Philip Morris International R and D


Philip Morris International R and D

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Iskandar A.R.,Philip Morris International R and D | Xiang Y.,Philip Morris International R and D | Frentzel S.,Philip Morris International R and D | Talikka M.,Philip Morris International R and D | And 8 more authors.
Toxicological Sciences | Year: 2015

Organotypic 3D 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 coculture 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 coculture 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: monoculture of bronchial epithelial cells without fibroblasts (BR) and coculture with fibroblasts (BRF) models. Adenylate kinase (AK)-based cytotoxicity, cytochrome P450 (CYP) 1A1/1B1 activity, tissue histology, and concentrations of secreted mediators into the basolateral media, as well as transcriptomes were evaluated following the CS exposure. The results demonstrated similar impact of CS on the AK-based cytotoxicity, CYP1A1/1B1 activity, and tissue histology in both models. However, a greater number of secreted mediators was identified in the basolateral media of the monoculture than in the coculture models. Furthermore, annotation analysis and network-based systems biology analysis of the transcriptomic profiles indicated a more prominent cellular stress and tissue damage following CS in the monoculture epitheliummodel without fibroblasts. Finally, our results indicated that an in vivo smoking-induced xenobiotic metabolismresponse of bronchial epithelial cells was better reflected from the in vitro CS-exposed coculture model. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Stinn W.,Philip Morris Research Laboratories GmbH | Buettner A.,Philip Morris Research Laboratories GmbH | Weiler H.,Philip Morris Research Laboratories GmbH | Friedrichs B.,Philip Morris Research Laboratories GmbH | And 7 more authors.
Toxicological Sciences | Year: 2013

Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease, yet there is little mechanistic information available in the literature. To improve this, laboratory models for cigarette mainstream smoke (MS) inhalation-induced chronic disease development are needed. The current study investigated the effects of exposing male A/J mice to MS (6h/day, 5 days/week at 150 and 300mg total particulate matter per cubic meter) for 2.5, 5, 10, and 18 months in selected combinations with postinhalation periods of 0, 4, 8, and 13 months. Histopathological examination of step-serial sections of the lungs revealed nodular hyperplasia of the alveolar epithelium and bronchioloalveolar adenoma and adenocarcinoma. At 18 months, lung tumors were found to be enhanced concentration dependently (up to threefold beyond sham exposure), irrespective of whether MS inhalation had been performed for the complete study duration or was interrupted after 5 or 10 months and followed by postinhalation periods. Morphometric analysis revealed an increase in the extent of emphysematous changes after 5 months of MS inhalation, which did not significantly change over the following 13 months of study duration, irrespective of whether MS exposure was continued or not. These changes were found to be accompanied by a complex pattern of transient and sustained pulmonary inflammatory changes that may contribute to the observed pathogeneses. Data from this study suggest that the A/J mouse model holds considerable promise as a relevant model for investigating smoking-related emphysema and adenocarcinoma development. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Sauer J.M.,Critical Path Institute | Hartung T.,University of Baltimore | Leist M.,University of Konstanz | Knudsen T.B.,U.S. Environmental Protection Agency | And 3 more authors.
International Journal of Toxicology | Year: 2015

Risk assessment, in the context of public health, is the process of quantifying the probability of a harmful effect to individuals or populations from human activities. With increasing public health concern regarding the potential risks associated with chemical exposure, there is a need for more predictive and accurate approaches to risk assessment. Developing such an approach requires a mechanistic understanding of the process by which xenobiotic substances perturb biological systems and lead to toxicity. Supplementing the shortfalls of traditional risk assessment with mechanistic biological data has been widely discussed but not routinely implemented in the evaluation of chemical exposure. These mechanistic approaches to risk assessment have been generally referred to as systems toxicology. This Symposium Overview article summarizes 4 talks presented at the 35th Annual Meeting of the American College of Toxicology. © The Author(s) 2015.

Gregg E.,ENI S.p.A | Bachmann T.,Philip Morris International R and D | Bito R.,Japan Tobacco Inc. | Cahours X.,Imperial Tobacco Group | And 5 more authors.
Beitrage zur Tabakforschung International/ Contributions to Tobacco Research | Year: 2013

In recent years, the increased availability of tobacco products other than conventional cigarettes, the use of puffing topography devices for smoking behaviour studies and the use of biomarkers to study smoke constituents exposure have generated the need for a more comprehensive set of definitions concerning smoking behaviour and exposure to smoke. The definitions offered in this paper are based on many years of practical experience and on consensus within a broad group of scientists working in these areas. It is intended that, with wider and more consistent usage, these definitions should reduce any misunderstandings and facilitate interpretation of future studies.

