration of metabolic activation with a predictive toxicogenomics signature to classify genotoxic versus nongenotoxic chemicals in human TK6 cells

PubMed Central

Buick, Julie K.; Moffat, Ivy; Williams, Andrew; Swartz, Carol D.; Recio, Leslie; Hyduke, Daniel R.; Li, Heng‐Hong; Fornace, Albert J.; Aubrecht, Jiri

2015-01-01

The use of integrated approaches in genetic toxicology, including the incorporation of gene expression data to determine the molecular pathways involved in the response, is becoming more common. In a companion article, a genomic biomarker was developed in human TK6 cells to classify chemicals as genotoxic or nongenotoxic. Because TK6 cells are not metabolically competent, we set out to broaden the utility of the biomarker for use with chemicals requiring metabolic activation. Specifically, chemical exposures were conducted in the presence of rat liver S9. The ability of the biomarker to classify genotoxic (benzo[a]pyrene, BaP; aflatoxin B1, AFB1) and nongenotoxic (dexamethasone, DEX; phenobarbital, PB) agents correctly was evaluated. Cells were exposed to increasing chemical concentrations for 4 hr and collected 0 hr, 4 hr, and 20 hr postexposure. Relative survival, apoptosis, and micronucleus frequency were measured at 24 hr. Transcriptome profiles were measured with Agilent microarrays. Statistical modeling and bioinformatics tools were applied to classify each chemical using the genomic biomarker. BaP and AFB1 were correctly classified as genotoxic at the mid‐ and high concentrations at all three time points, whereas DEX was correctly classified as nongenotoxic at all concentrations and time points. The high concentration of PB was misclassified at 24 hr, suggesting that cytotoxicity at later time points may cause misclassification. The data suggest that the use of S9 does not impair the ability of the biomarker to classify genotoxicity in TK6 cells. Finally, we demonstrate that the biomarker is also able to accurately classify genotoxicity using a publicly available dataset derived from human HepaRG cells. Environ. Mol. Mutagen. 56:520–534, 2015. © 2015 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. PMID:25733247

The eNanoMapper database for nanomaterial safety information.

PubMed

Jeliazkova, Nina; Chomenidis, Charalampos; Doganis, Philip; Fadeel, Bengt; Grafström, Roland; Hardy, Barry; Hastings, Janna; Hegi, Markus; Jeliazkov, Vedrin; Kochev, Nikolay; Kohonen, Pekka; Munteanu, Cristian R; Sarimveis, Haralambos; Smeets, Bart; Sopasakis, Pantelis; Tsiliki, Georgia; Vorgrimmler, David; Willighagen, Egon

2015-01-01

The NanoSafety Cluster, a cluster of projects funded by the European Commision, identified the need for a computational infrastructure for toxicological data management of engineered nanomaterials (ENMs). Ontologies, open standards, and interoperable designs were envisioned to empower a harmonized approach to European research in nanotechnology. This setting provides a number of opportunities and challenges in the representation of nanomaterials data and the integration of ENM information originating from diverse systems. Within this cluster, eNanoMapper works towards supporting the collaborative safety assessment for ENMs by creating a modular and extensible infrastructure for data sharing, data analysis, and building computational toxicology models for ENMs. The eNanoMapper database solution builds on the previous experience of the consortium partners in supporting diverse data through flexible data storage, open source components and web services. We have recently described the design of the eNanoMapper prototype database along with a summary of challenges in the representation of ENM data and an extensive review of existing nano-related data models, databases, and nanomaterials-related entries in chemical and toxicogenomic databases. This paper continues with a focus on the database functionality exposed through its application programming interface (API), and its use in visualisation and modelling. Considering the preferred community practice of using spreadsheet templates, we developed a configurable spreadsheet parser facilitating user friendly data preparation and data upload. We further present a web application able to retrieve the experimental data via the API and analyze it with multiple data preprocessing and machine learning algorithms. We demonstrate how the eNanoMapper database is used to import and publish online ENM and assay data from several data sources, how the "representational state transfer" (REST) API enables building user friendly interfaces and graphical summaries of the data, and how these resources facilitate the modelling of reproducible quantitative structure-activity relationships for nanomaterials (NanoQSAR).

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

PubMed Central

Preciados, Mark; Yoo, Changwon; Roy, Deodutta

2016-01-01

During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD—APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF—underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes—APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE—are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in addition to estrogen signaling, EEDs influencing NRF1 regulated communities of genes across genomic and epigenomic multiple networks may contribute in the development of complex chronic human brain health disorders. PMID:27983596

A review of the phylogeny, ecology and toxin production of bloom-forming Aphanizomenon spp. and related species within the Nostocales (cyanobacteria).

PubMed

Cirés, Samuel; Ballot, Andreas

2016-04-01

The traditional genus Aphanizomenon comprises a group of filamentous nitrogen-fixing cyanobacteria of which several memebers are able to develop blooms and to produce toxic metabolites (cyanotoxins), including hepatotoxins (microcystins), neurotoxins (anatoxins and saxitoxins) and cytotoxins (cylindrospermopsin). This genus, representing geographically widespread and extensively studied cyanobacteria, is in fact heterogeneous and composed of at least five phylogenetically distant groups (Aphanizomenon, Anabaena/Aphanizomenon like cluster A, Cuspidothrix, Sphaerospermopsis and Chrysosporum) whose taxonomy is still under revision. This review provides a thorough insight into the phylogeny, ecology, biogeography and toxicogenomics (cyr, sxt, and ana genes) of the five best documented "Aphanizomenon" species with special relevance for water risk assessment: Aphanizomenon flos-aquae, Aphanizomenon gracile, Cuspidothrix issatschenkoi, Sphaerospermopsis aphanizomenoides and Chrysosporum ovalisporum. Aph. flos-aquae, Aph. gracile and C. issatschenkoi have been reported from temperate areas only whereas S. aphanizomenoides shows the widest distribution from the tropics to temperate areas. Ch. ovalisporum is found in tropical, subtropical and Mediterranean areas. While all five species show moderate growth rates (0.1-0.4day -1 ) within a wide range of temperatures (15-30°C), Aph. gracile and A. flos-aquae can grow from around (or below) 10°C, whereas Ch. ovalisporum and S. aphanizomenoides are much better competitors at high temperatures over 30°C or even close to 35°C. A. gracile has been confirmed as the producer of saxitoxins and cylindrospermopsin, C. issatschenkoi of anatoxins and saxitoxins and Ch. ovalisporum of cylindrospermopsin. The suspected cylindrospermopsin or anatoxin-a production of A. flos-aquae or microcystin production of S. aphanizomenoides is still uncertain. This review includes a critical discussion on the the reliability of toxicity reports and on the invasive potential of "Aphanizomenon" species in a climate change scenario, together with derived knowledge gaps and research needs. As a whole, this work is intended to represent a key reference for scientists and water managers involved in the major challenges of identifying, preventing and mitigating toxic Aphanizomenon blooms. Copyright © 2015 Elsevier B.V. All rights reserved.

LiverTox: Advanced QSAR and Toxicogeomic Software for Hepatotoxicity Prediction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, P-Y.; Yuracko, K.

2011-02-25

YAHSGS LLC and Oak Ridge National Laboratory (ORNL) established a CRADA in an attempt to develop a predictive system using a pre-existing ORNL computational neural network and wavelets format. This was in the interest of addressing national needs for toxicity prediction system to help overcome the significant drain of resources (money and time) being directed toward developing chemical agents for commerce. The research project has been supported through an STTR mechanism and funded by the National Institute of Environmental Health Sciences beginning Phase I in 2004 (CRADA No. ORNL-04-0688) and extending Phase II through 2007 (ORNL NFE-06-00020). To attempt themore » research objectives and aims outlined under this CRADA, state-of-the-art computational neural network and wavelet methods were used in an effort to design a predictive toxicity system that used two independent areas on which to base the system’s predictions. These two areas were quantitative structure-activity relationships and gene-expression data obtained from microarrays. A third area, using the new Massively Parallel Signature Sequencing (MPSS) technology to assess gene expression, also was attempted but had to be dropped because the company holding the rights to this promising MPSS technology went out of business. A research-scale predictive toxicity database system called Multi-Intelligent System for Toxicogenomic Applications (MISTA) was developed and its feasibility for use as a predictor of toxicological activity was tested. The fundamental focus of the CRADA was an attempt and effort to operate the MISTA database using the ORNL neural network. This effort indicated the potential that such a fully developed system might be used to assist in predicting such biological endpoints as hepatotoxcity and neurotoxicity. The MISTA/LiverTox approach if eventually fully developed might also be useful for automatic processing of microarray data to predict modes of action. A technical paper describing the methods and technology used in the CRADA has been published. This paper was entitled “A Toxicity Evaluation and Predictive System Based on Neural Networks and Wavelets” and appeared in an American Chemical Society peer-reviewed publication this year (J. Chem. Inf. Model. 47: 676685, 2007). A patent application was filed but later abandoned.« less

What is the need for comparative effectiveness studies in IBD?

PubMed

Flasar, Mark H; Cross, Raymond K

2014-11-01

Unlike traditional clinical trial research, Comparative Effectiveness Research seeks to determine what is 'best' for a typical patient when deciding between effective options used in daily practice - a therapy, diagnostic test, or course of action. There is a clear need for Comparative Effectiveness Research in Inflammatory Bowel Disease, a point emphasized by the Institute of Medicine and supported by governmental agencies and escalating funding. This review highlights the rationale and support for Comparative Effectiveness Research, provides examples of Comparative Effectiveness Research in Inflammatory Bowel Disease, and outlines current and future focus for Comparative Effectiveness Research in Inflammatory Bowel Disease.

Comparative effectiveness.

PubMed

Brown, Gary C; Brown, Melissa M

2009-05-01

To familiarize the clinician with the concept of comparative effectiveness. Recent data support the concept that utility analysis is the quality-of-life instrument best able to perform comparative effectiveness analyses. The use of time tradeoff utilities for comparative effectiveness analyses in interventions across diverse specialties of medicine can be undertaken with both excellent reliability and superior construct validity. Physicians should familiarize themselves with quality-of-life instruments that can be used to assess the comparative effectiveness of healthcare interventions. Rather than delegating comparative effectiveness to others, physicians must become involved in creating and implementing comparative effectiveness standards. Physician involvement is crucial for the best interests of patients, as physicians most intimately understand the complexities and nuances associated with healthcare interventions.

75 FR 990 - HHS Intent To Publish Grant and Contract Solicitations for Comparative Effectiveness Research...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-07

... Publish Grant and Contract Solicitations for Comparative Effectiveness Research (CER) Projects With Funds... input, the Comparative Effectiveness Research- Coordination Implementation Team, the Federal Coordinating Council for Comparative Effectiveness Research (FCC), and the Institute of Medicine Report on CER...

A framework for understanding cancer comparative effectiveness research data needs.

PubMed

Carpenter, William R; Meyer, Anne-Marie; Abernethy, Amy P; Stürmer, Til; Kosorok, Michael R

2012-11-01

Randomized controlled trials remain the gold standard for evaluating cancer intervention efficacy. Randomized trials are not always feasible, practical, or timely and often don't adequately reflect patient heterogeneity and real-world clinical practice. Comparative effectiveness research can leverage secondary data to help fill knowledge gaps randomized trials leave unaddressed; however, comparative effectiveness research also faces shortcomings. The goal of this project was to develop a new model and inform an evolving framework articulating cancer comparative effectiveness research data needs. We examined prevalent models and conducted semi-structured discussions with 76 clinicians and comparative effectiveness research researchers affiliated with the Agency for Healthcare Research and Quality's cancer comparative effectiveness research programs. A new model was iteratively developed and presents cancer comparative effectiveness research and important measures in a patient-centered, longitudinal chronic care model better reflecting contemporary cancer care in the context of the cancer care continuum, rather than a single-episode, acute-care perspective. Immediately relevant for federally funded comparative effectiveness research programs, the model informs an evolving framework articulating cancer comparative effectiveness research data needs, including evolutionary enhancements to registries and epidemiologic research data systems. We discuss elements of contemporary clinical practice, methodology improvements, and related needs affecting comparative effectiveness research's ability to yield findings clinicians, policy makers, and stakeholders can confidently act on. Copyright © 2012 Elsevier Inc. All rights reserved.

A framework for understanding cancer comparative effectiveness research data needs

PubMed Central

Carpenter, William R; Meyer, Anne-Marie; Abernethy, Amy P.; Stürmer, Til; Kosorok, Michael R.

2012-01-01

Objective Randomized controlled trials remain the gold standard for evaluating cancer intervention efficacy. Randomized trials are not always feasible, practical, or timely, and often don’t adequately reflect patient heterogeneity and real-world clinical practice. Comparative effectiveness research can leverage secondary data to help fill knowledge gaps randomized trials leave unaddressed; however, comparative effectiveness research also faces shortcomings. The goal of this project was to develop a new model and inform an evolving framework articulating cancer comparative effectiveness research data needs. Study Design and Setting We examined prevalent models and conducted semi-structured discussions with 76 clinicians and comparative effectiveness research researchers affiliated with the Agency for Healthcare Research and Quality’s cancer comparative effectiveness research programs. Results A new model was iteratively developed, and presents cancer comparative effectiveness research and important measures in a patient-centered, longitudinal chronic care model better-reflecting contemporary cancer care in the context of the cancer care continuum, rather than a single-episode, acute-care perspective. Conclusion Immediately relevant for federally-funded comparative effectiveness research programs, the model informs an evolving framework articulating cancer comparative effectiveness research data needs, including evolutionary enhancements to registries and epidemiologic research data systems. We discuss elements of contemporary clinical practice, methodology improvements, and related needs affecting comparative effectiveness research’s ability to yield findings clinicians, policymakers, and stakeholders can confidently act on. PMID:23017633

75 FR 41867 - Request for Information on Development of an Inventory of Comparative Effectiveness Research

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-19

... Comparative Effectiveness Research AGENCY: Office of the Assistant Secretary for Planning and Evaluation... (ASPE) is developing a national inventory of comparative effectiveness research (CER) and CER-related... Federal Coordinating Council for Comparative Effectiveness Research, which defined CER as the: Conduct and...

Using Meta-analyses for Comparative Effectiveness Research

PubMed Central

Ruppar, Todd M.; Phillips, Lorraine J.; Chase, Jo-Ana D.

2012-01-01

Comparative effectiveness research seeks to identify the most effective interventions for particular patient populations. Meta-analysis is an especially valuable form of comparative effectiveness research because it emphasizes the magnitude of intervention effects rather than relying on tests of statistical significance among primary studies. Overall effects can be calculated for diverse clinical and patient-centered variables to determine the outcome patterns. Moderator analyses compare intervention characteristics among primary studies by determining if effect sizes vary among studies with different intervention characteristics. Intervention effectiveness can be linked to patient characteristics to provide evidence for patient-centered care. Moderator analyses often answer questions never posed by primary studies because neither multiple intervention characteristics nor populations are compared in single primary studies. Thus meta-analyses provide unique contributions to knowledge. Although meta-analysis is a powerful comparative effectiveness strategy, methodological challenges and limitations in primary research must be acknowledged to interpret findings. PMID:22789450

From comparative effectiveness research to patient-centered outcomes research: integrating emergency care goals, methods, and priorities.

PubMed

Meisel, Zachary F; Carr, Brendan G; Conway, Patrick H

2012-09-01

Federal legislation placed comparative effectiveness research and patient-centered outcomes research at the center of current and future national investments in health care research. The role of this research in emergency care has not been well described. This article proposes an agenda for researchers and health care providers to consider comparative effectiveness research and patient-centered outcomes research methods and results to improve the care for patients who seek, use, and require emergency care. This objective will be accomplished by (1) exploring the definitions, frameworks, and nomenclature for comparative effectiveness research and patient-centered outcomes research; (2) describing a conceptual model for comparative effectiveness research in emergency care; (3) identifying specific opportunities and examples of emergency care-related comparative effectiveness research; and (4) categorizing current and planned funding for comparative effectiveness research and patient-centered outcomes research that can include emergency care delivery. Copyright © 2012. Published by Mosby, Inc.

The comparative effectiveness and cost-effectiveness of vitreoretinal interventions.

PubMed

Brown, Melissa M; Brown, Gary C; Brown, Heidi C; Irwin, Blair; Brown, Kathryn S

2008-05-01

The comparative effectiveness of medical interventions has recently been emphasized in the literature, typically for interventions in a similar class. Value-based medicine, the practice of medicine based on the value (improvement in quality of life and/or length of life) conferred by medical interventions, allows a measure of comparative effectiveness of interventions across all of health care, no matter how disparate. This report discusses recent comparative effectiveness studies in the vitreoretinal literature. Vitreoretinal interventions have good to excellent comparative effectiveness compared with commonly utilized interventions across health care, such as treatment for osteoporosis and hyperlipidemia. They also tend to be cost-effective when an upper limit of $100 000/quality-adjusted life-year is utilized. Value can be measured using either or both of two outcomes - the quality-adjusted life-year gain and/or the percentage improvement in value - both of which allow for an evaluation of comparative effectiveness, which can be compared on the same scale for every intervention. This value can also be integrated with costs using the outcome of dollars expended per quality-adjusted life-year ($/quality-adjusted life-year, or the cost-utility ratio), which allows a comparison of cost-effectiveness across all interventions. The majority of vitreoretinal interventions confer considerable value and are cost-effective.

Comparative effectiveness: its role in the healthcare system.

PubMed

Brown, Melissa M; Luo, Betsy; Brown, Heidi C; Brown, Gary C

2009-05-01

To describe comparative effectiveness and assess its role in crafting new healthcare policy. Senate Bill S.3408 would establish a nongovernment-affiliated Healthcare Comparative Effectiveness Research Institute that would work with healthcare experts and stakeholders in healthcare to prioritize interventions and services to be studied. A value-based medicine system of standardized comparative effectiveness and cost-effectiveness data using utilities would allow physicians to assess the total value (improvement in quality of life and/or length of life) conferred by interventions. Standardized comparativeness and cost-effectiveness data will give physicians an information system to identify the interventions that confer the greatest value to patients, and thus deliver higher quality care than possible with evidence-based data alone while allowing the most cost-effective care.

Academic detailing can play a key role in assessing and implementing comparative effectiveness research findings.

PubMed

Fischer, Michael A; Avorn, Jerry

2012-10-01

Comparative effectiveness research evaluates the relative effectiveness, safety, and value of competing treatment options in clinically realistic settings. Such evaluations can be methodologically complex and difficult to interpret. There will be a growing need for critical evaluation of comparative effectiveness studies to assess the adequacy of their design and to put new information into a broader context. Equally important, this knowledge will have to be communicated to clinicians in a way that will actually change practice. We identify three challenges to effective dissemination of comparative effectiveness research findings: the difficulty of interpreting comparative effectiveness research data, the need for trusted sources of information, and the challenge of turning research results into clinical action. We suggest that academic detailing-direct outreach education that gives clinicians an accurate and unbiased synthesis of the best evidence for practice in a given clinical area-can translate comparative effectiveness research findings into actions that improve health care decision making and patient outcomes.

76 FR 44929 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-27

... proposed information collection project: ``Evaluation of ARRA Comparative Effectiveness Research... INFORMATION: Proposed Project Evaluation of ARRA Comparative Effectiveness Research Dissemination Contractor... for reviewing and disseminating Comparative Effectiveness Research (CER) and findings to clinicians...

Comparative Effectiveness of Acupuncture for Chronic Pain and Co-morbid Conditions in Veterans

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-1-0245 TITLE: Comparative Effectiveness of Acupuncture for Chronic Pain and Co- morbid Conditions in Veterans PRINCIPAL...2015 - 29 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Comparative Effectiveness of Acupuncture for Chronic Pain and Co-morbid Conditions in...acupuncture Comparative Effectiveness (PEACE) trial is to investigate EA and BFA (a form of auricular acupuncture) to guide the personalized delivery of

Cutting-edge technology for public health workforce training in comparative effectiveness research.

