Stephanie Boue

PMI Science · Biological Systems Research

A growing body of evidence links gut microbiota changes with inflammatory bowel disease (IBD), raising the potential benefit of exploiting metagenomics data for non-invasive IBD diagnostics. The sbv IMPROVER metagenomics diagnosis for inflammatory bowel disease challenge investigated computational metagenomics methods for discriminating IBD and non...

Background Selection of optimal computational strategies for analyzing metagenomics data is a decisive step in determining the microbial composition of a sample, and this procedure is complex because of the numerous tools currently available. The aim of this research was to summarize the results of crowdsourced sbv IMPROVER Microbiomics Challenge d...

Background: Selection of optimal computational strategies for analyzing metagenomics data is a decisive step in determining the microbial composition of a sample, and this procedure is complex because of the numerous tools currently available. The crowdsourced sbv IMPROVER Microbiomics Challenge and extended analyses benchmarked 21 off-the-shelf ta...

Smoking is a major cause of noncommunicable diseases, including lung cancer, chronic obstructive pulmonary disease (COPD), and cardiovascular diseases (CVDs). While the risk of smoking-related disease increases with the number of cigarettes smoked and the duration of smoking, it also decreases upon smoking cessation. The development of electronic n...

Systems toxicology is the integration of classical toxicology approaches with quantitative analysis of large sets of molecular and functional changes occurring across multiple levels of biological organization. Systems toxicology–based research enables identification of the biological mechanisms and molecular pathways that are affected by exposure...

The scientific assessment of electronic nicotine delivery products is based on a framework that considers both the known epidemiology of smoking and cessation and the natural law of toxicology. Here we describe the fundamental scientific principles underpinning this framework and how this can be implemented in a comprehensive assessment program tha...

The ability to reproducibly generate, collect, and administer aerosols is critical for characterization and preclinical assessment of electronic nicotine delivery products (ENDPs), such as electrically heated tobacco products and e-vapor products. The aerosols generated by ENDPs are qualitatively and quantitatively highly different from cigarette s...

Assessment of inhaled gases, aerosols, mixtures, or novel compounds includes preclinical rodent inhalation studies. The Organisation for Economic Co-operation and Development (OECD) provides guidance for designing and conducting such studies. Studies conducted in accordance with these guidelines have been shown to be suitable for assessing aerosols...

Smoking-related diseases generally occur after decades of smoking, and the reduction in excess risk following smoking cessation is slow. Therefore, epidemiological studies that aim to assess the reduction in disease risk associated with switching from cigarette smoking to the use of electronic nicotine delivery products (ENDPs) are difficult to exe...

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 st...

We conducted an inhalation study, in accordance with OECD Test Guideline 453, exposing A/J mice to Tobacco Heating System (THS) 2.2 aerosol or 3R4F reference cigarette smoke (CS) for up to 18 months to evaluate chronic toxicity and carcinogenicity. All exposed mice showed lower thymus and spleen weight, blood lymphocyte counts, and serum lipid conc...

Tobacco harm reduction is increasingly recognized as a promising approach to accelerate the decline in smoking prevalence and smoking-related population harm. Potential modified risk tobacco products (MRTPs) must undergo a rigorous premarket toxicological risk assessment. The ability to reproducibly generate, collect, and use aerosols is critical f...

Offering safer alternatives to cigarettes, such as e-cigarettes and heated tobacco products, to smokers who are not willing to quit could reduce the harm caused by smoking. Extensive and rigorous scientific studies are conducted to assess the relative risk of such potentially modified risk tobacco products compared with that of smoking cigarettes....

Low rates of reproducibility and translatability of data from nonclinical research have been reported. Major causes of irreproducibility include oversights in study design, failure to characterize reagents and protocols, a lack of access to detailed methods and data, and an absence of universally accepted and applied standards and guidelines. Speci...

The microbiome is an important factor in human health and disease; and is investigated to develop novel therapeutics. Metagenomics leverages advances in sequencing technologies and computational analysis to identify and quantify the microorganisms present in a sample. This field has, however, not yet reached maturity and the international metagenom...

The analysis of human microbiome is an exciting and rapidly expanding field of research. In the past decade, the biological relevance of the microbiome for human health has become evident. Microbiome comprises a complex collection of microorganisms, with their genes and metabolites, colonizing different body niches. It is now well known that the mi...

The US FDA defines modified risk tobacco products (MRTPs) as products that aim to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products. Establishing a product’s potential as an MRTP requires scientific substantiation including toxicity studies and measures of disease risk relative to those of cig...

Cigarette smoking entails chronic exposure to a mixture of harmful chemicals that trigger molecular changes over time, and is known to increase the risk of developing diseases. Risk assessment in the context of 21st century toxicology relies on the elucidation of mechanisms of toxicity and the identification of exposure response markers, usually fr...

