High content screening of NHBE cells at different time points (4h and 24h) exposed to multiple flavors. PROCESSED files contain annotation and values after raw data values of treatments are normalized against vehicle control.
Various electronic nicotine delivery systems (ENDS), of which electronic cigarettes (e-cigs) are the most recognized prototype, have been quickly gaining ground on conventional cigarettes because they are perceived as less harmful.... more
Various electronic nicotine delivery systems (ENDS), of which electronic cigarettes (e-cigs) are the most recognized prototype, have been quickly gaining ground on conventional cigarettes because they are perceived as less harmful. Research assessing the potential effects of ENDS exposure in humans is currently limited and inconclusive. New products are emerging with numerous variations in designs and performance parameters within and across brands. Acknowledging these challenges, we present here a proposed framework for an <i>in vitro</i> systems toxicology assessment of e-liquids and their aerosols, intended to complement the battery of assays for standard toxicity assessments. The proposed framework utilizes high-throughput toxicity assessments of e-liquids and their aerosols, in which the device-to-device variability is minimized, and a systems-level investigation of the cellular mechanisms of toxicity is an integral part. An analytical chemistry investigation is als...
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E-vapor products (EVP) have become popular alternatives for cigarette smokers who would otherwise continue to smoke. EVP research is challenging and complex, mostly because of the numerous and rapidly evolving technologies and designs as... more
E-vapor products (EVP) have become popular alternatives for cigarette smokers who would otherwise continue to smoke. EVP research is challenging and complex, mostly because of the numerous and rapidly evolving technologies and designs as well as the multiplicity of e-liquid flavors and solvents available on the market. There is an urgent need to standardize all stages of EVP assessment, from the production of a reference product to e-vapor generation methods and from physicochemical characterization methods to nonclinical and clinical exposure studies. The objective of this review is to provide a detailed description of selected experimental setups and methods for EVP aerosol generation and collection and exposure systems for their in vitro and in vivo assessment. The focus is on the specificities of the product that constitute challenges and require development of ad hoc assessment frameworks, equipment, and methods. In so doing, this review aims to support further studies, objecti...
Smoking has been associated with diseases of the lung, pulmonary airways and oral cavity. Cytologic, genomic and transcriptomic changes in oral mucosa correlate with oral pre-neoplasia, cancer and inflammation (e.g. periodontitis).... more
Smoking has been associated with diseases of the lung, pulmonary airways and oral cavity. Cytologic, genomic and transcriptomic changes in oral mucosa correlate with oral pre-neoplasia, cancer and inflammation (e.g. periodontitis). Alteration of smoking-related gene expression changes in oral epithelial cells is similar to that in bronchial and nasal epithelial cells. Using a systems toxicology approach, we have previously assessed the impact of cigarette smoke (CS) seen as perturbations of biological processes in human nasal and bronchial organotypic epithelial culture models. Here, we report our further assessment using in vitro human oral organotypic epithelium models. We exposed the buccal and gingival organotypic epithelial tissue cultures to CS at the air-liquid interface. CS exposure was associated with increased secretion of inflammatory mediators, induction of cytochrome P450s activity and overall weak toxicity in both tissues. Using microarray technology, gene-set analysis...
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Towards the development of a systems biology-based risk assessment approach for environmental toxicants, including tobacco products in a systems toxicology setting such as the “21st Century Toxicology”, we are building a series of... more
Towards the development of a systems biology-based risk assessment approach for environmental toxicants, including tobacco products in a systems toxicology setting such as the “21st Century Toxicology”, we are building a series of computable biological network models specific to non-diseased pulmonary and cardiovascular cells/tissues which capture the molecular events that can be activated following exposure to environmental toxicants. Here we extend on previous work and report on the construction and evaluation of a mechanistic network model focused on DNA damage response and the four main cellular fates induced by stress: autophagy, apoptosis, necroptosis, and senescence. In total, the network consists of 34 sub-models containing 1052 unique nodes and 1538 unique edges which are supported by 1231 PubMed-referenced literature citations. Causal node-edge relationships are described using the Biological Expression Language (BEL), which allows for the semantic representation of life s...