PubMed

Salinas-Miranda, Abraham A; Nash, Michelle C; Salemi, Jason L; Mbah, Alfred K; Salihu, Hamisu M

2013-06-01

A critical mass of public health practitioners with expertise in analytic techniques and best practices in comparative effectiveness research is needed to fuel informed decisions and improve the quality of health care. The purpose of this case study is to describe the development and formative evaluation of a technology-enhanced comparative effectiveness research learning curriculum and to assess its potential utility to improve core comparative effectiveness research competencies among the public health workforce. Selected public health experts formed a multidisciplinary research collaborative and participated in the development and evaluation of a blended 15-week comprehensive e-comparative effectiveness research training program, which incorporated an array of health informatics technologies. Results indicate that research-based organizations can use a systematic, flexible, and rapid means of instructing their workforce using technology-enhanced authoring tools, learning management systems, survey research software, online communities of practice, and mobile communication for effective and creative comparative effectiveness research training of the public health workforce.

76 FR 10900 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-28

... activity is designed to raise awareness of and utility of comparative effectiveness research by providing... proposed information collection project: ``Comparative Effectiveness Research--Continuing Education.'' In... Comparative Effectiveness Research--Continuing Education Previous dissemination efforts in health care...

The pragmatist's guide to comparative effectiveness research.

PubMed

Chandra, Amitabh; Jena, Anupam B; Skinner, Jonathan S

2011-01-01

Following an acrimonious health care reform debate involving charges of "death panels," in 2010, Congress explicitly forbade the use of cost-effectiveness analysis in government programs of the Patient Protection and Affordable Care Act. In this context, comparative effectiveness research emerged as an alternative strategy to understand better what works in health care. Put simply, comparative effectiveness research compares the efficacy of two or more diagnostic tests, treatments, or health care delivery methods without any explicit consideration of costs. To economists, the omission of costs from an assessment might seem nonsensical, but we argue that comparative effectiveness research still holds promise. First, it sidesteps one problem facing cost-effectiveness analysis--the widespread political resistance to the idea of using prices in health care. Second, there is little or no evidence on comparative effectiveness for a vast array of treatments: for example, we don't know whether proton-beam therapy, a very expensive treatment for prostate cancer (which requires building a cyclotron and a facility the size of a football field) offers any advantage over conventional approaches. Most drug studies compare new drugs to placebos, rather than "head-to-head" with other drugs on the market, leaving a vacuum as to which drug works best. Finally, the comparative effectiveness research can prove a useful first step even in the absence of cost information if it provides key estimates of treatment effects. After all, such effects are typically expensive to determine and require years or even decades of data. Costs are much easier to measure, and can be appended at a later date as financial Armageddon draws closer.

The role of randomized cluster crossover trials for comparative effectiveness testing in anesthesia: design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial.

PubMed

Spence, Jessica; Belley-Côté, Emilie; Lee, Shun Fu; Bangdiwala, Shrikant; Whitlock, Richard; LeManach, Yannick; Syed, Summer; Lamy, Andre; Jacobsohn, Eric; MacIsaac, Sarah; Devereaux, P J; Connolly, Stuart

2018-07-01

Increasingly, clinicians and researchers recognize that studies of interventions need to evaluate not only their therapeutic efficacy (i.e., the effect on an outcome in ideal, controlled settings) but also their real-world effectiveness in broad, unselected patient groups. Effectiveness trials inform clinical practice by comparing variations in therapeutic approaches that fall within the standard of care. In this article, we discuss the need for studies of comparative effectiveness in anesthesia and the limitations of individual patient randomized-controlled trials in determining comparative effectiveness. We introduce the concept of randomized cluster crossover trials as a means of answering questions of comparative effectiveness in anesthesia, using the design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial (Clinicaltrials.gov identifier NCT03053869).

77 FR 8871 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-15

... Agency for Healthcare Research and Quality's (AHRQ's) Effective Healthcare (EHC) Program and Comparative... Agency for Healthcare Research and Quality's (AHRQ's) Effective Healthcare (EHC) Program and Comparative... and use of comparative effectiveness research (CER). Although stakeholder engagement has been central...

77 FR 24718 - Scientific Information Request on Chronic Venous Ulcers Treatments

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-25

... Venous Ulcers: A Comparative Effectiveness Review of Treatment Modalities report, which is currently... improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review pursuant to Section 1013 of the Medicare...

Comparative effectiveness research.

PubMed

Hirsch, J A; Schaefer, P W; Romero, J M; Rabinov, J D; Sanelli, P C; Manchikanti, L

2014-09-01

The goal of comparative effectiveness research is to improve health care while dealing with the seemingly ever-rising cost. An understanding of comparative effectiveness research as a core topic is important for neuroradiologists. It can be used in a variety of ways. Its goal is to look at alternative methods of interacting with a clinical condition, ideally, while improving delivery of care. While the Patient-Centered Outcome Research initiative is the most mature US-based foray into comparative effectiveness research, it has been used more robustly in decision-making in other countries for quite some time. The National Institute for Health and Clinical Excellence of the United Kingdom is a noteworthy example of comparative effectiveness research in action. © 2014 by American Journal of Neuroradiology.

76 FR 77834 - Scientific Information Request on Intravascular Diagnostic and Imaging Medical Devices

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-14

... solicited to inform our Comparative Effectiveness Review of Intravascular Diagnostic Procedures and Imaging... scientific information on this device will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review...

76 FR 74789 - Scientific Information Request on Pressure Ulcer Treatment Medical Devices

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-01

... Strategies: A Comparative Effectiveness Review, which is currently being conducted by the Evidence-based... scientific information on these devices will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review...

77 FR 10748 - Scientific Information Request on Mechanical Prophylaxis of Venous Thromboembolism (VTE)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-23

... Comparative Effectiveness of Pharmacologic and Mechanical Prophylaxis of Venous Thromboembolism Among Special... device will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review pursuant to Section 1013 of the...

77 FR 11120 - Scientific Information Request on Treatment Strategies for Patients With Peripheral Artery...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-24

... is being solicited to inform our Comparative Effectiveness Review of Treatment Strategies for... scientific information on this device will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review...

77 FR 11123 - Scientific Information Request on Local Therapies for Unresectable Colorectal Cancer Metastases...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-24

... being solicited to inform our Comparative Effectiveness Review of Local Therapies for Unresectable... scientific information on this device will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review...

76 FR 66307 - Scientific Information Request on Phototherapy for Treatment of Chronic Plaque Psoriasis

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-26

... is being solicited to inform our Comparative Effectiveness Review of Biologic and Nonbiologic... comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review pursuant to Section 1013 of the Medicare Prescription Drug, Improvement, and...

Composite scores in comparative effectiveness research: counterbalancing parsimony and dimensionality in patient-reported outcomes.

PubMed

Schwartz, Carolyn E; Patrick, Donald L

2014-07-01

When planning a comparative effectiveness study comparing disease-modifying treatments, competing demands influence choice of outcomes. Current practice emphasizes parsimony, although understanding multidimensional treatment impact can help to personalize medical decision-making. We discuss both sides of this 'tug of war'. We discuss the assumptions, advantages and drawbacks of composite scores and multidimensional outcomes. We describe possible solutions to the multiple comparison problem, including conceptual hierarchy distinctions, statistical approaches, 'real-world' benchmarks of effectiveness and subgroup analysis. We conclude that comparative effectiveness research should consider multiple outcome dimensions and compare different approaches that fit the individual context of study objectives.

A Study Comparing the Pedagogical Effectiveness of Virtual Worlds and of Classical Methods

DTIC Science & Technology

2014-08-01

Approved for public release; distribution is unlimited. A Study Comparing the Pedagogical Effectiveness of Virtual Worlds and of Classical Methods...ABSTRACT A Study Comparing the Pedagogical Effectiveness of Virtual Worlds and of Classical Methods Report Title This experiment tests whether a virtual... PEDAGOGICAL EFFECTIVENESS OF VIRTUAL WORLDS AND OF TRADITIONAL TRAINING METHODS A Thesis by BENJAMIN PETERS

Osteopathic manipulative treatment: A systematic review and critical appraisal of comparative effectiveness and health economics research.

PubMed

Steel, Amie; Sundberg, Tobias; Reid, Rebecca; Ward, Lesley; Bishop, Felicity L; Leach, Matthew; Cramer, Holger; Wardle, Jon; Adams, Jon

2017-02-01

In recent years, evidence has emerged regarding the effectiveness of osteopathic manipulative treatments (OMT). Despite growing evidence in this field, there is need for appropriate research designs that effectively reflect the person-centred system of care promoted in osteopathy and provide data which can inform policy decisions within the healthcare system. The purpose of this systematic review is to identify, appraise and synthesise the evidence from comparative effectiveness and economic evaluation research involving OMT. A database search was conducted using CINAHL, PubMed, PEDro, AMED, SCOPUS and OSTMED.DR, from their inception to May 2015. Two separate searches were undertaken to identify original research articles encompassing the economic evaluation and comparative effectiveness of OMT. Identified comparative effectives studies were evaluated using the Cochrane risk of bias tool and appraised using the Good Reporting of Comparative Effectiveness (GRACE) principles. Identified economic studies were assessed with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines. Sixteen studies reporting the findings of comparative effectiveness (n = 9) and economic evaluation (n = 7) research were included. The comparative effectiveness studies reported outcomes for varied health conditions and the majority (n = 6) demonstrated a high risk of bias. The economic evaluations included a range of analyses and considerable differences in the quality of reporting were evident. Despite some positive findings, published comparative effectiveness and health economic studies in OMT are of insufficient quality and quantity to inform policy and practice. High quality, well-designed, research that aligns with international best practice is greatly needed to build a pragmatic evidence base for OMT. Copyright © 2016 Elsevier Ltd. All rights reserved.

77 FR 24959 - Scientific Information Request on Local Therapies for Unresectable Primary Hepatocellular Carcinoma

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-26

... solicited to inform our Comparative Effectiveness Review of Local Therapies for Unresectable Primary... device will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review pursuant to Section 1013 of the...

77 FR 24716 - Scientific Information Request on Medical Devices To Treat Otitis Media With Effusion

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-25

... devices. Scientific information is being solicited to inform our Comparative Effectiveness Review of... scientific information on this device will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review...

Electrophysiological study for comparing the effect of biological activity between type A botulinum toxins in rat gastrocnemius muscle.

PubMed

Kim, C-S; Jang, W S; Son, I P; Nam, S H; Kim, Y I; Park, K Y; Kim, B J; Kim, M N

2013-09-01

New cosmetic applications and products based on the effects of botulinum toxin (BTX) treatment have stimulated demand for this class of natural compounds. This demand generates the need for appropriate standardized protocols to test and compare the effectiveness of new BTX preparations. Based on the previously described electrophysiological methods, we measured and compared the inhibitory effects of two BTX type A (BTX-A) preparations on neuromuscular transmission through split-body test. The effectiveness was evaluated in terms of the compound muscle action potential (CMAP) and conduction velocity after BTX-A injection. We used a split-body method to compare two different BTX-As in the rat. Based on the changes in the CMAP, the two different BTX-As induced paralytic effect on the rat tibialis anterior muscle. However, the two different BTX-A preparations did not differ significantly in effectiveness and did not induce a delay in conduction velocity. The new BTX-A preparation used in this electrophysiological study had similar effect compared with the previously marketed BTX-A.[AQ: Please approve the edits made to the sentence "The new BTX-A preparation…") We propose that a split-body electrophysiological protocol will be useful in establishing the comparative effectiveness of new BTX products.

78 FR 42954 - Scientific Information Request on Imaging Tests for the Staging of Colorectal Cancer

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-18

.... Scientific information is being solicited to inform our Comparative Effectiveness Review of Imaging Tests for... scientific information on these devices will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review...

78 FR 38716 - Scientific Information Request on Imaging Tests for the Staging of Colorectal Cancer

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-27

.... Scientific information is being solicited to inform our Comparative Effectiveness Review of Imaging Tests for... scientific information on these devices will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review...

A Comparative Effectiveness Education Trial for Lifestyle Health Behavior Change in African Americans

ERIC Educational Resources Information Center

Halbert, Chanita Hughes; Bellamy, Scarlett; Briggs, Vanessa; Delmoor, Ernestine; Purnell, Joseph; Rogers, Rodney; Weathers, Benita; Johnson, Jerry C.

2017-01-01

Obesity and excess weight are significant clinical and public health issues that disproportionately affect African Americans because of physical inactivity and unhealthy eating. We compared the effects of alternate behavioral interventions on obesity-related health behaviors. We conducted a comparative effectiveness education trial in a…

Comparative effectiveness of colony-stimulating factors in febrile neutropenia prophylaxis: how results are affected by research design.

PubMed

Henk, Henry J; Li, Xiaoyan; Becker, Laura K; Xu, Hairong; Gong, Qi; Deeter, Robert G; Barron, Richard L

2015-01-01

To examine the impact of research design on results in two published comparative effectiveness studies. Guidelines for comparative effectiveness research have recommended incorporating disease process in study design. Based on the recommendations, we develop a checklist of considerations and apply the checklist in review of two published studies on comparative effectiveness of colony-stimulating factors. Both studies used similar administrative claims data, but different methods, which resulted in directionally different estimates. Major design differences between the two studies include: whether the timing of intervention in disease process was identified and whether study cohort and outcome assessment period were defined based on this temporal relationship. Disease process and timing of intervention should be incorporated into the design of comparative effectiveness studies.

The missing link in preconceptional care: the role of comparative effectiveness research.

PubMed

Salihu, Hamisu M; Salinas, Abraham; Mogos, Mulubrhan

2013-07-01

This paper discusses an important element that is missing from the existing algorithm of preconception care, namely, comparative effectiveness research (CER). To our knowledge, there has been limited assessment of the comparative effectiveness of diverse interventions that promote preconception health, conditions under which these are most effective, for which particular populations, and their comparative costs. CER can improve the decision making process for the funding, development, implementation, and evaluation of comprehensive preconception care programs, specifically by identifying the most effective interventions with acceptable costs to society. This paper will examine the framework behind preconception care and how the inclusion of comparative effectiveness research and evaluation into the existing algorithm of preconception care could foster improvement in maternal and child health. We discuss challenges and opportunities regarding the utilization of CER in the decision making process in preconception health, and finally, we provide recommendations for future directions.

The Missing Link in Preconceptional Care: The Role of Comparative Effectiveness Research

PubMed Central

Salihu, Hamisu M.; Salinas, Abraham; Mogos, Mulubrhan

2012-01-01

This paper discusses an important element that is missing from the existing algorithm of preconception care, namely, comparative effectiveness research (CER). To our knowledge, there has been limited assessment of the comparative effectiveness of diverse interventions that promote preconception health, conditions under which these are most effective, for which particular populations, and their comparative costs. CER can improve the decision making process for the funding, development, implementation, and evaluation of comprehensive preconception care programs, specifically by identifying the most effective interventions with acceptable costs to society. This paper will examine the framework behind preconception care and how the inclusion of comparative effectiveness research and evaluation into the existing algorithm of preconception care could foster improvement in maternal and child health. We discuss challenges and opportunities regarding the utilization of CER in the decision making process in preconception health, and finally, we provide recommendations for future directions. PMID:22718466

Decline in placebo-controlled trial results suggests new directions for comparative effectiveness research.

PubMed

Olfson, Mark; Marcus, Steven C

2013-06-01

The Affordable Care Act offers strong support for comparative effectiveness research, which entails comparisons among active treatments, to provide the foundation for evidence-based practice. Traditionally, a key form of research into the effectiveness of therapeutic treatments has been placebo-controlled trials, in which a specified treatment is compared to placebo. These trials feature high-contrast comparisons between treatments. Historical trends in placebo-controlled trials have been evaluated to help guide the comparative effectiveness research agenda. We investigated placebo-controlled trials reported in four leading medical journals between 1966 and 2010. We found that there was a significant decline in average effect size or average difference in efficacy (the ability to produce a desired effect) between the active treatment and placebo. On average, recently studied treatments offered only small benefits in efficacy over placebo. A decline in effect sizes in conventional placebo-controlled trials supports an increased emphasis on other avenues of research, including comparative studies on the safety, tolerability, and cost of treatments with established efficacy.

Simulation-based training for cardiac auscultation skills: systematic review and meta-analysis.

PubMed

McKinney, James; Cook, David A; Wood, David; Hatala, Rose

2013-02-01

The current review examines the effectiveness of simulation-based medical education (SBME) for training health professionals in cardiac physical examination and examines the relative effectiveness of key instructional design features. Data sources included a comprehensive, systematic search of MEDLINE, EMBASE, CINAHL, PsychINFO, ERIC, Web of Science, and Scopus through May 2011. Included studies investigated SBME to teach health profession learners cardiac physical examination skills using outcomes of knowledge or skill. We carried out duplicate assessment of study quality and data abstraction and pooled effect sizes using random effects. We identified 18 articles for inclusion. Thirteen compared SBME to no-intervention (either single group pre-post comparisons or SBME added to other instruction common to all learners, such as traditional bedside teaching), three compared SBME to other educational interventions, and two compared two SBME interventions. Meta-analysis of the 13 no-intervention comparison studies demonstrated that simulation-based instruction in cardiac auscultation was effective, with pooled effect sizes of 1.10 (95 % CI 0.49-1.72; p < 0.001; I(2) = 92.4 %) for knowledge outcomes and 0.87 (95 % CI 0.52-1.22; p < 0.001; I(2) = 91.5 %) for skills. In sub-group analysis, hands-on practice with the simulator appeared to be an important teaching technique. Narrative review of the comparative effectiveness studies suggests that SBME may be of similar effectiveness to other active educational interventions, but more studies are required. The quantity of published evidence and the relative lack of comparative effectiveness studies limit this review. SBME is an effective educational strategy for teaching cardiac auscultation. Future studies should focus on comparing key instructional design features and establishing SBME's relative effectiveness compared to other educational interventions.

76 FR 77833 - Scientific Information Request on CYP2C19 Variants and Platelet Reactivity Tests

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-14

... inform our Comparative Effectiveness Review of Testing of CYP2C19 Variants and Platelet Reactivity for... information on this device will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative effectiveness review pursuant to...

Automatic identification of comparative effectiveness research from Medline citations to support clinicians’ treatment information needs

PubMed Central

Zhang, Mingyuan; Fiol, Guilherme Del; Grout, Randall W.; Jonnalagadda, Siddhartha; Medlin, Richard; Mishra, Rashmi; Weir, Charlene; Liu, Hongfang; Mostafa, Javed; Fiszman, Marcelo

2014-01-01

Online knowledge resources such as Medline can address most clinicians’ patient care information needs. Yet, significant barriers, notably lack of time, limit the use of these sources at the point of care. The most common information needs raised by clinicians are treatment-related. Comparative effectiveness studies allow clinicians to consider multiple treatment alternatives for a particular problem. Still, solutions are needed to enable efficient and effective consumption of comparative effectiveness research at the point of care. Objective Design and assess an algorithm for automatically identifying comparative effectiveness studies and extracting the interventions investigated in these studies. Methods The algorithm combines semantic natural language processing, Medline citation metadata, and machine learning techniques. We assessed the algorithm in a case study of treatment alternatives for depression. Results Both precision and recall for identifying comparative studies was 0.83. A total of 86% of the interventions extracted perfectly or partially matched the gold standard. Conclusion Overall, the algorithm achieved reasonable performance. The method provides building blocks for the automatic summarization of comparative effectiveness research to inform point of care decision-making. PMID:23920677

Effect of alternative preservatives on the microbial quality, lipid stability and sensory evaluation of boerewors.

PubMed

Mathenjwa, S A; Hugo, C J; Bothma, C; Hugo, A

2012-06-01

Boerewors is a South African fresh sausage preserved with 450mg/kg sulphur dioxide (SO(2)). The preservative effects of rosemary (Ros; 260mg/kg) and chitosan (Chi; 10g/kg) were compared to SO(2). Eight boerewors models were formulated. Microbial, colour, lipid and sensory characteristics were evaluated. Chi and Chi in combination with other preservatives had a significant effect on reducing total bacterial, coliform and Enterobacteriaceae counts, comparable to SO(2). Chi, however, had a better effect on decreasing yeasts and mould counts than SO(2). Chi showed good colour properties comparable to SO(2). Ros showed comparable lipid stability to SO(2) but better when compared to Chi. Ros had a better effect on the sensory taste when compared to Chi, but SO(2) was still preferred. Reduced levels of 100mg/kg SO(2) showed good antimicrobial and colour effects in combination with Chi and in combination with Ros as antioxidant and improving the sensory properties. Alternative preservatives can be used to reduce the SO(2) content of boerewors. Copyright © 2012 Elsevier Ltd. All rights reserved.

