Publications by authors named "Frederik-Jan van Schooten"

67 Publications

Exhaled volatile organic compounds detect pulmonary exacerbations early in children with cystic fibrosis: results of a 1 year observational pilot study.

J Breath Res 2021 Feb 25;15(2):026012. Epub 2021 Feb 25.

Department of Paediatric Pulmonology, School for Public Health and Primary Health Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.

In patients with cystic fibrosis (CF), pulmonary exacerbations (PEx) have an important influence on well-being, quality of life, and lung function decline. Early detection combined with early treatment may prevent severe PEx. To determine whether early detection of PEx is possible by non-invasive markers (volatile organic compounds) in exhaled breath. In a 1 year prospective observational pilot study, 49 children with CF were studied. At clinical visits with an interval of 2 months, lung function, volatile organic compounds (VOCs) in exhaled breath by means of gas chromatography-time-of-flight-mass spectrometry, and medication use were assessed. PEx were recorded. Random forest (RF) classification modelling was used to select discriminatory VOCs, followed by building of receiver operating characteristic curves. An inverse relation between the predictive power of a set of VOCs and time between exhaled breath sampling and the onset of PEx was found. When this time period was within 7 d, the RF model with the nine most discriminatory VOCs was able to correctly predict 79% of the children with an upcoming PEx or remaining stable (sensitivity 79% and specificity 78%). This result was validated by means of bootstrapping within the RF classification model. PEx in children with CF can be detected at an early stage by means of exhaled VOCs. The highest predictive value was reached if time between sampling and the onset of an exacerbation was no longer than 7 d.
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http://dx.doi.org/10.1088/1752-7163/abda55DOI Listing
February 2021

Exhaled volatile organic compounds detect pulmonary exacerbations early in children with Cystic Fibrosis: results of a one-year observational pilot study.

J Breath Res 2021 Jan 11. Epub 2021 Jan 11.

Department of Toxicology, Maastricht University, Maastricht, Limburg, NETHERLANDS.

Background: In patients with Cystic fibrosis (CF), pulmonary exacerbations (PEx) have an important influence on well-being, quality of life, and lung function decline. Early detection combined with early treatment may prevent severe PEx.

Aim: To determine whether early detection of PEx is possible by non-invasive markers (volatile organic compounds) in exhaled breath.

Methods: In a one-year prospective observational pilot study, 49 children with CF were studied. At clinical visits with an interval of 2 months, lung function, volatile organic compounds (VOCs) in exhaled breath by means of gas chromatography-time-of-flight-mass spectrometry, and medication use were assessed. PEx were recorded. Random Forest (RF) classification modelling was used to select discriminatory VOCs, followed by building of Receiver Operating Characteristic curves.

Results: An inverse relation between the predictive power of a set of VOCs and time between exhaled breath sampling and the onset of PEx was found. When this time period was within 7 days, the RF model with the 9 most discriminatory VOCs was able to correctly predict 79% of the children with an upcoming PEx or remaining stable (sensitivity 79% and specificity 78%). This result was validated by means of bootstrapping within the RF classification model.

Conclusion: PEx in children with CF can be detected at an early stage by means of exhaled VOCs. The highest predictive value was reached if time between sampling and the onset of an exacerbation was no longer than 7 days.
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http://dx.doi.org/10.1088/1752-7163/abda55DOI Listing
January 2021

Ligation-Mediated Polymerase Chain Reaction Detection of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine and 5-Hydroxycytosine at the Codon 176 of the p53 Gene of Hepatitis C-Associated Hepatocellular Carcinoma Patients.

Int J Mol Sci 2020 Sep 15;21(18). Epub 2020 Sep 15.

Research Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy.

Molecular mechanisms underlying Hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) pathogenesis are still unclear. Therefore, we analyzed the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and other oxidative lesions at codon 176 of the p53 gene, as well as the generation of 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (MdG), in a cohort of HCV-related HCC patients from Italy. Detection of 8-oxodG and 5-hydroxycytosine (5-OHC) was performed by ligation mediated-polymerase chain reaction assay, whereas the levels of MdG were measured by chromatography and mass-spectrometry. Results indicated a significant 130% excess of 8-oxodG at -TGC- position of p53 codon 176 in HCV-HCC cases as compared to controls, after correction for age and gender, whereas a not significant increment of 5-OHC at -TGC- position was found. Then, regression models showed an 87% significant excess of MdG in HCV-HCC cases relative to controls. Our study provides evidence that increased adduct binding does not occur randomly on the sequence of the p53 gene but at specific sequence context in HCV-HCC patients. By-products of lipid peroxidation could also yield a role in HCV-HCC development. Results emphasize the importance of active oxygen species in inducing nucleotide lesions at a p53 mutational hotspot in HCV-HCC patients living in geographical areas without dietary exposure to aflatoxin B.
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http://dx.doi.org/10.3390/ijms21186753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555735PMC
September 2020

Constructing bi-plots for random forest: Tutorial.

Anal Chim Acta 2020 Sep 11;1131:146-155. Epub 2020 Jul 11.

Department of Pharmacology and Toxicology, School of Nutrition, Toxicology and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, the Netherlands. Electronic address:

Current technological developments have allowed for a significant increase and availability of data. Consequently, this has opened enormous opportunities for the machine learning and data science field, translating into the development of new algorithms in a wide range of applications in medical, biomedical, daily-life, and national security areas. Ensemble techniques are among the pillars of the machine learning field, and they can be defined as approaches in which multiple, complex, independent/uncorrelated, predictive models are subsequently combined by either averaging or voting to yield a higher model performance. Random forest (RF), a popular ensemble method, has been successfully applied in various domains due to its ability to build predictive models with high certainty and little necessity of model optimization. RF provides both a predictive model and an estimation of the variable importance. However, the estimation of the variable importance is based on thousands of trees, and therefore, it does not specify which variable is important for which sample group. The present study demonstrates an approach based on the pseudo-sample principle that allows for construction of bi-plots (i.e. spin plots) associated with RF models. The pseudo-sample principle for RF. is explained and demonstrated by using two simulated datasets, and three different types of real data, which include political sciences, food chemistry and the human microbiome data. The pseudo-sample bi-plots, associated with RF and its unsupervised version, allow for a versatile visualization of multivariate models, and the variable importance and the relation among them.
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http://dx.doi.org/10.1016/j.aca.2020.06.043DOI Listing
September 2020

Gene-environment interaction with smoking for increased non-muscle-invasive bladder cancer tumor size.