Research Interests: Bioinformatics, Evolutionary Biology, Computer Science, Informatics, Genomics, and 15 moreComputational Biology, Biotechnology, Cancer, Biomarkers, Biology, Biomedical informatics, Autophagy, DNA damage, Apoptosis, Bioscience, Biomedical Research, Clinical Medicine, Biological, Genetic modification, and Evidence Based
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Motivation: Inferring how humans respond to external cues such as drugs, chemicals, viruses or hormones, is an essential question in biomedicine. Very often, however, this question cannot be addressed since it is not possible to perform... more
Motivation: Inferring how humans respond to external cues such as drugs, chemicals, viruses or hormones, is an essential question in biomedicine. Very often, however, this question cannot be addressed since it is not possible to perform experiments in humans. A reasonable alternative consists of generating responses in animal models and “translating” those results to humans. The limitations of such translation, however, are far from clear, and systematic assessments of its actual potential are urgently needed. sbv IMPROVER (systems biology verification for Industrial Methodology for PROcess VErification in Research) was designed as a series of challenges to address translatability between humans and rodents. This collaborative crowd-sourcing initiative invited scientists from around the world to apply their own computational methodologies on a multi-layer systems biology dataset comprised of phosphoproteomics, transcriptomics, and cytokine data derived from normal human and rat bron...
Electronic nicotine delivery products (ENDPs) emit lower levels of toxicants than cigarettes, and, consequently, ENPD aerosols have the potential to be less toxic than cigarette smoke (CS). Toxicological assessment of ENDPs relies heavily... more
Electronic nicotine delivery products (ENDPs) emit lower levels of toxicants than cigarettes, and, consequently, ENPD aerosols have the potential to be less toxic than cigarette smoke (CS). Toxicological assessment of ENDPs relies heavily on in vitro studies to verify this assertion. First, a battery of standardized and validated regulatory toxicology assays is used to verify that ENDP aerosols are less cytotoxic and genotoxic than CS. Second, a systems toxicology approach is employed to gain a deeper understanding of the biological mechanisms affected by CS. This knowledge then allows quantification of the effects of ENDP aerosols on the mechanisms perturbed by CS and identification of potential new effects of ENDP aerosols. While regulatory toxicology assays rely on standardized prokaryotic and mammalian cells, systems toxicology aims to employ in vitro systems derived from primary human cells and more closely recapitulate the key features of human tissues and mechanisms linked to...
Smokers are exposed to the harmful and potentially harmful constituents generated by cigarette combustion. Discriminating the independent effects of nicotine from those of other chemicals present in cigarette smoke is difficult.... more
Smokers are exposed to the harmful and potentially harmful constituents generated by cigarette combustion. Discriminating the independent effects of nicotine from those of other chemicals present in cigarette smoke is difficult. Nevertheless, investigating circumstances in which individuals are exposed to nicotine without combustion—as with the use of smokeless tobacco products, nicotine replacement therapies, and, to some extent, e-vapor products—provides evidence on the possible health effects of nicotine. Where epidemiological data are lacking, nonclinical studies may provide mechanistic insights into nicotine's ability to modulate molecular and cellular processes. This chapter summarizes the current knowledge about the effects of nicotine exposure on the circulatory system, lungs, female and male reproductive organs, and developing fetus and critically reviews nicotine's potential involvement in cardiovascular diseases, lung cancer, and developmental defects. This chapte...
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Graphical abstract
Using an human small airway epithelium model, we assessed the biological impact of an aerosol from a candidate modified-risk tobacco product, the tobacco heating system (THS) 2.2, to investigate the potential reduced risk of THS2.2... more
Using an human small airway epithelium model, we assessed the biological impact of an aerosol from a candidate modified-risk tobacco product, the tobacco heating system (THS) 2.2, to investigate the potential reduced risk of THS2.2 aerosol exposure compared with cigarette smoke. Following the recommendations of the Institute of Medicine and the Tobacco Product Assessment Consortium, in which modified-risk tobacco products assessment should be performed in comparison with standard conventional products, the effects of the THS2.2 aerosol exposure on the small airway cultures were compared with those of 3R4F cigarette smoke. We used a approach whereby elucidation of toxic effects is derived not only from functional assay readouts but also from omics technologies. Cytotoxicity, ciliary beating function, secretion of pro-inflammatory mediators and histological assessment represented functional assays. The omics data included transcriptomic and miRNA profiles. Exposure-induced perturbatio...
