Research Kevin Lamote

Abstract

African trypanosomiasis is a tsetse fly transmitted disease indigenous for the African continent. Millions of people in 36 sub-Saharan African countries are currently at risk of this fatal infection. The current drugs are faced with limitations of toxicity and drug resistance and to date not a single effective vaccine is available. For both vaccine development and elimination endeavours, an adequate understanding of the immunology of infection onset, disease progression and distribution of parasites to tissue sanctuary niches is crucial. Our recent work has identified the skin and lungs as overlooked tissue reservoirs. Although they are sites of strong parasite proliferation, the limited organ-specific pathology has led us to overlook their importance in disease establishment and parasite transmission. Asymptomatic individuals who remain undiagnosed may pose a significant constraint for disease control. Understanding both colonization of skin and lungs as major reservoir tissues and specific parasite adaptations, will support the identification of parasite- or host-specific markers for diagnosis and increase our insight into the immunological basis of increased susceptibility to secondary pulmonary infections. Hence, we will use unbiased approaches linking parasite and tissue transcriptomes and evaluate the use of breathomics as novel diagnostic method.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Lamote Kevin
• Fellow: Mabille Dorien

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Pleural mesothelioma (PM) is a rare and aggressive cancer caused by historical exposure to asbestos fibres. It is characterised by poor prognosis, mainly due to advanced stage diagnosis which limits curative treatment. Currently, MPM diagnosis is based on the histological assessment of pleural effusion fluids or lung biopsies. Such procedures are invasive, often associated with comorbidity and limit the possibility of early diagnosis. Therefore, companion diagnostic biomarkers can massively improve the diagnostic process, especially when these biomarkers are able to detect MPM at an early stage. Several blood biomarkers, such as mesothelin and fibulin-3, have already been investigated. However, they lack sensitivity and/or specificity, which reduces their clinical utility as diagnostic tools, and urges a continued search for new MPM biomarkers. To this end, we are developing a non-invasive biomarker panel consisting of proteins in exhaled breath condensate (EBC). In the current project we aim to validate this panel.

Researcher(s)

• Promoter: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a cancer caused by historical exposure to asbestos fibres. It is a very aggressive type of cancer characterised by poor prognosis, mainly due to advanced stage diagnosis which limits curative treatment. Currently, MPM diagnosisis based on the histological assessment of pleural effusion fluids or lung biopsies. Such procedures are invasive, often associated with comorbidity and limit the possibility of early diagnosis. Therefore, companion diagnostic biomarkers that can be readily obtained, can massively improve the diagnostic process, especially when these biomarkers are able to detect MPM at an early stage. Analysis of the blood (plasma or serum) proteome may inform on the cancer phenotype, as it integrates all upstream genetic alterations, epigenetic regulations and environmental effects. Several biomarker candidates, such as mesothelin, osteopontin, thioredoxin, high mobility group protein B1 and fibulin‐3, have been investigated. However, they all lack sensitivity and/or specificity, reducing their clinical utility as diagnostic tools. As proteins in the blood proteome span a huge range of well over 10 orders of magnitude, the discovery of typically low abundant, potential tumour‐specific markers is hindered as such proteins are overshadowed by the most abundant blood proteins such as albumin. Tissue leakage proteins in particular are worth investigating as these proteins normally reside and function within cells, but can get released into the bloodstream as a result of cell death (due to tissue damage). To identify such low abundant tissue leakage proteins as proxies for lung diseases, we have applied a new proteomics approach which combines the isolation of low abundant proteins originating from cancer cells (tissue leakage proteins) with sensitive mass spectrometry‐based analysis. This approach allowed to improve the current detection limits of cancer‐related low abundant proteins in plasma samples. With this approach, we characterised a potential diagnostic biomarker panel based upon 161 plasma samples from MPM patients (n=46), asbestos‐exposed individuals (HAE; n=59), individuals with benign asbestos related disease (BARD; n=40) and healthy controls (HC; n=16). In this current follow‐up study, we aim to validate this biomarker panel and prepare it for large‐scale prospective clinical studies.

Researcher(s)

• Promoter: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

This project wants to take the next steps in volatomic research where it will not only be the aim to associate volatile organic compounds (VOCs) to pathology but also identify them and link their presence to the mechanisms that drive pathogenesis. This will involve the development and optimization of in vitro sampling tools for cell lines, tissues and animal studies. Research will focus upon assessing the value of the microbiome and inflammation on the volatile composition by studying the effects of pro- and antibiotics in a population of patients with irritable bowel syndrome and the role of volatiles at the intensive care unit for detecting inflammation. As carcinogenesis is related to both tumour-associated inflammation and an upregulated metabolism, the field of thoracic oncology will be explored, by validating and identifying volatiles found in the in vivo situation, developing, and optimizing in vitro headspace samplers and mice breath samplers allowing translational and basic research to be performed and to study VOC dynamics by treating cells and mice with chemo- and immunotherapy or induce pathway blockage. Lastly, the role of VOCs will be explored as early markers for health effects after exposure to environmental pollutants. This will help determine the effect of preventive measures and new safety threshold for exposure levels, which is expected to have a major societal impact. Ultimately, this project will generate a platform to integrate clinical and translational volatomics as central research field not only within LEMP but will also be accessible for all faculties and research groups interested at the university, thereby stimulating intra- and inter-university, and international collaborations.

