MicroRNA expression in serum samples of sulfur mustard veterans as a diagnostic gateway to improve care
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PROVIDER: PRJNA434578 | ENA |
REPOSITORIES: ENA
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Project description:Sulfur mustard is a vesicant chemical warfare agent, which has been used during Iraq-Iran-war. Many veterans and civilians still suffer from long-term complications of sulfur mustard exposure, especially in their lung. Although the lung lesions of these patients are similar to Chronic Obstructive Pulmonary Disease (COPD), there are some differences due to different etiology and clinical care. Less is known on the molecular mechanism of sulfur mustard patients and specific treatment options. microRNAs are master regulators of many biological pathways and proofed to be stable surrogate markers in body fluids. Based on that microRNA expression for serum samples of sulfur mustard patients were examined, to establish specific microRNA patterns as a basis for diagnostic use and insight into affected molecular pathways. Patients were categorized based on their long-term complications into three groups and microRNA serum levels were measured. The differentially regulated microRNAs and their corresponding gene targets were identified. Cell cycle arrest, ageing and TGF-beta signaling pathways showed up to be the most deregulated pathways. The candidate microRNA miR-143-3p could be validated on all individual patients. In a ROC analysis miR-143-3p turned out to be a suitable diagnostic biomarker in the mild and severe categories of patients. Further microRNAs which might own a link to the biology of the sulfur mustard patients are miR-365a-3p, miR-200a-3p, miR-663a. miR-148a-3p, which showed up only in a validation study, might be linked to the airway complications of the sulfur mustard patients. All the other candidate microRNAs do not directly link to COPD phenotype or lung complications. In summary the microRNA screening study characterizes several molecular difference in-between the clinical categories of the sulfur mustard exposure groups and established some useful microRNA biomarkers.
2018-03-01 | GSE110797 | GEO
Project description:Sulfur mustard (SM) is a potent alkylating agent. We are developing medical countermeasures to reduce the injury caused by SM exposure. Screening in the mouse ear vesicant model has identified three effective compounds: dimercaprol (British anti-lewisite), indomethacin, and octyl homovanillamide (OHV). To identify gene expression changes that correlate with compound efficacy we used oligonucleotide microarrays to compare gene expression profiles in vehicle-exposed skin, SM-exposed skin, and skin pretreated with each compound before SM exposure. Mice were topically exposed on the inner surface of the right ear to SM alone or pretreated for 15 min with one of the compounds and then exposed to SM. Left ears were vehicle-exposed. Ear tissue was harvested 24 hr later for ear weight determination (an endpoint indicating compound efficacy). The exposure groups were: methylene chloride (sulfur mustard vehicle); ethanol (drug vehicle); 0.08 mg sulfur mustard; 6.25 mg dimercaprol 15 min before 0.08 mg sulfur mustard; 1.34 mg indomethacin 15 min before 0.08 mg sulfur mustard; 0.6 mg octylhomovanillamide 15 min before 0.08 mg sulfur mustard; 6.25 mg dimercaprol alone; 1.34 mg indomethacin alone; 0.6 mg octylhomovanillamide alone. RNA was extracted from the tissues and used to generate oligonucleotide microarray probes. Principal component analysis of the gene expression data revealed partitioning of the samples based on drug treatment and SM exposure. Vehicle-exposed mouse ears clustered away from the other treatment groups. SM-exposed mouse ears pretreated with dimercaprol or OHV clustered more closely with vehicle-exposed ears, while SM-exposed mouse ears pretreated with indomethacin clustered more closely with SM-exposed ears. This clustering of the samples is supported by the ear weight data, in which the indomethacin group has ear weights closer to the SM-exposed group, whereas the dimercaprol and OHV groups have ear weights closer to the vehicle-exposed group. Correlation coefficients were calculated for each gene based on the correlation between gene expression level and ear weight. These data provide the basis for understanding what gene expression changes are important in the development of effective SM medical countermeasures. Experiment Overall Design: Exposure of mouse ears to sulfur mustard alone, sulfur mustard preceded by drug treatment, or vehicle compounds. Naive controls were also included. Biological replicates of at least n=3 were examined for each exposure condition.
2007-12-01 | E-GEOD-2950 | biostudies-arrayexpress
Project description:The bifunctional alkylating agent sulfur mustard (SM; bis-(2-dichloroethyl) sulfide) is a potent vesicating chemical that has previously been used as a chemical warfare agent. studies have shown that exposure to CWNA compounds induces damage in the brain and heart.
2016-08-30 | GSE54639 | GEO
Project description:Sulfur mustard (SM) is a potent vesicant that targets epithelial cells and tissues. Most vesicant research has been performed using bona fide SM; however, some studies have used simulants, most notably half mustard (2-chloroethyl ethylsulfide; CEES) and nitrogen mustard (mechlorethamine; NM). Although CEES and NM have similarities to SM and can cause vesication, there are distinct differences in the chemical structures and physical properties of these compounds that may impact their toxic effects. Microarray analysis of cultured primary human epidermal keratinocytes (HEK) exposed to each of these vesicants was performed to directly compare the transcriptional responses induced by these vesicants. HEK were exposed in triplicate to concentrations ranging from 0-1000 µM for SM and NM and 0-4000 µM for CEES. Cells were harvested at 1, 2, 4, 8, 16, and 24 h and the RNA isolated for microarray analysis. Transcriptional responses were phenotypically anchored to cell morphology. The dataset was filtered by exposure and timepoint, and an analysis of variance was performed using dose as the factor. The top 500 genes ranked by p-value were analyzed using gene ontology algorithms to identify biological pathways significantly affected by each vesicant. At 2 h post-exposure, p53 signaling, Erk/MAPK signaling, and BMP signaling were significantly affected by all three vesicants. At 4 h post-exposure, p53 signaling , B cell activating factor, and glucocorticoid receptor signaling were significantly affected by all three vesicants. At 8 h post-exposure, there were no significant pathways commonly affected by all three vesicants. These results suggest that, although there are similarities in the transcriptional responses to each of these vesicants, the transcriptional responses appear to differ over time. Thus, extrapolation of results obtained with one vesicant to other vesicants may be complex and may have important implications for the development of vesicant therapeutics.