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The biological impact of an aerosol of a potential modifiedrisk tobacco product, carbon heated tobacco product 1.2 (CHTP1.2), was comprehensively assessed for the first time in vitro using human small airway and nasal epithelial models... more
The biological impact of an aerosol of a potential modifiedrisk tobacco product, carbon heated tobacco product 1.2 (CHTP1.2), was comprehensively assessed for the first time in vitro using human small airway and nasal epithelial models following a systems toxicology approach. The potentially reduced effects of CHTP1.2 aerosol exposure were benchmarked against those of 3R4F cigarette smoke at similar nicotine concentrations. Experimental repetitions were conducted for which new batches of small airway and nasal cultures were exposed to CHTP1.2 aerosol or 3R4F smoke for 28 minutes. The biological impacts were determined based on a collection of endpoints including morphology, cytotoxicity, proinflammatory mediator profiles, cytochrome P450 1A1/1B1 activity, global mRNA and microRNA changes and proteome profiles. Alterations in mRNA expression were detected in cultures exposed to CHTP1.2 aerosol, without noticeable morphological changes and cytotoxicity, and minimal impact on proinflam...
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This study reports a comparative assessment of the biological impact of a heated tobacco aerosol from the tobacco heating system (THS) 2.2 and smoke from a combustible 3R4F cigarette. Human organotypic bronchial epithelial cultures were... more
This study reports a comparative assessment of the biological impact of a heated tobacco aerosol from the tobacco heating system (THS) 2.2 and smoke from a combustible 3R4F cigarette. Human organotypic bronchial epithelial cultures were exposed to an aerosol from THS2.2 (a candidate modified-risk tobacco product) or 3R4F smoke at similar nicotine concentrations. A systems toxicology approach was applied to enable a comprehensive exposure impact assessment. Culture histology, cytotoxicity, secreted pro-inflammatory mediators, ciliary beating, and genome-wide mRNA/miRNA profiles were assessed at various time points post-exposure. Series of experimental repetitions were conducted to increase the robustness of the assessment. At similar nicotine concentrations, THS2.2 aerosol elicited lower cytotoxicity compared with 3R4F smoke. No morphological change was observed following exposure to THS2.2 aerosol, even at nicotine concentration three times that of 3R4F smoke. Lower levels of secret...
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Smoking is one of the major lifestyle-related risk factors for periodontal diseases. Modified risk tobacco products (MRTP) offer a promising alternative in the harm reduction strategy for adult smokers unable to quit. Using a systems... more
Smoking is one of the major lifestyle-related risk factors for periodontal diseases. Modified risk tobacco products (MRTP) offer a promising alternative in the harm reduction strategy for adult smokers unable to quit. Using a systems toxicology approach, we investigated and compared the exposure effects of a reference cigarette (3R4F) and a heat-not-burn technology-based candidate MRTP, the Tobacco Heating System (THS) 2.2. Human gingival epithelial organotypic cultures were repeatedly exposed (3 days) for 28 min at two matching concentrations of cigarette smoke (CS) or THS2.2 aerosol. Results showed only minor histopathological alterations and minimal cytotoxicity upon THS2.2 aerosol exposure compared to CS (1% for THS2.2 aerosol vs. 30% for CS, at the high concentration). Among the 14 proinflammatory mediators analyzed, only 5 exhibited significant alterations with THS2.2 exposure compared with 11 upon CS exposure. Transcriptomic and metabolomic analysis indicated a general reduct...
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In vitro toxicology approaches have evolved, from a focus on molecular changes within a cell to understanding of toxicity-related mechanisms in systems that can mimic the in vivo environment. The recent development of three dimensional... more
In vitro toxicology approaches have evolved, from a focus on molecular changes within a cell to understanding of toxicity-related mechanisms in systems that can mimic the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offers a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure. The present study investigated further the application of in vitro human 3-D nasal epithelial culture models for toxicological assessment of inhalation exposure. Aligned with 3Rs strategy, this study aimed to explore the relevance of a human 3-D nasal culture model to assess the toxicological impact of aerosols generated from a candidate modified risk tobacco product (cMRTP), the Tobacco Heating System (THS)2.2, as compared with smoke gener...
