Research team

Laboratory Experimental Medicine and Pediatrics (LEMP)

Expertise

At the end of the previous century, it was discovered that exhaled breath, contains volatile organic compounds (VOCs). These VOCs originate from the human metabolism and could reflect changes herein. One of the major drivers of VOC production is inflammation, inducing a state called oxidative stress at the inflamed tissue, liberating VOCs. Next to this, several bacterial infections have shown to produce some VOCs specific for the strain, which could be used to detect several bacterial infections. Hence, a change in VOCs in the breath is an indication of disease or infection and could also be used to monitor disease after treatment has been initiated. The fact that breath sampling is non-invasive and does not need any forced breathing manoeuvres, it allows to be used as an ideal sampling tool for elderly people, young children and patients at the ICU, where blood sampling is sometimes experienced as painful or causes distress. Furthermore, inflammation is one of the hallmarks in cancer. Tumours are known to upregulate their metabolism and are known to escape an active immune system. These processes will influence the VOC composition in breath and hence, allow VOCs to also be used to diagnose cancer or monitor response after cancer treatment. However, up to today, the search for a breath test for diagnosing or monitoring cancer or inflammatory diseases is still in is initial discovery phase and has not yet been implemented into the clinic. Therefore, my research focusses on volatomics and breathomics by exploring the use of non-invasive breath analysis to elucidate the role of VOCs as tools for diagnosing or monitoring inflammatory and malignant diseases in vivo as by in vitro headspace analysis. Hence, the way to implement these “volatile biopsies” in a clinical diagnostic work-up could be achieved.

Implementation of breathomics in health and disease. 15/10/2020 - 30/04/2021

Abstract

The air we breathe is essential for a healthy live. Health and disease reflect in the exhaled air and already, diseases were linked to its scent. Breath contains both volatile organic compounds (VOCs), and non-volatile components (exhaled breath condensate (EBC), and exhaled particles (PEx)). These include metabolites, signalling molecules and cell constituents which relate to the individual's metabolism and are induced by (patho)fysiological processes as inflammation, infection or carcinogenesis in the body. Compounds in the breath are formed in the respiratory system or originate from processes in the body and are transported to the lungs where they can be exhaled. The molecular composition of VOCs and EBC, hence, may reflect both systemic and local processes in the airways, whereas the PEx specifically reflect the composition of the lining fluid of small airways. Since volatile chemicals are recognized as sources of disease, the molecular analysis, or so called 'omics' study of exhaled air ('breathomics') emerges as a paramount instrument in monitoring health and disease in a non-invasive way. Considering the breath volatiles, there are close to 1000 reported compounds in the breath, of which little are unambiguously identified. The compounds belonged to several chemical classes, of which hydrocarbons were the most numerous chemical family. Other well-represented classes were ketones, terpenes, heterocyclic compounds and aromatic compounds. Exhaled breath volatiles and non-volatiles are explored in patients with asthma, renal and liver diseases, lung cancer, chronic obstructive pulmonary disease, inflammatory lung disease, or metabolic disorders and have been shown promising as diagnostic biomarkers. Breath tests can furthermore be used for diagnosing specific enzymes' phenotypic functionality since exhaled metabolisation products of 13C-labeled compounds gives information about the activity of metabolisation enzymes, important information in supporting personalized medicine. VOCs can also originate from exogenous exposure, such as food and drugs intake, and inhalation of chemicals (environmental, occupational 'exposome'). It is a relevant matrix to study exposure, uptake metabolism and elimination of toxic chemicals. Breath analysis, and in general the human volatolome, was first reported to investigate VOCs over forty years ago. Since that time, many methodological and technical improvements have been made. The analysis of VOCs can be done either by chemical analysis or by pattern recognition. Therefore, this project will include the following instruments to measure VOCs: Gas Chromatography-quadrupole-time-of-flight-Mass Spectrometry, sensor technology (field asymmetric ion mobility spectrometry), and selected ion flow tube-mass spectrometry. This will be combined with liquid chromatography instruments considering the analysis of non-volatiles. To analyse the high-throughput data, supervised and unsupervised data mining techniques will be used. Although the 'breath' matrix is highly interesting, there is still a great need for validation, standardization, and improved sensitivity and specificity of the process of breath collection until breath analysis. This project has the ambition to study and explore exhaled breath in its most innovative way: full molecular profiling, including characterization and quantification of volatile and non-volatile breath compounds in vivo in patients, but also ex vivo and in experimental cellular/animal models for biological translation. Therefore, this project's applications are multiple, ranging from medical/toxicological applications for non-invasive monitoring and detection of disease in humans, to research on exhalations/perspirations in the headspace of cell lines, plants, or even consumer goods. This makes the facility an attractive centre for research for several disciplines.