Experimental studies clearly demonstrate a causal effect of cigarette smoking on cardiovascular disease. To reduce the individual risk and population harm caused by smoking, alternative products to cigarettes are being developed. We recently reported on an apolipoprotein E-deficient (Apoe−/-) mouse inhalation study that compared the effects of expo...

Systems toxicology intends to quantify the effect of toxic molecules in biological systems and unravel their mechanisms of toxicity. The development of advanced computational methods is required for analyzing and integrating high throughput data generated for this purpose as well as for extrapolating predictive toxicological outcomes and risk estim...

The US FDA defines modified risk tobacco products (MRTPs) as products that aim to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products. Establishing a product's potential as an MRTP requires scientific substantiation including toxicity studies and measures of disease risk relative to those of cig...

The objective of the study was to characterize the toxicity from sub-chronic inhalation of test atmospheres from the candidate modified risk tobacco product (MRTP), Tobacco Heating System version 2.2 (THS2.2), and to compare it with that of the 3R4F reference cigarette. A 90-day nose-only inhalation study on Sprague-Dawley rats was performed, combi...

Smoking is a major risk factor for several diseases including chronic obstructive pulmonary disease (COPD). To better understand the systemic effects of cigarette smoke exposure and mild to moderate COPD-and to support future biomarker development-we profiled the serum lipidomes of healthy smokers, smokers with mild to moderate COPD (GOLD stages 1...

Crowdsourcing is increasingly utilized for performing tasks in both natural language processing and biocuration. Although there have been many applications of crowdsourcing in these fields, there have been fewer high-level discussions of the methodology and its applicability to biocuration. This paper explores crowdsourcing for biocuration through...

Supplementary File 1. Biological Expression Language (BEL) functions and namespaces. Supplementary File 2. Network statistics for the Network Verification Challenge (NVC) v1.1 and v2.0 Bionet networks. Supplementary File 3. Network scores for the GSE28464 dataset from the NCBI GEO database.

Biological network models offer a framework for understanding disease by describing the relationships between the mechanisms involved in the regulation of biological processes. Crowdsourcing can efficiently gather feedback from a wide audience with varying expertise. In the Network Verification Challenge, scientists verified and enhanced a set of 4...

The human respiratory tract is exposed to numerous contaminants; traditional toxicity testing methods are insufficient to understand the extent of their biological impact and to recommend dose guidelines for safe exposure. Systems toxicology approaches are starting to shape the way for a better assessment of toxicity associated with inhaled substan...

Atherosclerosis-prone apolipoprotein E-deficient (Apoe(-/-)) mice display poor lipoprotein clearance with subsequent accumulation of cholesterol ester-enriched particles in the blood, which promote the development of atherosclerotic plaques. Therefore, the Apoe(-/-) mouse model is well established for the study of human atherosclerosis. The systemi...

The liver is one of the most important organs involved in elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains more than 7000 chemicals, including those that exert biological effects and cause smoking-related diseases. Though CS is not directly hepatotoxic, a growing body of evidence suggests that it may exacerb...

The successful use of specialized cells in regenerative medicine requires an optimization in the differentiation protocols that are currently used. Understanding the molecular events that take place during the differentiation of human pluripotent cells is essential for the improvement of these protocols and the generation of high quality differenti...

Knock down efficiency of different shRNAs against SETD7. (A) Levels of SETD7 mRNA normalized to GAPDH in undifferentiated ES[4] (UndES[4]), in vitro differentiated ES[4] for 15 days (DifES[4]) and 293T cells transduced with a non target shRNA (shSCR) and 5 different shRNAs against SETD7 (shSETD7). (B) Western blot showing the protein levels of SETD...

Expression (Log2) of the top 400 most differentially expressed genes between shSCR and shSETD7 induced (UP) or repressed (DOWN) during differentiation. (XLS)

Effects of the PFI-2 and Adox inhibitors in the methylation of the histone fraction. HeLa cells were labeled with [methyl-3H]-L-methionine for 3 h in the presence of protein-synthesis inhibitors, and in the presence of vehicle or the SETD7 inhibitor PFI-2 (5 μM) or the general methyltransferase inhibitor AdOx (20 μM). Acid extraction of histone fra...

Ranking of the top 700 most differentially expressed genes between pluripotent cells (iPSCs and ESCs) and fibroblast. (XLS)

Expression of genes downregulated during differentiation affected by the shSETD7. (A) mRNA levels of different pluripotency-related genes during differentiation in the shSCR (full lines) and the shSETD7 (dotted lines) cell lines. (B) Blox plot of the levels of expression of the upregulated genes depicted in Fig 2C and p-values of the differential e...

Expression of genes upregulated during differentiation affected by the shSETD7. (A) mRNA levels of several differentiation genes during differentiation in the shSCR (full lines) and the shSETD7 (dotted lines) cell lines. (B) Blox plot of the levels of expression of the downregulated genes depicted in Fig 2C and p-values of the differential expressi...