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Cigarette smoke (CS) has been reported to increase predisposition to oral cancer and is also recognized as a risk factor for many conditions including periodontal diseases, gingivitis and other benign mucosal disorders. Smoking cessation... more
Cigarette smoke (CS) has been reported to increase predisposition to oral cancer and is also recognized as a risk factor for many conditions including periodontal diseases, gingivitis and other benign mucosal disorders. Smoking cessation remains the most effective approach for minimizing risk of smoking-related diseases. However, reduction of harmful constituents by heating rather than combusting tobacco, without modifying the amount of nicotine, is a promising new paradigm in harm reduction. In this study we compared effects of exposure to aerosol derived from a candidate modified risk tobacco product, the tobacco heating system (THS) 2.2, with those of CS generated from the 3R4F reference cigarette. Human organotypic oral epithelial tissue cultures (EpiOral™, MatTek Corporation) were exposed for 28 min to 3R4F CS or THS2.2 aerosol, both diluted with air to comparable nicotine concentrations (0.32 or 0.51 mg nicotine/L aerosol/CS for 3R4F and 0.31 or 0.46 mg/L for THS2.2). We also ...
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The Family Smoking Prevention and Tobacco Control Act of 2009 established the Food and Drug Administration Center for Tobacco Products (FDA-CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco... more
The Family Smoking Prevention and Tobacco Control Act of 2009 established the Food and Drug Administration Center for Tobacco Products (FDA-CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed 'modified risk'. On 8-10 December 2014, IIVS organised a workshop conference, entitled Assessment of In Vitro COPD Models for Tobacco Regulatory Science, to bring together stakeholders representing regulatory agencies, academia, industry and animal protection, to address the research priorities articulated by the FDA-CTP. Specific topics were covered to assess the status of current in vitro technologies as they are applied to understanding the adverse pulmonary events resulting from tobacco product exposure, and in particular, the progression of chronic obstructive pulmonary disease (COPD). The four topics covered were: a) Inflammation and Oxidative Stress; b) Ciliary Dysfunction and Ion Transport; c) Goblet...
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Various electronic nicotine delivery systems (ENDS), of which electronic cigarettes (e-cigs) are the most recognized prototype, have been quickly gaining ground on conventional cigarettes because they are perceived as less harmful.... more
Various electronic nicotine delivery systems (ENDS), of which electronic cigarettes (e-cigs) are the most recognized prototype, have been quickly gaining ground on conventional cigarettes because they are perceived as less harmful. Research assessing the potential effects of ENDS exposure in humans is currently limited and inconclusive. New products are emerging with numerous variations in designs and performance parameters within and across brands. Acknowledging these challenges, we present here a proposed framework for an in vitro systems toxicology assessment of e-liquids and their aerosols, intended to complement the battery of assays for standard toxicity assessments. The proposed framework utilizes high-throughput toxicity assessments of e-liquids and their aerosols, in which the device-to-device variability is minimized, and a systems-level investigation of the cellular mechanisms of toxicity is an integral part. An analytical chemistry investigation is also included as a par...
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Les oligodendrocytes representent pour le systeme nerveux central des vertebres un avantage fondamental acquis au cours de l'evolution. En effet, cette cellule gliale a la formidable capacite de former une gaine de myeline autour de... more
Les oligodendrocytes representent pour le systeme nerveux central des vertebres un avantage fondamental acquis au cours de l'evolution. En effet, cette cellule gliale a la formidable capacite de former une gaine de myeline autour de nombreux axones a la fois permettant ainsi un gain d'espace et d'energie enorme. Cette gaine de myeline represente elle-meme un organite revolutionnaire. Elle permet d'augmenter la vitesse de propagation de l'influx nerveux par le phenomene de conduction saltatoire issu des proprietes isolantes de la myeline et de la concentration des canaux ioniques au niveau des nuds de ranvier. La comprehension du developpement des oligodendrocytes dans le systeme nerveux central represente un vaste domaine d'etudes dont les retombees sont directement associees a la recherche de therapies pour de graves maladies humaines comme la sclerose en plaques. Il apparait de plus en plus clairement que les oligodendrocytes soient impliques dans d'autres fonctions que la transmission du message nerveux. Dans le but d'etablir l'importance des oligodendrocytes dans le developpement du systeme nerveux central, nous avons cree dans le laboratoire par la technique de transgenese un nouveau modele animal : les souris mbp-tk. Grace au systeme d'ablation cellulaire appelle obliteration par la thymidine kinase, nous avons pu induire specifiquement la mort des precurseurs des oligodendrocytes en division. Cette methode nous a d'abord permis d'analyser la generation des oligodendrocytes au cours du developpement post-natal du cerveau. L'utilisation de ce modele animal nous a ensuite donne l'occasion d'etudier in vivo le role de l'oligodendrocyte dans la distribution de proteines axonales dans la region du nud de ranvier. Enfin, nous avons pu mettre en evidence l'implication des oligodendrocytes dans le developpement post-natal du cervelet.
