ORCID Profile
0000-0002-6154-0970
Current Organisation
KU Leuven
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Publisher: BMJ
Date: 22-12-2018
DOI: 10.1136/GUTJNL-2018-316888
Abstract: Acute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity. Following phenotypic characterisation, we performed RNA sequencing on CD14 + CD16 − monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function. Monocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14 + CD16 − monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores. In ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.
Publisher: MDPI AG
Date: 19-09-2014
Publisher: Springer Science and Business Media LLC
Date: 02-2017
DOI: 10.1038/NG0217-317B
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.MAD.2016.07.013
Abstract: The plant-derived decapeptide OSIP108 increases tolerance of yeast and human cells to apoptosis-inducing agents, such as copper and cisplatin. We performed a whole amino acid scan of OSIP108 and conducted structure-activity relationship studies on the induction of cisplatin tolerance (CT) in yeast. The use of cisplatin as apoptosis-inducing trigger in this study should be considered as a tool to better understand the survival-promoting nature of OSIP108 and not for purposes related to anti-cancer treatment. We found that charged residues (Arg, His, Lys, Glu or Asp) or a Pro on positions 4-7 improved OSIP108 activity by 10% or more. The variant OSIP108[G7P] induced the most pronounced tolerance to toxic concentrations of copper and cisplatin in yeast and/or HepG2 cells. Both OSIP108 and OSIP108[G7P] were shown to internalize equally into HeLa cells, but at a higher rate than the inactive OSIP108[E10A], suggesting that the peptides can internalize into cells and that OSIP108 activity is dependent on subsequent intracellular interactions. In conclusion, our studies demonstrated that tolerance/survival-promoting properties of OSIP108 can be significantly improved by single amino acid substitutions, and that these properties are dependent on (an) intracellular target(s), yet to be determined.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2021
DOI: 10.1186/S13023-021-01966-3
Abstract: Acute hepatic porphyria (AHP) is a rare, debilitating disease characterized by potentially life-threatening attacks often resulting in chronic symptoms that negatively impact daily functioning and quality of life. Symptoms of AHP prevent many in iduals from working and achieving lifetime work averages. The aim of this study was to apply a public economic framework to evaluate AHP in Belgium, taking into consideration a broad range of costs that are relevant to government in relation to social benefit payments and lifetime taxes paid. A public economic framework was developed exploring lifetime costs for government attributed to an in idual with AHP and recurrent attacks in Belgium. Work-activity and lifetime direct taxes paid, indirect consumption taxes and requirements for public benefits were estimated based on established clinical pathways for AHP and compared to the general population (GP). The model includes AHP-related healthcare costs and non-AHP healthcare costs for the GP. Lifetime earnings are reduced in an in idual with AHP by €347,802 per person (p.p.), translating to reduced lifetime taxes paid of €183,187 for an AHP in idual compared to the GP. We estimate increased lifetime disability benefit support of €247,242 for an AHP in idual compared to GP. Lifetime healthcare costs for a person with AHP were estimated to be €3,030,316 due to frequent hospitalisations associated with porphyria attacks compared to the GP. The lifetime costs for a person with 12 attacks per annum factoring in transfers, taxes and healthcare costs are estimated to be €3,460,745 p.p. Eliminating AHP attacks after 10 years of active disease, thus, enabling a person to return to work increases lifetime earnings by €224,575 p.p. Increased work activity in such in iduals would generate an estimated €118,284 p.p. over their lifetime. The elimination of AHP attacks could also lead to reductions in disability payments of €179,184 p.p. and healthcare cost savings of €1,511,027 p.p. Due to severe disability resulting from constant attacks, AHP patients with recurrent attacks incur significant public costs. Lifetime taxes paid are reduced as these attacks occur during peak earning and working years. In those patients, reducing AHP attacks can confer significant fiscal benefits for government, including reduced healthcare costs, reduced disability payments and improved tax revenue.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer New York
Date: 13-10-2018
DOI: 10.1007/978-1-4939-8769-6_7
Abstract: Here, we offer you a high-throughput assay to measure the ATP synthesis capacity in cells or isolated mitochondria. More specifically, the assay is linked to the mitochondrial' electron transport chain components of your interest being either through complex I (with or without a linkage to pyruvate dehydrogenase activity), through complex II, or through the electron transport flavoprotein and complex I (β-oxidation of fatty acids).
