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News Article | September 9, 2016
Site: http://www.rdmag.com/rss-feeds/all/rss.xml/all

Several professionals in the scientific world have increasingly acknowledged that in assessing the toxicity of chemicals, drugs and consumer products, animal use should be minimized and, where possible, data should be acquired using alternative in vitro based methodologies. This is part of the widely-recognized set of principles known as the ‘3Rs’ of scientific animal research: One of the goals of ‘21st Century Toxicology’, as set-out in the U.S. National Research Council’s landmark Vision and Strategy report, is to replace in vivo testing methodologies with in vitro procedures on human cells, followed by computational systems biology modelling to determine toxicological risk. The U.S. Food and Drug Administration has identified ‘modernizing toxicology’ as one of its priority areas and has furthermore explicitly expressed an interest in learning about new toxicity testing procedures that could help it meet these goals. As part of the ongoing assessment of Reduced-Risk Products (RRPs), products with the potential to reduce individual risk and population harm in comparison to cigarettes, Philip Morris International (PMI) has recently published two papers that demonstrate the potential of novel in vitro-based testing procedures to help realize the vision of 21st Century Toxicology. The RRP investigated is the Tobacco Heating System 2.2 (THS), a new technology that heats tobacco without burning it, thereby reducing or eliminating the formation of many of the harmful compounds that are produced by cigarettes. One study looked at the biological impact of THS aerosol on the oral epithelium, the other on the nasal epithelium. A third study is currently underway to assess the biological impact of THS aerosol on bronchial epithelial cells. The studies, published in the journals Chemical Research in Toxicology and ALTEX, used human cells grown in three-dimensional culture systems. The cultures were grown on top of an artificial membrane at the air-liquid interface, allowing them to develop ‘organotypic’ tissue complexity closely resembling that found in the human oral cavity and airways, respectively. Cultures were then exposed to either THS aerosol or cigarette smoke at various concentrations with comparable nicotine concentrations. The biological impact of exposure was assessed at time-points between four and 72 hours using a combination of well-established in vitro testing procedures and novel computational techniques. Multiple endpoints were analyzed. These included measurements of cytotoxicity, alterations in tissue morphology (histology), impact on processes involved in the metabolism of toxicants (xenobiotic metabolism response), secretion of pro-inflammatory mediators, and perturbation of genome-wide gene profiles. The nasal study also looked at ciliary function. The adopted computational techniques involved the processing of collected data through a set of literature-supported biological network models that are known to relate to respiratory disease, e.g., oxidative stress, osmotic stress and hypoxic stress (a total of 28 network models were used in the oral study, 29 in the nasal study). The biological impact of cigarette smoke and THS aerosol was then quantified through the assignment of Network Perturbation Amplitude (NPA) scores, and complemented by standard gene-set analysis. Multiple experimental repetitions were conducted (five in the nasal study, four in the oral study) in order to obtain robust, reliable and reproducible measurements. Taken together, the results of the two studies demonstrate that the biological impact of THS aerosol is predominantly non-significantly different from the air control exposure, and much reduced when compared with the impact of cigarette-smoke exposure. It was possible to induce findings of toxicity with THS, but only at significantly higher exposure concentrations of the aerosol than conventional cigarette smoke. There were also no additional or new findings of toxicity following THS aerosol exposure when compared with the toxicity elicited following cigarette smoke exposure. The studies have demonstrated not just the risk-reduction potential of THS in comparison with cigarettes, but also the ability to generate comprehensive and meaningful insights using human cell-based in vitro systems in combination with computational assessment strategies. The studies should be of interest to all scientists who are keen to further minimize the use of animals in the development of 21st Century Toxicology. They further have important implications for industries such as pharmaceuticals and biotechnology, as well as for regulatory bodies responsible for the scientific oversight of chemicals, drugs and a range of consumer products. Julia Hoeng is the director of Systems Toxicology, Biological Systems Research at Philip Morris International. Anita Iskandar is a scientist at Philip Morris International. Filippo Zanetti is a scientist at Philip Morris International.