Cigarette smoke increases the risk for respiratory and other diseases. Although smoking prevalence has declined over the years, millions of adults choose to continue to smoke. Modified risk tobacco products (MRTPs) are potentially... more
Cigarette smoke increases the risk for respiratory and other diseases. Although smoking prevalence has declined over the years, millions of adults choose to continue to smoke. Modified risk tobacco products (MRTPs) are potentially valuable tools for adult smokers that are unwilling to quit their habit. Here, we investigated the biological impact of a candidate MRTP, the tobacco-heating system (THS) 2.2, compared to that of the 3R4F reference cigarette in normal primary human bronchial epithelial cells. Chemical characterization of the THS 2.2 aerosol showed reduced levels of harmful constituents compared to those of a combustible cigarette. Multiparametric indicators of cellular toxicity were measured via real-time cellular analysis and high-content screening. The study was complemented by a whole transcriptome analysis, followed by computational approaches to identify and quantify perturbed molecular pathways. Exposure of cells to 3R4F cigarette smoke resulted in a dose-dependent r...
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Organotypic three dimensional cultures of epithelial cells are grown at the air-liquid interface (ALI) and resemble the in vivo counterparts. Although the complexity of in vivo cellular responses could be better manifested in co-culture... more
Organotypic three dimensional cultures of epithelial cells are grown at the air-liquid interface (ALI) and resemble the in vivo counterparts. Although the complexity of in vivo cellular responses could be better manifested in co-culture models in which additional cell-types such as fibroblasts were incorporated, the presence of another cell-type could mask the response of the other. This study reports the impact of whole cigarette smoke (CS) exposure on organotypic mono- and co-culture models to evaluate the relevancy of organotypic models for toxicological assessment of aerosols. Two organotypic bronchial models were directly exposed to low and high concentrations of CS of the reference research cigarette 3R4F: mono-culture of bronchial epithelial cells without fibroblasts (BR) and co-culture with fibroblasts (BRF) models. Adenylate kinase-based cytotoxicity, cytochrome P450 (CYP) 1A1/1B1 activity, tissue histology, and concentrations of secreted mediators into the basolateral medi...
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Oligodendrocytes are glial cells devoted to the production of myelin sheaths. Myelination of the CNS occurs essentially after birth. To delineate both the times of oligodendrocyte proliferation and myelination, as well as to study the... more
Oligodendrocytes are glial cells devoted to the production of myelin sheaths. Myelination of the CNS occurs essentially after birth. To delineate both the times of oligodendrocyte proliferation and myelination, as well as to study the consequence of dysmyelination in vivo, a model of inducible dysmyelination was developed. To achieve oligodendrocyte ablation, transgenic animals were generated that express the herpes virus 1 thymidine kinase (HSV1-TK) gene under the control of the myelin basic protein (MBP) gene promoter. The expression of the MBP-TK transgene in oligodendrocytes is not toxic on its own; however, toxicity can be selectively induced by the systemic injection of animals with nucleoside analogs, such as FIAU [1-(2-deoxy-2-fluoro-beta-delta-arabinofuranosyl)-5-iodouracil]. This system allows us to control the precise duration of the toxic insult and the degree of ablation of oligodendrocytes in vivo. We show that chronic treatment of MBP-TK mice with FIAU during the firs...