Transl Androl Urol 2020 Jun;9(3):1329-1337

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

Background: Urinary bladder cancer (UBC) is one of few cancers with an established gene-environment interaction (GxE) with smoking. However, it is unknown whether the interaction with tobacco use is present non-muscle invasive bladder cancer (NMIBC) and characteristics of prognostic relevance. We aimed to investigate if smoking status and/or smoking intensity interact with the effect of discovered variants on key NMIBC characteristics of tumor grade, stage, size, and patient age within the Bladder Cancer Prognosis Programme (BCPP) cohort.

Methods: Analyzed sample consisted of 546 NMIBC patients with valid smoking data from the BCPP. In a previous genome-wide association study (GWAS), we have identified 61 single nucleotide polymorphisms (SNPs) potentially associated with the NMIBC characteristics of tumor stage, grade, size, and patient age. In the current analysis, we have tested these SNPs for GxE with smoking.

Results: Out of 61 SNPs, 10 have showed suggestion (statistical significance level of P<0.05) for GxE with NMIBC tumor size rs35225990, rs188958632, rs180910528, rs74603364, rs187040828, rs144383242, rs117587674, rs113705641, rs2937268, and chromosome 14:38247577. All SNPs were located across loci of 1p31.3, 3p26.1, 6q14.1, 14q21.1, and 13q14.13. In addition, two of the tested polymorphisms were suggestive for interaction with smoking intensity (chromosome 14:38247577 and rs2937268).

Conclusions: Our study suggests interaction between genetic variance and smoking behavior for increased NMIBC tumor size at the time of diagnosis. Further replication is required to validate these findings.
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http://dx.doi.org/10.21037/tau-19-523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354298PMC
June 2020

Induction of apoptosis in Ogg1-null mouse embryonic fibroblasts by GSH depletion is independent of DNA damage.

Toxicol Lett 2020 Oct 22;332:27-35. Epub 2020 Jun 22.

School of Biosciences, The University of Birmingham, Birmingham, United Kingdom. Electronic address:

Reactive oxygen species (ROS) within the cell are rapidly detoxified by antioxidants such as glutathione. Depletion of glutathione will therefore increase levels of intracellular ROS, which can lead to oxidative DNA damage and the induction of apoptosis. The working hypothesis was that Ogg1 null mouse embryonic fibroblasts (mOgg1 MEFs) would be more sensitive in response to GSH depletion due to their deficiency in the removal of the oxidative DNA modification, 8-oxo-7,8-dihydroguanine (8-oxoG). Following GSH depletion, an increase in intracellular ROS and a subsequent induction of apoptosis was measured in mOgg1 MEFs; as expected. Unexpectedly, an elevated basal level of ROS was identified in mOgg1 MEFs compared to wild type MEFs; which we suggest is partly due to the differential expression of key anti-oxidant genes. The elevated basal ROS levels in mOgg1 MEFs were not accompanied by a deficiency in ATP production or a large increase in 8-oxoG levels. Although 8-oxoG levels did increase following GSH depletion in mOgg1 MEFs; this increase was significantly lower than observed following treatment with a non-toxic dose of hydrogen peroxide. Reconstitution of Ogg1 into mOgg1 MEFs resulted in an increased viability following glutathione depletion, however this rescue did not differ between a repair-proficient and a repair-impaired variant of Ogg1. The data indicates that induction of apoptosis in response to oxidative stress in mOgg1 MEFs is independent of DNA damage and OGG1-initiated DNA repair.
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http://dx.doi.org/10.1016/j.toxlet.2020.06.019DOI Listing
October 2020

Characteristic Human Individual Puffing Profiles Can Generate More TNCO than ISO and Health Canada Regimes on Smoking Machine When the Same Brand Is Smoked.

Int J Environ Res Public Health 2020 05 6;17(9). Epub 2020 May 6.

Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 3581 CD Maastricht, The Netherlands.

Human smoking behavior influences exposure to smoke toxicants and is important for risk assessment. In a prospective observational study, the smoking behavior of Marlboro smokers was measured for 36 h. Puff volume, duration, frequency, flow and inter-puff interval were recorded with the portable CReSSmicro™ device, as has often been done by other scientists. However, the use of the CReSSmicro™ device may lead to some registration pitfalls since the method of insertion of the cigarette may influence the data collection. Participants demonstrated consistent individual characteristic puffing behavior over the course of the day, enabling the creation of a personalized puffing profile. These puffing profiles were subsequently used as settings for smoking machine experiments and tar, nicotine and carbon monoxide (TNCO) emissions were generated. The application of human puffing profiles led to TNCO exposures more in the range of Health Canada Intense (HCI)-TNCO emissions than for those of the International Standardization Organization (ISO). Compared to the ISO regime, which applies a low puff volume relative to human smokers, the generation of TNCO may be at least two times higher than when human puffing profiles were applied on the smoking machine. Human smokers showed a higher puffing intensity than HCI and ISO because of higher puffing frequency, which resulted in more puffs per cigarette, than both HCI and ISO.
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http://dx.doi.org/10.3390/ijerph17093225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246490PMC
May 2020

The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice.

BMC Pulm Med 2020 Apr 29;20(1):112. Epub 2020 Apr 29.

IUF - Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Düsseldorf, DE, Germany.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal disease of which the etiology is still not fully understood. Current treatment comprises two FDA-approved drugs that can slow down yet not stop or reverse the disease. As IPF pathology is associated with an altered redox balance, adding a redox modulating component to current therapy might exert beneficial effects. Quercetin is a dietary antioxidant with strong redox modulating capacities that is suggested to exert part of its antioxidative effects via activation of the redox-sensitive transcription factor Nrf2 that regulates endogenous antioxidant levels. Therefore, the aim of the present study was to investigate if the dietary antioxidant quercetin can exert anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrogenesis through Nrf2-dependent restoration of redox imbalance.

Methods: Homozygous Nrf2 deficient mice and their wildtype littermates were fed a control diet without or with 800 mg quercetin per kg diet from 7 days prior to a single 1 μg/2 μl per g BW bleomycin challenge until they were sacrificed 14 days afterwards. Lung tissue and plasma were collected to determine markers of fibrosis (expression of extracellular matrix genes and histopathology), inflammation (pulmonary gene expression and plasma levels of tumor necrosis factor-α (TNFα) and keratinocyte chemoattrachtant (KC)), and redox balance (pulmonary gene expression of antioxidants and malondialdehyde-dG (MDA)- DNA adducts).

