14 results on '"van Mil, Saskia"'
Search Results
2. Identification of FDA-approved drugs targeting the Farnesoid X Receptor
- Author
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van de Wiel, Sandra M W, Bijsmans, Ingrid T G W, van Mil, Saskia W C, van de Graaf, Stan F J, van de Wiel, Sandra M W, Bijsmans, Ingrid T G W, van Mil, Saskia W C, and van de Graaf, Stan F J
- Published
- 2019
3. Farnesoid X receptor and bile acids regulate vitamin A storage
- Author
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CMM Groep Van Mil, Child Health, Cancer, Saeed, Ali, Yang, Jing, Heegsma, Janette, Groen, Albert K., van Mil, Saskia W.C., Paulusma, Coen C., Zhou, Lu, Wang, Bangmao, Faber, Klaas Nico, CMM Groep Van Mil, Child Health, Cancer, Saeed, Ali, Yang, Jing, Heegsma, Janette, Groen, Albert K., van Mil, Saskia W.C., Paulusma, Coen C., Zhou, Lu, Wang, Bangmao, and Faber, Klaas Nico
- Published
- 2019
4. Identification of FDA-approved drugs targeting the Farnesoid X Receptor
- Author
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CMM Groep Van Mil, Cancer, Child Health, van de Wiel, Sandra M W, Bijsmans, Ingrid T G W, van Mil, Saskia W C, van de Graaf, Stan F J, CMM Groep Van Mil, Cancer, Child Health, van de Wiel, Sandra M W, Bijsmans, Ingrid T G W, van Mil, Saskia W C, and van de Graaf, Stan F J
- Published
- 2019
5. The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression
- Author
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Bijsmans, Ingrid T G W, Guercini, Chiara, Ramos Pittol, José M., Omta, Wienand, Milona, Alexandra, Lelieveld, Daphne, Egan, David A., Pellicciari, Roberto, Gioiello, Antimo, van Mil, Saskia W C, Bijsmans, Ingrid T G W, Guercini, Chiara, Ramos Pittol, José M., Omta, Wienand, Milona, Alexandra, Lelieveld, Daphne, Egan, David A., Pellicciari, Roberto, Gioiello, Antimo, and van Mil, Saskia W C
- Published
- 2015
6. The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression
- Author
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CMM Groep Van Mil, UMC Utrecht, CMM Sectie Celbiologie, CMM Cell Screening Center, Cancer, Child Health, Bijsmans, Ingrid T G W, Guercini, Chiara, Ramos Pittol, José M., Omta, Wienand, Milona, Alexandra, Lelieveld, Daphne, Egan, David A., Pellicciari, Roberto, Gioiello, Antimo, van Mil, Saskia W C, CMM Groep Van Mil, UMC Utrecht, CMM Sectie Celbiologie, CMM Cell Screening Center, Cancer, Child Health, Bijsmans, Ingrid T G W, Guercini, Chiara, Ramos Pittol, José M., Omta, Wienand, Milona, Alexandra, Lelieveld, Daphne, Egan, David A., Pellicciari, Roberto, Gioiello, Antimo, and van Mil, Saskia W C
- Published
- 2015
7. Farnesoid X receptor and bile acids regulate vitamin A storage.
- Author
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Saeed A, Yang J, Heegsma J, Groen AK, van Mil SWC, Paulusma CC, Zhou L, Wang B, and Faber KN
- Subjects
- Acyltransferases metabolism, Animals, Bile Acids and Salts metabolism, Chenodeoxycholic Acid analogs & derivatives, Chenodeoxycholic Acid metabolism, Chenodeoxycholic Acid pharmacology, Cholic Acid metabolism, Cholic Acid pharmacology, Hepatocytes drug effects, Hepatocytes metabolism, Mice, Mice, Knockout, Bile Acids and Salts pharmacology, Liver metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Vitamin A metabolism
- Abstract
The nuclear receptor Farnesoid X Receptor (FXR) is activated by bile acids and controls multiple metabolic processes, including bile acid, lipid, carbohydrate, amino acid and energy metabolism. Vitamin A is needed for proper metabolic and immune control and requires bile acids for efficient intestinal absorption and storage in the liver. Here, we analyzed whether FXR regulates vitamin A metabolism. Compared to control animals, FXR-null mice showed strongly reduced (>90%) hepatic levels of retinol and retinyl palmitate and a significant reduction in lecithin retinol acyltransferase (LRAT), the enzyme responsible for hepatic vitamin A storage. Hepatic reintroduction of FXR in FXR-null mice induced vitamin A storage in the liver. Hepatic vitamin A levels were normal in intestine-specific FXR-null mice. Obeticholic acid (OCA, 3 weeks) treatment rapidly reduced (>60%) hepatic retinyl palmitate levels in mice, concurrent with strongly increased retinol levels (>5-fold). Similar, but milder effects were observed in cholic acid (12 weeks)-treated mice. OCA did not change hepatic LRAT protein levels, but strongly reduced all enzymes involved in hepatic retinyl ester hydrolysis, involving mostly post-transcriptional mechanisms. In conclusion, vitamin A metabolism in the mouse liver heavily depends on the FXR and FXR-targeted therapies may be prone to cause vitamin A-related pathologies.