2018-06-15 | GSE29604 | GEO
Project description:Sulfur mustard (HD) is a vesicating agent that targets the eyes, skin, and lungs, producing skin burns, conjunctivitis, and compromised respiratory function. Underlying mechanisms of this damage are a critical area of research for the development of medical countermeasures. This study utilized mRNA analysis to evaluate molecular effects of HD on lung tissue from anesthetized swine inhalationally exposed to HD
2016-09-01 | GSE73088 | GEO
Project description:To further investigate the potential molecular basis of the therapeutic effects of the mixture of salvianolic acids from Salvia miltiorrhiza and total flavonoids from Anemarrhena asphodeloides (MSTF) on sulfur mustard (SM) damage, gene expression analysis was conducted on rats liver tissues using microarrays.
2014-11-05 | GSE62994 | GEO
Project description:Sulfur mustard (HD) is a vesicating agent that targets the eyes, skin, and lungs, producing skin burns, conjunctivitis, and compromised respiratory function. Underlying mechanisms of this damage are a critical area of research for the development of medical countermeasures. This study utilized mRNA analysis to evaluate molecular effects of HD on lung tissue from anesthetized swine inhalationally exposed to HD Anesthetized large swine were exposed for 10 minutes to either air, 60 ug/kg (low), or 100ug/kg (medium) HD vapor. At 12 hours, animals were euthanized, lungs removed and dissected by lobe, and stabilized in RNAlater. Total RNA was isolated and processed for hybridization to Affymetrix Porcine GeneChip.
2016-09-01 | E-GEOD-73088 | biostudies-arrayexpress
Project description:Male Sprague-Dawley rats were exposed to saline, isopropyl alcohol, 1mg/kg, 3mg/kg or 6 mg/kg sulfur mustard for 30 min, 1 hr, 3 hr, 6 hr, or 24 hr before analysis of lung tissue by oligonucleotide array analysis.
2007-09-14 | E-GEOD-1888 | biostudies-arrayexpress
Project description:Sulfur mustard (HD) is a potent alkylating agent that induces cutaneous injury. The molecular mechanisms of cutaneous injury are not completely understood, and the molecular pathways involved in post-exposure wound healing are not well characterized. To elucidate these molecular pathways for the purpose of identifying potential therapeutic targets, we used oligonucleotide microarrays to identify gene expression profile changes induced by HD in porcine skin, an established animal model of HD injury and wound healing. Female Yorkshire crossbred pigs were exposed to neat HD to generate a superficial dermal (second degree) injury. Skin punch biopsies were collected at 1 h, 2 h, 4 h, 24 h, 48 h, 72 h, 7 d, 14 d or 21 d post-exposure. Biopsies were scored for histopathology, and RNA extracted from biopsies was used for microarray analysis. Gene expression profiles were analyzed for significant temporal response to HD by analysis of variance (false discovery corrected p<0.05). Gene expression profiles were also correlated (Pearson linear correlation |r|>0.7, false discovery corrected p<0.05) to histopathology scores to identify molecular pathways significantly correlated with specific clinical endpoints of injury and repair. Several pathways linked to aspects of inflammatory response and cell cycle checkpoint regulation were altered by HD exposure through 72 h. Several of these inflammatory pathways were highly correlated with clinical endpoints assessed through 72 h, including epidermal necrosis and vesicle formation. Pathways linked to inflammation were also highly correlated with 7-21 d total histopathology scores, suggesting that inflammation is continual through the course of injury and healing. Specific therapeutic targets were identified within these inflammatory pathways, and potential therapeutics were also identified for future drug screening efforts.
2018-06-15 | GSE29588 | GEO
Project description:Sulfur mustard is a vesicant chemical warfare agent, which has been used during Iraq-Iran-war. Many veterans and civilians still suffer from long-term complications of sulfur mustard exposure, especially in their lung. Although the lung lesions of these patients are similar to Chronic Obstructive Pulmonary Disease (COPD), there are some differences due to different etiology and clinical care. Less is known on the molecular mechanism of sulfur mustard patients and specific treatment options. microRNAs are master regulators of many biological pathways and proofed to be stable surrogate markers in body fluids. Based on that microRNA expression for serum samples of sulfur mustard patients were examined, to establish specific microRNA patterns as a basis for diagnostic use and insight into affected molecular pathways. Patients were categorized based on their long-term complications into three groups and microRNA serum levels were measured. The differentially regulated microRNAs and their corresponding gene targets were identified. Cell cycle arrest, ageing and TGF-beta signaling pathways showed up to be the most deregulated pathways. The candidate microRNA miR-143-3p could be validated on all individual patients. In a ROC analysis miR-143-3p turned out to be a suitable diagnostic biomarker in the mild and severe categories of patients. Further microRNAs which might own a link to the biology of the sulfur mustard patients are miR-365a-3p, miR-200a-3p, miR-663a. miR-148a-3p, which showed up only in a validation study, might be linked to the airway complications of the sulfur mustard patients. All the other candidate microRNAs do not directly link to COPD phenotype or lung complications. In summary the microRNA screening study characterizes several molecular differences in-between the clinical categories of the sulfur mustard exposure groups and established some useful microRNA biomarkers. qPCR raw data is available via the Gene Expression Omnibus https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE110797.
| S-EPMC5864010 | biostudies-literature