AHRQ series paper 1: comparing medical interventions: AHRQ and the effective health-care program.

PubMed

Slutsky, Jean; Atkins, David; Chang, Stephanie; Sharp, Beth A Collins

2010-05-01

In 2005, the Agency for Healthcare Research and Quality established the Effective Health Care (EHC) Program. The EHC Program aims to provide understandable and actionable information for patients, clinicians, and policy makers. The Evidence-based Practice Centers are one of the cornerstones of the EHC Program. Three key elements guide the EHC Program and thus, the conduct of Comparative Effectiveness Reviews by the EPC Program. Comparative Effectiveness Reviews introduce several specific challenges in addition to the familiar issues raised in a systematic review or meta-analysis of a single intervention. The articles in this series together form the current Methods Guide for Comparative Effectiveness Reviews of the EHC Program.

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Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-09

... comparative visuals, and using vaguer language. This study is designed to apply the existing comparative... Effectiveness) studies designed to explore comparative effectiveness. When this large project is completed, FDA... Request; Experimental Study of Comparative Direct-to-Consumer Advertising AGENCY: Food and Drug...

Comparative effectiveness regulations and pharmaceutical innovation.

PubMed

Vernon, John A; Golec, Joseph H; Stevens, J Stedman

2010-01-01

As healthcare reform evolves and takes shape, comparative effectiveness research (CER) appears to be one of the central topics on the national healthcare agenda. Over the past couple of years, comparative effectiveness has been explicitly incorporated in more than ten bills. For example, the passage of the American Recovery and Reinvestment Act of 2009 authorized $US1.1 billion for CER. Comparative effectiveness, when costs are formally considered, offers the hope of efficient resource allocation within US healthcare markets. However, the future operationalization and implementation of comparative effectiveness is uncertain, and there exist potentially negative, and unintended, consequences under certain scenarios. One example, and the focus of this article, is pharmaceutical innovation. Incentives for pharmaceutical R&D could be affected if drug development costs increase as a result of firms having to bear, directly or indirectly, the costs of running larger, randomized, head-to-head comparative effectiveness trials. While this may or may not be the case with current and future comparative effectiveness legislation and its subsequent implementation, the potential consequences for pharmaceutical innovation warrant recognition. This is the purpose of the article. To achieve this goal, we develop several models of clinical trial design, drug development costs and R&D investment. By example, we shed light on the causal links between the models and the ways in which industry R&D investment can be affected.

Which design for which question? An exploration toward a translation table for comparative effectiveness research.

PubMed

Montori, Victor M; Kim, Simon P; Guyatt, Gordon H; Shah, Nilay D

2012-05-01

In this paper, we explore the relative value that different methods offer in answering some stereotypical comparative effectiveness research questions with the goal of informing development of a 'translation table'--a selection tool for choosing appropriate methods for specific comparative effectiveness research questions. This paper was written as a parallel effort to Greenfield and Kaplan (also in this volume) to support the endeavor described in the manuscript by Tunis et al. (also in this volume). Originally based on four cases, the current article has been shortened to two cases for the current discussion. These cases represent research priorities proposed to orient the work of the Patient-Centered Outcomes Research Institute, comparative clinical effectiveness and comparative health services.

Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation.

PubMed

Edwards, Steven J; Barton, Samantha; Thurgar, Elizabeth; Trevor, Nicola

2015-01-01

Ovarian cancer is the fifth most common cancer in the UK, and the fourth most common cause of cancer death. Of those people successfully treated with first-line chemotherapy, 55-75% will relapse within 2 years. At this time, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrent, advanced ovarian cancer. To determine the comparative clinical effectiveness and cost-effectiveness of topotecan (Hycamtin(®), GlaxoSmithKline), pegylated liposomal doxorubicin hydrochloride (PLDH; Caelyx(®), Schering-Plough), paclitaxel (Taxol(®), Bristol-Myers Squibb), trabectedin (Yondelis(®), PharmaMar) and gemcitabine (Gemzar(®), Eli Lilly and Company) for the treatment of advanced, recurrent ovarian cancer. Electronic databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) and trial registries were searched, and company submissions were reviewed. Databases were searched from inception to May 2013. A systematic review of the clinical and economic literature was carried out following standard methodological principles. Double-blind, randomised, placebo-controlled trials, evaluating topotecan, PLDH, paclitaxel, trabectedin and gemcitabine, and economic evaluations were included. A network meta-analysis (NMA) was carried out. A de novo economic model was developed. For most outcomes measuring clinical response, two networks were constructed: one evaluating platinum-based regimens and one evaluating non-platinum-based regimens. In people with platinum-sensitive disease, NMA found statistically significant benefits for PLDH plus platinum, and paclitaxel plus platinum for overall survival (OS) compared with platinum monotherapy. PLDH plus platinum significantly prolonged progression-free survival (PFS) compared with paclitaxel plus platinum. Of the non-platinum-based treatments, PLDH monotherapy and trabectedin plus PLDH were found to significantly increase OS, but not PFS, compared with topotecan monotherapy. In people with platinum-resistant/-refractory (PRR) disease, NMA found no statistically significant differences for any treatment compared with alternative regimens in OS and PFS. Economic modelling indicated that, for people with platinum-sensitive disease and receiving platinum-based therapy, the estimated probabilistic incremental cost-effectiveness ratio [ICER; incremental cost per additional quality-adjusted life-year (QALY)] for paclitaxel plus platinum compared with platinum was £24,539. Gemcitabine plus carboplatin was extendedly dominated, and PLDH plus platinum was strictly dominated. For people with platinum-sensitive disease and receiving non-platinum-based therapy, the probabilistic ICERs associated with PLDH compared with paclitaxel, and trabectedin plus PLDH compared with PLDH, were estimated to be £25,931 and £81,353, respectively. Topotecan was strictly dominated. For people with PRR disease, the probabilistic ICER associated with topotecan compared with PLDH was estimated to be £324,188. Paclitaxel was strictly dominated. As platinum- and non-platinum-based treatments were evaluated separately, the comparative clinical effectiveness and cost-effectiveness of these regimens is uncertain in patients with platinum-sensitive disease. For platinum-sensitive disease, it was not possible to compare the clinical effectiveness and cost-effectiveness of platinum-based therapies with non-platinum-based therapies. For people with platinum-sensitive disease and treated with platinum-based therapies, paclitaxel plus platinum could be considered cost-effective compared with platinum at a threshold of £30,000 per additional QALY. For people with platinum-sensitive disease and treated with non-platinum-based therapies, it is unclear whether PLDH would be considered cost-effective compared with paclitaxel at a threshold of £30,000 per additional QALY; trabectedin plus PLDH is unlikely to be considered cost-effective compared with PLDH. For patients with PRR disease, it is unlikely that topotecan would be considered cost-effective compared with PLDH. Randomised controlled trials comparing platinum with non-platinum-based treatments might help to verify the comparative effectiveness of these regimens. This study is registered as PROSPERO CRD42013003555. The National Institute for Health Research Health Technology Assessment programme.

Addressing Informatics Barriers to Conducting Observational Comparative Effectiveness Research: A Comparative Case Analysis

ERIC Educational Resources Information Center

Boone, Christopher P. D.

2013-01-01

Background: The U.S. health care system has been under immense scrutiny for ever-increasing costs and poor health outcomes for its patients. Comparative Effectiveness Research (CER) has emerged as a generally accepted practice by providers, policy makers, and scientists as an approach to identify the most clinical- and cost-effective interventions…

Bumetanide, a new loop diuretic.

PubMed

Carrière, S; Dandavino, R

1976-10-01

The effect of bumetanide on renal function has been compared with that of furosemide and a placebo in a double-blind study of 9 healthy young men. The sequence for oral administration of the drug was subjected to a random assignation based upon the Latin-square methodology under three different conditions. (1) Normal hydration: The administration of bumetanide (2 mg) produced within the next 4 hr a diuresis comparable to that induced by 80 mg of furosemide. Urinary excretion of sodium, potassium, chloride, calcium, and uric acid also followed comparable patterns. Phosphaturia occurred only under bumetanide. The effect of bumetanide seemed longer lasting. (2) Water loading: The effects of bumetanide and furosemide were comparable with the exception of the phosphaturic effect induced by bumetanide. The action of both diuretics on the diluting segment of the nephron was well demonstrated by the marked depression of CH2O. (3) Water deprivation: The effects of the two diuretics were comparable, including depression tCH20. In none of these conditions did the placebo produce any significant effect.

Biosimilar medicines and cost-effectiveness

PubMed Central

Simoens, Steven

2011-01-01

Given that biosimilars are agents that are similar but not identical to the reference biopharmaceutical, this study aims to introduce and describe specific issues related to the economic evaluation of biosimilars by focusing on the relative costs, relative effectiveness, and cost-effectiveness of biosimilars. Economic evaluation assesses the cost-effectiveness of a medicine by comparing the costs and outcomes of a medicine with those of a relevant comparator. The assessment of cost-effectiveness of a biosimilar is complicated by the fact that evidence needed to obtain marketing authorization from a registration authority does not always correspond to the data requirements of a reimbursement authority. In particular, this relates to the availability of adequately powered equivalence or noninferiority studies, the need for comparative data about the effectiveness in a real-world setting rather than the efficacy in a structured setting, and the use of health outcome measures instead of surrogate endpoints. As a biosimilar is likely to be less expensive than the comparator (eg, the reference biopharmaceutical), the assessment of the cost-effectiveness of a biosimilar depends on the relative effectiveness. If appropriately designed and powered clinical studies demonstrate equivalent effectiveness between a biosimilar and the comparator, then a cost-minimization analysis identifies the least expensive medicine. If there are differences in the effectiveness of a biosimilar and the comparator, other techniques of economic evaluation need to be employed, such as cost-effectiveness analysis or cost-utility analysis. Given that there may be uncertainty surrounding the long-term safety (ie, risk of immunogenicity and rare adverse events) and effectiveness of a biosimilar, the cost-effectiveness of a biosimilar needs to be calculated at multiple time points throughout the life cycle of the product. PMID:21935330

Examining the use of comparative and cost-effectiveness analyses in radiology.

PubMed

Goehler, Alexander; Gazelle, G Scott

2014-11-01

This article explores key principles of comparative effectiveness analysis--in particular, how radiologic comparative and cost-effectiveness studies differ from other clinical trials. Exemplary studies are reviewed to show how comparative effectiveness has been implemented in radiology and how future studies might be conducted. Finally, the article closes with a discussion of several additional key themes relevant to quality and value in clinical radiology going forward. Comparative effectiveness is likely to require a paradigm shift in thinking within the discipline. For new radiologic applications to be accepted, we will need to show at least a significant change in treatment planning and at best a meaningful change in patient outcomes. This shift will require a forward-thinking approach to robust evidence generation for new imaging modalities or indications and the inclusion of other modes of value demonstration such as clinical decision support and intelligent data mining.

Comparative effectiveness research for the clinician researcher: a framework for making a methodological design choice.

PubMed

Williams, Cylie M; Skinner, Elizabeth H; James, Alicia M; Cook, Jill L; McPhail, Steven M; Haines, Terry P

2016-08-17

Comparative effectiveness research compares two active forms of treatment or usual care in comparison with usual care with an additional intervention element. These types of study are commonly conducted following a placebo or no active treatment trial. Research designs with a placebo or non-active treatment arm can be challenging for the clinician researcher when conducted within the healthcare environment with patients attending for treatment.A framework for conducting comparative effectiveness research is needed, particularly for interventions for which there are no strong regulatory requirements that must be met prior to their introduction into usual care. We argue for a broader use of comparative effectiveness research to achieve translatable real-world clinical research. These types of research design also affect the rapid uptake of evidence-based clinical practice within the healthcare setting.This framework includes questions to guide the clinician researcher into the most appropriate trial design to measure treatment effect. These questions include consideration given to current treatment provision during usual care, known treatment effectiveness, side effects of treatments, economic impact, and the setting in which the research is being undertaken.

Feasibility and Design Options for a Potential Entity to Research the Comparative Effectiveness of Medical Treatments.

PubMed

Hussey, Peter S; Gillen, Emily M; McGlynn, Elizabeth A

2011-01-01

In 2008, the Massachusetts state legislature mandated an examination of the feasibility of the state's participation in establishing a comparative effectiveness center (CEC) and requested recommendations for the entity's design. "Comparative effectiveness" research involves the direct comparative assessment of the efficacy and cost-effectiveness of health care interventions and strategies. The center's findings would guide purchasing and payment decisions related to medical procedures, devices, drugs, and biologics by public- and private-sector organizations. The state has several options in terms of its approach to comparative effectiveness research. It could establish an interstate CEC that synthesizes existing findings for regional decisionmakers, it could establish an interstate CEC that supports new research, it could join an existing CEC, it could join the Drug Effectiveness Review Project and the Medicare Evidence-Based Decisions Project and also establish a regional center, or it could elect not to establish a CEC at all. An exploration of the options and the types of research that could be sponsored reveals that all of the options are potentially feasible, but the legislature's decision with regard to design must consider the level of prioritization of comparative effectiveness research relative to other approaches to improving health care quality and reducing spending growth.

Comparative Effectiveness of Conservative Management Compared to Cryotherapy in Localized Prostate Cancer Patients.

PubMed

Shah, Surbhi; Young, Henry N; Cobran, Ewan K

2018-06-01

The high frequency of treatment-related side effects for men with localized prostate cancer creates uncertainty for treatment outcomes. This study assessed the comparative effectiveness of treatment-related side effects associated with conservative management and cryotherapy in patients with localized prostate cancer. A retrospective longitudinal cohort study was conducted, using the linked data of the Surveillance, Epidemiology, and End Results and Medicare, which included patients diagnosed from 2000 through year 2013, and their Medicare claims information from 2000 through 2014. To compare the differences in baseline characteristics and treatment-related side effects between the study cohorts, χ 2 tests were conducted. Multivariate logistic regression was used to assess the association between treatment selection and side effects. There were 7,998 and 3,051 patients in the conservative management and cryotherapy cohort, respectively. The likelihood of erectile dysfunction, lower urinary tract obstruction, urinary fistula, urinary incontinence, and hydronephrosis was reported to be significantly lower (53%, 35%, 69%, 65%, and 36%, respectively) in the conservative management cohort. Conservative management had a lower likelihood of treatment-related side effects compared to cryotherapy. However, further research is needed to compare other significant long-term outcomes such as costs associated with these treatment choices and quality of life.

Pathfinders and Problem Solving: Comparative Effects of Two Cognitive-Behavioral Programs among Men and Women Offenders in Community and Prison

ERIC Educational Resources Information Center

Spiropoulos, Georgia V.; Spruance, Lisa; Van Voorhis, Patricia; Schmitt, Michelle M.

2005-01-01

The effects of "Problem Solving" (Taymans & Parese, 1998) are compared across small diversion and prison samples for men and women. A second program, "Pathfinders" (Hansen, 1993), was compared to the Problem Solving program among incarcerated women offenders to determine whether its focus upon empowerment and relationships enhanced the effects of…

Role of practice-based research networks in comparative effectiveness research.

PubMed

Hartung, Daniel M; Guise, Jeanne-Marie; Fagnan, Lyle J; Davis, Melinda M; Stange, Kurt C

2012-01-01

Comparative effectiveness research fundamentally reorients how clinical evidence is generated and used with the goal of providing actionable information to decision-makers. To achieve this, it is vital that decision-makers and the research enterprise are engaged from research inception, to evidence generation and translation. Practice-based research networks are affiliated clinicians in diverse communities with the goal of conducting research to improve care. Practice-based research networks have the potential to advance all phases of the comparative effectiveness research cycle. The aim of this paper is to explore current and potential roles of practice-based research networks in conducting comparative effectiveness research.

Role of practice-based research networks in comparative effectiveness research

PubMed Central

Hartung, Daniel M; Guise, Jeanne-Marie; Fagnan, Lyle J; Davis, Melinda M; Stange, Kurt C

2012-01-01

Comparative effectiveness research fundamentally reorients how clinical evidence is generated and used with the goal of providing actionable information to decision-makers. To achieve this, it is vital that decision-makers and the research enterprise are engaged from research inception, to evidence generation and translation. Practice-based research networks are affiliated clinicians in diverse communities with the goal of conducting research to improve care. Practice-based research networks have the potential to advance all phases of the comparative effectiveness research cycle. The aim of this paper is to explore current and potential roles of practice-based research networks in conducting comparative effectiveness research. PMID:23105964

Comparative effectiveness in urology: a state of the art review utilizing a systematic approach.

PubMed

Bandari, Jathin; Wessel, Charles B; Jacobs, Bruce L

2017-07-01

Comparative effectiveness research plays a vital role in healthcare delivery by guiding evidence-based practices. We performed a state-of-the-art review of comparative effectiveness research in the urology literature for 2016, utilizing a systematic approach. Seven high-impact papers are reviewed in detail. Across the breadth of urology, there were several important studies in comparative effectiveness research, of which we will highlight two randomized controlled trials and five observational trials: radiotherapy, prostatectomy, and active monitoring have equivalent mortality outcomes in patients with localized prostate cancer; the ideal modality of patient education is yet to be determined, and written education has minimal effect on patient perception of prostate specific antigen screening; robotic prostatectomy is associated with higher perioperative complication rates on a population basis; racial disparities exist in incontinence rates after treatment for localized prostate cancer, but not in irritative, bowel, or sexual function; androgen deprivation therapy is associated with higher fracture, peripheral artery disease, and cardiac-related complications than bilateral orchiectomy; robotic and open cystectomy offer comparable cancer-specific mortality and perioperative outcomes; and bonuses for low-cost hospitals can inadvertently reward low-quality hospitals. There have been major advancements in comparative effectiveness research in urology in 2016.

Evaluating drug efficacy and toxicology in three dimensions: using synthetic extracellular matrices in drug discovery.

PubMed

Prestwich, Glenn D

2008-01-01

The acceptance of the new paradigm of 3-D cell culture is currently constrained by the lack of a biocompatible material in the marketplace that offers ease of use, experimental flexibility, and a seamless transition from in vitro to in vivo applications. I describe the development of a covalently cross-linked mimic of the extracellular matrix (sECM), now commercially available, for 3-D culture of cells in vitro and for translational use in vivo. These bio-inspired, biomimetic materials can be used "as is" in drug discovery, toxicology, cell banking, and, ultimately, medicine. For cell therapy and the development of clinical combination products, the sECM biomaterials must be highly reproducible, manufacturable, approvable, and affordable. To obtain integrated, functional, multicellular systems that recapitulate tissues and organs, the needs of the true end users, physicians and patients, must dictate the key design criteria. In chemical terms, the sECM consists of chemically-modified hyaluronan (HA), other glycosaminoglycans (GAGs), and ECM polypeptides containing thiol residues that are cross-linked using biocompatible polyvalent electrophiles. For example, co-cross-linking the semisynthetic thiol-modified HA-like GAG with thiol-modified gelatin produces Extracel as a hydrogel. This hydrogel may be formed in situ in the presence of cells or tissues to provide an injectable cell-delivery vehicle. Alternately, an Extracel hyrogel can be lyophilized to create a macroporous scaffold, which can then be employed for 3-D cell culture. In this Account, we describe four applications of sECMs that are relevant to the evaluation of drug efficacy and drug toxicity. First, the uses of sECMs to promote both in vitro and in vivo growth of healthy cellularized 3-D tissues are summarized. Primary or cell-line-derived cells, including fibroblasts, chondrocytes, hepatocytes, adult and embryonic stem cells, and endothelial and epithelial cells have been used. Second, primary hepatocytes retain their biochemical phenotypes and achieve greater longevity in 3-D culture in Extracel. This constitutes a new 3-D method for rapid evaluation of hepatotoxicity in vitro. Third, cancer cell lines are readily grown in 3-D culture in Extracel, offering a method for rapid evaluation of new anticancer agents in a more physiological ex vivo tumor model. This system has been used to evaluate signal transduction modifiers obtained from our research on lipid signaling. Fourth, a new "tumor engineering" xenograft model uses orthotopic injection of Extracel-containing tumor cells in nude mice. This approach allows production of patient-specific mice using primary human tumor samples and offers a superior metastatic cancer model. Future applications of the injectable cell delivery and 3-D cell culture methods include chemoattractant and angiogenesis assays, high-content automated screening of chemical libraries, pharmacogenomic and toxicogenomic studies with cultured organoids, and personalized treatment models. In summary, the sECM technology offers a versatile "translational bridge" from in vitro to in vivo to facilitate drug discovery in both academic and pharmaceutical laboratories.