- Published
- 2019
- Full Text
- View/download PDF
8. Identification of FDA-approved drugs targeting the Farnesoid X Receptor.
- Author
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van de Wiel SMW, Bijsmans ITGW, van Mil SWC, and van de Graaf SFJ
- Subjects
- Bile Acids and Salts metabolism, Biosensing Techniques, Cell Line, Drug Approval, Drug Repositioning, Fluorescence Resonance Energy Transfer, High-Throughput Screening Assays, Humans, Isoxazoles chemistry, Isoxazoles pharmacology, Ivermectin analogs & derivatives, Ivermectin chemistry, Ivermectin pharmacology, Ligands, Molecular Structure, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Cytoplasmic and Nuclear metabolism, United States, United States Food and Drug Administration, Receptors, Cytoplasmic and Nuclear agonists
- Abstract
The farnesoid X receptor (FXR) belongs to the nuclear receptor family and is activated by bile acids. Multiple, chemically rather diverse, FXR agonists have been developed and several of these compounds are currently tested in clinical trials for NAFLD and cholestasis. Here, we investigated possible FXR-agonism or antagonism of existing FDA/EMA-approved drugs. By using our recently developed FRET-sensor, containing the ligand binding domain of FXR (FXR-LBD), 1280 FDA-approved drugs were screened for their ability to activate FXR in living cells using flow cytometry. Fifteen compounds induced the sensor for more than twenty percent above background. Real-time confocal microscopy confirmed that avermectin B1a, gliquidone, nicardipine, bepridil and triclosan activated the FRET sensor within two minutes. These compounds, including fluticasone, increased mRNA expression of FXR target genes OSTα and OSTβ in Huh7 cells, and in most cases also of MRP2, SHP and FGF19. Finally, avermectin B1a, gliquidone, nicardipine and bepridil significantly increased IBABP promoter activity in a luciferase reporter assay in a dose-dependent manner. In conclusion, six FDA/EMA-approved drugs currently used in the clinical practice exhibit moderate agonistic FXR activity. This may on the one hand explain (undesired) side-effects, but on the other hand may form an opportunity for polypharmacology.
- Published
- 2019
- Full Text
- View/download PDF
9. Effective CRISPR/Cas9-mediated correction of a Fanconi anemia defect by error-prone end joining or templated repair.
- Author
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van de Vrugt HJ, Harmsen T, Riepsaame J, Alexantya G, van Mil SE, de Vries Y, Bin Ali R, Huijbers IJ, Dorsman JC, Wolthuis RMF, and Te Riele H
- Subjects
- Animals, Cells, Cultured, DNA Repair, Ear, Fibroblasts, Mice, Mouse Embryonic Stem Cells, CRISPR-Cas Systems genetics, Fanconi Anemia genetics, Fanconi Anemia therapy, Fanconi Anemia Complementation Group F Protein genetics, Gene Editing methods, Genetic Therapy methods
- Abstract
Fanconi anemia (FA) is a cancer predisposition syndrome characterized by congenital abnormalities, bone marrow failure, and hypersensitivity to aldehydes and crosslinking agents. For FA patients, gene editing holds promise for therapeutic applications aimed at functionally restoring mutated genes in hematopoietic stem cells. However, intrinsic FA DNA repair defects may obstruct gene editing feasibility. Here, we report on the CRISPR/Cas9-mediated correction of a disruptive mutation in Fancf. Our experiments revealed that gene editing could effectively restore Fancf function via error-prone end joining resulting in a 27% increased survival in the presence of mitomycin C. In addition, templated gene correction could be achieved after double strand or single strand break formation. Although templated gene editing efficiencies were low (≤6%), FA corrected embryonic stem cells acquired a strong proliferative advantage over non-corrected cells, even without imposing genotoxic stress. Notably, Cas9 nickase activity resulted in mono-allelic gene editing and avoidance of undesired mutagenesis. In conclusion: DNA repair defects associated with FANCF deficiency do not prohibit CRISPR/Cas9 gene correction. Our data provide a solid basis for the application of pre-clinical models to further explore the potential of gene editing against FA, with the eventual aim to obtain therapeutic strategies against bone marrow failure.
