21 research outputs found
Crowd-Sourced Verification of Computational Methods and Data in Systems Toxicology: A Case Study with a Heat-Not-Burn Candidate Modified Risk Tobacco Product
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
estimates. To ensure the performance and reliability of the methods
and verify conclusions from systems toxicology data analysis, it is
important to conduct unbiased evaluations by independent third parties.
As a case study, we report here the results of an independent verification
of methods and data in systems toxicology by crowdsourcing. The sbv
IMPROVER systems toxicology computational challenge aimed to evaluate
computational methods for the development of blood-based gene expression
signature classification models with the ability to predict smoking
exposure status. Participants created/trained models on blood gene
expression data sets including smokers/mice exposed to 3R4F (a reference
cigarette) or noncurrent smokers/Sham (mice exposed to air). Participants
applied their models on unseen data to predict whether subjects classify
closer to smoke-exposed or nonsmoke exposed groups. The data sets
also included data from subjects that had been exposed to potential
modified risk tobacco products (MRTPs) or that had switched to a MRTP
after exposure to conventional cigarette smoke. The scoring of anonymized
participantsâ predictions was done using predefined metrics.
The top 3 performersâ methods predicted class labels with area
under the precision recall scores above 0.9. Furthermore, although
various computational approaches were used, the crowdâs results
confirmed our own data analysis outcomes with regards to the classification
of MRTP-related samples. Mice exposed directly to a MRTP were classified
closer to the Sham group. After switching to a MRTP, the confidence
that subjects belonged to the smoke-exposed group decreased significantly.
Smoking exposure gene signatures that contributed to the group separation
included a core set of genes highly consistent across teams such as
AHRR, LRRN3, SASH1, and P2RY6. In conclusion, crowdsourcing constitutes
a pertinent approach, in complement to the classical peer review process,
to independently and unbiasedly verify computational methods and data
for risk assessment using systems toxicology
Table1_Systems biology reveals anatabine to be an NRF2 activator.XLSX
Anatabine, an alkaloid present in plants of the Solanaceae family (including tobacco and eggplant), has been shown to ameliorate chronic inflammatory conditions in mouse models, such as Alzheimerâs disease, Hashimotoâs thyroiditis, multiple sclerosis, and intestinal inflammation. However, the mechanisms of action of anatabine remain unclear. To understand the impact of anatabine on cellular systems and identify the molecular pathways that are perturbed, we designed a study to examine the concentration-dependent effects of anatabine on various cell types by using a systems pharmacology approach. The resulting dataset, consisting of measurements of various omics data types at different time points, was analyzed by using multiple computational techniques. To identify concentration-dependent activated pathways, we performed linear modeling followed by gene set enrichment. To predict the functional partners of anatabine and the involved pathways, we harnessed the LINCS L1000 datasetâs wealth of information and implemented integer linear programming on directed graphs, respectively. Finally, we experimentally verified our key computational predictions. Using an appropriate luciferase reporter cell system, we were able to demonstrate that anatabine treatment results in NRF2 (nuclear factor-erythroid factor 2-related factor 2) translocation, and our systematic phosphoproteomic assays showed that anatabine treatment results in activation of MAPK signaling. While there are certain areas to be explored in deciphering the exact anti-inflammatory mechanisms of action of anatabine and other NRF2 activators, we believe that anatabine constitutes an interesting molecule for its therapeutic potential in NRF2-related diseases.</p
Image2_Systems biology reveals anatabine to be an NRF2 activator.JPEG
Anatabine, an alkaloid present in plants of the Solanaceae family (including tobacco and eggplant), has been shown to ameliorate chronic inflammatory conditions in mouse models, such as Alzheimerâs disease, Hashimotoâs thyroiditis, multiple sclerosis, and intestinal inflammation. However, the mechanisms of action of anatabine remain unclear. To understand the impact of anatabine on cellular systems and identify the molecular pathways that are perturbed, we designed a study to examine the concentration-dependent effects of anatabine on various cell types by using a systems pharmacology approach. The resulting dataset, consisting of measurements of various omics data types at different time points, was analyzed by using multiple computational techniques. To identify concentration-dependent activated pathways, we performed linear modeling followed by gene set enrichment. To predict the functional partners of anatabine and the involved pathways, we harnessed the LINCS L1000 datasetâs wealth of information and implemented integer linear programming on directed graphs, respectively. Finally, we experimentally verified our key computational predictions. Using an appropriate luciferase reporter cell system, we were able to demonstrate that anatabine treatment results in NRF2 (nuclear factor-erythroid factor 2-related factor 2) translocation, and our systematic phosphoproteomic assays showed that anatabine treatment results in activation of MAPK signaling. While there are certain areas to be explored in deciphering the exact anti-inflammatory mechanisms of action of anatabine and other NRF2 activators, we believe that anatabine constitutes an interesting molecule for its therapeutic potential in NRF2-related diseases.</p
Image1_Systems biology reveals anatabine to be an NRF2 activator.JPEG