The potential of imaging techniques as a screening tool for colorectal cancer: a cost-effectiveness analysis.

PubMed

Greuter, Marjolein J E; Berkhof, Johannes; Fijneman, Remond J A; Demirel, Erhan; Lew, Jie-Bin; Meijer, Gerrit A; Stoker, Jaap; Coupé, Veerle M H

2016-07-01

Imaging may be promising for colorectal cancer (CRC) screening, since it has test characteristics comparable with colonoscopy but is less invasive. We aimed to assess the potential of CT colonography (CTC) and MR colonography (MRC) in terms of (cost-effectiveness) using the Adenoma and Serrated pathway to Colorectal CAncer model. We compared several CTC and MRC strategies with 5- or 10-yearly screening intervals with no screening, 10-yearly colonoscopy screening and biennial faecal immunochemical test (FIT) screening. We assumed trial-based participation rates in the base-case analyses and varied the rates in sensitivity analyses. Incremental lifetime costs and health effects were estimated from a healthcare perspective. The health gain of CTC and MRC was similar and ranged from 0.031 to 0.048 life-year gained compared with no screening, for 2-5 screening rounds. Lifetime costs per person for MRC strategies were €60-110 higher than those for CTC strategies with an equal number of screening rounds. All imaging-based strategies were cost-effective compared with no screening. FIT screening was the dominant screening strategy, leading to most LYG and highest cost-savings. Compared with three rounds of colonoscopy screening, CTC with five rounds was found to be cost-effective in an incremental analysis of imaging strategies. Assumptions on screening participation have a major influence on the ordering of strategies in terms of costs and effects. CTC and MRC have potential for CRC screening, compared with no screening and compared with three rounds of 10-yearly colonoscopy screening. When taking FIT screening as the reference, imaging is not cost-effective. Participation is an important driver of effectiveness and cost estimates. This is the first study to assess the cost-effectiveness of MRC screening for CRC.

78 FR 22263 - Agency Information Collection Activities; Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-15

... produce effectiveness and comparative effectiveness research. The Effective Health Care Program also... materials and translation products that are currently available are designed to help practicing clinicians... started developing some tools, such as faculty slide sets based on comparative effectiveness reviews of...

Comparative effect of propolis of honey bee and some herbal extracts on Candida albicans.

PubMed

Gavanji, Shahin; Larki, Behrouz

2017-03-01

To determine the effect of propolis on Candida albicans and to compare it with the effects of some other herbal extracts and antibiotics on this pathogenic fungi. The extracts of propolis, Thymus vulgaris, Caryophillium aromaticus, Echinophora platyloba, Allium cepa and Cinnamomum zeylanicum were prepared and the antifungi effects of the extracts were examined on Candida albicans ATCC10231 using disc-diffusion assay and micro-broth dilution. The minimum fungicidal concentration (MFC) and minimum inhibitory concentrations (MIC) as well as inhibition zone were evaluated and the anti fungi effects of herbal extracts were compared with amphotricin B and nystatin at the times of 24, 48 and 72 h. Data analysis was performed using t test. Obtained results showed that propolis extract with MIC 90 and MFC equal to 39 and 65 μg/mL, respectively, possess the highest antifungal activity when compared with other studied extracts. The extracts of Allium cepa and Thymus vulgaris, with MFC of 169 and 137 μg/mL, respectively, showed the lowest effects on the fungi. Also nystatin and amphotricin B yielded better effects on the tested fungi compared with the effects of all studied extracts on Candida albicans. Propolis extract is effective in controlling Candida albicans. However, the issue requires further investigation on samples in animals and performing toxicological examinations.

Comparing the Effects of Elementary Music and Visual Arts Lessons on Standardized Mathematics Test Scores

ERIC Educational Resources Information Center

King, Molly Elizabeth

2016-01-01

The purpose of this quantitative, causal-comparative study was to compare the effect elementary music and visual arts lessons had on third through sixth grade standardized mathematics test scores. Inferential statistics were used to compare the differences between test scores of students who took in-school, elementary, music instruction during the…

Comparative effectiveness research in clinical practice.

PubMed

Lawrence, William F; Chang, Stephanie; Kane, Robert L; Wilt, Timothy J

2014-08-01

The Agency for Healthcare Research and Quality (AHRQ) has funded systematic reviews of comparative effectiveness research in 17 areas over the last 10 years as part of a federal mandate. These reviews provide a reliable and unbiased source of comprehensive information about the effectiveness and risks of treatment alternatives for patients and clinicians. This article describes comparative effectiveness research, provides an overview of how physicians can use it in clinical practice, and references important contributions made by the Minnesota Evidence-based Practice Center.

Comparative effectiveness research in hand surgery.

PubMed

Johnson, Shepard P; Chung, Kevin C

2014-08-01

Comparative effectiveness research (CER) is a concept initiated by the Institute of Medicine and financially supported by the federal government. The primary objective of CER is to improve decision making in medicine. This research is intended to evaluate the effectiveness, benefits, and harmful effects of alternative interventions. CER studies are commonly large, simple, observational, and conducted using electronic databases. To date, there is little comparative effectiveness evidence within hand surgery to guide therapeutic decisions. To draw conclusions on effectiveness through electronic health records, databases must contain clinical information and outcomes relevant to hand surgery interventions, such as patient-related outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.

76 FR 30364 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-25

... professionals, and other clinicians. This activity is designed to raise awareness of and utility of comparative... proposed information collection project: ``Comparative Effectiveness Research-Continuing Education.'' In... Comparative Effectiveness Research-Continuing Education Previous dissemination efforts in health care research...

Comparative-effectiveness research in distributed health data networks.

PubMed

Toh, S; Platt, R; Steiner, J F; Brown, J S

2011-12-01

Comparative-effectiveness research (CER) can be conducted within a distributed health data network. Such networks allow secure access to separate data sets from different data partners and overcome many practical obstacles related to patient privacy, data security, and proprietary concerns. A scalable network architecture supports a wide range of CER activities and meets the data infrastructure needs envisioned by the Federal Coordinating Council for Comparative Effectiveness Research.

Cost-effectiveness of computed tomography colonography in colorectal cancer screening: a systematic review.

PubMed

Hanly, Paul; Skally, Mairead; Fenlon, Helen; Sharp, Linda

2012-10-01

The European Code Against Cancer recommends individuals aged ≥ 50 should participate in colorectal cancer screening. CT-colonography (CTC) is one of several screening tests available. We systematically reviewed evidence on, and identified key factors influencing, cost-effectiveness of CTC screening. PubMed, Medline, and the Cochrane library were searched for cost-effectiveness or cost-utility analyses of CTC-based screening, published in English, January 1999 to July 2010. Data was abstracted on setting, model type and horizon, screening scenario(s), comparator(s), participants, uptake, CTC performance and cost, effectiveness, ICERs, and whether extra-colonic findings and medical complications were considered. Sixteen studies were identified from the United States (n = 11), Canada (n = 2), and France, Italy, and the United Kingdom (1 each). Markov state-transition (n = 14) or microsimulation (n = 2) models were used. Eleven considered direct medical costs only; five included indirect costs. Fourteen compared CTC with no screening; fourteen compared CTC with colonoscopy-based screening; fewer compared CTC with sigmoidoscopy (8) or fecal tests (4). Outcomes assessed were life-years gained/saved (13), QALYs (2), or both (1). Three considered extra-colonic findings; seven considered complications. CTC appeared cost-effective versus no screening and, in general, flexible sigmoidoscopy and fecal occult blood testing. Results were mixed comparing CTC to colonoscopy. Parameters most influencing cost-effectiveness included: CTC costs, screening uptake, threshold for polyp referral, and extra-colonic findings. Evidence on cost-effectiveness of CTC screening is heterogeneous, due largely to between-study differences in comparators and parameter values. Future studies should: compare CTC with currently favored tests, especially fecal immunochemical tests; consider extra-colonic findings; and conduct comprehensive sensitivity analyses.

Cost Effectiveness Ratio: Evaluation Tool for Comparing the Effectiveness of Similar Extension Programs

ERIC Educational Resources Information Center

Jayaratne, K. S. U.

2015-01-01

Extension educators have been challenged to be cost effective in their educational programming. The cost effectiveness ratio is a versatile evaluation indicator for Extension educators to compare the cost of achieving a unit of outcomes or educating a client in similar educational programs. This article describes the cost effectiveness ratio and…

77 FR 11121 - Scientific Information Request on Treatment of Atrial Fibrillation

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-24

... fibrillation medical devices. Scientific information is being solicited to inform our Comparative Effectiveness... unpublished pertinent scientific information on this device will improve the quality of this comparative effectiveness review. AHRQ is requesting this scientific information and conducting this comparative...

76 FR 10367 - Agency Information Collection Request; 60-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-24

.... Proposed Project: Research Evaluation and Impact Assessment of ARRA Comparative Effectiveness Research... under real-world conditions in diverse populations and clinical practice settings, that is, comparative... Coordinating Council on Comparative Effectiveness Research (FCCCER) to help coordinate and minimize duplicative...

Does comparative effectiveness research promote rationing of cancer care?

PubMed

Peppercorn, Jeffrey; Zafar, S Yousuf; Houck, Kevin; Ubel, Peter; Meropol, Neal J

2014-03-01

Comparative effectiveness research aims to inform health-care decisions by patients, clinicians, and policy makers. However, questions related to what information is relevant, and how to view the relative attributes of alternative interventions have political, social, and medical considerations. In particular, questions about whether cost is a relevant factor, and whether cost-effectiveness is a desirable or necessary component of such research, have become increasingly controversial as the area has gained prominence. Debate has emerged about whether comparative effectiveness research promotes rationing of cancer care. At the heart of this debate are questions related to the role and limits of patient autonomy, physician discretion in health-care decision making, and the nature of scientific knowledge as an objective good. In this article, we examine the role of comparative effectiveness research in the USA, UK, Canada, and other health-care systems, and the relation between research and policy. As we show, all health systems struggle to balance access to cancer care and control of costs; comparative effectiveness data can clarify choices, but does not itself determine policy or promote rationing of care. Copyright © 2014 Elsevier Ltd. All rights reserved.

Establishing the infrastructure to conduct comparative effectiveness research toward the elimination of disparities: a community-based participatory research framework.

PubMed

Wilson, Danyell S; Dapic, Virna; Sultan, Dawood H; August, Euna M; Green, B Lee; Roetzheim, Richard; Rivers, Brian

2013-11-01

In Tampa, Florida, researchers have partnered with community- and faith-based organizations to create the Comparative Effectiveness Research for Eliminating Disparities (CERED) infrastructure. Grounded in community-based participatory research, CERED acts on multiple levels of society to enhance informed decision making (IDM) of prostate cancer screening among Black men. CERED investigators combined both comparative effectiveness research and community-based participatory research to design a trial examining the effectiveness of community health workers and a digitally enhanced patient decision aid to support IDM in community settings as compared with "usual care" for prostate cancer screening. In addition, CERED researchers synthesized evidence through the development of systematic literature reviews analyzing the effectiveness of community health workers in changing knowledge, attitudes and behaviors of African American adults toward cancer prevention and education. An additional systematic review analyzed chemoprevention agents for prostate cancer as an emerging technique. Both of these reviews, and the comparative effectiveness trial supporting the IDM process, add to CERED's goal of providing evidence to eliminate cancer health disparities.

Establishing the Infrastructure to Conduct Comparative Effectiveness Research Toward the Elimination of Disparities: A Community-Based Participatory Research Framework

PubMed Central

Wilson, Danyell S.; Dapic, Virna; Sultan, Dawood H.; August, Euna M.; Green, B. Lee; Roetzheim, Richard; Rivers, Brian

2014-01-01

In Tampa, Florida, researchers have partnered with community- and faith-based organizations to create the Comparative Effectiveness Research for Eliminating Disparities (CERED) infrastructure. Grounded in community-based participatory research, CERED acts on multiple levels of society to enhance informed decision making (IDM) of prostate cancer screening among Black men. CERED investigators combined both comparative effectiveness research and community-based participatory research to design a trial examining the effectiveness of community health workers and a digitally enhanced patient decision aid to support IDM in community settings as compared with “usual care” for prostate cancer screening. In addition, CERED researchers synthesized evidence through the development of systematic literature reviews analyzing the effectiveness of community health workers in changing knowledge, attitudes and behaviors of African American adults toward cancer prevention and education. An additional systematic review analyzed chemoprevention agents for prostate cancer as an emerging technique. Both of these reviews, and the comparative effectiveness trial supporting the IDM process, add to CERED’s goal of providing evidence to eliminate cancer health disparities. PMID:23431128

Anti-TNF-A therapy about infliximab and adalimamab for the effectiveness in ulcerative colitis compared with conventional therapy: a meta-analysis.

PubMed

Zhou, Zheng; Dai, Cong; Liu, Wei-Xin

2015-01-01

TNF-α has an important role in the pathogenesis of ulcerative colitis (UC). It seems that anti-TNF-α therapy is beneficial in the treatment of UC. The aim was to assess the effectiveness of Infliximab and Adalimamab with UC compared with conventional therapy. The Pubmed and Embase databases were searched for studies investigating the efficacy of infliximab and adalimumab on UC. Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy, but those had not a statistically significant effects in clinical remission (RR = 1.63; 95% CI 0.84 to 3.18) and reduction of colectomy rate (RR = 0.54; 95% CI 0.26 to 1.12) of UC. And adalimumab had a statistically significant effects in induction of clinical remission (RR = 1.82; 95% CI 1.24 to 2.67) and clinical response (RR = 1.36; 95% CI 1.13 to 1.64) of UC compared with conventional therapy. Our meta-analyses suggested that Infliximab had a statistically significant effects in induction of clinical response of UC compared with conventional therapy and adalimumab had a statistically significant effects in induction of clinical remission and clinical response of UC compared with conventional therapy.

Anti-TNF-A Therapy about Infliximab and Adalimamab for the Effectiveness in Ulcerative Colitis Compared with Conventional Therapy: A Meta-Analysis.

PubMed

Zhou, Zheng; Dai, Cong; Liu, Wei-xin

2015-06-01

TNF-α has an important role in the pathogenesis of ulcerative colitis (UC). It seems that anti-TNF-α therapy is beneficial in the treatment of UC. The aim was to assess the effectiveness of Infliximab and Adalimamab with UC compared with con- ventional therapy. The Pubmed and Embase databases were searched for studies investigating the efficacy of infliximab and adalimumab on UC. Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy, but those had not a statistically significant effects in clinical remission (RR = 1.63; 95% CI 0.84 to 3.18) and reduction of colectomy rate (RR = 0.54; 95% CI 0.26 to 1.12) of UC. And adalimumab had a statistically significant effects in induction of clinical remission (RR =1.82; 95% CI 1.24 to 2.67) and clinical response (RR =1.36; 95% CI 1.13 to 1.64) of UC compared with conventional therapy. Our meta-analyses suggested that Infliximab had a statistically significant effects in induction of clinical response of UC compared with conventional therapy and adalimumab had a statistically significant effects in induction of clinical remission and clinical response of UC compared with conventional therapy.

ECONOMICS OF INDIVIDUALIZATION IN COMPARATIVE EFFECTIVENESS RESEARCH AND A BASIS FOR A PATIENT-CENTERED HEALTH CARE

PubMed Central

Basu, Anirban

2011-01-01

The United States aspires to use information from comparative effectiveness research (CER) to reduce waste and contain costs without instituting a formal rationing mechanism or compromising patient or physician autonomy with regard to treatment choices. With such ambitious goals, traditional combinations of research designs and analytical methods used in CER may lead to disappointing results. In this paper, I study how alternate regimes of comparative effectiveness information help shape the marginal benefits (demand) curve in the population and how such perceived demand curves impact decision-making at the individual patient level and welfare at the societal level. I highlight the need to individualize comparative effectiveness research in order to generate the true (normative) demand curve for treatments. I discuss methodological principles that guide research designs for such studies. Using an example of the comparative effect of substance abuse treatments on crime, I use novel econometric methods to salvage individualized information from an existing dataset. PMID:21601299

Economics of individualization in comparative effectiveness research and a basis for a patient-centered health care.

PubMed

Basu, Anirban

2011-05-01

The United States aspires to use information from comparative effectiveness research (CER) to reduce waste and contain costs without instituting a formal rationing mechanism or compromising patient or physician autonomy with regard to treatment choices. With such ambitious goals, traditional combinations of research designs and analytical methods used in CER may lead to disappointing results. In this paper, I study how alternate regimes of comparative effectiveness information help shape the marginal benefits (demand) curve in the population and how such perceived demand curves impact decision-making at the individual patient level and welfare at the societal level. I highlight the need to individualize comparative effectiveness research in order to generate the true (normative) demand curve for treatments. I discuss methodological principles that guide research designs for such studies. Using an example of the comparative effect of substance abuse treatments on crime, I use novel econometric methods to salvage individualized information from an existing dataset. Copyright © 2011 Elsevier B.V. All rights reserved.

Value-based medicine, comparative effectiveness, and cost-effectiveness analysis of topical cyclosporine for the treatment of dry eye syndrome.

PubMed

Brown, Melissa M; Brown, Gary C; Brown, Heidi C; Peet, Jonathan; Roth, Zachary

2009-02-01

To assess the comparative effectiveness and cost-effectiveness (cost-utility) of a 0.05% emulsion of topical cyclosporine (Restasis; Allergan Inc, Irvine, California) for the treatment of moderate to severe dry eye syndrome that is unresponsive to conventional therapy. Data from 2 multicenter, randomized, clinical trials and Food and Drug Administration files for topical cyclosporine, 0.05%, emulsion were used in Center for Value-Based Medicine analyses. Analyses included value-based medicine as a comparative effectiveness analysis and average cost-utility analysis using societal and third-party insurer cost perspectives. Outcome measures of comparative effectiveness were quality-adjusted life-year (QALY) gain and percentage of improvement in quality of life, and for cost-effectiveness were cost-utility ratio (CUR) using dollars per QALY. Topical cyclosporine, 0.05%, confers a value gain (comparative effectiveness) of 0.0319 QALY per year compared with topical lubricant therapy, a 4.3% improvement in quality of life for the average patient with moderate to severe dry eye syndrome that is unresponsive to conventional lubricant therapy. The societal perspective incremental CUR for cyclosporine over vehicle therapy is $34,953 per QALY and the societal perspective average CUR is $11,199 per QALY. The third-party-insurer incremental CUR is $37,179 per QALY, while the third-party-insurer perspective average CUR is $34,343 per QALY. Topical cyclosporine emulsion, 0.05%, confers considerable patient value and is a cost-effective therapy for moderate to severe dry eye syndrome that is unresponsive to conventional therapy.

Preference-based comparative effectiveness and cost–effectiveness: a review and relevance of value-based medicine for vitreoretinal interventions.