Results: Mice fed the enriched diet for 7 days prior to the bleomycin challenge had significantly enhanced plasma and pulmonary quercetin levels (11.08 ± 0.73 μM versus 7.05 ± 0.2 μM) combined with increased expression of Nrf2 and Nrf2-responsive genes compared to mice fed the control diet in lung tissue. Upon bleomycin treatment, quercetin-fed mice displayed reduced expression of collagen (COL1A2) and fibronectin (FN1) and a tendency of reduced inflammatory lesions (2.8 ± 0.7 versus 1.9 ± 0.8). These beneficial effects were accompanied by reduced pulmonary gene expression of TNFα and KC, but not their plasma levels, and enhanced Nrf2-induced pulmonary antioxidant defences. In Nrf2 deficient mice, no effect of the dietary antioxidant on either histology or inflammatory lesions was observed.

Conclusion: Quercetin exerts anti-fibrogenic and anti-inflammatory effects on bleomycin-induced pulmonary damage in mice possibly through modulation of the redox balance by inducing Nrf2. However, quercetin could not rescue the bleomycin-induced pulmonary damage indicating that quercetin alone cannot ameliorate the progression of IPF.
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http://dx.doi.org/10.1186/s12890-020-1142-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191795PMC
April 2020

Implementation of quality controls is essential to prevent batch effects in breathomics data and allow for cross-study comparisons.

J Breath Res 2020 03 19;14(2):026012. Epub 2020 Mar 19.

Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research, Maastricht University, Maastricht, The Netherlands.

Exhaled breath analysis has become a promising monitoring tool for various ailments by identifying volatile organic compounds (VOCs) as indicative biomarkers excreted in the human body. Throughout the process of sampling, measuring, and data processing, non-biological variations are introduced in the data leading to batch effects. Algorithmic approaches have been developed to cope with within-study batch effects. Batch differences, however, may occur among different studies too, and up-to-date, ways to correct for cross-study batch effects are lacking; ultimately, cross-study comparisons to verify the uniqueness of found VOC profiles for a specific disease may be challenging. This study applies within-study batch-effect-correction approaches to correct for cross-study batch effects; suggestions are made that may help prevent the introduction of cross-study variations. Three batch-effect-correction algorithms were investigated: zero-centering, combat, and the analysis of covariance framework. The breath samples were collected from inflammatory bowel disease ([Formula: see text]), chronic liver disease ([Formula: see text]), and irritable bowel syndrome ([Formula: see text]) patients at different periods, and they were analysed via gas chromatography-mass spectrometry. Multivariate statistics were used to visualise and verify the results. The visualisation of the data before any batch-effect-correction technique was applied showed a clear distinction due to probable batch effects among the datasets of the three cohorts. The visualisation of the three datasets after implementing all three correction techniques showed that the batch effects were still present in the data. Predictions made using partial least squares discriminant analysis and random forest confirmed this observation. The within-study batch-effect-correction approaches fail to correct for cross-study batch effects present in the data. The present study proposes a framework for systematically standardising future breathomics data by using internal standards or quality control samples at regular analysis intervals. Further knowledge regarding the nature of the unsolicited variations among cross-study batches must be obtained to move the field further.
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http://dx.doi.org/10.1088/1752-7163/ab7b8dDOI Listing
March 2020

Germline polymorphisms in the Von Hippel-Lindau and Hypoxia-inducible factor 1-alpha genes, gene-environment and gene-gene interactions and renal cell cancer.

Sci Rep 2020 01 10;10(1):137. Epub 2020 Jan 10.

Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.

We investigated the relationship between germline single nucleotide polymorphisms (SNPs) in Von Hippel-Lindau (VHL) and Hypoxia-inducible factor 1-alpha (HIF1A), and their gene-environment and gene-gene interactions, and clear-cell RCC (ccRCC) risk. Furthermore, we assessed the relationship between VHL SNPs and VHL promoter methylation. Three VHL polymorphisms and one HIF1A polymorphism were genotyped in the Netherlands Cohort Study. In 1986, 120,852 participants aged 55-69 completed a self-administered questionnaire on diet and lifestyle and toenail clippings were collected. Toenail DNA was genotyped using the Sequenom MassARRAY platform. After 20.3 years, 3004 subcohort members and 406 RCC cases, of which 263 ccRCC cases, were eligible for multivariate case-cohort analyses. VHL_rs779805 was associated with RCC (Hazard Ratio (HR) 1.53; 95% Confidence Interval (CI) 1.07-2.17) and ccRCC risk (HR 1.88; 95% CI 1.25-2.81). No associations were found for other SNPs. Potential gene-environment interactions were found between alcohol consumption and selected SNPs. However, none remained statistically significant after multiple comparison correction. No gene-gene interactions were observed between VHL and HIF1A. VHL promoter methylation was not associated with VHL SNPs. VHL SNPs may increase (cc)RCC susceptibility. No associations were found between gene-environment and gene-gene interactions and (cc)RCC risk and between VHL promoter methylation and VHL SNPs.
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http://dx.doi.org/10.1038/s41598-019-56980-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954183PMC
January 2020

Genome-wide Association Study for Tumour Stage, Grade, Size, and Age at Diagnosis of Non-muscle-invasive Bladder Cancer.

Eur Urol Oncol 2019 07 15;2(4):381-389. Epub 2018 Sep 15.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; Department of Complex Genetics, Maastricht University, The Netherlands.

Background: Non-muscle-invasive bladder cancer (NMIBC) causes a considerable health burden due to the high recurrence and progression rates. Past studies have identified multiple candidate loci associated with NMIBC prognosis, albeit lacking validation. Moreover, scarce reports exist on genetic susceptibility to independent prognostic predictors of NMIBC, such as stage or grade.

Objective: To investigate genetic associations with NMIBC tumour and patient characteristics at the time of diagnosis.

Design, Setting, And Participants: A sample of 653 NMIBC cases comes from the Bladder Cancer Prognosis Programme. Replication of the significant findings was conducted in the Nijmegen Bladder Cancer Study cohort (N=1470).

Outcome Measurements And Statistical Analysis: A genome-wide association study (GWAS) was carried out for outcomes of tumour size (as a continuous variable in centimetres), stage (Tis and T1 vs Ta), grade (G3 vs G2 and G1), and age (as continuous [years] and dichotomous [70.2 yr as a cut-off] variables).