Meskauskiene R.,NEBION AG | Laule O.,ETH Zurich | Laule O.,NEBION AG | Ivanov N.V.,Philip Morris International R and D | And 5 more authors.
Plant Methods | Year: 2013

Background: It is generally accepted that controlled vocabularies are necessary to systematically integrate data from various sources. During the last decade, several plant ontologies have been developed, some of which are community specific or were developed for a particular purpose. In most cases, the practical application of these ontologies has been limited to systematically storing experimental data. Due to technical constraints, complex data structures and term redundancies, it has been difficult to apply them directly into analysis tools.Results: Here, we describe a simplified and cross-species compatible set of controlled vocabularies for plant anatomy, focussing mainly on monocotypledonous and dicotyledonous crop and model plants. Their content was designed primarily for their direct use in graphical visualization tools. Specifically, we created annotation vocabularies that can be understood by non-specialists, are minimally redundant, simply structured, have low tree depth, and we tested them practically in the frame of Genevestigator.Conclusions: The application of the proposed ontologies enabled the aggregation of data from hundreds of experiments to visualize gene expression across tissue types. It also facilitated the comparison of expression across species. The described controlled vocabularies are maintained by a dedicated curation team and are available upon request. © 2013 Meskauskiene et al.; licensee BioMed Central Ltd.

Zimmermann P.,NEBION AG | Bleuler S.,NEBION AG | Laule O.,NEBION AG | Martin F.,Philip Morris International R and D | And 7 more authors.
BioData Mining | Year: 2014

Reference datasets are often used to compare, interpret or validate experimental data and analytical methods. In the field of gene expression, several reference datasets have been published. Typically, they consist of individual baseline or spike-in experiments carried out in a single laboratory and representing a particular set of conditions.Here, we describe a new type of standardized datasets representative for the spatial and temporal dimensions of gene expression. They result from integrating expression data from a large number of globally normalized and quality controlled public experiments. Expression data is aggregated by anatomical part or stage of development to yield a representative transcriptome for each category. For example, we created a genome-wide expression dataset representing the FDA tissue panel across 35 tissue types. The proposed datasets were created for human and several model organisms and are publicly available at. © 2014Zimmermann et al.; licensee BioMed Central Ltd.

Ivanov N.V.,Philip Morris International R and D | Poussin C.,Philip Morris International R and D | Boue S.,Philip Morris International R and D | Martin F.,Philip Morris International R and D | And 4 more authors.
BCB 2015 - 6th ACM Conference on Bioinformatics, Computational Biology, and Health Informatics | Year: 2015

Risk assessment in the context of 21st century toxicology relies on the elucidation and understanding of mechanisms of toxicity. For that purpose, datasets generated by high-throughput technologies (e.g., high-throughput/content screening) combined with various omics data types are now generated in vitro to test large and diverse set of chemicals (e.g. ToxCast). The development of relevant computational approaches for the analysis and integration of these big data remains challenging and requires qualitative and quantitative evaluation. The current scope of sbv IMPROVER (Industrial Methodology for Process Verification in Research; is the verification of methods and concepts in systems biology research via challenges opened to the scientific community. Previous challenges brought new insights on methods and their associated results that address questions about diagnostic signatures, the translatability of biological responses/processes across species, and the relevance of biological causal network models. A new sbv IMPROVER challenge will be introduced aiming at evaluating (i) methodologies for the identification of specific biomarkers of exposure and (ii) the predictability by omics data of toxicity mechanisms when cells/tissues in vitro or whole organisms are exposed to individual chemical molecules or mixtures. Participants will be provided with high quality data sets to develop predictive models/classifiers. For this challenge, the integration of a priori biological knowledge in the development of computational approaches may be required to enable biological interpretability/understanding of the predictions. The results and post-challenge analyses will be shared with the scientific community, and will open new avenues in the field of systems toxicology. Copyright is held by the author/owner(s).