Effect of methylation by SETD7 in the seconday structure of H1.4 in solution and bound to DNA. (A) Effect of methylation by SETD7 in the seconday structure of H1.4 in solution and bound to DNA. A, Mass spectrometry spectra of in vitro methylated H1.4 with 4 methyl groups incorporated on average, compared to unmethylated protein. (B) Infrared spectr...

Smoking of combustible cigarettes has a major impact on human health. Using a systems toxicology approach in a model of chronic obstructive pulmonary disease (C57BL/6 mice), we assessed the health consequences in mice of an aerosol derived from a prototype modified risk tobacco product (pMRTP) as compared to conventional cigarettes. We investigated...

Smoking cigarettes is a major risk factor in the development and progression of cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). Modified risk tobacco products (MRTPs) are being developed to reduce smoking-related health risks. The goal of this study was to investigate hallmarks of COPD and CVD over an 8-month period i...

The impact of cigarette smoke (CS), a major cause of lung diseases, on the composition and metabolism of lung lipids is incompletely understood. Here, we integrated quantitative lipidomics and proteomics to investigate exposure effects on lung lipid metabolism in a C57BL/6 and an Apolipoprotein E-deficient (Apoe(-/-)) mouse study. In these studies,...

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 (...

Toxicity of nebulized nicotine (Nic) and nicotine/pyruvic acid mixtures (Nic/Pyr) was characterized in a 28-day Organization for Economic Co-operation and Development 412 inhalation study with additional transcriptomic and lipidomic analyses. Sprague-Dawley rats were nose-only exposed, 6 h/day, 5 days/week to filtered air, saline, nicotine (50 µg/l...

Atherosclerosis is a progressive inflammatory thickening of the arterial wall resulting from increased cellularity and the accumulation of lipids, cellular debris, and extracellular matrix. Conventional determinations of plasma lipoproteins have resulted in a wealth of clinical data documenting the correlation between low- and high-density lipoprot...

Mouse models are useful for studying cigarette smoke (CS)-induced chronic pulmonary pathologies such as lung emphysema. To enhance translation of large-scale omics data from mechanistic studies into pathophysiological changes, we have developed computational tools based on reverse causal reasoning (RCR). In the present study we applied a systems bi...

The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airways for which therapeutic options currently are limited after diagnosis, even in its earliest st...

Modified risk tobacco products (MRTP) are designed to reduce smoking-related health risks. A murine model of chronic obstructive pulmonary disease (COPD) was applied to investigate classical toxicology end points plus systems toxicology (transcriptomics and proteomics). C57BL/6 mice were exposed to conventional cigarette smoke (3R4F), fresh air (sh...

With the wealth of publications and data available, powerful and transparent computational approaches are required to represent measured data and scientific knowledge in a computable and searchable format. We developed a set of biological network models, scripted in the Biological Expression Language, that reflect causal signaling pathways across a...

Cigarette smoke (CS) has a major impact on lung biology and may result in the development of lung diseases such as chronic obstructive pulmonary disease or lung cancer. To understand the underlying mechanisms of disease development, it would be important to examine the impact of CS exposure directly on lung tissues. However, this approach is diffic...

The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airways for which therapeutic options currently are limited after diagnosis, even in its earliest st...

A pilot reputation-based collaborative network biology platform, Bionet, was developed for use in the sbv IMPROVER Network Verification Challenge to verify and enhance previously developed networks describing key aspects of lung biology. Bionet was successful in capturing a more comprehensive view of the biology associated with each network using t...

Epidemiological evidence indicates that exposure to combustion-derived particles is linked to an increased risk of cardiovascular disease. Despite this strong association, there remains a lack of data that can be used to identify the molecular mechanisms through which exposure to particulate matter (PM) leads to adverse cardiovascular events. The b...

While the ever-increasing amounts of scientific data provide a more detailed description of toxic effects, it is not trivial to extract information that will contribute to a better biological understanding. Sophisticated computational methods have been developed to separate mathematically the biological signal from the noise in high-throughput data...

The sbv IMPROVER (systems biology verification—Industrial Methodology for Process Verification in Research) process aims to help companies verify component steps or tasks in larger research workflows for industrial applications. IMPROVER is built on challenges posed to the community that draws on the wisdom of crowds to assess the most suitable met...

Background 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 und...

The biological responses to external cues such as drugs, chemicals, viruses and hormones, is an essential question in biomedicine and in the field of toxicology, and cannot be easily studied in humans. Thus, biomedical research has continuously relied on animal models for studying the impact of these compounds and attempted to 'translate' the resul...

Hepatic lipid metabolism is profoundly affected by cigarette smoke; which likely contributes to the atherogenicplasma lipid profile observed in cigarette smokers. There is, however, a paucity of data on the identification ofmolecular networks and mechanisms responsible for the reduction of cardiovascular risk in former smokerscompared to the risk o...