Results And Limitations: Significant (p<5E-08) associations (N=61) with tumour size, stage, grade, and age were identified in the GWAS discovery stage. None of the variants were independently significantly associated in the replication cohort. A meta-analysis of both cohorts suggests that rs180940944 (13q13.3 locus, NBEA) was associated with tumour size as a continuous variable (ß=0.9cm, p=2.92E-09). However, other single nucleotide polymorphisms in this region did not show evidence of association in the meta-analysis.

Conclusions: Our study suggests that rs180940944 (NBEA) is associated with an increased NMIBC tumour size at the time of diagnosis. Given study limitations, further replication is essential to validate the finding.

Patient Summary: The current study reports on a genome-wide association study on non-muscle-invasive bladder cancer tumour and patient characteristics. We suggest that NBEA gene might be associated with increased tumour size at the time of diagnosis. The result must be replicated to establish validity.
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http://dx.doi.org/10.1016/j.euo.2018.08.020DOI Listing
July 2019

Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma.

Am J Respir Crit Care Med 2019 08;200(4):444-453

1Respiratory Medicine, GIGA I3, CHU Sart-Tilman, Liege, Belgium.

Analysis of exhaled breath for asthma phenotyping using endogenously generated volatile organic compounds (VOCs) offers the possibility of noninvasive diagnosis and therapeutic monitoring. Induced sputum is indeed not widely available and markers of neutrophilic asthma are still lacking. To determine whether analysis of exhaled breath using endogenously generated VOCs can be a surrogate marker for recognition of sputum inflammatory phenotypes. We conducted a prospective study on 521 patients with asthma recruited from the University Asthma Clinic of Liege. Patients underwent VOC measurement, fraction of exhaled nitric oxide (Fe) spirometry, sputum induction, and gave a blood sample. Subjects with asthma were classified in three inflammatory phenotypes according to their sputum granulocytic cell count. In the discovery study, seven potential biomarkers were highlighted by gas chromatography-mass spectrometry in a training cohort of 276 patients with asthma. In the replication study ( = 245), we confirmed four VOCs of interest to discriminate among asthma inflammatory phenotypes using comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry. Hexane and 2-hexanone were identified as compounds with the highest classification performance in eosinophilic asthma with accuracy comparable to that of blood eosinophils and Fe. Moreover, the combination of Fe, blood eosinophils, and VOCs gave a very good prediction of eosinophilic asthma (area under the receiver operating characteristic curve, 0.9). For neutrophilic asthma, the combination of nonanal, 1-propanol, and hexane had a classification performance similar to Fe or blood eosinophils in eosinophilic asthma. Those compounds were found in higher levels in neutrophilic asthma. Our study is the first attempt to characterize VOCs according to sputum granulocytic profile in a large population of patients with asthma and provide surrogate markers for neutrophilic asthma.
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http://dx.doi.org/10.1164/rccm.201811-2210OCDOI Listing
August 2019

Redox Imbalance in Idiopathic Pulmonary Fibrosis: A Role for Oxidant Cross-Talk Between NADPH Oxidase Enzymes and Mitochondria.

Antioxid Redox Signal 2019 11 5;31(14):1092-1115. Epub 2019 Apr 5.

Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont.

Idiopathic pulmonary fibrosis (IPF) is a progressive age-related lung disease with a median survival of only 3 years after diagnosis. The pathogenic mechanisms behind IPF are not clearly understood, and current therapeutic approaches have not been successful in improving disease outcomes. IPF is characterized by increased production of reactive oxygen species (ROS), primarily by NADPH oxidases (NOXes) and mitochondria, as well as altered antioxidant defenses. Recent studies have identified the NOX isoform NOX4 as a key player in various important aspects of IPF pathology. In addition, mitochondrial dysfunction is thought to enhance pathological features of IPF, in part by increasing mitochondrial ROS (mtROS) production and altering cellular metabolism. Recent findings indicate reciprocal interactions between NOX enzymes and mitochondria, which affect regulation of NOX activity as well as mitochondrial function and mtROS production, and collectively promote epithelial injury and profibrotic signaling. The precise molecular mechanisms by which ROS from NOX or mitochondria contribute to IPF pathology are not known. This review summarizes the current knowledge with respect to the various aspects of ROS imbalance in the context of IPF and its proposed roles in disease development, with specific emphasis on the importance of inappropriate NOX activation, mitochondrial dysfunction, and the emerging evidence of NOX-mitochondria cross-talk as important drivers in IPF pathobiology.
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http://dx.doi.org/10.1089/ars.2019.7742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767863PMC
November 2019

Limited clinical value of exhaled volatile organic compound measurements in childhood asthma.

ERJ Open Res 2018 Oct 12;4(4). Epub 2018 Nov 12.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

http://ow.ly/Z2d930lpZ60.
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http://dx.doi.org/10.1183/23120541.00026-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230817PMC
October 2018

Volatile metabolites in breath strongly correlate with gut microbiome in CD patients.

Anal Chim Acta 2018 Sep 30;1025:1-11. Epub 2018 Mar 30.

NUTRIM School of Nutrition and Translational Research in Metabolism, Department Pharmacology & Toxicology, Maastricht University, The Netherlands.

Microbiota composition and its metabolic capacity are very important for host health. Evidence suggests that gut microbiome is involved in the metabolites production by host-microbiome interaction. These metabolites can be absorbed in blood and excreted in exhaled air. Although, profiles of gut microbiota and exhaled metabolites were associated with gastrointestinal diseases, a direct link between them has not yet been investigated. The aim of the study was to investigate the relation between volatiles in breath and gut microbiome in active and quiescent Crohn's disease (CD) via a multivariate statistical approach. Canonical correlation analysis (CCA) was used to assess the relation between exhaled metabolites and faecal bacterial species. From 68 CD patients, 184 repeated faecal and breath samples were collected (92 active and 92 quiescent disease). The microbiota composition was assessed by the pyrosequencing of the 16 S rRNA V1-V3 gene region and breath metabolites by gas chromatography mass spectrometry. In active disease, CCA analysis identified 18 metabolites significantly correlated with 19 faecal bacterial taxa (R = 0.91 p-value 3.5*10-4). In quiescent disease 17 volatile metabolites were correlated with 17 bacterial taxa (R = 0.96 p-value 2.8*10-4). Nine metabolites and three bacteria taxa overlapped in active and inactive CD. This is the first study that shows a significant relation between gut microbiome and exhaled metabolites, and was found to differ between active and quiescent CD, indicating various underlying mechanisms. Unravelling this link is essential to increase our understanding on the functional effects of the microbiome and may provide new leads for microbiome-targeted intervention.
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http://dx.doi.org/10.1016/j.aca.2018.03.046DOI Listing
September 2018

The Role of Genetic Variants in the Association between Dietary Acrylamide and Advanced Prostate Cancer in the Netherlands Cohort Study on Diet and Cancer.