- Published
- 2019
- Full Text
- View/download PDF
10. Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy number changes.
- Author
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Kooi IE, Mol BM, Massink MP, Ameziane N, Meijers-Heijboer H, Dommering CJ, van Mil SE, de Vries Y, van der Hout AH, Kaspers GJ, Moll AC, Te Riele H, Cloos J, and Dorsman JC
- Subjects
- Humans, Sequence Analysis, DNA, Gene Dosage, Mutation, Retinoblastoma pathology, Retinoblastoma Binding Proteins genetics, Ubiquitin-Protein Ligases genetics
- Abstract
Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control.
- Published
- 2016
- Full Text
- View/download PDF
11. The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression.
- Author
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Bijsmans IT, Guercini C, Ramos Pittol JM, Omta W, Milona A, Lelieveld D, Egan DA, Pellicciari R, Gioiello A, and van Mil SW
- Subjects
- Animals, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacology, Gene Expression, Genes, Reporter, Hep G2 Cells, Humans, Ligands, Mice, Models, Molecular, Molecular Conformation, Molecular Docking Simulation, Mometasone Furoate chemistry, Mometasone Furoate pharmacology, NF-kappa B metabolism, Promoter Regions, Genetic, Protein Binding, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Cytoplasmic and Nuclear genetics, Transcription Factor RelA metabolism, Tumor Necrosis Factor-alpha metabolism, Tumor Necrosis Factor-alpha pharmacology, Gene Expression Regulation drug effects, Inflammation genetics, Inflammation metabolism, Mometasone Furoate metabolism, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
The Farnesoid X receptor (FXR) regulates bile salt, glucose and cholesterol homeostasis by binding to DNA response elements, thereby activating gene expression (direct transactivation). FXR also inhibits the immune response via tethering to NF-κB (tethering transrepression). FXR activation therefore has therapeutic potential for liver and intestinal inflammatory diseases. We aim to identify and develop gene-selective FXR modulators, which repress inflammation, but do not interfere with its metabolic capacity. In a high-throughput reporter-based screen, mometasone furoate (MF) was identified as a compound that reduced NF-κB reporter activity in an FXR-dependent manner. MF reduced mRNA expression of pro-inflammatory cytokines, and induction of direct FXR target genes in HepG2-GFP-FXR cells and intestinal organoids was minor. Computational studies disclosed three putative binding modes of the compound within the ligand binding domain of the receptor. Interestingly, mutation of W469A residue within the FXR ligand binding domain abrogated the decrease in NF-κB activity. Finally, we show that MF-bound FXR inhibits NF-κB subunit p65 recruitment to the DNA of pro-inflammatory genes CXCL2 and IL8. Although MF is not suitable as selective anti-inflammatory FXR ligand due to nanomolar affinity for the glucocorticoid receptor, we show that separation between metabolic and anti-inflammatory functions of FXR can be achieved.
- Published
- 2015
- Full Text
- View/download PDF
12. Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated.