Research Interests: In Situ Hybridization, Brain, Optic Nerve, Mice, Female, and 13 moreAnimals, Male, The, Glial Fibrillary Acidic Protein, Sciatic Nerve, Thymidine Kinase, Transgenic Mouse Technology, Myelin Sheath, Gliosis, Psychology and Cognitive Sciences, Demyelinating diseases, Medical and Health Sciences, and myelin basic protein
The membrane of myelinated axons is divided into functionally distinct domains characterized by the enrichment of specific proteins. The mechanisms responsible for this organization have not been fully identified. To further address the... more
The membrane of myelinated axons is divided into functionally distinct domains characterized by the enrichment of specific proteins. The mechanisms responsible for this organization have not been fully identified. To further address the role of oligodendrocytes in the functional segmentation of the axolemma in vivo, the distribution of nodal (Na(+) channels, ankyrin G), paranodal (paranodin/contactin-associated-protein) and juxtaparanodal (Kv1.1 K(+) channels) axonal markers, was studied in the brain of MBP-TK and jimpy mice. In MBP-TK transgenic mice, oligodendrocyte ablation was selectively induced by FIAU treatment before and during the onset of myelination. In jimpy mice, oligodendrocytes degenerate spontaneously within the first postnatal weeks after the onset of myelination. Interestingly, in MBP-TK mice treated for 1-20 days with FIAU, despite the ablation of more than 95% of oligodendrocytes, the protein levels of all tested nodal markers was unaltered. Nevertheless, these p...
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We recently constructed a computable cell proliferation network (CPN) model focused on lung tissue to unravel complex biological processes and their exposure-related perturbations from molecular profiling data. The CPN consists of edges... more
We recently constructed a computable cell proliferation network (CPN) model focused on lung tissue to unravel complex biological processes and their exposure-related perturbations from molecular profiling data. The CPN consists of edges and nodes representing upstream controllers of gene expression largely generated from transcriptomics datasets using Reverse Causal Reasoning (RCR). Here, we report an approach to biologically verify the correctness of upstream controller nodes using a specifically designed, independent lung cell proliferation dataset. Normal human bronchial epithelial cells were arrested at G1/S with a cell cycle inhibitor. Gene expression changes and cell proliferation were captured at different time points after release from inhibition. Gene set enrichment analysis demonstrated cell cycle response specificity via an overrepresentation of proliferation related gene sets. Coverage analysis of RCR-derived hypotheses returned statistical significance for cell cycle re...
Research Interests: Pharmacology, Bioinformatics, Evolutionary Biology, Pathology, Oncology, and 15 moreInformatics, Genomics, Computational Biology, Biotechnology, Cancer, Biomarkers, Biology, Biomedical informatics, Medicine, Bioscience, Microarray, Clinical Medicine, Biological, Genetic modification, and Evidence Based
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Capturing the effects of exposure in a specific target organ is a major challenge in risk assessment. Exposure to cigarette smoke (CS) implicates the field of tissue injury in the lung as well as nasal and airway epithelia. Xenobiotic... more
Capturing the effects of exposure in a specific target organ is a major challenge in risk assessment. Exposure to cigarette smoke (CS) implicates the field of tissue injury in the lung as well as nasal and airway epithelia. Xenobiotic metabolism in particular becomes an attractive tool for chemical risk assessment because of its responsiveness against toxic compounds, including those present in CS. This study describes an efficient integration from transcriptomic data to quantitative measures, which reflect the responses against xenobiotics that are captured in a biological network model. We show here that our novel systems approach can quantify the perturbation in the network model of xenobiotic metabolism. We further show that this approach efficiently compares the perturbation upon CS exposure in bronchial and nasal epithelial cellsin vivosamples obtained from smokers. Our observation suggests the xenobiotic responses in the bronchial and nasal epithelial cells of smokers were si...
Research Interests: Risk assessment, Humans, Smoking, Lung, Smoke, and 5 moreBiomed, Epithelial cells, Xenobiotics, Risk Assessment, and Nose
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Exposure to cigarette smoke (CS) is linked to the development of respiratory diseases, and there is a need to understand the mechanisms whereby CS causes damage. Although animal models have provided valuable insights into smoking-related... more
Exposure to cigarette smoke (CS) is linked to the development of respiratory diseases, and there is a need to understand the mechanisms whereby CS causes damage. Although animal models have provided valuable insights into smoking-related respiratory tract damage, modern toxicity testing calls for reliable in vitro models as alternatives for animal experimentation. We report on a repeated whole mainstream CS exposure of nasal and bronchial organotypic tissue cultures that mimic the morphological, physiological, and molecular attributes of the human respiratory tract. Despite the similar cellular staining and cytokine secretion in both tissue types, the transcriptomic analyses in the context of biological network models identified similar and diverse biological processes that were impacted by CS-exposed nasal and bronchial cultures. Our results demonstrate that nasal and bronchial tissue cultures are appropriate in vitro models for the assessment of CS-induced adverse effects in the r...