Nutr Cancer 2018 May-Jun;70(4):620-631. Epub 2018 Apr 26.

a Department of Epidemiology , GROW - School for Oncology and Developmental Biology, Maastricht University , Maastricht , The Netherlands.

To investigate the association between dietary acrylanide and advanced prostate cancer, we examined acrylamide-gene interactions for advanced prostate cancer risk by using data from the Netherlands Cohort Study. Participants (n = 58,279 men) completed a baseline food frequency questionnaire (FFQ), from which daily acrylamide intake was calculated. At baseline, 2,411 men were randomly selected from the full cohort for case-cohort analysis. Fifty eight selected single nucleotide polymorphisms (SNPs) and two gene deletions in genes in acrylamide metabolism, DNA repair, sex steroid systems, and oxidative stress were analyzed. After 20.3 years of follow-up, 1,608 male subcohort members and 948 advanced prostate cancer cases were available for Cox analysis. Three SNPs showed a main association with advanced prostate cancer risk after multiple testing correction: catalase (CAT) rs511895, prostaglandin-endoperoxide synthase 2 (PTGS2) rs5275, and xeroderma pigmentosum group C (XPC) rs2228001. With respect to acrylamide-gene interactions, only rs1800566 in NAD(P)H quinone dehydrogenase 1 (NQO1) and rs2301241 in thioredoxin (TXN) showed a nominally statistically significant multiplicative interaction with acrylamide intake for advanced prostate cancer risk. After multiple testing corrections, none were statistically significant. In conclusion, no clear evidence was found for interaction between acrylamide intake and selected genetic variants for advanced prostate cancer risk.
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http://dx.doi.org/10.1080/01635581.2018.1460682DOI Listing
February 2019

Fruit and vegetable intake and the risk of recurrence in patients with non-muscle invasive bladder cancer: a prospective cohort study.

Cancer Causes Control 2018 06 17;29(6):573-579. Epub 2018 Apr 17.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

Introduction: There is some evidence that greater consumption of fruit and vegetables decreases the risk of bladder cancer. The role of fruit and vegetables in bladder cancer recurrence is still unknown.

Objective: The role of total fruit and vegetable intake in relation to the risk of developing bladder cancer recurrence in a prospective cohort study.

Methods: 728 patients with non-muscle invasive bladder cancer (NMIBC), who completed self-administrated questionnaires on fruit and vegetable intake at time of diagnosis (over the year before diagnosis) and 1 year after diagnosis, were included. Hazard ratios and 95% confidence intervals were calculated by multivariable Cox regression for developing recurrent bladder cancer in relation to fruit and vegetable intake.

Results: During 2,051 person-years of follow-up [mean (SD) follow-up 3.7 (1.5) years], 241 (33.1%) of the included 728 NMIBC patients developed a recurrence of bladder cancer. The sum of total fruit and vegetables before diagnosis was not related to a first bladder cancer recurrence (HR 1.07; 95% CI 0.78-1.47, p = 0.66). No association was found between greater consumption of fruit and vegetables over the year before diagnosis and the risk of developing multiple recurrences of bladder cancer (HR 1.02; 95% CI 0.90-1.15, p = 0.78). Among the remaining 389 NMIBC patients who reported on fruit and vegetable intake 1 year after diagnosis, no association was found between greater consumption of fruit and vegetables and a first recurrence of bladder cancer (HR 0.65; 95% CI 0.42-1.01, p = 0.06) nor with multiple recurrences of bladder cancer (HR 1.00, 95% CI 0.85-1.18, p = 1.00). Similar results were obtained when investigating the association between total intakes of fruit and vegetables separately and bladder cancer recurrence.

Conclusion: Results from this study did not indicate a protective role for total fruit and vegetables in the development of a recurrence of NMIBC.
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http://dx.doi.org/10.1007/s10552-018-1029-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938309PMC
June 2018

Interaction between dietary acrylamide intake and genetic variants for estrogen receptor-positive breast cancer risk.

Eur J Nutr 2019 Apr 14;58(3):1033-1045. Epub 2018 Feb 14.

Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, The Netherlands.

Purpose: The association between dietary acrylamide intake and estrogen receptor-positive (ER+) breast cancer risk in epidemiological studies is inconsistent. By analyzing gene-acrylamide interactions for ER+ breast cancer risk, we aimed to clarify the role of acrylamide intake in ER+ breast cancer etiology.

Methods: The prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55-69 years. At baseline, a random subcohort of 2589 women was sampled from the total cohort for a case-cohort analysis approach. Dietary acrylamide intake of subcohort members (n = 1449) and ER+ breast cancer cases (n = 844) was assessed with a food frequency questionnaire. We genotyped single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism, sex steroid systems, oxidative stress and DNA repair. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis, based on 20.3 years of follow-up.

Results: Unexpectedly, there was a statistically non-significant inverse association between acrylamide and ER+ breast cancer risk among all women but with no clear dose-response relationship, and no association among never smokers. Among the results for 57 SNPs and 2 gene deletions, rs1056827 in CYP1B1, rs2959008 and rs7173655 in CYP11A1, the GSTT1 gene deletion, and rs1052133 in hOGG1 showed a statistically significant interaction with acrylamide intake for ER+ breast cancer risk.

Conclusions: This study did not provide evidence for a positive association between acrylamide intake and ER+ breast cancer risk. If anything, acrylamide was associated with a decreased ER+ breast cancer risk. The interaction with SNPs in CYP1B1 and CYP11A1 suggests that acrylamide may influence ER+ breast cancer risk through sex hormone pathways.
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http://dx.doi.org/10.1007/s00394-018-1619-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499753PMC
April 2019

Paternal Exposure to Environmental Chemical Stress Affects Male Offspring's Hepatic Mitochondria.