- Author
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Harinck F, Kluijt I, van Mil SE, Waisfisz Q, van Os TA, Aalfs CM, Wagner A, Olderode-Berends M, Sijmons RH, Kuipers EJ, Poley JW, Fockens P, and Bruno MJ
- Subjects
- Adult, Cohort Studies, Fanconi Anemia Complementation Group N Protein, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Prevalence, Breast Neoplasms genetics, Mutation, Nuclear Proteins genetics, Pancreatic Neoplasms genetics, Tumor Suppressor Proteins genetics
- Abstract
PALB2-mutation carriers not only have an increased risk for breast cancer (BC) but also for pancreatic cancer (PC). Thus far, PALB2 mutations have been mainly found in PC patients from families affected by both PC and BC. As it is well known that the prevalence of gene mutations varies between different populations, we studied the prevalence of PALB2 mutations in a Dutch cohort of non-BRCA1/2 familial PC (FPC) families and in non-BRCA1/2 familial BC (FBC) families with at least one PC case. Mutation analysis included direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and was performed in a total of 64 patients from 56 distinct families (28 FPC families, 28 FBC families). In total, 31 patients (48%) originated from FPC families; 24 were FPC patients (77%), 6 had a personal history of BC (19%) and 1 was a suspected carrier (3.2%). The remaining 33 patients (52%) were all female BC patients of whom 31 (94%) had a family history of PC and 2 (6.1%) had a personal history of PC. In none of these 64 patients a PALB2 mutation was found. Therefore, PALB2 does not have a major causal role in familial clustering of PC and BC in non-BRCA1/2 families in the Dutch population.
- Published
- 2012
- Full Text
- View/download PDF
13. Progranulin mutations in Dutch familial frontotemporal lobar degeneration.
- Author
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Bronner IF, Rizzu P, Seelaar H, van Mil SE, Anar B, Azmani A, Donker Kaat L, Rosso S, Heutink P, and van Swieten JC
- Subjects
- Aged, Amino Acid Sequence, Animals, Codon, Nonsense, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Netherlands, Pedigree, Progranulins, Dementia genetics, Frameshift Mutation, Intercellular Signaling Peptides and Proteins genetics, Mutation, Missense
- Abstract
Mutations in the progranulin (PGRN) gene have recently been identified in frontotemporal lobar degeneration with ubiquitin inclusions linked to chromosome 17q21. We report here the finding of two novel frameshift mutations and three possible pathogenic missense mutations in the PGRN gene. Furthermore, we determined the frequency of PGRN mutations in familial cases recruited from a large population-based study of frontotemporal lobar degeneration carried out in The Netherlands.
- Published
- 2007
- Full Text
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14. Fic1 is expressed at apical membranes of different epithelial cells in the digestive tract and is induced in the small intestine during postnatal development of mice.
- Author
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van Mil SW, van Oort MM, van den Berg IE, Berger R, Houwen RH, and Klomp LW
- Subjects
- Animals, Bile Ducts cytology, Bile Ducts growth & development, Bile Ducts physiology, Cell Polarity physiology, Epithelial Cells cytology, Gene Expression Regulation, Developmental, Humans, Intestinal Mucosa cytology, Intestines growth & development, Intestines physiology, Liver growth & development, Liver physiology, Mice, Mice, Inbred C57BL, Pancreas growth & development, Pancreas physiology, Phospholipid Transfer Proteins, Stomach growth & development, Stomach physiology, Adenosine Triphosphatases genetics, Adenosine Triphosphatases metabolism, Epithelial Cells physiology, Intestinal Mucosa growth & development, Intestinal Mucosa physiology
- Abstract
Mutations in ATP8B1 are associated with FIC1 disease, an autosomal recessive disorder in which intrahepatic cholestasis is the predominant manifestation. ATP8B1 encodes FIC1, which is expressed in several tissues, most prominently in the intestine, pancreas, and stomach and, to a much lesser extent, in the liver. In this study, Fic1 localization and expression during postnatal development was examined in healthy mice. Immunoblot and RT-PCR analysis indicated Fic1 is expressed abundantly in regions of the adult gastrointestinal tract of humans and mice. Immunohistochemistry revealed that Fic1 was localized to the apical membranes of enterocytes, pancreatic acinar cells, gastric pit epithelial cells, and hepatocytes and cholangiocytes. Subsequent analysis of early postnatal expression revealed that Fic1 expression in the small intestine was limited or absent at the age of 7 and 14 d and increased significantly with maturation. In contrast, pancreatic, hepatic, and gastric Fic1 expression was not diminished during the first 3 wk of postnatal development. In conclusion, these data show that Fic1 is expressed in a tissue-specific and developmentally regulated fashion at the apical membranes of epithelial cells. We speculate that the developing bile salt pool in the maturing intestine accounts for the increase in Fic1 protein expression in this tissue.
- Published
- 2004
- Full Text
- View/download PDF
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