News Article | September 9, 2016
Site: http://www.rdmag.com/rss-feeds/all/rss.xml/all

Several professionals in the scientific world have increasingly acknowledged that in assessing the toxicity of chemicals, drugs and consumer products, animal use should be minimized and, where possible, data should be acquired using alternative in vitro based methodologies. This is part of the widely-recognized set of principles known as the ‘3Rs’ of scientific animal research: One of the goals of ‘21st Century Toxicology’, as set-out in the U.S. National Research Council’s landmark Vision and Strategy report, is to replace in vivo testing methodologies with in vitro procedures on human cells, followed by computational systems biology modelling to determine toxicological risk. The U.S. Food and Drug Administration has identified ‘modernizing toxicology’ as one of its priority areas and has furthermore explicitly expressed an interest in learning about new toxicity testing procedures that could help it meet these goals. As part of the ongoing assessment of Reduced-Risk Products (RRPs), products with the potential to reduce individual risk and population harm in comparison to cigarettes, Philip Morris International (PMI) has recently published two papers that demonstrate the potential of novel in vitro-based testing procedures to help realize the vision of 21st Century Toxicology. The RRP investigated is the Tobacco Heating System 2.2 (THS), a new technology that heats tobacco without burning it, thereby reducing or eliminating the formation of many of the harmful compounds that are produced by cigarettes. One study looked at the biological impact of THS aerosol on the oral epithelium, the other on the nasal epithelium. A third study is currently underway to assess the biological impact of THS aerosol on bronchial epithelial cells. The studies, published in the journals Chemical Research in Toxicology and ALTEX, used human cells grown in three-dimensional culture systems. The cultures were grown on top of an artificial membrane at the air-liquid interface, allowing them to develop ‘organotypic’ tissue complexity closely resembling that found in the human oral cavity and airways, respectively. Cultures were then exposed to either THS aerosol or cigarette smoke at various concentrations with comparable nicotine concentrations. The biological impact of exposure was assessed at time-points between four and 72 hours using a combination of well-established in vitro testing procedures and novel computational techniques. Multiple endpoints were analyzed. These included measurements of cytotoxicity, alterations in tissue morphology (histology), impact on processes involved in the metabolism of toxicants (xenobiotic metabolism response), secretion of pro-inflammatory mediators, and perturbation of genome-wide gene profiles. The nasal study also looked at ciliary function. The adopted computational techniques involved the processing of collected data through a set of literature-supported biological network models that are known to relate to respiratory disease, e.g., oxidative stress, osmotic stress and hypoxic stress (a total of 28 network models were used in the oral study, 29 in the nasal study). The biological impact of cigarette smoke and THS aerosol was then quantified through the assignment of Network Perturbation Amplitude (NPA) scores, and complemented by standard gene-set analysis. Multiple experimental repetitions were conducted (five in the nasal study, four in the oral study) in order to obtain robust, reliable and reproducible measurements. Taken together, the results of the two studies demonstrate that the biological impact of THS aerosol is predominantly non-significantly different from the air control exposure, and much reduced when compared with the impact of cigarette-smoke exposure. It was possible to induce findings of toxicity with THS, but only at significantly higher exposure concentrations of the aerosol than conventional cigarette smoke. There were also no additional or new findings of toxicity following THS aerosol exposure when compared with the toxicity elicited following cigarette smoke exposure. The studies have demonstrated not just the risk-reduction potential of THS in comparison with cigarettes, but also the ability to generate comprehensive and meaningful insights using human cell-based in vitro systems in combination with computational assessment strategies. The studies should be of interest to all scientists who are keen to further minimize the use of animals in the development of 21st Century Toxicology. They further have important implications for industries such as pharmaceuticals and biotechnology, as well as for regulatory bodies responsible for the scientific oversight of chemicals, drugs and a range of consumer products. Julia Hoeng is the director of Systems Toxicology, Biological Systems Research at Philip Morris International. Anita Iskandar is a scientist at Philip Morris International. Filippo Zanetti is a scientist at Philip Morris International.