Toxicol Sci 2018 03;162(1):241-250

Department of Pharmacology & Toxicology, NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, 6200MD Maastricht, The Netherlands.

Preconceptional paternal exposures may affect offspring's health, which cannot be explained by mutations in germ cells, but by persistent changes in the regulation of gene expression. Therefore, we investigated whether pre-conceptional paternal exposure to benzo[a]pyrene (B[a]P) could alter the offspring's phenotype. Male C57BL/6 mice were exposed to B[a]P by gavage for 6 weeks, 3× per week, and were crossed with unexposed BALB-c females 6 weeks after the final exposure. The offspring was kept under normal feeding conditions and was sacrificed at 3 weeks of age. Analysis of the liver proteome by 2D-gel electrophoresis and mass spectrometry indicated that proteins involved in mitochondrial function were significantly downregulated in the offspring of exposed fathers. This down-regulation of mitochondrial proteins was paralleled by a reduction in mitochondrial DNA copy number and reduced activity of citrate synthase and β-hydroxyacyl-CoA dehydrogenase, but in male offspring only. Surprisingly, analysis of hepatic mRNA expression revealed a male-specific up-regulation of the genes, whose proteins were downregulated, including Aldh2 and Ogg1. This discrepancy could be related to several selected microRNA (miRNA)'s that regulate the translation of these proteins; miRNA-122, miRNA-129-2-5p, and miRNA-1941 were upregulated in a gender-specific manner. Since mitochondria are thought to be a source of intracellular reactive oxygen species, we additionally assessed oxidatively-induced DNA damage. Both 8-hydroxy-deoxyguanosine and malondialdehyde-dG adduct levels were significantly reduced in male offspring of exposed fathers. In conclusion, we show that paternal exposure to B[a]P can regulate mitochondrial metabolism in offspring, which may have profound implications for our understanding of health and disease risk inherited from fathers.
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http://dx.doi.org/10.1093/toxsci/kfx246DOI Listing
March 2018

A European Respiratory Society technical standard: exhaled biomarkers in lung disease.

Eur Respir J 2017 04 26;49(4). Epub 2017 Apr 26.

Philips Research, High Tech Campus 11, Eindhoven, The Netherlands.

Breath tests cover the fraction of nitric oxide in expired gas (), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for , official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and , new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice.
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http://dx.doi.org/10.1183/13993003.00965-2016DOI Listing
April 2017

Interactions between dietary acrylamide intake and genes for ovarian cancer risk.

Eur J Epidemiol 2017 05 8;32(5):431-441. Epub 2017 Apr 8.

Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, The Netherlands.

Some epidemiological studies observed a positive association between dietary acrylamide intake and ovarian cancer risk but the causality needs to be substantiated. By analyzing gene-acrylamide interactions for ovarian cancer risk for the first time, we aimed to contribute to this. The prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55-69 years. At baseline in 1986, a random subcohort of 2589 women was sampled from the total cohort for a case cohort analysis approach. Dietary acrylamide intake of subcohort members and ovarian cancer cases (n = 252, based on 20.3 years of follow-up) was assessed with a food frequency questionnaire. We selected single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism and in genes involved in the possible mechanisms of acrylamide-induced carcinogenesis (effects on sex steroid systems, oxidative stress and DNA damage). Genotyping was done on DNA from toenails through Agena's MassARRAY iPLEX platform. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis. Among the results for 57 SNPs and 2 gene deletions, there were no statistically significant interactions between acrylamide and gene variants after adjustment for multiple testing. However, there were several nominally statistically significant interactions between acrylamide intake and SNPs in the HSD3B1/B2 gene cluster: (rs4659175 (p interaction = 0.04), rs10923823 (p interaction = 0.06) and its proxy rs7546652 (p interaction = 0.05), rs1047303 (p interaction = 0.005), and rs6428830 (p interaction = 0.05). Although in need of confirmation, results of this study suggest that acrylamide may cause ovarian cancer through effects on sex hormones.
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http://dx.doi.org/10.1007/s10654-017-0244-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506210PMC
May 2017

Can exhaled volatile organic compounds predict asthma exacerbations in children?

J Breath Res 2017 03 1;11(1):016016. Epub 2017 Mar 1.

Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.

Background: Asthma control does not yet meet the goals of asthma management guidelines. Non-invasive monitoring of airway inflammation may help to improve the level of asthma control in children.

Objectives: (1) To identify a set of exhaled volatile organic compounds (VOCs) that is most predictive for an asthma exacerbation in children. (2) To elucidate the chemical identity of predictive biomarkers.

Methods: In a one-year prospective observational study, 96 asthmatic children participated . During clinical visits at 2 month intervals, asthma control, fractional exhaled nitric oxide, lung function (FEV, FEV/VC) and VOCs in exhaled breath were determined by means of gas chromatography time-of-flight mass spectrometry. Random Forrest classification modeling was used to select predictive VOCs, followed by plotting of receiver operating characteristic-curves (ROC-curves).

Results: An inverse relationship was found between the predictive power of a set of VOCs and the time between sampling of exhaled breath and the onset of exacerbation. The sensitivity and specificity of the model predicting exacerbations 14 days after sampling were 88% and 75%, respectively. The area under the ROC-curve was 90%. The sensitivity for prediction of asthma exacerbations within 21 days after sampling was 63%. In total, 7 VOCs were selected for the classification model: 3 aldehydes, 1 hydrocarbon, 1 ketone, 1 aromatic compound, and 1 unidentified VOC.

Conclusion: VOCs in exhaled breath showed potential for predicting asthma exacerbations in children within 14 days after sampling. Before using this in clinical practice, the validity of predicting asthma exacerbations should be studied in a larger cohort.
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http://dx.doi.org/10.1088/1752-7163/aa5a8bDOI Listing
March 2017

The influence of single nucleotide polymorphisms on the association between dietary acrylamide intake and endometrial cancer risk.

Sci Rep 2016 10 7;6:34902. Epub 2016 Oct 7.

Department of Epidemiology, School for Oncology &Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands.