Researcher(s)

• Promoter: Lamote Kevin
• Fellow: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project website

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer of the pleural lining of the thoracic cavity, mainly caused by historical asbestos exposure. MPM is characterised by a long latency period (30-50 years) between initial asbestos exposure and diagnosis; the latter often delayed due to nonspecific symptoms which manifest at advanced stage. This delay leaves patients with a poor prognosis, with a median survival of 9-11 months. In recent years, immune checkpoint blockade (ICB) therapy emerged as a promising treatment modality for MPM. Unfortunately, despite an improvement in the outcome of ICB responders, the number of responders remains low, urging the need for predictive biomarkers. To this end, a new type of biomarker, volatile organic compounds (VOCs), has been discovered in exhaled breath. Preliminary work showed that VOCs could differentiate 12 responders from 6 non-responders to MPM treatment (chemo- and immunotherapy) with 89% accuracy. However, whether these differences in VOCs arise from treatment itself or if they reflect the tumour's response to treatment is yet to be determined. The goal of this research is hence to investigate the dynamics of these biomarkers in MPM mice treated with ICB and correlating their presence with specific immune profiles. The origin of the VOCs could be determined and mechanistically linked to immune responses and ultimately lead to a non-invasive test to optimize personalised therapy.

Researcher(s)

• Promoter: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Volatile and semivolatile chemicals are recognised as byproducts of disease, boosting volatile analysis as paramount instrument to monitor health and disease, personalize health care and objectively establish the effect of different treatment strategies. Next to volatile organic compounds (VOCs), semivolatile compounds (SVOCS) are present in the environment and in biological matrices, but most of them need to be chemically and structurally identified and their role in health and disease is yet to be explored. In this proposal, we describe the set-up of a highend GCxGC-QTOF-MS facility for analysis of VOCs and SVOCs in biological samples like breath, blood, urine, faeces of humans and animals, and in the headspace of cells. The goal is to set up an infrastructure that allows to assess and investigate multiple biological sample types and their headspace for monitoring health and disease, to identify disease biomarkers, to intensify research on the environmental health issues of modern life, and to tackle the hurdles presently encountered in the metabolomics analysis of steroids and small organic acids. By this means, we intend to team up and complement with international volatomics research groups. In Flanders, such a specialised facility is lacking, and will be unique. It combines high sensitivity, ultralow detection limits for analysis and validation of the molecular composition of biological and headspace samples, with specific sampling devices and advanced data processing.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Covaci Adrian
• Co-promoter: Lamote Kevin
• Co-promoter: Lapperre Therese
• Co-promoter: Laukens Kris
• Co-promoter: Samson Roeland
• Co-promoter: van Meerbeeck Jan
• Co-promoter: van Nuijs Alexander
• Co-promoter: Wouters An

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Particulate matter (PM) and black carbon (BC) exposure pose a major environmental risk factor to our health, since it is estimated to have caused 4.2 million premature deaths in 2016. Although a significant amount of research has been invested in determining health effects related to air pollution on adults, still relatively few research exists on the most vulnerable part of the population, namely children. More specifically, research is missing on acute responses on respiratory functioning (RF) and on neurobehavioral abilities (NBA) of children due to PM and BC pollution. Children's exposure to atmospheric pollution is of special concern because their immune system, lungs and neuropsychological abilities are not fully developed yet when exposure begins, raising the possibility of more severe health outcomes than observed in adults. This project aims at determining the acute impacts of (dynamic) air pollution exposure on healthy children's RF and NBA. To do so, this project will conduct a monitoring campaign at the school and home environment of children of age 9-11, to evaluate PM and BC exposure and its short-term effect on RF and NBA. In extend, the project will combine high-resolution air quality monitoring of PM and BC using mobile sensors, with early RF and NBA responses, in order to monitor students on their way to and from school. With changes in behavior and a shift in transport modes, we then aim to observe possible changes in effects on RF and NBA.

Researcher(s)

• Promoter: Samson Roeland
• Co-promoter: Lamote Kevin
• Co-promoter: Verhulst Stijn
• Fellow: Hendrickx Hanne

Research team(s)

• Biobased sustainability engineering (SUSTAIN)

Project type(s)

