A5073778392- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Alzheimer's disease research and treatments
- ATP Synthase and ATPases Research
- Hemoglobin structure and function
- Neonatal Health and Biochemistry
- Peptidase Inhibition and Analysis
- Metabolomics and Mass Spectrometry Studies
- Neuroscience and Neuropharmacology Research
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Heme Oxygenase-1 and Carbon Monoxide
- Intensive Care Unit Cognitive Disorders
- Ubiquitin and proteasome pathways
- Chemical Synthesis and Analysis
- Clinical Nutrition and Gastroenterology
- Glycosylation and Glycoproteins Research
- Cardiovascular Effects of Exercise
- Neurological diseases and metabolism
- Glycogen Storage Diseases and Myoclonus
- Liver Disease and Transplantation
- Autophagy in Disease and Therapy
KU Leuven
2018-2025
VIB-KU Leuven Center for Cancer Biology
2018-2025
St George's, University of London
2023
Abzena (United Kingdom)
2015-2022
Babraham Institute
2017-2022
UCLouvain
2016-2017
The University of Melbourne
2012-2015
Murdoch Children's Research Institute
2012-2015
Helsinki Children's Hospital
2015
University of Helsinki
2015
To improve both the homogeneity and stability of ADCs, we have developed site-specific drug-conjugating reagents that covalently rebridge reduced disulfide bonds. The new comprise a drug, linker, bis-reactive conjugating moiety is capable undergoing reaction with sulfur atoms derived from bond in antibodies antibody fragments. A rebridging reagent comprising monomethyl auristatin E (MMAE) was prepared conjugated to trastuzumab (TRA). 78% conversion ADC drug ratio (DAR) 4 achieved no...
Neuronal development in the human cerebral cortex is considerably prolonged compared with that of other mammals. We explored whether mitochondria influence species-specific timing cortical neuron maturation. By comparing and mouse neuronal maturation at high temporal cell resolution, we found a slower neurons mouse, together lower metabolic activity, particularly oxidative phosphorylation. Stimulation metabolism resulted accelerated vitro vivo, leading to cells weeks ahead time, whereas its...
Genetic, clinical, histopathological and biomarker data strongly support Beta-amyloid (Aβ) induced spreading of Tau-pathology beyond entorhinal cortex (EC), as a crucial process in conversion from preclinical cognitively normal to Alzheimer's Disease (AD), while the underlying mechanism remains unclear. In vivo models have reproducibly recapitulated Aβ-induced Tau-pathology. Tau pathology was thereby also by aggregated Aβ, functionally connected brain areas, reminiscent prion-like seeding...
Background Frameshift mutations in microsatellite instability high (MSI-High) colorectal cancers are a potential source of targetable neo-antigens. Many nonsense transcripts subject to rapid degradation due nonsense-mediated decay (NMD), but with cMS the last exon or near exon-exon junction have intrinsic resistance (NMD). NMD-resistant therefore likely expressed mutant proteins MSI-High tumours. Methods Using antibodies conserved N-termini predicted proteins, we analysed cancer cell lines...
The conjugation of monomethyl auristatin E (MMAE) to trastuzumab using a reduction bis-alkylation approach that is capable rebridging reduced (native) antibody interchain disulfide bonds has been previously shown produce homogeneous and stable conjugate with drug-to-antibody ratio (DAR) 4 as the major product. Here, we further investigate potency DAR conjugates prepared by comparing lower drug loaded variants maleimide linker based possessing typical mixed profiles. Serum stability, HER2...
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 exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism extracellular nutrients than developmental regulators. Specifically, we increasing amino acids beyond the nutritional need of HLCs HepG2 induces glucose...
The efficacy of protein-based medicines can be compromised by their rapid clearance from the blood circulatory system. Achieving optimal pharmacokinetics is a key requirement for successful development safe medicines. Protein PEGylation clinically proven strategy to increase circulation half-life One limitation that there are few strategies achieve site-specific conjugation PEG protein. Here, we describe covalent site-specifically polyhistidine tag (His-tag) on His-tag was achieved with...
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 investigate whether metabolic rewiring reinstates their phagocytic inflammatory capacity.Following phenotypic characterisation, performed RNA sequencing on CD14+CD16- from decompensated alcoholic cirrhosis. Additionally, an vitro model mimicking...