It is unclear whether the association between dietary acrylamide intake and endometrial cancer risk as observed in some epidemiological studies reflects a causal relationship. We aimed at clarifying the causality by analyzing acrylamide-gene interactions for endometrial cancer risk. The prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55-69 years. At baseline, a random subcohort of 2589 women was selected for a case cohort analysis approach. Acrylamide intake of subcohort members and endometrial cancer cases (n = 315) was assessed with a food frequency questionnaire. Single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism, sex steroid systems, oxidative stress and DNA repair were assessed through a MassARRAY iPLEX Platform. Interaction between acrylamide and SNPs was assessed with Cox proportional hazards analysis, based on 11.3 years of follow-up. Among the results for 57 SNPs and 2 gene deletions, there were no statistically significant interactions after adjustment for multiple testing. However, there were nominally statistically significant interactions for SNPs in acrylamide-metabolizing enzymes: CYP2E1 (rs915906 and rs2480258) and the deletions of GSTM1 and GSTT1. Although in need of confirmation, the interactions between acrylamide intake and CYP2E1 SNPs contribute to the evidence for a causal relationship between acrylamide and endometrial cancer risk.
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http://dx.doi.org/10.1038/srep34902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054678PMC
October 2016

Predictive Factors for Anastomotic Leakage After Colorectal Surgery: Study Protocol for a Prospective Observational Study (REVEAL Study).

JMIR Res Protoc 2016 Jun 9;5(2):e90. Epub 2016 Jun 9.

Department of General Surgery, Maastricht University Medical Centre, Maastricht, Netherlands.

Background: Anastomotic leakage (AL) remains the most important complication following colorectal surgery, and is associated with high morbidity and mortality rates. Previous research has focused on identifying risk factors and potential biomarkers for AL, but the sensitivity of these tests remains poor.

Objective: This prospective multicenter observational study aims at combining multiple parameters to establish a diagnostic algorithm for colorectal AL.

Methods: This study aims to include 588 patients undergoing surgery for colorectal carcinoma. Patients will be eligible for inclusion when surgery includes the construction of a colorectal anastomosis. Patient characteristics will be collected upon consented inclusion, and buccal swabs, breath, stool, and blood samples will be obtained prior to surgery. These samples will allow for the collection of information regarding patients' inflammatory status, genetic predisposition, and intestinal microbiota. Additionally, breath and blood samples will be taken postoperatively and patients will be strictly observed during their in-hospital stay, and the period shortly thereafter.

Results: This study has been open for inclusion since August 2015.

Conclusions: An estimated 8-10% of patients will develop AL following surgery, and they will be compared to non-leakage patients. The objectives of this study are twofold. The primary aim is to establish and validate a diagnostic algorithm for the pre-operative prediction of the risk of AL development using a combination of inflammatory, immune-related, and genetic parameters. Previously established risk factors and novel parameters will be incorporated into this algorithm, which will aid in the recognition of patients who are at risk for AL. Based on these results, recommendations can be made regarding the construction of an anastomosis or deviating stoma, and possible preventive strategies. Furthermore, we aim to develop a new algorithm for the post-operative diagnosis of AL at an earlier stage, which will positively reflect on short-term survival rates.

Trial Registration: Clinicaltrials.gov: NCT02347735; https://clinicaltrials.gov/ct2/show/NCT02347735 (archived by WebCite at http://www.webcitation.org/6hm6rxCsA).
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http://dx.doi.org/10.2196/resprot.5477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919551PMC
June 2016

Quantified relations between exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies.

Int J Epidemiol 2016 06 20;45(3):857-70. Epub 2016 Apr 20.

Department of Complex Genetics, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK, Department of Complex Genetics, CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, The Netherlands.

Background: Smoking is a major risk factor for bladder cancer (BC). This meta-analysis updates previous reviews on smoking characteristics and BC risk, and provides a more quantitative estimation of the dose-response relationship between smoking characteristics and BC risk.

Methods: In total, 89 studies comprising data from 57 145 BC cases were included and summary odds ratios (SORs) were calculated. Dose-response meta-analyses modelled relationships between smoking intensity, duration, pack-years and cessation and BC risk. Sources of heterogeneity were explored and sensitivity analyses were conducted to test the robustness of findings.

Results: Current smokers (SOR = 3.14, 95% CI = 2.53-3.75) and former smokers(SOR = 1.83, 95% CI = 1.52-2.14) had an increased risk of BC compared with never smokers. Age at first exposure was negatively associated with BC risk. BC risk increased gradually by smoking duration and a risk plateau at smoking 15 cigarettes a day and 50 pack-years was observed. Smoking cessation is most beneficial from 20 years before diagnosis. The population-attributable risk of BC for smokers has decreased from 50% to 43% in men and from 35% to 26% in women from Europe since estimated in 2000. Results were homogeneous between sources of heterogeneity, except for lower risk estimates found in studies of Asian populations.

Conclusions: Active smokers are at an increased risk of BC. Dose-response meta-analyses showed a BC risk plateau for smoking intensity and indicate that even after long-term smoking cessation, an elevated risk of bladder cancer remains.
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http://dx.doi.org/10.1093/ije/dyw044DOI Listing
June 2016

A profile of volatile organic compounds in exhaled air as a potential non-invasive biomarker for liver cirrhosis.

Sci Rep 2016 Jan 29;6:19903. Epub 2016 Jan 29.

Department of Pharmacology and Toxicology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands.

Early diagnosis of liver cirrhosis may prevent progression and development of complications. Liver biopsy is the current standard, but is invasive and associated with morbidity. We aimed to identify exhaled volatiles within a heterogeneous group of chronic liver disease (CLD) patients that discriminates those with compensated cirrhosis (CIR) from those without cirrhosis, and compare this with serological markers. Breath samples were collected from 87 CLD and 34 CIR patients. Volatiles in exhaled air were measured by gas chromatography mass spectrometry. Discriminant Analysis was performed to identify the optimal panel of serological markers and VOCs for classifying our patients using a random training set of 27 CIR and 27 CLD patients. Two randomly selected independent internal validation sets and permutation test were used to validate the model. 5 serological markers were found to distinguish CIR and CLD patients with a sensitivity of 0.71 and specificity of 0.84. A set of 11 volatiles discriminated CIR from CLD patients with sensitivity of 0.83 and specificity of 0.87. Combining both did not further improve accuracy. A specific exhaled volatile profile can predict the presence of compensated cirrhosis among CLD patients with a higher accuracy than serological markers and can aid in reducing liver biopsies.
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http://dx.doi.org/10.1038/srep19903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731784PMC
January 2016

Analysis of volatile organic compounds in exhaled breath to diagnose ventilator-associated pneumonia.