PubMed

Brown, Melissa M; Brown, Gary C; Lieske, Heidi B; Lieske, P Alexander

2012-05-01

This analysis discusses the comparative effectiveness and cost-effectiveness of vitreoretinal interventions, measured in quality-adjusted life years (QALYs) and percentage patient value (PPV gain, or improvement in quality of life and/or length of life). The material is relevant since the Patient Protection and Affordable Care Act enacted by Congress with the support of the President has emphasized the critical importance of patient-based preferences. The majority of preference-based, comparative effectiveness and cost-effectiveness vitreoretinal interventions assessed in the US healthcare literature are Value-Based Medicine analyses, thus comparable. These interventions confer a mean patient (human) value gain (improvement in quality of life) of 8.3% [SD 6.3%, 95% confidence interval (CI) + 2.6%]. The average cost-utility of these vitreoretinal interventions is US$23 026/QALY (SD US$24 508, 95% CI + US$8770). Most vitreoretinal interventions are very cost effective using a conventional US standard of US$50 000/QALY as the upper anchor for a very cost-effective intervention, and the World Health Organization of approximately US$142 200/QALY as the upper anchor for a cost-effective intervention. Most vitreoretinal interventions confer considerable patient value and are very cost effective. Further standardization across healthcare is needed in the preference-based, comparative and cost-utility (cost-effectiveness) arena. The metrics of PPV (percentage patient value) gain and US$/PPV (dollars expended per percentage patient value gain) or financial value gain may be more user-friendly than the QALY.

The Economic Effects of Cognitive and Educational Differences Among Low-Ability and Blue-Collar Origin Men: A Comparative Analysis.

ERIC Educational Resources Information Center

Olneck, Michael R.

This study used five data sets to investigate the effects of measured cognitive skills on educational attainment, and the effects of cognitive skills and educational attainment on occupational status and earning among men with low test scores, as compared to men with high test scores, and among men with blue-collar fathers, as compared to men with…

32 CFR 750.46 - Applicable law.

Code of Federal Regulations, 2012 CFR

2012-07-01

... determining liability and the effect of contributory or comparative negligence on claimant's right of recovery... effect of contributory or comparative negligence by the claimant to determine the relative merits of the claim. If there is no foreign law on contributory or comparative negligence, apply traditional rules of...

32 CFR 750.46 - Applicable law.

Code of Federal Regulations, 2014 CFR

2014-07-01

... determining liability and the effect of contributory or comparative negligence on claimant's right of recovery... effect of contributory or comparative negligence by the claimant to determine the relative merits of the claim. If there is no foreign law on contributory or comparative negligence, apply traditional rules of...

32 CFR 750.46 - Applicable law.

Code of Federal Regulations, 2013 CFR

2013-07-01

... determining liability and the effect of contributory or comparative negligence on claimant's right of recovery... effect of contributory or comparative negligence by the claimant to determine the relative merits of the claim. If there is no foreign law on contributory or comparative negligence, apply traditional rules of...

32 CFR 750.46 - Applicable law.

Code of Federal Regulations, 2010 CFR

2010-07-01

... determining liability and the effect of contributory or comparative negligence on claimant's right of recovery... effect of contributory or comparative negligence by the claimant to determine the relative merits of the claim. If there is no foreign law on contributory or comparative negligence, apply traditional rules of...

32 CFR 750.46 - Applicable law.

Code of Federal Regulations, 2011 CFR

2011-07-01

... determining liability and the effect of contributory or comparative negligence on claimant's right of recovery... effect of contributory or comparative negligence by the claimant to determine the relative merits of the claim. If there is no foreign law on contributory or comparative negligence, apply traditional rules of...

The comparative effects of ICI 118551 and propranolol on essential tremor.

PubMed Central

Jefferson, D; Wharrad, H J; Birmingham, A T; Patrick, J M

1987-01-01

1. The effects of the selective beta 2-adrenoceptor antagonist ICI 118551 on essential tremor, heart rate and blood pressure were compared with those of propranolol. 2. ICI 118551 (150 mg daily for 7 days) and propranolol (120 mg daily for 7 days) were about equally effective in reducing essential tremor (by about 40%) and were more effective than placebo. 3. When compared with the effect of placebo, propranolol reduced blood pressure and exercise heart rate whereas ICI 118551 had no significant effect on blood pressure and produced a small but significant reduction in exercise-induced tachycardia. 4. ICI 118551 may be useful in the management of essential tremor while having fewer cardiovascular side-effects than non-selective beta-adrenoceptor antagonists. PMID:2894217

Cost-effectiveness of nivolumab for recurrent or metastatic head and neck cancer☆.

PubMed

Ward, Matthew C; Shah, Chirag; Adelstein, David J; Geiger, Jessica L; Miller, Jacob A; Koyfman, Shlomo A; Singer, Mendel E

2017-11-01

Nivolumab is the first drug to demonstrate a survival benefit for platinum-refractory recurrent or metastatic head and neck cancer. We performed a cost-utility analysis to assess the economic value of nivolumab as compared to alternative standard agents in this context. Using data from the CheckMate 141 trial, we constructed a Markov simulation model from the US payer's perspective to evaluate the cost-effectiveness of nivolumab compared to physician choice of either cetuximab, methotrexate or docetaxel. Alternative strategies considered included: single-agent cetuximab, methotrexate or docetaxel, or first testing for PD-L1 to select for nivolumab. Costs were extracted from Medicare and utilities from the literature and CheckMate. Probabilistic sensitivity analysis (PSA) was used to evaluate parameter uncertainty. $100,000/QALY was the primary threshold for cost-effectiveness. When comparing nivolumab to the standard arm of CheckMate, nivolumab demonstrated an incremental cost-effectiveness ratio (ICER) of $140,672/QALY. When comparing standard therapies, methotrexate was the most cost-effective with similar results for docetaxel. Nivolumab was cost-effective compared to single-agent cetuximab (ICER $89,786/QALY). Treatment selection by PD-L1 immunohistochemistry did not markedly improve the cost-effectiveness of nivolumab. Factors likely to positively impact the cost-effectiveness of nivolumab include better baseline quality-of-life, poor tolerability of standard treatments and/or a lower cost of nivolumab. Nivolumab is preferred to single-agent cetuximab but requires a willingness-to-pay of at least $150,000/QALY to be considered cost-effective when compared to docetaxel or methotrexate. Selection by PD-L1 does not markedly improve the cost-effectiveness of nivolumab. This informs patient selection and clinical care-path development. Copyright © 2017 Elsevier Ltd. All rights reserved.

78 FR 38981 - Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-28

... ``LIMITED COMPETITION: ENHANCING INVESTMENTS COMPARATIVE EFFECTIVENESS RESEARCH RESOURCES GRANTS (R01... COMPETITION: ENHANCING INVESTMENTS COMPARATIVE EFFECTIVENESS RESEARCH RESOURCES GRANTS (R01)'' are to be...

HETEROGENEITY IN TREATMENT EFFECT AND COMPARATIVE EFFECTIVENESS RESEARCH.

PubMed

Luo, Zhehui

2011-10-01

The ultimate goal of comparative effectiveness research (CER) is to develop and disseminate evidence-based information about which interventions are most effective for which patients under what circumstances. To achieve this goal it is crucial that researchers in methodology development find appropriate methods for detecting the presence and sources of heterogeneity in treatment effect (HTE). Comparing with the typically reported average treatment effect (ATE) in randomized controlled trials and non-experimental (i.e., observational) studies, identifying and reporting HTE better reflect the nature and purposes of CER. Methodologies of CER include meta-analysis, systematic review, design of experiments that encompasses HTE, and statistical correction of various types of estimation bias, which is the focus of this review.

Effect Size as the Essential Statistic in Developing Methods for mTBI Diagnosis.

PubMed

Gibson, Douglas Brandt

2015-01-01

The descriptive statistic known as "effect size" measures the distinguishability of two sets of data. Distingishability is at the core of diagnosis. This article is intended to point out the importance of effect size in the development of effective diagnostics for mild traumatic brain injury and to point out the applicability of the effect size statistic in comparing diagnostic efficiency across the main proposed TBI diagnostic methods: psychological, physiological, biochemical, and radiologic. Comparing diagnostic approaches is difficult because different researcher in different fields have different approaches to measuring efficacy. Converting diverse measures to effect sizes, as is done in meta-analysis, is a relatively easy way to make studies comparable.

Health economic evaluation of patients treated for nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus: secondary analysis of a multicenter randomized clinical trial of vancomycin and linezolid.

PubMed

Niederman, Michael S; Chastre, Jean; Solem, Caitlyn T; Wan, Yin; Gao, Xin; Myers, Daniela E; Haider, Seema; Li, Jim Z; Stephens, Jennifer M

2014-09-01

Results from studies comparing health care resource use (HCRU), costs of treatment, and cost-effectiveness of linezolid compared with vancomycin therapy in the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia are limited in the published literature. We therefore conducted an analysis to compare the HCRU, costs of treatment, and cost-effectiveness of linezolid compared with vancomycin in the treatment of hospitalized patients with MRSA nosocomial pneumonia using data from a Phase IV clinical trial. The economic effect of moderate to severe adverse events (MSAEs) and the development of renal failure were also evaluated. We performed a post hoc analysis of data from a Phase IV, double-blind, randomized, comparator-controlled, multicenter trial that compared linezolid and vancomycin treatment in patients with MRSA nosocomial pneumonia. HCRU and costs were compared based on treatment, development of MSAEs, and development of renal failure using data from the modified intent-to-treat population. Predictors of costs were evaluated using generalized linear models. A piggyback cost-effectiveness analysis was conducted to assess the incremental cost-effectiveness ratio of linezolid versus vancomycin, given the significantly higher clinical success of linezolid compared with vancomycin found in the trial. Overall, HCRU and costs were similar between the linezolid and vancomycin treatment groups; drug costs were significantly higher and dialysis costs significantly lower for linezolid- compared with vancomycin-treated patients. Total treatment costs were approximately $8000 higher (P = .046) for patients who developed renal failure compared with those who did not. Renal failure occurred more commonly in patients randomized to receive vancomycin (15%) compared with linezolid (4%; P < .001). Region, ventilator-associated pneumonia, clinical failure, and development of renal failure were associated with significantly higher total costs. The point estimate incremental cost-effectiveness ratio for linezolid compared with vancomycin was $16,516 per treatment success, with linezolid dominant in 24% and dominated in <2% of bootstrapped samples. This phase 4 clinical trial conducted in patients with MRSA-confirmed nosocomial pneumonia reveals that linezolid- compared with vancomycin-treated patients had similar HCRU and total overall costs. Fewer patients developed renal failure during the study while taking linezolid compared with vancomycin, and patients with a documented MSAE or renal failure had increased HCRU and costs. In summary, linezolid may be a cost-effective treatment strategy in MRSA-confirmed nosocomial pneumonia. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Supporting Imagers' VOICE: A National Training Program in Comparative Effectiveness Research and Big Data Analytics.

PubMed

Kang, Stella K; Rawson, James V; Recht, Michael P

2017-12-05

Provided methodologic training, more imagers can contribute to the evidence basis on improved health outcomes and value in diagnostic imaging. The Value of Imaging Through Comparative Effectiveness Research Program was developed to provide hands-on, practical training in five core areas for comparative effectiveness and big biomedical data research: decision analysis, cost-effectiveness analysis, evidence synthesis, big data principles, and applications of big data analytics. The program's mixed format consists of web-based modules for asynchronous learning as well as in-person sessions for practical skills and group discussion. Seven diagnostic radiology subspecialties and cardiology are represented in the first group of program participants, showing the collective potential for greater depth of comparative effectiveness research in the imaging community. Copyright © 2017 American College of Radiology. Published by Elsevier Inc. All rights reserved.

The Effects of Print Comparative Political Advertising on Political Decision-Making and Participation.

ERIC Educational Resources Information Center

Pinkleton, Bruce E.

1998-01-01

Examines intended and unintended effects of print comparative political advertising on political decision making, voting preferences, and situational election involvement among a sample of communication and business undergraduate students. Suggests that comparative advertising reduces targeted-candidate voting preferences while avoiding most forms…

Comparing the Cost-Effectiveness of Simulation Modalities: A Case Study of Peripheral Intravenous Catheterization Training

ERIC Educational Resources Information Center

Isaranuwatchai, Wanrudee; Brydges, Ryan; Carnahan, Heather; Backstein, David; Dubrowski, Adam

2014-01-01

While the ultimate goal of simulation training is to enhance learning, cost-effectiveness is a critical factor. Research that compares simulation training in terms of educational- and cost-effectiveness will lead to better-informed curricular decisions. Using previously published data we conducted a cost-effectiveness analysis of three…

[Mirtazapine versus other antidepressive agents for depression].

PubMed

Knud Larsen, Jens

2012-11-12

A Cochrane analysis compared efficacy and side effects of mirtazapine with other antidepressants. After six weeks of treatment no reliable difference of efficacy between mirtazapine, selective serotonin reuptake inhibitors (SSRI), noradrenaline reuptake inhibitors or tricyclic antidepressants was found. The side effects like increased sleep and weight gain were compared by treatment with mirtazapine and treatment with SSRI antidepressants. The very fact of the sleep effect and the fast onset of action have probably increased the effect size compared with SSRI antidepressants. The results of the Cochrane analysis cannot for certain be generalized to inpatients, as other studies have found tricyclic antidepressants to be especially effective.

How Is Pelvic Pain Treated?

MedlinePlus

... chronic pelvic pain therapies for women: Comparative effectiveness (Comparative Effectiveness Review No. 41). Rockville, MD: Agency for Healthcare Research and Quality. National Kidney and Urologic Diseases Information ...

76 FR 38663 - Agency Information Collection Activities; Proposed Collection; Comment Request; Experimental...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-01

... on the Experimental Study of Comparative Direct-to-Consumer (DTC) Advertising. This study is designed... indirect comparisons, using comparative visuals, and using vaguer language. This study is designed to apply... Effectiveness) studies designed to explore comparative effectiveness. When this large project is completed, FDA...

Comparative PV LCOE calculator | Photovoltaic Research | NREL

Science.gov Websites

Use the Comparative Photovoltaic Levelized Cost of Energy Calculator (Comparative PV LCOE Calculator) to calculate levelized cost of energy (LCOE) for photovoltaic (PV) systems based on cost effect on LCOE to determine whether a proposed technology is cost-effective, perform trade-off analysis

Comparative Effects of Stimulant Drugs in Hyperkinetic Children.

ERIC Educational Resources Information Center

Conners, C. Keith

The study compared the efficacy, side effects, and safety of magnesium pemoline (Cylert) and destroamphetamine (Dexedrine) as compared with placebo. Subjects were 81 children, ages 6-12 years, who evidenced one or more signs of minimal brain dysfunction, and were referred with major complaints of hyperactivity, short attention span,…

Comparative effectiveness of Tai Chi versus physical therapy for knee osteoarthritis: a randomized trial

USDA-ARS?s Scientific Manuscript database

Background: Few remedies effectively treat long-term pain and disability from knee osteoarthritis. Studies suggest that Tai Chi alleviates symptoms, but no trials have directly compared Tai Chi with standard therapies for osteoarthritis. Objective: To compare Tai Chi with standard physical therapy f...

Comparing the effects of low-dose contraceptive pills to control dysfunctional uterine bleeding by oral and vaginal methods.

PubMed

Mehrabian, Ferdous; Abbassi, Fariba

2013-09-01

Background and Objective : Contraceptive pills are generally taken orally and can cause side effects such as nausea, vomiting and hypertension. The vaginal use of these pills can reduce such complications. Our objective was to compare the efficacy and side effects of low dose contraceptive pills by oral and vaginal route in the management of dysfunctional uterine bleeding-(DUB) Methods: This comparative observational study was conducted at Beheshti and Alzahra (SA) teaching hospitals, affiliated to Isfahan University of Medical Sciences in 2010-2011. One hundred women who presented with DUB were randomly assigned into two groups of equal number, receiving the low dose oral contraceptive pills by oral or vaginal route for three month. The amount and duration of bleeding were compared at the beginning and at the end of the study and side effects by these two methods compared. The results of this study showed that both oral and vaginal routes effectively reduced the duration and amount of bleeding due to DUB after three courses of treatment. This effect was better in the vaginal method compared with oral administration (P = 0.03). Regarding the side effects, nausea and vomiting were significantly higher in the oral group than in the vaginal group (P = 0.03). Vulvovaginitis infection was more frequent in the vaginal group than in the oral group (P = 0.03). Low dose contraceptive pills are effective in reducing the amount, time, and duration of bleeding in patients with DUB. In addition, reduction of gastrointestinal side effects by vaginal route helps to use these pills by the patient with proper training of physicians, midwives and patients.

Comparable effects of exercise and analgesics for pain secondary to knee osteoarthritis: a meta-analysis of trials included in Cochrane systematic reviews.

PubMed

Henriksen, Marius; Hansen, Julie B; Klokker, Louise; Bliddal, Henning; Christensen, Robin

2016-07-01

Evidence of comparative effectiveness of different treatment approaches is important for clinical decision-making, yet absent for most recommended treatments of knee osteoarthritis pain. The objective of this study was to estimate the comparative effectiveness of exercise versus orally administered analgesics for pain in patients with knee osteoarthritis. The Cochrane Database of systematic reviews was searched for meta-analyses of randomized controlled studies comparing exercise or analgesics with a control group (placebo or usual care) and with pain as an outcome. Individual study estimates were identified and effect sizes were calculated from group differences. We combined study-level effects on pain with a random effects meta-analysis and compared effect sizes between exercise trials and trials with analgesic interventions. We included six Cochrane reviews (four pharmacology, two exercise). From these, 54 trials were eligible (20 pharmacology, 34 exercise), with 9806 participants (5627 pharmacology, 4179 exercise). The pooled effect size of pharmacological pain interventions was 0.41 (95% CI: 0.23-0.59) and for exercise 0.46 standardized mean difference (95% CI: 0.34-0.59). There was no statistically significant difference between the two types of intervention (difference: 0.06 standardized mean difference [95% CI: -0.28-0.16; p = 0.61]). This meta-epidemiological study provides indirect evidence that for knee osteoarthritis pain, the effects from exercise and from oral analgesics are comparable. These results may support shared decision-making where a patient for some reason is unable to exercise or who consider exercise as unviable and analgesics as a more feasible choice. PROSPERO registration: CRD42013006924.

Comparative effectiveness of lipid-lowering treatments to reduce cardiovascular disease.

PubMed

Suh, Dong-Churl; Griggs, Scott K; Henderson, Emmett R; Lee, Seung-Mi; Park, Taehwan

2018-02-01

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is a new treatment option for patients with hypercholesterolemia. The objective of this study was to systematically review the cost-effectiveness of lipid-lowering agents. Areas covered: Based on Pubmed, Embase, and Cochrane Database of Systematic Reviews, we identified 29 relevant articles. Studies found statins were cost-effective compared with placebo or no treatment in general. Atorvastatin was reported to be cost-effective against simvastatin. In most cases, rosuvastatin was more cost-effective than atorvastatin or simvastatin. Additionally, ezetimibe was considered to be cost-effective compared with no treatment for statin intolerant patients. For patients not meeting treatment goals with their statins, switching to ezetimibe plus simvastatin was consistently reported cost-effective. The cost-effectiveness of ezetimibe plus a hybrid of a statin varied by the source of clinical data and cost of ezetimibe. Finally, the cost-effectiveness of PCSK9 inhibitor plus a statin against statin monotherapy was uncertain. The PCSK9 inhibitor plus a stain was cost-ineffective compared with ezetimibe plus a statin. Expert commentary: Drug costs and treatment efficacy were the key drivers of the cost-effectiveness results in prior analyses. Future evaluations are warranted to reflect the decreasing drug prices and the long-term treatment effects of PCSK9 inhibitors.

Cost-effectiveness of peer role play and standardized patients in undergraduate communication training.

PubMed

Bosse, Hans Martin; Nickel, Martin; Huwendiek, Sören; Schultz, Jobst Hendrik; Nikendei, Christoph

2015-10-24

The few studies directly comparing the methodological approach of peer role play (RP) and standardized patients (SP) for the delivery of communication skills all suggest that both methods are effective. In this study we calculated the costs of both methods (given comparable outcomes) and are the first to generate a differential cost-effectiveness analysis of both methods. Medical students in their prefinal year were randomly assigned to one of two groups receiving communication training in Pediatrics either with RP (N = 34) or 19 individually trained SP (N = 35). In an OSCE with standardized patients using the Calgary-Cambridge Referenced Observation Guide both groups achieved comparable high scores (results published). In this study, corresponding costs were assessed as man-hours resulting from hours of work of SP and tutors. A cost-effectiveness analysis was performed. Cost-effectiveness analysis revealed a major advantage for RP as compared to SP (112 vs. 172 man hours; cost effectiveness ratio .74 vs. .45) at comparable performance levels after training with both methods. While both peer role play and training with standardized patients have their value in medical curricula, RP has a major advantage in terms of cost-effectiveness. This could be taken into account in future decisions.