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Exposure to environmental stressors such as cigarette smoke (CS) elicits a variety of biological responses in humans, including the induction of inflammatory responses. These responses are especially pronounced in the lung, where... more
Exposure to environmental stressors such as cigarette smoke (CS) elicits a variety of biological responses in humans, including the induction of inflammatory responses. These responses are especially pronounced in the lung, where pulmonary cells sit at the interface between the body's internal and external environments. We combined a literature survey with a computational analysis of multiple transcriptomic data sets to construct a computable causal network model (the Inflammatory Process Network (IPN)) of the main pulmonary inflammatory processes. The IPN model predicted decreased epithelial cell barrier defenses and increased mucus hypersecretion in human bronchial epithelial cells, and an attenuated pro-inflammatory (M1) profile in alveolar macrophages following exposure to CS, consistent with prior results. The IPN provides a comprehensive framework of experimentally supported pathways related to CS-induced pulmonary inflammation. The IPN is freely available to the scientifi...
Research Interests: Bioinformatics, Evolutionary Biology, Oncology, Informatics, Genomics, and 15 moreComputational Biology, Biotechnology, Cancer, Biomarkers, Biology, Life Sciences, Biomedical informatics, Medicine, Bioscience, Biomedical Research, Microarray, Clinical Medicine, Biological, Genetic modification, and Evidence Based
Numerous inflammation-related pathways have been shown to play important roles in atherogenesis. Rapid and efficient assessment of the relative influence of each of those pathways is a challenge in the era of "omics" data... more
Numerous inflammation-related pathways have been shown to play important roles in atherogenesis. Rapid and efficient assessment of the relative influence of each of those pathways is a challenge in the era of "omics" data generation. The aim of the present work was to develop a network model of inflammation-related molecular pathways underlying vascular disease to assess the degree of translatability of preclinical molecular data to the human clinical setting. We constructed and evaluated the Vascular Inflammatory Processes Network (V-IPN), a model representing a collection of vascular processes modulated by inflammatory stimuli that lead to the development of atherosclerosis. Utilizing the V-IPN as a platform for biological discovery, we have identified key vascular processes and mechanisms captured by gene expression profiling data from four independent datasets from human endothelial cells (ECs) and human and murine intact vessels. Primary ECs in culture from multiple d...
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Inferring how humans respond to external cues such as drugs, chemicals, viruses or hormones is an essential question in biomedicine. Very often, however, this question cannot be addressed because it is not possible to perform experiments... more
Inferring how humans respond to external cues such as drugs, chemicals, viruses or hormones is an essential question in biomedicine. Very often, however, this question cannot be addressed because it is not possible to perform experiments in humans. A reasonable alternative consists of generating responses in animal models and 'translating' those results to humans. The limitations of such translation, however, are far from clear, and systematic assessments of its actual potential are urgently needed. sbv IMPROVER ( S: ystems B: iology V: erification for I: ndustrial M: ethodology for PRO: cess VE: rification in R: esearch) was designed as a series of challenges to address translatability between humans and rodents. This collaborative crowd-sourcing initiative invited scientists from around the world to apply their own computational methodologies on a multilayer systems biology dataset composed of phosphoproteomics, transcriptomics and cytokine data derived from normal human a...
Research Interests: Bioinformatics, Algorithms, Systems Biology, Cytokines, Biological Sciences, and 13 moreSoftware, Humans, Mathematical Sciences, Animals, Phosphorylation, Gene Regulatory Networks, Behavioral Animal Models, Rats, Epithelial cells, Species Specificity, Translational Medical Research, Gene Expression Regulation, and Gene expression profiling
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Oligodendrocytes (OLs) are the glial cells of the central nervous system and are classically known to form myelin sheaths around most axons of higher vertebrates. Whether these cells might have other roles, in particular during... more
Oligodendrocytes (OLs) are the glial cells of the central nervous system and are classically known to form myelin sheaths around most axons of higher vertebrates. Whether these cells might have other roles, in particular during development, has not been studied. Taking advantage of a transgenic mouse model in which OLs can be selectively killed in a desired time-frame, we have investigated the impact of OL ablation on cerebellar development. OL ablation was induced during the first 3 postnatal weeks, a time at which cerebellum development is ongoing. Strikingly, OL ablation triggers a profound perturbation of the known cerebellum developmental program, characterized by the disorganization of the cortical layers, abnormal foliation and a complete alteration of Purkinje cell dendritic arborization and axonal fasciculation. This phenotype is accompained by decreased granule cell density, a disorganized Bergmann glia network and impaired migration of interneurons in the molecular layer....
