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The pathophysiology, including the impact of gene expression, of polymyalgia rheumatica (PMR) remains elusive. We profiled the gene expression in muscle tissue in PMR patients before and after glucocorticoid (GC) treatment.
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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 in apolipoprotein E-deficient mice exposed to conventional cigarette smoke (CS) or to the aerosol of a candidate MRTP, tobacco heating system (THS) 2.2. In addition to chronic exposure, cessation or switching to THS2.2 after 2 months of CS exposure was assessed. Engaging a systems toxicology approach, exposure effects were investigated using physiology and histology combined with transcriptomics, lipidomics, and proteomics. CS induced nasal epithelial hyperplasia and metaplasia, lung inflammation, and emphysematous changes (impaired pulmonary function and alveolar damage). Atherogenic effects of CS exposure included altered lipid profiles and aortic plaque formation. Exposure to THS2.2 aerosol (nicotine concentration matched to CS, 29.9?mg/m3) neither induced lung inflammation or emphysema nor did it consistently change the lipid profile or enhance the plaque area. Cessation or switching to THS2.2 reversed the inflammatory responses and halted progression of initial emphysematous changes and the aortic plaque area. Biological processes, including senescence, inflammation, and proliferation, were significantly impacted by CS but not by THS2.2 aerosol. Both, cessation and switching to THS2.2 reduced these perturbations to almost sham exposure levels. In conclusion, in this mouse model cessation or switching to THS2.2 retarded the progression of CS-induced atherosclerotic and emphysematous changes, while THS2.2 aerosol alone had minimal adverse effects.
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Smoking of combustible cigarettes has a major impact on human health, so the tobacco industry is developing modified risk tobacco products (MRTP) to reduce this health risk. Using a systems toxicology approach in a model of chronic obstructive pulmonary disease (C57BL/6 mice), we assessed the potential of such a prototype (pMRTP) to reduce health risk. We investigated physiological endpoints in parallel with transcriptomics, lipidomics, and proteomics profiles in mice exposed to conventional cigarette smoke (3R4F) or a pMRTP aerosol for up to 7 months. We also included a cessation group and a switching-to-pMRTP group (after 2 months of 3R4F exposure) in addition to the control (fresh air-exposed) group, to understand the potential risk reduction of switching to pMRTP compared with continuous 3R4F exposure. The present manuscript describes the study design, setup, and implementation, as well as the generation, processing, and quality control analysis of the toxicology and 'omics' datasets that are accessible in public repositories for further studies.
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As part of current harm reduction strategies, candidate modified risk tobacco products (MRTP) are developed to offer adult smokers who want to continue using tobacco product an alternative to cigarettes while potentially reducing individual risk and population harm compared to smoking cigarettes. One of these candidate MRTPs is the Tobacco Heating System (THS) 2.2 which does not burn tobacco, but instead heats it, thus producing significantly reduced levels of harmful and potentially harmful constituents (HPHC) compared with combustible cigarettes (CC). A controlled, parallel group, open-label clinical study was conducted with subjects randomized to three monitored groups: (1) switching from CCs to THS2.2; (2) continuous use of non-menthol CC brand (CC arm); or (3) smoking abstinence (SA arm) for five days. Exposure response was assessed by measuring biomarkers of exposure to selected HPHCs. To complement the classical exposure response measurements, we have used the previously reported whole blood derived gene signature that can distinguish current smokers from either non-smokers or former smokers with high specificity and sensitivity. We tested the small signature consisting of only 11 genes on the blood transcriptome of subjects enrolled in the clinical study and showed a reduced exposure response in subjects that either stopped smoking or switched to a candidate MRTP, the THS2.2, compared with subjects who continued smoking their regular tobacco product.
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Gene expression signatures help to provide a global and robust view of biological processes in normal and pathological situations. Additionally, such signatures can be used in toxicology to assess both the level and impact of toxicant exposure, which is in line with the 21st century vision of toxicology. An 11 gene signature extracter by Martin et al. assist us in the evaluation of the reduction in exposure response in subjects enrolled in PMI clinical trials for THS 2.2 and THS 2.2 menthol assessment. The signature was applied to gene expression profiles from blood after 5-day cessation confinement studies, which showed a consistent decrease of the signature scores. Similarly, upon switching to THS2.2 for 5 days, a significant decrease in the signature score was consistently observed. Finally, in a study where a 5-day confinement period was followed by an 85-day ambulatory period, a similar decrease was observed for both cessation and switching to mentholated THS2.2.