Revision Arthroscopic Repair Versus Latarjet Procedure in Patients With Recurrent Instability After Initial Repair Attempt: A Cost-Effectiveness Model.

PubMed

Makhni, Eric C; Lamba, Nayan; Swart, Eric; Steinhaus, Michael E; Ahmad, Christopher S; Romeo, Anthony A; Verma, Nikhil N

2016-09-01

To compare the cost-effectiveness of arthroscopic revision instability repair and Latarjet procedure in treating patients with recurrent instability after initial arthroscopic instability repair. An expected-value decision analysis of revision arthroscopic instability repair compared with Latarjet procedure for recurrent instability followed by failed repair attempt was modeled. Inputs regarding procedure cost, clinical outcomes, and health utilities were derived from the literature. Compared with revision arthroscopic repair, Latarjet was less expensive ($13,672 v $15,287) with improved clinical outcomes (43.78 v 36.76 quality-adjusted life-years). Both arthroscopic repair and Latarjet were cost-effective compared with nonoperative treatment (incremental cost-effectiveness ratios of 3,082 and 1,141, respectively). Results from sensitivity analyses indicate that under scenarios of high rates of stability postoperatively, along with improved clinical outcome scores, revision arthroscopic repair becomes increasingly cost-effective. Latarjet procedure for failed instability repair is a cost-effective treatment option, with lower costs and improved clinical outcomes compared with revision arthroscopic instability repair. However, surgeons must still incorporate clinical judgment into treatment algorithm formation. Level IV, expected value decision analysis. Copyright © 2016. Published by Elsevier Inc.

How Are Pelvic Floor Disorders Commonly Treated?

MedlinePlus

... incontinence in adult women: Diagnosis and comparative effectiveness. Comparative effectiveness review no. 36. Rockville, MD: Agency for Healthcare Research and Quality. National Kidney and Urologic Diseases Information ...

Cost-effectiveness of vedolizumab compared with infliximab, adalimumab, and golimumab in patients with ulcerative colitis in the United Kingdom.

PubMed

Wilson, Michele R; Bergman, Annika; Chevrou-Severac, Helene; Selby, Ross; Smyth, Michael; Kerrigan, Matthew C

2018-03-01

To examine the clinical and economic impact of vedolizumab compared with infliximab, adalimumab, and golimumab in the treatment of moderately to severely active ulcerative colitis (UC) in the United Kingdom (UK). A decision analytic model in Microsoft Excel was used to compare vedolizumab with other biologic treatments (infliximab, adalimumab, and golimumab) for the treatment of biologic-naïve patients with UC in the UK. Efficacy data were obtained from a network meta-analysis using placebo as the common comparator. Other inputs (e.g., unit costs, adverse-event disutilities, probability of surgery, mortality) were obtained from published literature. Costs were presented in 2012/2013 British pounds. Outcomes included quality-adjusted life-years (QALYs). Costs and outcomes were discounted by 3.5% per year. Incremental cost-effectiveness ratios were presented for vedolizumab compared with other biologics. Univariate and multivariate probabilistic sensitivity analyses were conducted to assess model robustness to parameter uncertainty. The model predicted that anti-tumour necrosis factor-naïve patients on vedolizumab would accrue more QALY than patients on other biologics. The incremental results suggest that vedolizumab is a cost-effective treatment compared with adalimumab (incremental cost-effectiveness ratio of £22,735/QALY) and dominant compared with infliximab and golimumab. Sensitivity analyses suggest that results are most sensitive to treatment response and transition probabilities. However, vedolizumab is cost-effective irrespective of variation in any of the input parameters. Our model predicted that treatment with vedolizumab improves QALY, increases time in remission and response, and is a cost-effective treatment option compared with all other biologics for biologic-naïve patients with moderately to severely active UC.

Beware of Kinked Frontiers: A Systematic Review of the Choice of Comparator Strategies in Cost-Effectiveness Analyses of Human Papillomavirus Testing in Cervical Screening.

PubMed

O'Mahony, James F; Naber, Steffie K; Normand, Charles; Sharp, Linda; O'Leary, John J; de Kok, Inge M C M

2015-12-01

To systematically review the choice of comparator strategies in cost-effectiveness analyses (CEAs) of human papillomavirus testing in cervical screening. The PubMed, Web of Knowledge, and Scopus databases were searched to identify eligible model-based CEAs of cervical screening programs using human papillomavirus testing. The eligible CEAs were reviewed to investigate what screening strategies were chosen for analysis and how this choice might have influenced estimates of the incremental cost-effectiveness ratio (ICER). Selected examples from the reviewed studies are presented to illustrate how the omission of relevant comparators might influence estimates of screening cost-effectiveness. The search identified 30 eligible CEAs. The omission of relevant comparator strategies appears likely in 18 studies. The ICER estimates in these cases are probably lower than would be estimated had more comparators been included. Five of the 30 studies restricted relevant comparator strategies to sensitivity analyses or other subanalyses not part of the principal base-case analysis. Such exclusion of relevant strategies from the base-case analysis can result in cost-ineffective strategies being identified as cost-effective. Many of the CEAs reviewed appear to include insufficient comparator strategies. In particular, they omit strategies with relatively long screening intervals. Omitting relevant comparators matters particularly if it leads to the underestimation of ICERs for strategies around the cost-effectiveness threshold because these strategies are the most policy relevant from the CEA perspective. Consequently, such CEAs may not be providing the best possible policy guidance and lead to the mistaken adoption of cost-ineffective screening strategies. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Estimating, Testing, and Comparing Specific Effects in Structural Equation Models: The Phantom Model Approach

ERIC Educational Resources Information Center

Macho, Siegfried; Ledermann, Thomas

2011-01-01

The phantom model approach for estimating, testing, and comparing specific effects within structural equation models (SEMs) is presented. The rationale underlying this novel method consists in representing the specific effect to be assessed as a total effect within a separate latent variable model, the phantom model that is added to the main…

Comparing Indirect Effects in SEM: A Sequential Model Fitting Method Using Covariance-Equivalent Specifications

ERIC Educational Resources Information Center

Chan, Wai

2007-01-01

In social science research, an indirect effect occurs when the influence of an antecedent variable on the effect variable is mediated by an intervening variable. To compare indirect effects within a sample or across different samples, structural equation modeling (SEM) can be used if the computer program supports model fitting with nonlinear…

Cost-effectiveness analysis of acute kidney injury biomarkers in pediatric cardiac surgery.

PubMed

Petrovic, Stanislava; Bogavac-Stanojevic, Natasa; Lakic, Dragana; Peco-Antic, Amira; Vulicevic, Irena; Ivanisevic, Ivana; Kotur-Stevuljevic, Jelena; Jelic-Ivanovic, Zorana

2015-01-01

Acute kidney injury (AKI) is significant problem in children with congenital heart disease (CHD) who undergo cardiac surgery. The economic impact of a biomarker-based diagnostic strategy for AKI in pediatric populations undergoing CHD surgery is unknown. The aim of this study was to perform the cost effectiveness analysis of using serum cystatin C (sCysC), urine neutrophil gelatinase-associated lipocalin (uNGAL) and urine liver fatty acid-binding protein (uL-FABP) for the diagnosis of AKI in children after cardiac surgery compared with current diagnostic method (monitoring of serum creatinine (sCr) level). We developed a decision analytical model to estimate incremental cost-effectiveness of different biomarker-based diagnostic strategies compared to current diagnostic strategy. The Markov model was created to compare the lifetime cost associated with using of sCysC, uNGAL, uL-FABP with monitoring of sCr level for the diagnosis of AKI. The utility measurement included in the analysis was quality-adjusted life years (QALY). The results of the analysis are presented as the incremental cost-effectiveness ratio (ICER). Analysed biomarker-based diagnostic strategies for AKI were cost-effective compared to current diagnostic method. However, uNGAL and sCys C strategies yielded higher costs and lower effectiveness compared to uL-FABP strategy. uL-FABP added 1.43 QALY compared to current diagnostic method at an additional cost of $8521.87 per patient. Therefore, ICER for uL-FABP compared to sCr was $5959.35/QALY. Our results suggest that the use of uL-FABP would represent cost effective strategy for early diagnosis of AKI in children after cardiac surgery.

A Comparative Study of Natural Antimicrobial Delivery Systems for Microbial Safety and Quality of Fresh-Cut Lettuce.

PubMed

Hill, Laura E; Oliveira, Daniela A; Hills, Katherine; Giacobassi, Cassie; Johnson, Jecori; Summerlin, Harvey; Taylor, T Matthew; Gomes, Carmen L

2017-05-01

Nanoencapsulation can provide a means to effectively deliver antimicrobial compounds and enhance the safety of fresh produce. However, to date there are no studies which directly compares how different nanoencapsulation systems affect fresh produce safety and quality. This study compared the effects on quality and safety of fresh-cut lettuce treated with free and nanoencapsulated natural antimicrobial, cinnamon bark extract (CBE). A challenge study compared antimicrobial efficacy of 3 different nanoencapsulated CBE systems. The most effective antimicrobial treatment against Listeria monocytogenes was chitosan-co-poly-N-isopropylacrylamide (chitosan-PNIPAAM) encapsulated CBE, with a reduction on bacterial load up to 2 log 10 CFU/g (P < 0.05) compared to the other encapsulation systems when fresh-cut lettuce was stored at 5 °C and 10 °C for 15 d. Subsequently, chitosan-PNIPAAM-CBE nanoparticles (20, 40, and 80 mg/mL) were compared to a control and free CBE (400, 800, and 1600 μg/mL) for its effects on fresh-cut lettuce quality over 15 d at 5 °C. By the 10th day, the most effective antimicrobial concentration was 80 mg/mL for chitosan-PNIPAAM-CBE, up to 2 log 10 CFU/g reduction (P < 0.05), compared with the other treatments. There was no significant difference between control and treated samples up to day 10 for the quality attributes evaluated. Chitosan-PNIPAAM-CBE nanoparticles effectively inhibited spoilage microorganisms' growth and extended fresh-cut lettuce shelf-life. Overall, nanoencapsulation provided a method to effectively deliver essential oil and enhanced produce safety, while creating little to no detrimental quality changes on the fresh-cut lettuce. © 2017 Institute of Food Technologists®.

Statistical Power of Alternative Structural Models for Comparative Effectiveness Research: Advantages of Modeling Unreliability.

PubMed

Coman, Emil N; Iordache, Eugen; Dierker, Lisa; Fifield, Judith; Schensul, Jean J; Suggs, Suzanne; Barbour, Russell

2014-05-01

The advantages of modeling the unreliability of outcomes when evaluating the comparative effectiveness of health interventions is illustrated. Adding an action-research intervention component to a regular summer job program for youth was expected to help in preventing risk behaviors. A series of simple two-group alternative structural equation models are compared to test the effect of the intervention on one key attitudinal outcome in terms of model fit and statistical power with Monte Carlo simulations. Some models presuming parameters equal across the intervention and comparison groups were underpowered to detect the intervention effect, yet modeling the unreliability of the outcome measure increased their statistical power and helped in the detection of the hypothesized effect. Comparative Effectiveness Research (CER) could benefit from flexible multi-group alternative structural models organized in decision trees, and modeling unreliability of measures can be of tremendous help for both the fit of statistical models to the data and their statistical power.

Measure once, cut twice--adding patient-reported outcome measures to the electronic health record for comparative effectiveness research.

PubMed

Wu, Albert W; Kharrazi, Hadi; Boulware, L Ebony; Snyder, Claire F

2013-08-01

This article presents the current state of patient-reported outcome measures and explains new opportunities for leveraging the recent adoption of electronic health records to expand the application of patient-reported outcomes in both clinical care and comparative effectiveness research. Historic developments of patient-reported outcome, electronic health record, and comparative effectiveness research are analyzed in two dimensions: patient centeredness and digitization. We pose the question, "What needs to be standardized around the collection of patient-reported outcomes in electronic health records for comparative effectiveness research?" We identified three converging trends: the progression of patient-reported outcomes toward greater patient centeredness and electronic adaptation; the evolution of electronic health records into personalized and fully digitized solutions; and the shift toward patient-oriented comparative effectiveness research. Related to this convergence, we propose an architecture for patient-reported outcome standardization that could serve as a first step toward a more comprehensive integration of patient-reported outcomes with electronic health record for both practice and research. The science of patient-reported outcome measurement has matured sufficiently to be integrated routinely into electronic health records and other electronic health solutions to collect data on an ongoing basis for clinical care and comparative effectiveness research. Further efforts and ideally coordinated efforts from various stakeholders are needed to refine the details of the proposed framework for standardization. Copyright © 2013 Elsevier Inc. All rights reserved.

Sedative Effects of Levocetirizine: A Systematic Review and Meta-Analysis of Randomized Controlled Studies.

PubMed

Snidvongs, Kornkiat; Seresirikachorn, Kachorn; Khattiyawittayakun, Likhit; Chitsuthipakorn, Wirach

2017-02-01

As a substrate of P-glycoprotein, levocetirizine should not cause sedative effects. However, while cetirizine, a mixture of levocetirizine and dextrocetirizine, can slightly penetrate the blood brain barrier, the sedative effects of levocetirizine are still under study. The aim of this study was to investigate the sedative effects of levocetirizine. An electronic literature search was performed using Medline and EMBASE from January 01, 2001 through August 6, 2015. Randomized controlled trials (RCTs) comparing levocetirizine with other antihistamines or placebo for patients with allergy and healthy subjects were selected. Primary outcome was risk ratio between levocetirizine and comparators. Secondary outcome was change in psychomotor speed. Data were pooled for meta-analysis using a fixed-effect model. Forty-eight studies of 18,014 patients met the inclusion criteria. When compared to placebo, levocetirizine produced modest sedative effects (RR: 1.67; 95% CI 1.17, 2.38). However, when compared to other second-generation antihistamines, sedative effects of levocetirizine did not differ (RR: 1.23; 95% CI 0.96, 1.58). In subgroup analysis, there was no difference between the sedative effects of levocetirizine and fexofenadine (RR: 1.7; 95% CI 0.59, 4.88), desloratadine (RR: 1.58; 95% CI 0.9, 2.77), loratadine (RR: 1.56; 95% CI 0.28, 8.56), bilastine (RR: 1.17; 95% CI 0.48, 2.84), olopatadine (RR: 1.09; 95% CI 0.81, 1.47), azelastine (RR: 0.19; 95% CI 0.01, 3.68) and rupatadine (RR: 1.47; 95% CI 0.14, 15.72). When compared to first-generation antihistamines, levocetirizine had less sedative effects and less change of reaction time (mean difference: -250.76 s; 95% CI -338.53, -162.98). Levocetirizine has modest sedative effects with a risk ratio of 1.67 when compared with placebo. The sedative effects observed for levocetirizine are not different from other second-generation antihistamines.

Reading and listening in people with aphasia: effects of syntactic complexity.

PubMed

DeDe, Gayle

2013-11-01

The purpose of this study was to compare online effects of syntactic complexity in written and spoken sentence comprehension in people with aphasia (PWA) and adults with no brain damage (NBD). The participants in Experiment 1 were NBD older and younger adults (n = 20 per group). The participants in Experiment 2 were 10 PWA. In both experiments, the participants read and listened to sentences in self-paced reading and listening tasks. The experimental materials consisted of object cleft sentences (e.g., It was the girl who the boy hugged.) and subject cleft sentences (e.g., It was the boy who hugged the girl.). The predicted effects of syntactic complexity were observed in both Experiments 1 and 2: Reading and listening times were longer for the verb in sentences with object compared to subject relative clauses. The NBD controls showed exaggerated effects of syntactic complexity in reading compared to listening. The PWA did not show different modality effects from the NBD participants. Although effects of syntactic complexity were somewhat exaggerated in reading compared with listening, both the PWA and the NBD controls showed similar effects in both modalities.

Using indirect comparisons to compare interventions within a Cochrane review: a tool for comparative effectiveness research.

PubMed

Agapova, Maria; Devine, Emily B; Nguyen, Hiep; Wolf, Fredric M; Inoue, Lurdes Y T

2014-07-01

Assessing relative performance among competing interventions is an important part of comparative effectiveness research. Bayesian indirect comparisons add information to existing Cochrane reviews, such as which intervention is likely to perform best. However, heterogeneity variance priors may influence results and, potentially, clinical guidance. We highlight the features of Bayesian indirect comparisons using a case study of a Cochrane review update in asthma care. The probability that one self-management educational intervention outperforms others is estimated. Simulation studies investigate the effect of heterogeneity variance prior distributions. Results suggest a 55% probability that individual education is best, followed by combination (39%) and group (6%). The intervention with few trials was sensitive to prior distributions. Bayesian indirect comparisons updates of Cochrane reviews are valuable comparative effectiveness research tools.

Design of the North Carolina Prostate Cancer Comparative Effectiveness and Survivorship Study (NC ProCESS).

PubMed

Chen, Ronald C; Carpenter, William R; Kim, Mimi; Hendrix, Laura H; Agans, Robert P; Meyer, Anne-Marie; Hoffmeyer, Anna; Reeve, Bryce B; Nielsen, Matthew E; Usinger, Deborah S; Strigo, Tara S; Jackman, Anne M; Anderson, Mary; Godley, Paul A

2015-01-01

The North Carolina Prostate Cancer Comparative Effectiveness & Survivorship Study (NC ProCESS) was designed in collaboration with stakeholders to compare the effectiveness of different treatment options for localized prostate cancer. Using the Rapid Case Ascertainment system of the North Carolina Central Cancer Registry, 1,419 patients (57% of eligible) with newly-diagnosed localized prostate cancer were enrolled from January 2011 to June 2013, on average 5 weeks after diagnosis. All participants were enrolled prior to treatment and this population-based cohort is sociodemographically diverse. Prospective follow-up continues to collect data on treatments received, disease control, survival and patient-reported outcomes. This study highlights several important considerations regarding stakeholder involvement, study design and generalizability regarding comparative effectiveness research in prostate cancer.

Enabling comparative effectiveness research with informatics: show me the data!

PubMed

Safdar, Nabile M; Siegel, Eliot; Erickson, Bradley J; Nagy, Paul

2011-09-01

Both outcomes researchers and informaticians are concerned with information and data. As such, some of the central challenges to conducting successful comparative effectiveness research can be addressed with informatics solutions. Specific informatics solutions which address how data in comparative effectiveness research are enriched, stored, shared, and analyzed are reviewed. Imaging data can be made more quantitative, uniform, and structured for researchers through the use of lexicons and structured reporting. Secure and scalable storage of research data is enabled through data warehouses and cloud services. There are a number of national efforts to help researchers share research data and analysis tools. There is a diverse arsenal of informatics tools designed to meet the needs of comparative effective researchers. Copyright © 2011 AUR. Published by Elsevier Inc. All rights reserved.

78 FR 5805 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-28

... comparative effectiveness research. The Effective Health Care Program also translates research findings into a... that are currently available are designed to help practicing clinicians, consumers/patients, and..., such as faculty slide sets based on comparative effectiveness reviews of the literature, to reach this...