Klein M.S.,University of Regensburg | Almstetter M.F.,University of Regensburg | Almstetter M.F.,Biological Systems Research | Nurnberger N.,University of Regensburg | And 6 more authors.
Journal of Proteome Research | Year: 2013

The objective of this study was to investigate the relationship between the concentrations of 19 amino acids, glucose, and seven carboxylic acids in the blood and milk of dairy cows and their correlations with established markers of ketosis. To that end, blood plasma and milk specimens were collected throughout lactation in two breeds of dairy cows of different milk yield. Plasma concentrations of glucose, pyruvate, lactate, α-aminobutyrate, β-hydroxybutyrate (BHBA), and most amino acids, except for glutamate and aspartate, were on average 9.9-fold higher than their respective milk levels. In contrast, glutamate, aspartate, and the Krebs cycle intermediates succinate, fumarate, malate, and citrate were on average 9.1-fold higher in milk than in plasma. For most metabolites, with the exception of BHBA and threonine, no significant correlations were observed between their levels in plasma and milk. Additionally, milk levels of acetone showed significant direct relationships with the glycine-to-alanine ratio and the BHBA concentration in plasma. The marked decline in plasma concentrations of glucose, pyruvate, lactate, and alanine in cows with plasma BHBA levels above the diagnostic cutoff point for subclinical ketosis suggests that these animals fail to meet their glucose demand and, as a consequence, rely increasingly on ketone bodies as a source of energy. The concomitant increase in plasma glycine may reflect not only the excessive depletion of protein reserves but also a potential deficiency of vitamin B6. © 2013 American Chemical Society. Source


Martin F.,Biological Systems Research | Sewer A.,Biological Systems Research | Talikka M.,Biological Systems Research | Xiang Y.,Biological Systems Research | And 2 more authors.
BMC Bioinformatics | Year: 2014

Background: High-throughput measurement technologies such as microarrays provide complex datasets reflecting mechanisms perturbed in an experiment, typically a treatment vs. control design. Analysis of these information rich data can be guided based on a priori knowledge, such as networks or set of related proteins or genes. Among those, cause-and-effect network models are becoming increasingly popular and more than eighty such models, describing processes involved in cell proliferation, cell fate, cell stress, and inflammation have already been published. A meaningful systems toxicology approach to study the response of a cell system, or organism, exposed to bio-active substances requires a quantitative measure of dose-response at network level, to go beyond the differential expression of single genes.Results: We developed a method that quantifies network response in an interpretable manner. It fully exploits the (signed graph) structure of cause-and-effect networks models to integrate and mine transcriptomics measurements. The presented approach also enables the extraction of network-based signatures for predicting a phenotype of interest. The obtained signatures are coherent with the underlying network perturbation and can lead to more robust predictions across independent studies. The value of the various components of our mathematically coherent approach is substantiated using several in vivo and in vitro transcriptomics datasets. As a proof-of-principle, our methodology was applied to unravel mechanisms related to the efficacy of a specific anti-inflammatory drug in patients suffering from ulcerative colitis. A plausible mechanistic explanation of the unequal efficacy of the drug is provided. Moreover, by utilizing the underlying mechanisms, an accurate and robust network-based diagnosis was built to predict the response to the treatment.Conclusion: The presented framework efficiently integrates transcriptomics data and " cause and effect" network models to enable a mathematically coherent framework from quantitative impact assessment and data interpretation to patient stratification for diagnosis purposes. © 2014 Martin et al.; licensee BioMed Central Ltd. Source


Luettich K.,Biological Systems Research | Xiang Y.,Biological Systems Research | Iskandar A.,Biological Systems Research | Sewer A.,Biological Systems Research | And 10 more authors.
Interdisciplinary Toxicology | Year: 2014

The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening model in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops lung tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smokerelated lung tumors in the A/J mouse model using mRNA and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression interaction term analysis of lung tumors and surrounding nontumorous parenchyma samples from animals that were exposed to either 300 mg/m3 MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis® (IPA®) indicated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism and a deregulation of potentially oncogenic miRNA in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA, which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene expression signature and show its utility in distinguishing between cigarette smoke-related and spontaneous lung tumors © 2014 Interdisciplinary Toxicology. Source

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