Anatabine, an alkaloid present in plants of the Solanaceae family (including tobacco and eggplant), has been shown to ameliorate chronic inflammatory conditions in mouse models, such as Alzheimerâs disease, Hashimotoâs thyroiditis, multiple sclerosis, and intestinal inflammation. However, the mechanisms of action of anatabine remain unclear. To understand the impact of anatabine on cellular systems and identify the molecular pathways that are perturbed, we designed a study to examine the concentration-dependent effects of anatabine on various cell types by using a systems pharmacology approach. The resulting dataset, consisting of measurements of various omics data types at different time points, was analyzed by using multiple computational techniques. To identify concentration-dependent activated pathways, we performed linear modeling followed by gene set enrichment. To predict the functional partners of anatabine and the involved pathways, we harnessed the LINCS L1000 datasetâs wealth of information and implemented integer linear programming on directed graphs, respectively. Finally, we experimentally verified our key computational predictions. Using an appropriate luciferase reporter cell system, we were able to demonstrate that anatabine treatment results in NRF2 (nuclear factor-erythroid factor 2-related factor 2) translocation, and our systematic phosphoproteomic assays showed that anatabine treatment results in activation of MAPK signaling. While there are certain areas to be explored in deciphering the exact anti-inflammatory mechanisms of action of anatabine and other NRF2 activators, we believe that anatabine constitutes an interesting molecule for its therapeutic potential in NRF2-related diseases.</p
Toxicity of aerosols of nicotine and pyruvic acid (separate and combined) in SpragueâDawley rats in a 28-day OECD 412 inhalation study and assessment of systems toxicology
<div><p></p><p>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. SpragueâDawley rats were nose-only exposed, 6âh/day, 5 days/week to filtered air, saline, nicotine (50â”g/l), sodium pyruvate (NaPyr, 33.9â”g/l) or equimolar Nic/Pyr mixtures (18, 25 and 50â”g nicotine/l). Saline and NaPyr caused no health effects, but rats exposed to nicotine-containing aerosols had decreased body weight gains and concentration-dependent increases in liver weight. Blood neutrophil counts were increased and lymphocyte counts decreased in rats exposed to nicotine; activities of alkaline phosphatase and alanine aminotransferase were increased, and levels of cholesterol and glucose decreased. The only histopathologic finding in non-respiratory tract organs was increased liver vacuolation and glycogen content. Respiratory tract findings upon nicotine exposure (but also some phosphate-buffered saline aerosol effects) were observed only in the larynx and were limited to adaptive changes. Gene expression changes in the lung and liver were very weak. Nic and Nic/Pyr caused few significant changes (including Cyp1a1 gene upregulation). Changes were predominantly related to energy metabolism and fatty acid metabolism but did not indicate an obvious toxicity-related response. Nicotine exposure lowered plasma lipids, including cholesteryl ester (CE) and free cholesterol and, in the liver, phospholipids and sphingolipids. Nic, NaPyr and Nic/Pyr decreased hepatic triacylglycerol and CE. In the lung, Nic and Nic/Pyr increased CE levels. These data suggest that only minor biologic effects related to inhalation of Nic or Nic/Pyr aerosols were observed in this 28-day study.</p></div
Smoke chemistry
<p>The file contains the concentrations of 58 harmful and potentially harmful constituents measured in aerosols from 3R4F and the pMRTP.</p
<i>In Vitro</i> Systems Toxicology Assessment of a Candidate Modified Risk Tobacco Product Shows Reduced Toxicity Compared to That of a Conventional Cigarette
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 response in most toxicity end points.
Moreover, we found a significant level of perturbation in multiple
biological pathways, particularly in those related to cellular stress.
By contrast, exposure to THS 2.2 resulted in an overall lower biological
impact. At 3R4F doses, no toxic effects were observed. A toxic response
was observed for THS 2.2 in some functional end points, but the responses
occurred at doses between 3 and 15 times higher than those of 3R4F.
The level of biological network perturbation was also significantly
reduced following THS 2.2 aerosol exposure compared to that of 3R4F
cigarette smoke. Taken together, the data suggest that THS 2.2 aerosol
is less toxic than combustible cigarette smoke and thus may have the
potential to reduce the risk for smoke-related diseases
Additional file 3 of Crowdsourced benchmarking of taxonomic metagenome profilers: lessons learned from the sbv IMPROVER Microbiomics challenge
Additional file 3
Additional file 5 of Crowdsourced benchmarking of taxonomic metagenome profilers: lessons learned from the sbv IMPROVER Microbiomics challenge
Additional file 5
A framework for <i>in vitro</i> systems toxicology assessment of e-liquids
<p>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 also included as a part of the framework to provide accurate and reliable chemistry data solidifying the toxicological assessment. In its simplest form, the framework comprises of three main layers: (1) high-throughput toxicity screening of e-liquids using primary human cell culture systems; (2) toxicity-related mechanistic assessment of selected e-liquids, and (3) toxicity-related mechanistic assessment of their aerosols using organotypic airâliquid interface airway culture systems. A systems toxicology assessment approach is leveraged to enable in-depth analyses of the toxicity-related cellular mechanisms of e-liquids and their aerosols. We present example use cases to demonstrate the suitability of the framework for a robust <i>in vitro</i> assessment of e-liquids and their aerosols.</p