Primary mitochondrial diseases (PMD) are a large, heterogeneous group of genetic disorders affecting function, mostly by disrupting the oxidative phosphorylation (OXPHOS) system. Understanding cellular metabolic re-wiring occurring in PMD is crucial for development novel diagnostic tools and treatments, as often complex to diagnose most them currently have no effective therapy.To characterize consequences OXPHOS dysfunction based on signature, design new therapeutic strategies.In vitro...
Mitochondrial dysfunction plays a pivotal role in the progression of Alzheimer's disease (AD), and yet mechanisms underlying impairment mitochondrial function AD remain elusive. Recent evidence suggested for Presenilins (PS1 or PS2) function. Mutations PSs, catalytic subunits γ-secretase complex, are responsible majority inherited cases (FAD). PSs were shown to be present mitochondria particularly enriched mitochondria-associated membranes (MAM), where PS2 is involved calcium shuttling...
Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is broad transcription regulator. It essential in Drosophila, and haploinsufficiency human KANSL1 subunit results Koolen-de Vries syndrome. Here, we perform genome-wide RNAi screen identify BET protein BRD4 as an evolutionary conserved co-factor NSL complex. Using...
Inherited metabolic disorders (IMDs) are genetic that occur in as many 1:2500 births worldwide. Nevertheless, they quite rare individually and even more is the co-occurrence of two IMDs one individual. To better understand cross-talk between glycosylation changes deficient energy metabolism, its potential effect on outcomes, we evaluated patient fibroblasts with likely pathogenic variants PGM1 NDUFA13 derived from a who passed away at 16 years age. The presented characteristic PGM1-CDG...
Friedreich ataxia (FRDA) is an autosomal recessive disease characterised by neurodegeneration and cardiomyopathy that caused insufficiency of the mitochondrial protein, frataxin. Our previous studies described generation FRDA induced pluripotent stem cell lines (FA3 FA4 iPS) retained genetic characteristics this disease. Here we extend these studies, showing neural derivatives FA iPS cells are able to differentiate into functional neurons, which don't show altered susceptibility death, have...
Cystic fibrosis (CF) is a life-threatening disorder characterised by decreased pulmonary mucociliary and pathogen clearance, an exaggerated inflammatory response leading to progressive lung damage. CF caused bi-allelic pathogenic variants of the cystic transmembrane conductance regulator (CFTR) gene, which encodes chloride channel. CFTR expressed in endothelial cells (ECs) EC dysfunction has been reported patients, but role for this ion channel ECs regarding disease progression poorly...
Abstract The T61I mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a protein residing the mitochondrial intermembrane space (IMS), causes an autosomal dominant form of Parkinson’s disease (PD), but underlying pathogenic mechanisms are not well understood. Here, we compared subcellular localization and solubility wild-type (WT) mutant CHCHD2 human cells. We found that targeting both WT depended on four cysteine residues C-terminal (CHCH) N-terminal predicted...
Mitochondrial dysfunction causes a range of early-onset neurological diseases and contributes to neurodegenerative conditions. The mechanisms damage however are poorly understood, as accessing relevant tissue from patients is difficult, appropriate models limited. Hence, we assessed mitochondrial function in neurologically primary cell lines CI (complex I) deficient Ndufs4 KO (knockout) mouse (Ndufs4fky/fky) modelling aspects the disease LS (Leigh syndrome), well MEFs (mouse embryonic...
Efficient site-specific PEGylation of hemoglobin as a novel component safer blood substitute.
Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals date. As the field matures, much attention has focused upon key factors required produce safe and efficacious ADCs. Recently role that linker-payload reagent design on properties of ADCs been highlighted an important consideration for developers. We investigated effect incorporating hydrophilic macrocycles into structures in vitro vivo behavior Bis-sulfone based...
We identified Mrpl44 in a search for mammalian proteins that contain RNase III domains. This protein was previously found association with the mitochondrial ribosome of bovine liver extracts. However, precise localization had been unclear. Here, we show by immunofluorescence microscopy and subcellular fractionation is localized to matrix mitochondria. it can form multimers, confirm part large subunit ribosome. By manipulating its expression, may be important regulating expression...
Octreotide is increasingly being used in the treatment of acromegaly. It effectively suppresses growth hormone secretion but also has inhibitory effects on gastrointestinal regulatory peptides and induces gallbladder paresis, which may predispose to gallstone formation. In nine acromegalic patients receiving long-term octreotide emptying, assessed by 99Tc-EHIDA scintigraphy after a standard fatty meal, was significantly impaired (p < 0.005) when compared with normal healthy control subjects....