Publisher: MDPI AG
Date: 10-10-2019
Abstract: Primary mitochondrial disease (PMD) is a large group of genetic disorders directly affecting mitochondrial function. Although next generation sequencing technologies have revolutionized the diagnosis of these disorders, biochemical tests remain essential and functional confirmation of the critical genetic diagnosis. While enzymological testing of the mitochondrial oxidative phosphorylation (OXPHOS) complexes remains the gold standard, oxygraphy could offer several advantages. To this end, we compared the diagnostic performance of both techniques in a cohort of 34 genetically defined PMD patient fibroblast cell lines. We observed that oxygraphy slightly outperformed enzymology for sensitivity (79 ± 17% versus 68 ± 15%, mean and 95% CI), and had a better discriminatory power, identifying 58 ± 17% versus 35 ± 17% as “very likely” for oxygraphy and enzymology, respectively. The techniques did, however, offer synergistic diagnostic prediction, as the sensitivity rose to 88 ± 11% when considered together. Similarly, the techniques offered varying defect specific information, such as the ability of enzymology to identify isolated OXPHOS deficiencies, while oxygraphy pinpointed PDHC mutations and captured POLG mutations that were otherwise missed by enzymology. In summary, oxygraphy provides useful information for the diagnosis of PMD, and should be considered in conjunction with enzymology for the diagnosis of PMD.
Publisher: European Respiratory Society (ERS)
Date: 12-11-2020
DOI: 10.1183/13993003.00261-2020
Abstract: Cystic fibrosis (CF) is a life-threatening disorder characterised by decreased pulmonary mucociliary and pathogen clearance, and an exaggerated inflammatory response leading to progressive lung damage. CF is caused by bi-allelic pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel. CFTR is expressed in endothelial cells (ECs) and EC dysfunction has been reported in CF patients, but a role for this ion channel in ECs regarding CF disease progression is poorly described. We used an unbiased RNA sequencing approach in complementary models of CFTR silencing and blockade (by the CFTR inhibitor CFTRinh-172) in human ECs to characterise the changes upon CFTR impairment. Key findings were further validated in vitro and in vivo in CFTR-knockout mice and ex vivo in CF patient-derived ECs. Both models of CFTR impairment revealed that EC proliferation, migration and autophagy were downregulated. Remarkably though, defective CFTR function led to EC activation and a persisting pro-inflammatory state of the endothelium with increased leukocyte adhesion. Further validation in CFTR-knockout mice revealed enhanced leukocyte extravasation in lung and liver parenchyma associated with increased levels of EC activation markers. In addition, CF patient-derived ECs displayed increased EC activation markers and leukocyte adhesion, which was partially rescued by the CFTR modulators VX-770 and VX-809. Our integrated analysis thus suggests that ECs are no innocent bystanders in CF pathology, but rather may contribute to the exaggerated inflammatory phenotype, raising the question of whether normalisation of vascular inflammation might be a novel therapeutic strategy to ameliorate the disease severity of CF.
Publisher: Oxford University Press (OUP)
Date: 24-06-2008
DOI: 10.1093/BRAIN/AWN113
Publisher: Elsevier BV
Date: 04-2019
Publisher: Springer Science and Business Media LLC
Date: 13-03-2020
DOI: 10.1038/S41467-020-15058-6
Abstract: Predicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma cells exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism and extracellular nutrients than on developmental regulators. Specifically, we demonstrate that increasing extracellular amino acids beyond the nutritional need of HLCs and HepG2 cells induces glucose independence, mitochondrial function, and the acquisition of a transcriptional profile that is closer to PHHs. Moreover, we show that these high levels of amino acids are sufficient to drive HLC and HepG2 drug biotransformation and liver-toxin sensitivity to levels similar to those in PHHs. In conclusion, we provide data indicating that extracellular nutrient levels represent a major determinant of cellular maturity and can be utilized to guide stem cell differentiation to the hepatic lineage.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2016
DOI: 10.1038/NG.3661
Publisher: Elsevier BV
Date: 05-2019
No related grants have been discovered for David Cassiman.