Aydin N.,Philip Morris International R and D | Chardonnens F.,Philip Morris International R and D | Rotach M.,Philip Morris International R and D
Beitrage zur Tabakforschung International/ Contributions to Tobacco Research | Year: 2012

Because many physicochemical properties of tobacco are highly sensitive to its moisture content, the determination of water level is an important parameter for tobacco characterization. A headspace volumetric Karl Fischer titration (HS-V-KFT) method is presented for the quantification of water content in different finished tobacco materials. The parameters affecting the extraction of water from the tobacco materials were the sample size and the oven temperature which have been optimized. The extraction of water from the samples was achieved within a reasonable time (<25 min) with a sample size of 200 mg and an optimum temperature of between 90 °C and 100 °C. The results of the water determination by HS-V-KFT at the optimized parameters were in good agreement with those obtained by standard volumetric Karl Fischer titration. HS-V-KFT showed very good repeatability (RSD r 0.9%) and intermediate precision (RSD iR 1.1%). With respect to a considerable time saving, solvent consumption reduction, precision and accuracy, HS-V-KFT can therefore be suggested as the method of choice to determine water amount in finished tobacco products.

Boue S.,Philip Morris International R and D | Tarasov K.,Zora Biosciences Oy | Janis M.,Zora Biosciences Oy | Lebrun S.,Philip Morris International R and D | And 9 more authors.
Atherosclerosis | Year: 2012

Objective: Although relationships between smoking and cardiovascular diseases (CVD), and between CVD and lipids are established, the direct impact of smoking on lipidomes is not well understood. We investigated the effect of mainstream cigarette smoke (CS) exposure on plasma, liver, and aorta molecular lipid profiles, and liver transcriptome in the ApoE-/- mouse, a well-established mouse model for human atherogenesis. Methods: Plasma, liver, and aorta samples from ApoE-/- mice exposed to CS or fresh air (sham) for six months were extracted for lipids using robotic-assisted method and analyzed by mass spectrometry. Gene expression in the liver was obtained on microarrays. Development of atherosclerosis in the aorta was further assessed by plaque size in the aortic arch and lipoprotein concentration in plasma and plaque. Results: CS increased most lipid classes and molecular lipid species. In plasma, free cholesterol, ceramides, cerebrosides, and most phospholipids were increased in CS-exposed mice. In the liver, several lipid species including free and esterified cholesterol, triacylglycerols, phospholipids, sphingomyelins, and ceramides were elevated. In the aorta, more than 2-fold higher cholesteryl ester (CE), lysophosphatidylcholine, and glucosyl/galactosylceramide levels were seen. Moreover, CS exposure induced a significant decrease in several plasma CE and phosphatidylcholine species that contained polyunsaturated fatty acids. Genes involved in amino acid and lipid metabolism showed perturbed transcription profiles in the liver. Conclusion: We have quantified some of the molecular changes that accompany the increase of plaque size that is accelerated by CS exposure in the aortae of ApoE-/- mice. These results suggest that specific changes in the lipidome and transcriptome, for example in ceramide and polyunsaturated fatty acid species, may be associated with atherosclerosis. © 2012 Elsevier Ireland Ltd.

Laino T.,IBM | Tuma C.,IBM | Moor P.,Philip Morris International R and D | Martin E.,Philip Morris International R and D | And 3 more authors.
Journal of Physical Chemistry A | Year: 2012

Propylene glycol and triacetin are chemical compounds, commonly used as food additives. Though the usage of the pure chemicals is not considered harmful when used as dietary supplements, little is known about the nature of their thermal degradation products and the impact they may have on human health. For these reasons, in this manuscript we investigate the thermal decomposition mechanisms of both neutral propylene glycol and triacetin in the gas phase by a novel simulation framework. This is based on a free energy sampling methodology followed by an accurate energy refinement. Structures, Gibbs free energy barriers, and rate constants at 800 K were computed for the different steps involved in the two pyrolytic processes. The thermal decomposition mechanisms found theoretically for propylene glycol and triacetin were validated by a qualitative experimental investigation using gas-phase chromatography-mass spectroscopy, with excellent agreement. The results provide a validation of the novel simulation framework and shed light on the potential hazard to the health that propylene glycol and triacetin may have when exposed to high temperatures. © 2012 American Chemical Society.

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