Sci Rep 2015 Nov 26;5:17179. Epub 2015 Nov 26.

Department of Pharmacology and Toxicology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.

Ventilator-associated pneumonia (VAP) is a nosocomial infection occurring in the intensive care unit (ICU). The diagnostic standard is based on clinical criteria and bronchoalveolar lavage (BAL). Exhaled breath analysis is a promising non-invasive method for rapid diagnosis of diseases and contains volatile organic compounds (VOCs) that can differentiate diseased from healthy individuals. The aim of this study was to determine whether analysis of VOCs in exhaled breath can be used as a non-invasive monitoring tool for VAP. One hundred critically ill patients with clinical suspicion of VAP underwent BAL. Before BAL, exhaled air samples were collected and analysed by gas chromatography time-of-flight mass spectrometry (GC-tof-MS). The clinical suspicion of VAP was confirmed by BAL diagnostic criteria in 32 patients [VAP(+)] and rejected in 68 patients [VAP(-)]. Multivariate statistical comparison of VOC profiles between VAP(+) and VAP(-) revealed a subset of 12 VOCs that correctly discriminated between those two patient groups with a sensitivity and specificity of 75.8% ± 13.5% and 73.0% ± 11.8%, respectively. These results suggest that detection of VAP in ICU patients is possible by examining exhaled breath, enabling a simple, safe and non-invasive approach that could diminish diagnostic burden of VAP.
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http://dx.doi.org/10.1038/srep17179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660425PMC
November 2015

Exhaled Molecular Fingerprinting in Diagnosis and Monitoring: Validating Volatile Promises.

Trends Mol Med 2015 Oct;21(10):633-644

Department of Respiratory Medicine, Academic Medical Centre, University of Medical Centre Amsterdam, The Netherlands.

Medical diagnosis and phenotyping increasingly incorporate information from complex biological samples. This has promoted the development and clinical application of non-invasive metabolomics in exhaled air (breathomics). In respiratory medicine, expired volatile organic compounds (VOCs) are associated with inflammatory, oxidative, microbial, and neoplastic processes. After recent proof of concept studies demonstrating moderate to good diagnostic accuracies, the latest efforts in breathomics are focused on optimization of sensor technologies and analytical algorithms, as well as on independent validation of clinical classification and prediction. Current research strategies are revealing the underlying pathophysiological pathways as well as clinically-acceptable levels of diagnostic accuracy. Implementing recent guidelines on validating molecular signatures in medicine will enhance the clinical potential of breathomics and the development of point-of-care technologies.
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http://dx.doi.org/10.1016/j.molmed.2015.08.001DOI Listing
October 2015

Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene.

Toxicol Sci 2015 Aug 23;146(2):213-25. Epub 2015 Apr 23.

Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom.

Pulmonary inflammation can contribute to the development of lung cancer in humans. We investigated whether pulmonary inflammation alters the genotoxicity of polycyclic aromatic hydrocarbons (PAHs) in the lungs of mice and what mechanisms are involved. To model nonallergic acute inflammation, mice were exposed intranasally to lipopolysaccharide (LPS; 20 µg/mouse) and then instilled intratracheally with benzo[a]pyrene (BaP; 0.5 mg/mouse). BaP-DNA adduct levels, measured by (32)P-postlabeling analysis, were approximately 3-fold higher in the lungs of LPS/BaP-treated mice than in mice treated with BaP alone. Pulmonary Cyp1a1 enzyme activity was decreased in LPS/BaP-treated mice relative to BaP-treated mice suggesting that pulmonary inflammation impacted on BaP-induced Cyp1a1 activity in the lung. Our results showed that Cyp1a1 appears to be important for BaP detoxification in vivo and that the decrease of pulmonary Cyp1a1 activity in LPS/BaP-treated mice results in a decrease of pulmonary BaP detoxification, thereby enhancing BaP genotoxicity (ie, DNA adduct formation) in the lung. Because less BaP was detoxified by Cyp1a1 in the lungs of LPS/BaP-treated mice, more BaP circulated via the blood to extrapulmonary tissues relative to mice treated with BaP only. Indeed, we observed higher BaP-DNA adduct levels in livers of LPS/BaP-treated mice compared with BaP-treated mice. Our results indicate that pulmonary inflammation could be a critical determinant in the induction of genotoxicity in the lung by PAHs like BaP. Cyp1a1 appears to be involved in both BaP bioactivation and detoxification although the contribution of other enzymes to BaP-DNA adduct formation in lung and liver under inflammatory conditions remains to be explored.
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http://dx.doi.org/10.1093/toxsci/kfv086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517052PMC
August 2015

Canonical autophagy does not contribute to cellular radioresistance.

Radiother Oncol 2015 Mar 13;114(3):406-12. Epub 2015 Mar 13.

Department of Radiation Oncology (Maastro Lab), GROW School for Oncology & Developmental Biology, Maastricht University Medical Center+, The Netherlands. Electronic address:

Background: (Pre)clinical studies indicate that autophagy inhibition increases response to anti-cancer therapies. Although promising, due to contradicting reports, it remains unclear if radiation therapy changes autophagy activity and if autophagy inhibition changes the cellular intrinsic radiosensitivity. Discrepancies may result from different assays and models through off-target effects and influencing other signaling routes. In this study, we directly compared the effects of genetic and pharmacological inhibition of autophagy after irradiation in human cancer cell lines.

Materials And Methods: Changes in autophagy activity after ionizing radiation (IR) were assessed by flux analysis in eight cell lines. Clonogenic survival, DNA damage (COMET-assay) and H2AX phosphorylation were assessed after chloroquine or 3-methyladenine pretreatment and after ATG7 or LC3b knockdown.

Results: IR failed to induce autophagy and chloroquine failed to change intrinsic radiosensitivity of cells. Interestingly, 3-methyladenine and ATG7- or LC3b-deficiency sensitized cancer cells to irradiation. Surprisingly, the radiosensitizing effect of 3-methyladenine was also observed in ATG7 and LC3b deficient cells and was associated with attenuated γ-H2AX formation and DNA damage repair.

Conclusion: Our data demonstrate that the anti-tumor effects of chloroquine are independent of changes in intrinsic radioresistance. Furthermore, ATG7 and LC3b support radioresistance independent of canonical autophagy that involves lysosomal degradation.
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http://dx.doi.org/10.1016/j.radonc.2015.02.019DOI Listing
March 2015