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Gene expression profiling data can be used in toxicology to assess both the level and impact of toxicant exposure, aligned with a vision of 21st century toxicology. Here, we present a whole blood-derived gene signature that can distinguish current smokers from either nonsmokers or former smokers with high specificity and sensitivity. Such a signature that can be measured in a surrogate tissue (whole blood) may help in monitoring smoking exposure as well as discontinuation of exposure when the primarily impacted tissue (e.g., lung) is not readily accessible. The signature consisted of LRRN3, SASH1, PALLD, RGL1, TNFRSF17, CDKN1C, IGJ, RRM2, ID3, SERPING1, and FUCA1. Several members of this signature have been previously described in the context of smoking. The signature translated well across species and could distinguish mice that were exposed to cigarette smoke from ones exposed to air only or had been withdrawn from cigarette smoke exposure. Finally, the small signature of only 11 genes could be converted into a polymerase chain reaction-based assay that could serve as a marker to monitor compliance with a smoking abstinence protocol.
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Gene expression profiling data can be used in toxicology to assess both the level and impact of toxicant exposure, aligned with a vision of 21st century toxicology. Here, we present a whole blood-derived gene signature that can distinguish current smokers from either nonsmokers or former smokers with high specificity and sensitivity. Such a signature that can be measured in a surrogate tissue (whole blood) may help in monitoring smoking exposure as well as discontinuation of exposure when the primarily impacted tissue (e.g., lung) is not readily accessible. The signature consisted of LRRN3, SASH1, PALLD, RGL1, TNFRSF17, CDKN1C, IGJ, RRM2, ID3, SERPING1, and FUCA1. Several members of this signature have been previously described in the context of smoking. The signature translated well across species and could distinguish mice that were exposed to cigarette smoke from ones exposed to air only or had been withdrawn from cigarette smoke exposure. Finally, the small signature of only 11 genes could be converted into a polymerase chain reaction-based assay that could serve as a marker to monitor compliance with a smoking abstinence protocol.
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Apart from the induction of host immune responses, any influence mediated by the presence of bacterial signalling molecules inside host cells on the latter’s physiology remains poorly defined. To determine the effects of the presence of ppGpp, cdiAMP and cdiGMP in the cytosol on the functioning of a simple eukaryotic cell, we have heterologously expressed enzymes for their synthesis in the budding yeast Saccharomyces cerevisiae. Transcriptome analysis was employed to measure any effects on gene transcription following induction of synthetase expression.
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The herbicide safener fenclorim is used to protect rice from damage by the herbicide pretilachlor, whilst the structural analogue 4-chloro-6-methyl-2-phenylpyrimidine (CMP) is unable safen rice. Fenclorim and CMP were applied to rice cultures to determine differences in the transcriptional response to a safener and a non-active analogue at four and 24 hours. Rice N1 cell suspension cultures were treated with fenclorim or 4-chloro-6-methyl-2-phenylpyrimidine (CMP) dissolved in acetone to achieve a final concentration of 100uM. The final acetone concentration of 0.1% was replicated in control cell suspension cultures. Samples were taken at four and twenty-four hours post addition in biological triplicate. Suspension cultures were routinely maintained at 25 C in the dark.
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Nephrotic syndrome (NS) occurs when the glomerular filtration barrier becomes excessively permeable leading to massive proteinuria. In childhood NS, dysregulation of the immune system has been implicated and increasing evidence points to the central role of podocytes in the pathogenesis. Children with NS are typically treated with an empiric course of glucocorticoid (Gc) therapy; a class of steroids that are activating ligands for the glucocorticoid receptor (GR) transcription factor. Although Gc-therapy has been the cornerstone of NS management for decades, the mechanism of action, and target cell, remain poorly understood. We tested the hypothesis that Gc acts directly on the podocyte to produce clinically useful effects without involvement of the immune system. In human podocytes, we demonstrated that the basic GR-signalling mechanism is intact and that Gc induced an increase in podocyte barrier function. To gain mechanistic insight we performed RNA microarray and ChIP-sequencing and identified Gc regulation of motility genes.
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