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Exposure to cigarette smoke is a leading cause of lung diseases including chronic obstructive pulmonary disease and cancer. Cigarette smoke is a complex aerosol containing over 6000 chemicals and thus it is difficult to determine... more
Exposure to cigarette smoke is a leading cause of lung diseases including chronic obstructive pulmonary disease and cancer. Cigarette smoke is a complex aerosol containing over 6000 chemicals and thus it is difficult to determine individual contributions to overall toxicity as well as the molecular mechanisms by which smoke constituents exert their effects. We selected three well-known harmful and potentially harmful constituents (HPHCs) in tobacco smoke, acrolein, formaldehyde and catechol, and established a high-content screening method using normal human bronchial epithelial cells, which are the first bronchial cells in contact with cigarette smoke. The impact of each HPHC was investigated using 13 indicators of cellular toxicity complemented with a microarray-based whole-transcriptome analysis followed by a computational approach leveraging mechanistic network models to identify and quantify perturbed molecular pathways. HPHCs were evaluated over a wide range of concentrations and at different exposure time points (4, 8, and 24 h). By high-content screening, the toxic effects of the three HPHCs could be observed only at the highest doses. Whole-genome transcriptomics unraveled toxicity mechanisms at lower doses and earlier time points. The most prevalent toxicity mechanisms observed were DNA damage/growth arrest, oxidative stress, mitochondrial stress, and apoptosis/necrosis. A combination of multiple toxicological end points with a systems-based impact assessment allows for a more robust scientific basis for the toxicological assessment of HPHCs, allowing insight into time- and dose-dependent molecular perturbations of specific biological pathways. This approach allowed us to establish an in vitro systems toxicology platform that can be applied to a broader selection of HPHCs and their mixtures and can serve more generally as the basis for testing the impact of other environmental toxicants on normal bronchial epithelial cells.
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Background High-throughput measurement technologies produce data sets that have the potential to elucidate the biological impact of disease, drug treatment, and environmental agents on humans. The scientific community faces an ongoing... more
Background High-throughput measurement technologies produce data sets that have the potential to elucidate the biological impact of disease, drug treatment, and environmental agents on humans. The scientific community faces an ongoing challenge in the analysis of these rich data sources to more accurately characterize biological processes that have been perturbed at the mechanistic level. Here, a new approach is built on previous methodologies in which high-throughput data was interpreted using prior biological knowledge of cause and effect relationships. These relationships are structured into network models that describe specific biological processes, such as inflammatory signaling or cell cycle progression. This enables quantitative assessment of network perturbation in response to a given stimulus. Results Four complementary methods were devised to quantify treatment-induced activity changes in processes described by network models. In addition, companion statistics were develop...
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Background Critical to advancing the systems-level evaluation of complex biological processes is the development of comprehensive networks and computational methods to apply to the analysis of systems biology data (transcriptomics,... more
Background Critical to advancing the systems-level evaluation of complex biological processes is the development of comprehensive networks and computational methods to apply to the analysis of systems biology data (transcriptomics, proteomics/phosphoproteomics, metabolomics, etc.). Ideally, these networks will be specifically designed to capture the normal, non-diseased biology of the tissue or cell types under investigation, and can be used with experimentally generated systems biology data to assess the biological impact of perturbations like xenobiotics and other cellular stresses. Lung cell proliferation is a key biological process to capture in such a network model, given the pivotal role that proliferation plays in lung diseases including cancer, chronic obstructive pulmonary disease (COPD), and fibrosis. Unfortunately, no such network has been available prior to this work. Results To further a systems-level assessment of the biological impact of perturbations on non-diseased ...