Behavioural therapies versus treatment as usual for depression

PubMed Central

Caldwell, Deborah; Hunot, Vivien; Moore, Theresa HM; Davies, Philippa; Jones, Hannah; Lewis, Glyn; Churchill, Rachel

2014-01-01

This is the protocol for a review and there is no abstract. The objectives are as follows: To examine the effectiveness and acceptability of all BT approaches compared with treatment as usual/waiting list/attention placebo control conditions for acute depression.To examine the effectiveness and acceptability of different BT approaches (behavioural therapy, behavioural activation, social skills training and relaxation training) compared with treatment as usual/waiting list/attention placebo control conditions for acute depression.To examine the effectiveness and acceptability of all BT approaches compared with different types of comparator (standard care, no treatment, waiting list, attention placebo) for acute depression. PMID:25411561

Humanistic therapies versus treatment as usual for depression

PubMed Central

Davies, Philippa; Hunot, Vivien; Moore, Theresa HM; Caldwell, Deborah; Jones, Hannah; Lewis, Glyn; Churchill, Rachel

2014-01-01

This is the protocol for a review and there is no abstract. The objectives are as follows: To examine the effectiveness and acceptability of all humanistic therapies compared with treatment as usual/waiting list/attention placebo control conditions for acute depression.To examine the effectiveness and acceptability of different humanistic therapy models (person-centred, gestalt, process-experiential, transactional analysis, existential and non-directive therapies) compared with treatment as usual/waiting list/attention placebo control conditions for acute depression.To examine the effectiveness and acceptability of all humanistic therapies compared with different types of comparator (standard care, no treatment, waiting list, attention placebo) for acute depression. PMID:25408624

A matching framework to improve causal inference in interrupted time-series analysis.

PubMed

Linden, Ariel

2018-04-01

Interrupted time-series analysis (ITSA) is a popular evaluation methodology in which a single treatment unit's outcome is studied over time and the intervention is expected to "interrupt" the level and/or trend of the outcome, subsequent to its introduction. When ITSA is implemented without a comparison group, the internal validity may be quite poor. Therefore, adding a comparable control group to serve as the counterfactual is always preferred. This paper introduces a novel matching framework, ITSAMATCH, to create a comparable control group by matching directly on covariates and then use these matches in the outcomes model. We evaluate the effect of California's Proposition 99 (passed in 1988) for reducing cigarette sales, by comparing California to other states not exposed to smoking reduction initiatives. We compare ITSAMATCH results to 2 commonly used matching approaches, synthetic controls (SYNTH), and regression adjustment; SYNTH reweights nontreated units to make them comparable to the treated unit, and regression adjusts covariates directly. Methods are compared by assessing covariate balance and treatment effects. Both ITSAMATCH and SYNTH achieved covariate balance and estimated similar treatment effects. The regression model found no treatment effect and produced inconsistent covariate adjustment. While the matching framework achieved results comparable to SYNTH, it has the advantage of being technically less complicated, while producing statistical estimates that are straightforward to interpret. Conversely, regression adjustment may "adjust away" a treatment effect. Given its advantages, ITSAMATCH should be considered as a primary approach for evaluating treatment effects in multiple-group time-series analysis. © 2017 John Wiley & Sons, Ltd.

Cost-effectiveness analysis of mammography and clinical breast examination strategies

PubMed Central

Ahern, Charlotte Hsieh; Shen, Yu

2009-01-01

Purpose Breast cancer screening by mammography and clinical breast exam are commonly used for early tumor detection. Previous cost-effectiveness studies considered mammography alone or did not account for all relevant costs. In this study, we assessed the cost-effectiveness of screening schedules recommended by three major cancer organizations and compared them with alternative strategies. We considered costs of screening examinations, subsequent work-up, biopsy, and treatment interventions after diagnosis. Methods We used a microsimulation model to generate women’s life histories, and assessed screening and treatment impacts on survival. Using statistical models, we accounted for age-specific incidence, preclinical disease duration, and age-specific sensitivity and specificity for each screening modality. The outcomes of interest were quality-adjusted life years (QALYs) saved and total costs with a 3% annual discount rate. Incremental cost-effectiveness ratios were used to compare strategies. Sensitivity analyses were performed by varying some of the assumptions. Results Compared to guidelines from the National Cancer Institute and the U.S. Preventive Services Task Force, alternative strategies were more efficient. Mammography and clinical breast exam in alternating years from ages 40 to 79 was a cost-effective alternative compared to the guidelines, costing $35,500 per QALY saved compared with no screening. The American Cancer Society guideline was the most effective and the most expensive, costing over $680,000 for an added QALY compared to the above alternative. Conclusion Screening strategies with lower costs and benefits comparable to those currently recommended should be considered for implementation in practice and for future guidelines. PMID:19258473

Cost-effectiveness of ceftolozane/tazobactam compared with piperacillin/tazobactam as empiric therapy based on the in-vitro surveillance of bacterial isolates in the United States for the treatment of complicated urinary tract infections.

PubMed

Kauf, Teresa L; Prabhu, Vimalanand S; Medic, Goran; Borse, Rebekah H; Miller, Benjamin; Gaultney, Jennifer; Sen, Shuvayu S; Basu, Anirban

2017-04-28

A challenge in the empiric treatment of complicated urinary tract infection (cUTI) is identifying the initial appropriate antibiotic therapy (IAAT), which is associated with reduced length of stay and mortality compared with initial inappropriate antibiotic therapy (IIAT). We evaluated the cost-effectiveness of ceftolozane/tazobactam compared with piperacillin/tazobactam (one of the standard of care antibiotics), for the treatment of hospitalized patients with cUTI. A decision-analytic Monte Carlo simulation model was developed to compare the costs and effectiveness of empiric treatment with either ceftolozane/tazobactam or piperacillin/tazobactam in hospitalized adult patients with cUTI infected with Gram-negative pathogens in the US. The model applies the baseline prevalence of resistance as reported by national in-vitro surveillance data. In a cohort of 1000 patients, treatment with ceftolozane/tazobactam resulted in higher total costs compared with piperacillin/tazobactam ($36,413 /patient vs. $36,028/patient, respectively), greater quality-adjusted life years (QALYs) (9.19/patient vs. 9.13/patient, respectively) and an incremental cost-effectiveness ratio (ICER) of $6128/QALY. Ceftolozane/tazobactam remained cost-effective at a willingness to pay of $100,000 per QALY compared to piperacillin/tazobactam over a range of input parameter values during one-way and probabilistic sensitivity analysis. Model results show that ceftolozane/tazobactam is likely to be cost-effective compared with piperacillin/tazobactam for the empiric treatment of hospitalized cUTI patients in the United States.

Cost-effectiveness of novel algorithms for rapid diagnosis of tuberculosis in HIV-infected individuals in Uganda.

PubMed

Shah, Maunank; Dowdy, David; Joloba, Moses; Ssengooba, Willy; Manabe, Yukari C; Ellner, Jerrold; Dorman, Susan E

2013-11-28

Xpert MTB/RIF ('Xpert') and urinary lateral-flow lipoarabinomannan (LF-LAM) assays offer rapid tuberculosis (TB) diagnosis. This study evaluated the cost-effectiveness of novel diagnostic algorithms utilizing combinations of Xpert and LF-LAM for the detection of active TB among people living with HIV. Cost-effectiveness analysis using data from a comparative study of LF-LAM and Xpert, with a target population of HIV-infected individuals with signs/symptoms of TB in Uganda. A decision-analysis model compared multiple strategies for rapid TB diagnosis:sputum smear-microscopy; sputum Xpert; smear-microscopy combined with LF-LAM; and Xpert combined with LF-LAM. Primary outcomes were the costs and DALY's averted for each algorithm. Cost-effectiveness was represented using incremental cost-effectiveness ratios (ICER). Compared with an algorithm of Xpert testing alone, the combination of Xpert with LF-LAM was considered highly cost-effective (ICER $57/DALY-averted) at a willingness to pay threshold of Ugandan GDP per capita. Addition of urine LF-LAM testing to smear-microscopy was a less effective strategy than Xpert replacement of smear-microscopy, but was less costly and also considered highly cost-effective (ICER $33 per DALY-averted) compared with continued usage of smear-microscopy alone. Cost-effectiveness of the Xpert plus LF-LAM algorithm was most influenced by HIV/ART costs and life-expectancy of patients after TB treatment. The addition of urinary LF-LAM to TB diagnostic algorithms for HIV-infected individuals is highly cost-effective compared with usage of either sputum smear-microscopy or Xpert alone.

Does understanding relational terminology mediate effects of intervention on compare word problems?

PubMed

Schumacher, Robin F; Fuchs, Lynn S

2012-04-01

The purpose of this study was to assess whether understanding relational terminology (i.e., more, less, and fewer) mediates the effects of intervention on compare word problems. Second-grade classrooms (N=31) were randomly assigned to one of three conditions: researcher-designed word-problem intervention, researcher-designed calculation intervention, or business-as-usual (teacher-designed) control. Students in word-problem intervention classrooms received instruction on the compare problem type, which included a focus on understanding relational terminology within compare word problems. Analyses, which accounted for variance associated with classroom clustering, indicated that (a) compared with the calculation intervention and business-as-usual conditions, word-problem intervention significantly increased performance on all three subtypes of compare problems and on understanding relational terminology, and (b) the intervention effect was fully mediated by students' understanding of relational terminology for one subtype of compare problems and partially mediated by students' understanding of relational terminology for the other two subtypes. Copyright © 2011 Elsevier Inc. All rights reserved.

JIM-13-0560 R1: Propensity scores for confounder adjustment when assessing the effects of medical interventions using non-experimental study designs

PubMed Central

Stürmer, Til; Wyss, Richard; Glynn, Robert J.; Brookhart, M. Alan

2014-01-01

Treatment effects, especially when comparing two or more therapeutic alternatives as in comparative effectiveness research, are likely to be heterogeneous across age, gender, co-morbidities, and co-medications. Propensity scores (PSs), an alternative to multivariable outcome models to control for measured confounding, have specific advantages in the presence of heterogeneous treatment effects. Implementing PSs using matching or weighting allows us to estimate different overall treatment effects in differently defined populations. Heterogeneous treatment effects can also be due to unmeasured confounding concentrated in those treated contrary to prediction. Sensitivity analyses based on PSs can help to assess such unmeasured confounding. PSs should be considered a primary or secondary analytic strategy in non-experimental medical research, including pharmacoepidemiology and non-experimental comparative effectiveness research. PMID:24520806

A cost-effectiveness comparison of embryo donation with oocyte donation.

PubMed

Finger, Reginald; Sommerfelt, Carol; Freeman, Melanie; Wilson, Carrie K; Wade, Amy; Daly, Douglas

2010-02-01

To compare the cost-effectiveness of embryo donation (ED) to that of oocyte donation (OD). Calculation of cost-effectiveness ratios (costs per outcome achieved) using data derived from clinical practices. In vitro fertilization centers and embryo donation programs. Infertile couples undergoing oocyte donation or embryo donation. Oocyte donation or embryo donation cycles. Cost-effectiveness ratios. For a single cycle, ED is approximately twice as cost-effective as OD, with a cost-effectiveness ratio of $21,990 per live delivery compared to 40,600 dollars. When strategies of up to three cycles (to achieve one live delivery) are used, ED costs 13,505 dollars per live delivery compared to 31,349 dollars for OD. Cost-effectiveness is a compelling reason for infertile couples to consider embryo donation. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Photodynamic Therapy for Actinic Keratoses: A Randomized Prospective Non-sponsored Cost-effectiveness Study of Daylight-mediated Treatment Compared with Light-emitting Diode Treatment.

PubMed

Neittaanmäki-Perttu, Noora; Grönroos, Mari; Karppinen, Toni; Snellman, Erna; Rissanen, Pekka

2016-02-01

Daylight-mediated photodynamic therapy (DL-PDT) is considered as effective as conventional PDT using artificial light (light-emitting diode (LED)-PDT) for treatment of actinic keratoses (AK). This randomized prospective non-sponsored study assessed the cost-effectiveness of DL-PDT compared with LED-PDT. Seventy patients with 210 AKs were randomized to DL-PDT or LED-PDT groups. Effectiveness was assessed at 6 months. The costs included societal costs and private costs, including the time patients spent in treatment. Results are presented as incremental cost-effectiveness ratio (ICER). The total costs per patient were significantly lower for DL-PDT (€132) compared with LED-PDT (€170), giving a cost saving of €38 (p = 0.022). The estimated probabilities for patients' complete response were 0.429 for DL-PDT and 0.686 for LED-PDT; a difference in probability of being healed of 0.257. ICER showed a monetary gain of €147 per unit of effectiveness lost. DL-PDT is less costly and less effective than LED-PDT. In terms of cost-effectiveness analysis, DL-PDT provides lower value for money compared with LED-PDT.

Clinical safety and effectiveness of transversus abdominis plane (TAP) block in post-operative analgesia: a systematic review and meta-analysis.

PubMed

Ma, Ning; Duncan, Joanna K; Scarfe, Anje J; Schuhmann, Susanne; Cameron, Alun L

2017-06-01

Transversus abdominis plane (TAP) blocks can provide analgesia postoperatively for a range of surgeries. Abundant clinical trials have assessed TAP block showing positive analgesic effects. This systematic review assesses safety and effectiveness outcomes of TAP block in all clinical settings, comparing with both active (standard care) and inactive (placebo) comparators. PubMed, EMBASE, The Cochrane Library and the University of York CRD databases were searched. RCTs were screened for their eligibility and assessed for risk of bias. Meta-analyses were performed on available data. TAP block showed an equivalent safety profile to all comparators in the incidence of nausea (OR = 1.07) and vomiting (OR = 0.81). TAP block was more effective in reducing morphine consumption [MD = 13.05, 95% CI (8.33, 51.23)] and in delaying time to first analgesic request [MD = 123.49, 95% CI (48.59, 198.39)]. Postoperative pain within 24 h was reduced or at least equivalent in TAP block compared to its comparators. Therefore, TAP block is a safe and effective procedure compared to standard care, placebo and other analgesic techniques. Further research is warranted to investigate whether the TAP block technique can be improved by optimizing dose and technique-related factors.

Comparative effectiveness research: what to do when experts disagree about risks.

PubMed

Lie, Reidar K; Chan, Francis K L; Grady, Christine; Ng, Vincent H; Wendler, David

2017-06-19

Ethical issues related to comparative effectiveness research, or research that compares existing standards of care, have recently received considerable attention. In this paper we focus on how Ethics Review Committees (ERCs) should evaluate the risks of comparative effectiveness research. We discuss what has been a prominent focus in the debate about comparative effectiveness research, namely that it is justified when "nothing is known" about the comparative effectiveness of the available alternatives. We argue that this focus may be misleading. Rather, we should focus on the fact that some experts believe that the evidence points in favor of one intervention, whereas other experts believe that the evidence favors the alternative(s). We will then introduce a case that illustrates this point, and based on that, discuss how ERCs should deal with such cases of expert disagreement. We argue that ERCs have a duty to assess the range of expert opinions and based on that assessment arrive at a risk judgment about the study under consideration. We also argue that assessment of expert disagreement is important for the assignment of risk level to a clinical trial: what is the basis for expert opinions, how strong is the evidence appealed to by various experts, and how can clinical trial monitoring affect the possible increased risk of clinical trial participation.

The Effectiveness of Problem-Based Instruction: A Comparative Study of Instructional Methods and Student Characteristics

ERIC Educational Resources Information Center

Mergendoller, John R.; Maxwell, Nan L.; Bellisimo, Yolanda

2006-01-01

This study compared the effectiveness of problem-based learning (PBL) and traditional instructional approaches in developing high-school students' macroeconomics knowledge and examined whether PBL was differentially effective with students demonstrating different levels of four aptitudes: verbal ability, interest in economics, preference for group…

Comparing Higher Education Practices and Cultural Competences in Kenya and the United States

ERIC Educational Resources Information Center

Musamali, Kennedy; Martin, Barbara N.

2016-01-01

Examined within this paper are effective leadership practices across two cultures. Specifically, this study examined the relationship between cultural competency and effective leadership practices in higher education institutions. A quantitative design was used to investigate and compare effective practices of educational leaders in two distinct…

Effective Collection Developers: Librarians or Faculty?

ERIC Educational Resources Information Center

Vidor, David L.; Futas, Elizabeth

1988-01-01

A study at the Emory University School of Business Administration library compared the effectiveness of faculty members and librarians as book selectors. Effectiveness was measured by comparing selected titles with the Baker list published by the Harvard Business School and with business periodical reviews, and by examining circulation records.…

COMPARING BEHAVIORAL DOSE-EFFECT CURVES FOR HUMANS AND LABORATORY ANIMALS ACUTELY EXPOSED TO TOLUENE.

EPA Science Inventory

The utility of laboratory animal data in toxicology depends upon the ability to generalize the results quantitatively to humans. To compare the acute behavioral effects of inhaled toluene in humans to those in animals, dose-effect curves were fitted by meta-analysis of published...

Pressure ulcer risk assessment and prevention: a systematic comparative effectiveness review.

PubMed

Chou, Roger; Dana, Tracy; Bougatsos, Christina; Blazina, Ian; Starmer, Amy J; Reitel, Katie; Buckley, David I

2013-07-02

Pressure ulcers are associated with substantial health burdens but may be preventable. To review the clinical utility of pressure ulcer risk assessment instruments and the comparative effectiveness of preventive interventions in persons at higher risk. MEDLINE (1946 through November 2012), CINAHL, the Cochrane Library, grant databases, clinical trial registries, and reference lists. Randomized trials and observational studies on effects of using risk assessment on clinical outcomes and randomized trials of preventive interventions on clinical outcomes. Multiple investigators abstracted and checked study details and quality using predefined criteria. One good-quality trial found no evidence that use of a pressure ulcer risk assessment instrument, with or without a protocolized intervention strategy based on assessed risk, reduces risk for incident pressure ulcers compared with less standardized risk assessment based on nurses' clinical judgment. In higher-risk populations, 1 good-quality and 4 fair-quality randomized trials found that more advanced static support surfaces were associated with lower risk for pressure ulcers compared with standard mattresses (relative risk range, 0.20 to 0.60). Evidence on the effectiveness of low-air-loss and alternating-air mattresses was limited, with some trials showing no clear differences from advanced static support surfaces. Evidence on the effectiveness of nutritional supplementation, repositioning, and skin care interventions versus usual care was limited and had methodological shortcomings, precluding strong conclusions. Only English-language articles were included, publication bias could not be formally assessed, and most studies had methodological shortcomings. More advanced static support surfaces are more effective than standard mattresses for preventing ulcers in higher-risk populations. The effectiveness of formal risk assessment instruments and associated intervention protocols compared with less standardized assessment methods and the effectiveness of other preventive interventions compared with usual care have not been clearly established.

Cost effectiveness of long-acting risperidone in Sweden.

PubMed

Hensen, Marja; Heeg, Bart; Löthgren, Mickael; van Hout, Ben

2010-01-01

In Sweden, risperidone long-acting injectable (RLAI) is generally used in a population of schizophrenia patients who are at a high risk of being non-compliant. However, RLAI might also be suitable for use in the general schizophrenia population. To analyse the clinical and economic effects of RLAI in the Swedish treatment practice using a discrete-event simulation (DES) model. Treatment outcomes and direct costs were analysed for both the high-risk non-compliant patient population and the general schizophrenia population. An existing DES model was adapted to simulate the treatment of schizophrenia in Sweden. Model inputs were based on literature research and supplemented with expert opinion. In the high-risk non-compliant schizophrenia population, RLAI was compared with haloperidol LAI. The analysis was built upon differences in symptom reduction, time between relapses, compliance and adverse effect profile between the two drugs. Main outcomes were the predicted incremental (discounted) costs (€) and effects (QALYs). In the general schizophrenia population, RLAI was compared with oral olanzapine. This analysis was built upon differences in compliance and adverse effects between the drugs. Multivariate probabilistic sensitivity analyses (PSA) were carried out to assess the sensitivity of the results of the two analyses. In the high-risk non-compliant patient population, RLAI was predicted to generate 0.103 QALYs per patient over 3 years while realizing cost savings of €5013 (year 2007 values) compared with haloperidol LAI. The main driver of the cost effectiveness of RLAI was the difference in Positive and Negative Syndrome Scale (PANSS) reduction between the two drugs, followed by the difference in adverse effects. The PSA showed that, in this setting, RLAI had a probability of 100% of being cost effective at a willingness-to-pay (WTP) threshold of €43,300 per QALY gained, compared with haloperidol LAI. The probability that RLAI combines additional effectiveness with cost savings compared with haloperidol LAI was estimated at 94%. When analysing RLAI in the general schizophrenia population, it was predicted to generate 0.043 QALYs and save €239 per patient over 5 years compared with olanzapine. Compliance was the main driver of the cost effectiveness of RLAI in this scenario. In the PSA it was shown that RLAI had a probability of 78% of being cost effective at a WTP threshold of €43,300 per QALY gained, compared with olanzapine. The estimated probability that RLAI combines additional effectiveness with cost savings was 50% and the probability that RLAI is less effective and more costly than olanzapine was negligible (0.2%). Treatment with RLAI is suggested to result in improved QALYs combined with cost savings compared with haloperidol LAI among the Swedish, high-risk non-compliant schizophrenia patient population. In the general schizophrenia population, RLAI also resulted in positive incremental QALYs and cost savings, when compared with olanzapine. However, the estimates used in the model for compliance and symptom reduction need further validation through naturalistic-based studies with reasonable follow-up to more definitely establish the real-life differences between RLAI and the comparators in the considered patient populations and to further reduce the uncertainty of these parameters.