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A novel proteomics-based approach to find more accurate biomarkers for mesothelioma. 01/01/2019 - 31/12/2020

Abstract

Malignant pleural mesothelioma (MPM) is a cancer caused by long-term exposure to asbestos. MPM is very aggressive with poor prognosis. Currently, high levels of mesothelin in blood, in combination with other invasive tests, help to diagnose MPM, but mesothelin levels do not suffice by themselves as correct diagnostic biomarkers. Here, we aim at performing a proteomic study on blood plasma samples from MPM patients which combines for the first time two approaches being selection of low abundant proteins originating from cancer cells (tissue leakage proteins), and sensitive mass spectrometrybased analysis, recently successfully introduced in clinical proteomics. Our workflow is based on dedicated protein selection and overall analytical sensitivity, both that are currently missing in blood biomarkers studies.

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Validating breath analysis for the case finding of pleural mesothelioma and lung cancer in at risk populations. 01/05/2018 - 30/04/2021

Abstract

Approximately 75% of patients with lung cancer present with advanced disease and hence, have a bad prognosis. For those with stage 1 disease, the chance of cure is up to 70%. Therefore, companion diagnostics, which may aid identification of those with early stage lung cancer, will play an important role in future screening programs. It is assumed that lung cancer starts as an intrapulmonary nodule, before expanding and spreading to loco-regional lymph nodes and resulting in distant metastases. Because all cancer cells are characterized by an uncontrolled growth that changes their metabolism, the detection of the resulting metabolites may be a novel diagnostic tool to differentiate between early stage lung cancer among incidental pulmonary nodules. Subsets of these metabolites are volatile and are exhaled as so-called volatile organic compounds (VOCs). Analysis of those VOCs suggests they differ between patients with advanced lung cancer and healthy controls. This study aims to validate the use of a high-throughput breath analysis technique in a population of patients who present with an incidental pulmonary nodule. This study will be a case-control study. Six hundred consecutive patients with various underlying conditions and in whom a pulmonary nodule is found on CT scan performed in the course of their illness, will be invited to participate and will be asked to provide a breath sample prior to the diagnostic procedures –if any- for this nodule. Breath sampling is a non-invasive procedure that will require the patient to breath normally into a facemask for 10 minutes to collect 2.5L of breath. The resulting samples will be analysed by Field Asymmetrical Ion Mobility Spectrometry (FAIMS). The resulting VOC profiles will be used to generate a diagnostic algorithm in order to try to differentiate between benign and malignant nodules. The results of this study will provide detailed insights into the accuracy of the test for the detection of early stage lung cancer in incidentally found pulmonary nodules and will form the base for a subsequent study in a population at high risk for the development of lung cancer ((ex-)smokers of at least 15 pack years with emphysema). If sufficiently accurate for early stage disease, analysis of breath VOCs could help implement large-scale screening for lung cancer, significantly decreasing the morbidity and mortality of the disease.

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Analysis of Volatile Organic Compounds from mesothelioma cells with ion mobility spectrometry (IMS). 01/04/2018 - 31/03/2019

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-related disease with dismal prognosis. In order to improve early detection and management, breath analysis as a new, non-invasive tool for the diagnosis is being explored in previous MesoBreath studies. However, to increase the specificity of the diagnostic breath model, the aim of this study is (I) to compare and identify the volatile organic compounds (VOCs) emitted from different MPM cell lines with Ion Mobility Spectrometry (IMS), (ii) correlate VOCs from MPM cells with VOCs in the breath of MPM patients and (iii) correlate VOCs with MPM pathogenesis in order to find biological links between the model and the disease pathogenesis.

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