• Research Project

Abstract

The Laboratory of Experimental Medicine and Pediatrics - within the Faculty of Medicine and Health Sciences and closely linked to the Antwerp University Hospital - focusses its research on the study of inflammation in a clinically relevant context built on interdisciplinary methodologies and collaborations. To remain in the forefront of research we perform ground-breaking experimental, as well as clinical and translational research from bench to bedside and vice versa, using innovative and high-end methodologies including organoids, rodent models, cell cultures, different next-generation omics approaches and clinical trials. We challenge you to write down a project that will have an added value to one of the research lines currently explored at LEMP (www.uantwerpen.be/en/research-groups/lemp) and briefly described below. Loss of mucosal barrier integrity is a significant contributor in the pathophysiology of mucosal inflammatory/infectious diseases (e.g. IBD, gastrointestinal cancers, RSV, COVID-19). The role of transmembrane mucins, as epithelial signalling receptors mediating barrier dysfunction, is poorly understood. Furthermore, the presence of genetic differences in mucin genes can give rise via alternative splicing to a large repertoire of structurally diverse mucin mRNA isoforms encoding similar biological functions or altering protein function resulting in progression towards disease. Currently, the mucin mRNA isoform landscape implicated in mucosal barrier dysfunction is a field to discover. Volatile organic compounds (VOCs) are compounds that are by-products of cell metabolism and induced by inflammation. The human body houses thousands of VOCs which are exhaled and can serve as non-invasive markers for disease. Hence, breathomics is applied to search for clinically relevant diagnostic, prognostic and predictive biomarkers for inflammation-related diseases in adults and children (thoracic cancers, COVID-19, asthma, COPD, BPD in neonates, gastrointestinal diseases) and to monitor the effect of air pollution on human health. However, there is a need for further identification and data mining of volatiles, linking VOCs to metabolic processes. Chronic low-grade inflammation is a key factor in obesity. As its treatment remains challenging over all age groups, research focusses on new treatment strategies for obesity, that minimize dropout and weight regain. Pathophysiological processes (hypoxia) that lead to comorbidities like cardiovascular and metabolic morbidity and obstructive sleep apnoea are also of interest. Kidney transplantation is the best treatment for patients with end-stage renal disease. As diagnosis requires invasive procedures, there is a need of sensitive, non-invasive markers of an early-stage acute rejection and the early diagnosis of glomerular damage in children and adults with various underlying diseases (diabetes, obesity or sickle cell anaemia). Visceral pain is a key feature of the gastrointestinal disorders IBD and IBS. The management of visceral hypersensitivity is challenging and requires further research towards new treatment targets. Unravelling the immunopathogenesis of chronic Hepatitis B infections is essential in the quest for novel treatment approaches. While the ineffective T-cell responses are well-known, B cells have been left largely understudied, urging a deeper understanding of the role of the humoral immune response in chronic HBV at the level of HBV-specific antibody production and of the phenotypic/functional level of B cells. Non-Alcoholic Fatty Liver Disease (NAFLD) is the global leading cause of chronic liver disease but pharmacological treatment remains poorly successful. Changes in liver hemodynamics and in parenchymal oxygenation contribute to the steatohepatitis and progressive disease worsening and are a potential drugable target. Furthermore, the role of NAFLD on extrahepatic vascular alterations contributing to cardiovascular disease warrants further study.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Lamote Kevin
• Co-promoter: Ledeganck Kristien
• Co-promoter: Smet Annemieke
• Co-promoter: Van Eyck Annelies
• Fellow: Oosterlinck Baptiste

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Exposure to air pollution is an important public health issue and has been associated with burden of disease, and increased mortality and morbidity. However, there is no safe threshold under which no health effects occur and only associations have been found so far. The goal of this pilot project is to prove the causal relation by assessing the impact of air pollution exposure on health and respiratory functioning, by combining air pollution monitoring with lung response measurements and exhaled breath analysis in order to minimize morbidity.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Co-promoter: De Winter Benedicte
• Co-promoter: Lamote Kevin
• Co-promoter: Lapperre Therese
• Co-promoter: Samson Roeland

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Particulate matter (PM) and black carbon (BC) exposure is a major environmental risk factor to our health since it is estimated to have caused 4.2 million premature deaths in 2016. Although a significant amount of research has been invested in determining health effects related to air pollution on adults, still relatively few research exists on the most vulnerable part of the population, namely children. More specifically, research is missing on acute responses on respiratory functioning (RF) and on neurobehavioral abilities (NBA) of children due to PM and BC pollution. Children's exposure to atmospheric pollution is of special concern because their immune system, lungs and neuropsychological abilities are not fully developed yet when exposure begins, raising the possibility of more severe health outcomes than observed in adults. This project aims at determining the acute impacts of (dynamic) air pollution exposure on children's RF and NBA. To do so, this project will conduct a monitoring campaign at the school and home environment of children of age 9-11, to evaluate the exposure to PM and BC and its short-term effect on RF and NBA. In extent, the project will combine high-resolution air quality monitoring of PM and BC using mobile sensors, with early RFand NBA responses, in order to monitor students on their way to and from school. With changes in behavior and a shift in transport modes, we then aim to observe possible changes in effects on RF and NBA.

Researcher(s)

• Promoter: Samson Roeland
• Co-promoter: Lamote Kevin
• Co-promoter: Verhulst Stijn
• Fellow: Hendrickx Hanne

Research team(s)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Fellow: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Fellow: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Lamote Kevin

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project