Treating Localized Prostate Cancer

MedlinePlus

... Prostate Cancer: Update of a 2008 Systematic Review . Comparative Effectiveness Review No. 146. (Prepared by the ECRI ... Prostate Cancer Research Protocol Archived March 29, 2013 Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer: ...

Cost-effectiveness of botulinum toxin a versus anticholinergic medications for idiopathic urge incontinence.

PubMed

Wu, Jennifer M; Siddiqui, Nazema Y; Amundsen, Cindy L; Myers, Evan R; Havrilesky, Laura J; Visco, Anthony G

2009-05-01

We assessed the cost-effectiveness of botulinum toxin A injection compared to anticholinergic medications for the treatment of idiopathic urge incontinence. A Markov decision analysis model was developed to compare the costs in 2008 U. S. dollars and effectiveness in quality adjusted life-years of botulinum toxin A injection and anticholinergic medications. The analysis was conducted from a societal perspective with a 2-year time frame using 3-month cycles. The primary outcome was the incremental cost-effectiveness ratio, defined as the difference in cost (botulinum toxin A cost--anticholinergic cost) divided by the difference in effectiveness (botulinum toxin A quality adjusted life-years--anticholinergic quality adjusted life-years). While the botulinum strategy was more expensive ($4,392 vs $2,563) it was also more effective (1.63 vs 1.50 quality adjusted life-years) compared to the anticholinergic regimen. The calculated incremental cost-effectiveness ratio was $14,377 per quality adjusted life-year, meaning that botulinum toxin A cost $14,377 per quality adjusted life-year gained. A strategy is often considered cost-effective when the incremental cost-effectiveness ratio is less than $50,000 per quality adjusted life-year. Given this definition botulinum toxin A is cost-effective compared to anticholinergics. To determine if there are situations in which anticholinergics would become cost-effective we performed sensitivity analyses. Anticholinergics become cost-effective if compliance exceeds 75% (33% in the base case) and if the botulinum toxin A procedure cost exceeds $3,875 ($1,690 in the base case). For the remainder of the sensitivity analyses botulinum toxin A remained cost-effective. Botulinum toxin A injection was cost-effective compared to anticholinergic medications for the treatment of refractory urge incontinence. Anticholinergics become cost-effective if patients are highly compliant with medications or if the botulinum procedure costs increase substantially.

Social Comparison Framing in Health News and Its Effect on Perceptions of Group Risk

PubMed Central

Bigman, Cabral A.

2013-01-01

News about health disparities often compares health risks faced by different demographic groups. Does this social comparison produce a contrast effect? It was hypothesized that when two racial groups are compared, people would perceive the relatively more at-risk group to be more, and the less at-risk group to be less, at-risk than if the same risk information was presented without the comparative reference group. Three experiments with Black and White respondents tested effects of intergroup social comparison framing (SCF) on perceptions of risk for sexually transmitted infections and skin cancer. SCF (including one White and two Black disparity frames) did not raise respondents’ perceived risk regarding the more at-risk racial group, but consistently lowered respondents’ risk ratings for the less at-risk racial group. The finding that the same statistic was perceived differently in comparative and non-comparative contexts underscores the importance of considering effects of communication about disparities. PMID:23829419

75 FR 20854 - Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-21

... Initiative in Comparative Effectiveness (CHOICE) Grants (R01) applications are to be reviewed and discussed... Initiative in Comparative Effectiveness (CHOICE) Grants (R01). Date: April 28-30, 2010 (Open on April 28 from...

75 FR 20852 - Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-21

... Dissemination of AHRQ Comparative Effectiveness Research Products (iADAPT) (R18) applications are to be reviewed... Dissemination of AHRQ Comparative Effectiveness Research Products (iADAPT) (R18). Date: April 29-30, 2010 (Open...

A Comparative Study on Power Point Presentation and Traditional Lecture Method in Material Understandability, Effectiveness and Attitude

ERIC Educational Resources Information Center

Sewasew, Daniel; Mengestle, Missaye; Abate, Gebeyehu

2015-01-01

The aim of this study was to compare PPT and traditional lecture method in material understandability, effectiveness and attitude among university students. Comparative descriptive survey research design was employed to answer the research questions raised. Four hundred and twenty nine participants were selected randomly using stratified sampling…

Outcomes of Group Care for Youth: A Review of Comparative Studies

ERIC Educational Resources Information Center

Lee, Bethany R.; Bright, Charlotte L.; Svoboda, Deborah V.; Fakunmoju, Sunday; Barth, Richard P.

2011-01-01

Objective: The purpose of this study was to review empirical evidence of the effects of placement in group care compared to other interventions. Method: Two-group empirical studies were identified and effect sizes for all reported outcomes were calculated. Results: Nineteen two-group studies were found that compared group care with family foster…

Antileukotriene Reverts the Early Effects of Inflammatory Response of Distal Parenchyma in Experimental Chronic Allergic Inflammation

PubMed Central

Gobbato, Nathália Brandão; de Souza, Flávia Castro Ribas; Fumagalli, Stella Bruna Napolitano; Lopes, Fernanda Degobbi Tenório Quirino dos Santos; Prado, Carla Máximo; Martins, Milton Arruda; Tibério, Iolanda de Fátima Lopes Calvo; Leick, Edna Aparecida

2013-01-01

Aims. Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation. Methods. GP have inhaled ovalbumin (OVA group-2x/week/4weeks). After the 4th inhalation, GP were treated with montelukast or dexamethasone. After 72 hours of the 7th inhalation, GP were anesthetised, and lungs were removed and submitted to histopathological evaluation. Results. Montelukast and dexamethasone treatments reduced the number of eosinophils in airway wall and distal lung parenchyma compared to OVA group (P < 0.05). On distal parenchyma, both treatments were effective in reducing RANTES, NF-κB, and fibronectin positive cells compared to OVA group (P < 0.001). Montelukast was more effective in reducing eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (P < 0.001), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (P < 0.001). On airway walls, montelukast and dexamethasone were effective in reducing IGF-I, RANTES, and fibronectin positive cells compared to OVA group (P < 0.05). Dexamethasone was more effective in reducing the number of eotaxin and NF-κB positive cells than Montelukast (P < 0.05). Conclusions. In this animal model, both treatments were effective in modulating allergic inflammation and remodeling distal lung parenchyma and airway wall, contributing to a better control of the inflammatory response. PMID:24151607

Can we maximize both value and quality in gynecologic cancer care? A work in progress.

PubMed

Havrilesky, Laura J; Fountain, Cynthia

2014-01-01

Value is defined as desirable health outcomes achieved per monetary unit spent. Comparative effectiveness research and cost-effectiveness research are methods that have been developed to quantify effectiveness and value to inform management decisions. In this article we review the comparative and cost-effectiveness literature in the field of ovarian cancer treatment. Studies have shown that improved ovarian cancer survival is associated with complete primary surgical cytoreduction, with treatment at high volume facilities by subspecialist providers (gynecologic oncologists) and with National Comprehensive Cancer Network (NCCN) guideline-adherent care in both surgical staging and chemotherapy regimens. Intraperitoneal/intravenous chemotherapy (compared with intravenous alone) has been associated with improved survival and cost-effectiveness. Bevacizumab for primary and maintenance therapy has been found to not be cost-effective (even in selective subsets) despite a small progression-free survival (PFS) advantage. For platinum-sensitive recurrent ovarian cancer, secondary cytoreduction and platinum-based combinations are associated with improved overall survival (OS); several platinum-based combinations have also been found cost-effective. For platinum-resistant recurrence, single agent therapy and supportive care are cost-effective compared with combination therapies. Although little prospective clinical research has been done around end-of-life care, one study reported that for platinum-resistant ovarian cancer, palliative intervention would potentially reduce costs and increase quality adjusted life years compared with usual care (based on improvement in quality of life [QOL]). Overall, cost comparisons of individual chemotherapy regimens are highly dependent on market prices of novel therapeutic agents.

Cost-Effectiveness of Interventions to Prevent and Control Diabetes Mellitus: A Systematic Review

PubMed Central

Li, Rui; Zhang, Ping; Barker, Lawrence E.; Chowdhury, Farah M.; Zhang, Xuanping

2010-01-01

OBJECTIVE To synthesize the cost-effectiveness (CE) of interventions to prevent and control diabetes, its complications, and comorbidities. RESEARCH DESIGN AND METHODS We conducted a systematic review of literature on the CE of diabetes interventions recommended by the American Diabetes Association (ADA) and published between January 1985 and May 2008. We categorized the strength of evidence about the CE of an intervention as strong, supportive, or uncertain. CEs were classified as cost saving (more health benefit at a lower cost), very cost-effective (≤$25,000 per life year gained [LYG] or quality-adjusted life year [QALY]), cost-effective ($25,001 to $50,000 per LYG or QALY), marginally cost-effective ($50,001 to $100,000 per LYG or QALY), or not cost-effective (>$100,000 per LYG or QALY). The CE classification of an intervention was reported separately by country setting (U.S. or other developed countries) if CE varied by where the intervention was implemented. Costs were measured in 2007 U.S. dollars. RESULTS Fifty-six studies from 20 countries met the inclusion criteria. A large majority of the ADA recommended interventions are cost-effective. We found strong evidence to classify the following interventions as cost saving or very cost-effective: (I) Cost saving— 1) ACE inhibitor (ACEI) therapy for intensive hypertension control compared with standard hypertension control; 2) ACEI or angiotensin receptor blocker (ARB) therapy to prevent end-stage renal disease (ESRD) compared with no ACEI or ARB treatment; 3) early irbesartan therapy (at the microalbuminuria stage) to prevent ESRD compared with later treatment (at the macroalbuminuria stage); 4) comprehensive foot care to prevent ulcers compared with usual care; 5) multi-component interventions for diabetic risk factor control and early detection of complications compared with conventional insulin therapy for persons with type 1 diabetes; and 6) multi-component interventions for diabetic risk factor control and early detection of complications compared with standard glycemic control for persons with type 2 diabetes. (II) Very cost-effective— 1) intensive lifestyle interventions to prevent type 2 diabetes among persons with impaired glucose tolerance compared with standard lifestyle recommendations; 2) universal opportunistic screening for undiagnosed type 2 diabetes in African Americans between 45 and 54 years old; 3) intensive glycemic control as implemented in the UK Prospective Diabetes Study in persons with newly diagnosed type 2 diabetes compared with conventional glycemic control; 4) statin therapy for secondary prevention of cardiovascular disease compared with no statin therapy; 5) counseling and treatment for smoking cessation compared with no counseling and treatment; 6) annual screening for diabetic retinopathy and ensuing treatment in persons with type 1 diabetes compared with no screening; 7) annual screening for diabetic retinopathy and ensuing treatment in persons with type 2 diabetes compared with no screening; and 8) immediate vitrectomy to treat diabetic retinopathy compared with deferred vitrectomy. CONCLUSIONS Many interventions intended to prevent/control diabetes are cost saving or very cost-effective and supported by strong evidence. Policy makers should consider giving these interventions a higher priority. PMID:20668156

Comparative Evolution of an Archetypal Adaptive Radiation: Innovation and Opportunity in Anolis Lizards.

PubMed

Poe, Steven; de Oca, Adrián Nieto-Montes; Torres-Carvajal, Omar; de Queiroz, Kevin; Velasco, Julián A; Truett, Brad; Gray, Levi N; Ryan, Mason J; Köhler, Gunther; Ayala-Varela, Fernando; Latella, Ian

2018-06-01

Adaptive radiation is a widely recognized pattern of evolution wherein substantial phenotypic change accompanies rapid speciation. Adaptive radiation may be triggered by environmental opportunities resulting from dispersal to new areas or via the evolution of traits, called key innovations, that allow for invasion of new niches. Species sampling is a known source of bias in many comparative analyses, yet classic adaptive radiations have not been studied comparatively with comprehensively sampled phylogenies. In this study, we use unprecedented comprehensive phylogenetic sampling of Anolis lizard species to examine comparative evolution in this well-studied adaptive radiation. We compare adaptive radiation models within Anolis and in the Anolis clade and a potential sister lineage, the Corytophanidae. We find evidence for island (i.e., opportunity) effects and no evidence for trait (i.e., key innovation) effects causing accelerated body size evolution within Anolis. However, island effects are scale dependent: when Anolis and Corytophanidae are analyzed together, no island effect is evident. We find no evidence for an island effect on speciation rate and tenuous evidence for greater speciation rate due to trait effects. These results suggest the need for precision in treatments of classic adaptive radiations such as Anolis and further refinement of the concept of adaptive radiation.

Therapies for Children With Autism Spectrum Disorder

MedlinePlus

... information in this guide comes from the reports, Comparative Effectiveness of Therapies for Children With Autism Spectrum ... Behavioral Interventions Update Clinician Summary September 23, 2014 Comparative Effectiveness of Therapies for Children With Autism Spectrum ...

Measure Once, Cut Twice – Adding Patient-Reported Outcome Measures to the Electronic Health Record for Comparative Effectiveness Research

PubMed Central

Wu, Albert W.; Kharrazi, Hadi; Boulware, L. Ebony; Snyder, Claire F.

2013-01-01

Objective This paper presents the current state of patient-reported outcome measures, and explains new opportunities for leveraging the recent adoption of electronic health records to expand the application of patient-reported outcomes in both clinical care and comparative effectiveness research. Study Design and Setting Historic developments of patient-reported outcome, electronic health record, and comparative effectiveness research are analyzed in two dimensions: patient-centeredness and digitization. We pose the question: “What needs to be standardized around the collection of patient-reported outcomes in electronic health records for comparative effectiveness research?” Results We identified three converging trends: the progression of patient-reported outcomes toward greater patient centeredness and electronic adaptation; the evolution of electronic health records into personalized and fully digitized solutions; the shift toward patient-oriented comparative effectiveness research. Related to this convergence, we propose an architecture for patient-reported outcome standardization that could serve as a first step toward a more comprehensive integration of patient-reported outcomes with electronic health record for both practice and research. Conclusion The science of patient-reported outcome measurement has matured sufficiently to be integrated routinely into electronic health records and other e-health solutions to collect data on an ongoing basis for clinical care and comparative effectiveness research. Further efforts and ideally coordinated efforts from various stakeholders are needed to refine the details of the proposed framework for standardization. PMID:23849145

The Comparability of the Standardized Mean Difference Effect Size across Different Measures of the Same Construct: Measurement Considerations

ERIC Educational Resources Information Center

Nugent, William R.

2006-01-01

One of the most important effect sizes used in meta-analysis is the standardized mean difference (SMD). In this article, the conditions under which SMD effect sizes based on different measures of the same construct are directly comparable are investigated. The results show that SMD effect sizes from different measures of the same construct are…

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis.

PubMed

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra/rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept [corrected]. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis

PubMed Central

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra, rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs. PMID:26356639

The influence of presentation format on the "bigger is better" (BIB) effect.

PubMed

Bromgard, Gregg D; Trafimow, David; Silvera, David H

2013-04-01

Two experiments tested the "bigger is better" (BIB) effect, whereby bigger objects are perceived more favorably than smaller ones. In Experiment 1, participants directly compared pairs of objects and a strong BIB effect was obtained for both positively and negatively valenced stimuli. In Experiment 2, comparative and absolute evaluations were combined in a single experiment and the BIB effect was mediated for positively and negatively valenced stimuli. Taken in combination, the data support a complex hypothesis that pair-wise presentations induce a comparative process that causes a BIB effect. But when objects are evaluated separately, size and valence interact such that increased size evokes more positive ratings of positive objects and more negative ratings for negative objects.

PAH effects on meio- and microbial benthic communities strongly depend on bioavailability.

PubMed

Lindgren, J Fredrik; Hassellöv, Ida-Maja; Dahllöf, Ingela

2014-01-01

The effects of anthropogenic pollutants in dissimilar habitats can vary depending on differences in bioavailability. The factors determining bioavailability are not yet fully understood. This study was performed to evaluate whether analysis of total PAH concentrations in sediments is a satisfactory measurement to indicate environmental effects or if bioavailability is needed to be taken into account. We have here performed a 60-day experiment, where nominal PAH concentrations of 1,300 μg/kg sediment were added to three different marine sediments. Meiofaunal and microbial communities were analyzed for alterations in community response at 30 and 60 days. Results showed that bioavailability of PAHs varied between the three different sediments. Nonetheless, the petroleum addition gave rise to significant negative effects on all three sediments at both time points. The two direct measurements of toxicity on the microbial community, potential nitrification and denitrification, displayed a lower effect of the PAH addition in the muddy sediment at both time points, compared to the other two sediment types. No effects were seen in the analysis of meiofaunal community structure. Measurements of PAH bioavailability in the three sediment types concurred with the results from the microbial community, revealing a lower bioavailability in the muddy sediment compared to the other two sediment types, 34% compared to sandy and 18% compared to organic at day 0. At day 60 it was 61% lower compared to sandy and 20% lower compared to organic. The negative effects of the PAH addition on the microbial nitrogen cycle were in six out of eight cases best correlated to the amount of alkylated bioavailable PAH in the sediments, and thus microbial nitrogen cycle is a possible good indicator for assessing PAH-induced stress. The results presented here have implications for risk analysis studies of petroleum-contaminated marine sediments; consequently, sediment characteristics and its effects on bioavailability are important to include. In addition, these results add to the understanding that bioavailability measurements of PAHs are a more correct assessment compared to measurements of total PAH concentrations, and need to be included when estimating effects of PAHs in marine benthic communities. Copyright © 2013 Elsevier B.V. All rights reserved.

Opportunities and Challenges in Using Studies without a Control Group in Comparative Effectiveness Reviews

ERIC Educational Resources Information Center

Paulus, Jessica K.; Dahabreh, Issa J.; Balk, Ethan M.; Avendano, Esther E.; Lau, Joseph; Ip, Stanley

2014-01-01

When examining the evidence on therapeutic interventions to answer a comparative effectiveness research question, one should consider all studies that are informative on the interventions' causal effects. "Single group studies" evaluate outcomes longitudinally in cohorts of subjects who are managed with a single treatment strategy.…

Effectiveness of an Online Graduate Preparation Program

ERIC Educational Resources Information Center

Brucato, Brittany; Neimeyer, Greg J.

2011-01-01

The present study reports the results of a controlled examination of the effectiveness of an online graduate preparation program, the Virtual Advisor. The effects of the Virtual Advisor were compared to a website preparation group and a wait-list control group. Results indicated that, compared to the control group, students who utilized the…

"Families" in International Context: Comparing Institutional Effects across Western Societies

ERIC Educational Resources Information Center

Cooke, Lynn Prince; Baxter, Janeen

2010-01-01

We review comparative evidence of institutional effects on families in Western societies. We focus on 2 key aspects of family life: gendered divisions of labor and people's transitions into, within, and out of relationships. Many individual-level models assume the effects are robust across countries. The international evidence over the past decade…

Comparing Single Case Design Overlap-Based Effect Size Metrics from Studies Examining Speech Generating Device Interventions

ERIC Educational Resources Information Center

Chen, Mo; Hyppa-Martin, Jolene K.; Reichle, Joe E.; Symons, Frank J.

2016-01-01

Meaningfully synthesizing single case experimental data from intervention studies comprised of individuals with low incidence conditions and generating effect size estimates remains challenging. Seven effect size metrics were compared for single case design (SCD) data focused on teaching speech generating device use to individuals with…