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Citations: 1319
H-Index: 18
i10-index: 28
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2021
Boullosa, Laurie Freire; Loenhout, Jinthe Van; Flieswasser, Tal; Waele, Jorrit De; Hermans, Christophe; Lambrechts, Hilde; Cuypers, Bart; Laukens, Kris; Bartholomeus, Esther; Siozopoulou, Vasiliki; Vos, Winnok H De; Peeters, Marc; Smits, Evelien L J; Deben, Christophe
In: Redox Biology, pp. 101949, 2021, ISSN: 2213-2317.
@article{BOULLOSA2021101949,
title = {Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer},
author = {Laurie Freire Boullosa and Jinthe Van Loenhout and Tal Flieswasser and Jorrit De Waele and Christophe Hermans and Hilde Lambrechts and Bart Cuypers and Kris Laukens and Esther Bartholomeus and Vasiliki Siozopoulou and Winnok H De Vos and Marc Peeters and Evelien L J Smits and Christophe Deben},
url = {https://www.sciencedirect.com/science/article/pii/S2213231721000975},
doi = {https://doi.org/10.1016/j.redox.2021.101949},
issn = {2213-2317},
year = {2021},
date = {2021-01-01},
journal = {Redox Biology},
pages = {101949},
abstract = {Auranofin (AF) is an FDA-approved antirheumatic drug with anticancer properties that acts as a thioredoxin reductase 1 (TrxR) inhibitor. The exact mechanisms through which AF targets cancer cells remain elusive. To shed light on the mode of action, this study provides an in-depth analysis on the molecular mechanisms and immunogenicity of AF-mediated cytotoxicity in the non-small cell lung cancer (NSCLC) cell line NCI-H1299 (p53 Null) and its two isogenic derivates with mutant p53 R175H or R273H accumulation. TrxR is highly expressed in a panel of 72 NSCLC patients, making it a valid druggable target in NSCLC for AF. The presence of mutant p53 overexpression was identified as an important sensitizer for AF in (isogenic) NSCLC cells as it was correlated with reduced thioredoxin (Trx) levels in vitro. Transcriptome analysis revealed dysregulation of genes involved in oxidative stress response, DNA damage, granzyme A (GZMA) signaling and ferroptosis. Although functionally AF appeared a potent inhibitor of GPX4 in all NCI-H1299 cell lines, the induction of lipid peroxidation and consequently ferroptosis was limited to the p53 R273H expressing cells. In the p53 R175H cells, AF mainly induced large-scale DNA damage and replication stress, leading to the induction of apoptotic cell death rather than ferroptosis. Importantly, all cell death types were immunogenic since the release of danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation occurred irrespective of (mutant) p53 expression. Finally, we show that AF sensitized cancer cells to caspase-independent natural killer cell-mediated killing by downregulation of several key targets of GZMA. Our data provides novel insights on AF as a potent, clinically available, off-patent cancer drug by targeting mutant p53 cancer cells through distinct cell death mechanisms (apoptosis and ferroptosis). In addition, AF improves the innate immune response at both cytostatic (natural killer cell-mediated killing) and cytotoxic concentrations (dendritic cell maturation).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Houtven, Joris Van; Cuypers, Bart; Meysman, Pieter; Hooyberghs, Jef; Laukens, Kris; Valkenborg, Dirk
Constrained Standardization of Count Data from Massive Parallel Sequencing Journal Article
In: Journal of Molecular Biology, pp. 166966, 2021, ISSN: 0022-2836.
@article{VANHOUTVEN2021166966,
title = {Constrained Standardization of Count Data from Massive Parallel Sequencing},
author = {Joris Van Houtven and Bart Cuypers and Pieter Meysman and Jef Hooyberghs and Kris Laukens and Dirk Valkenborg},
url = {https://www.sciencedirect.com/science/article/pii/S0022283621001674},
doi = {https://doi.org/10.1016/j.jmb.2021.166966},
issn = {0022-2836},
year = {2021},
date = {2021-01-01},
journal = {Journal of Molecular Biology},
pages = {166966},
abstract = {In high-throughput omics disciplines like transcriptomics, researchers face a need to assess the quality of an experiment prior to an in-depth statistical analysis. To efficiently analyze such voluminous collections of data, researchers need triage methods that are both quick and easy to use. Such a normalization method for relative quantitation, CONSTANd, was recently introduced for isobarically-labeled mass spectra in proteomics. It transforms the data matrix of abundances through an iterative, convergent process enforcing three constraints: (I) identical column sums; (II) each row sum is fixed (across matrices) and (III) identical to all other row sums. In this study, we investigate whether CONSTANd is suitable for count data from massively parallel sequencing, by qualitatively comparing its results to those of DESeq2. Further, we propose an adjustment of the method so that it may be applied to identically balanced but differently sized experiments for joint analysis. We find that CONSTANd can process large data sets at well over 1 million count records per second whilst mitigating unwanted systematic bias and thus quickly uncovering the underlying biological structure when combined with a PCA plot or hierarchical clustering. Moreover, it allows joint analysis of data sets obtained from different batches, with different protocols and from different labs but without exploiting information from the experimental setup other than the delineation of samples into identically processed sets (IPSs). CONSTANd’s simplicity and applicability to proteomics as well as transcriptomics data make it an interesting candidate for integration in multi-omics workflows.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hees, Stijn Van; Cuypers, Bart; Bourgeois, Stefan; Groothuismink, Zwier M A; Meysman, Pieter; der Vlies, Pieter Van; de Knegt, Rob; Vonghia, Luisa; Michielsen, Peter; Francque, Sven; Laukens, Kris; Boonstra, Andre; Vanwolleghem, Thomas
Sorted B cell transcriptomes point towards actively regulated B cell responses during ongoing chronic hepatitis B infections Journal Article
In: Cellular Immunology, vol. 362, pp. 104283, 2021, ISSN: 0008-8749.
@article{VANHEES2021104283,
title = {Sorted B cell transcriptomes point towards actively regulated B cell responses during ongoing chronic hepatitis B infections},
author = {Stijn Van Hees and Bart Cuypers and Stefan Bourgeois and Zwier M A Groothuismink and Pieter Meysman and Pieter Van der Vlies and Rob de Knegt and Luisa Vonghia and Peter Michielsen and Sven Francque and Kris Laukens and Andre Boonstra and Thomas Vanwolleghem},
url = {https://www.sciencedirect.com/science/article/pii/S0008874921000022},
doi = {https://doi.org/10.1016/j.cellimm.2021.104283},
issn = {0008-8749},
year = {2021},
date = {2021-01-01},
journal = {Cellular Immunology},
volume = {362},
pages = {104283},
abstract = {The natural course of chronic hepatitis B virus (HBV) infections follows distinct clinical disease phases, characterized by fluctuating levels of serum HBV DNA and ALT. The immune cells and their features that govern these clinical disease transitions remain unknown. In the current study, we performed RNA sequencing on purified B cells from blood (n = 42) and liver (n = 10) of healthy controls and chronic HBV patients. We found distinct gene expression profiles between healthy controls and chronic HBV patients, as evidenced by 190 differentially expressed genes (DEG), but also between the clinical phenotypes of a chronic HBV infection (17\textendash110 DEG between each phase). Numerous immune pathways, including the B cell receptor pathway were upregulated in liver B cells when compared to peripheral B cells. Further investigation of the detected DEG suggested an activation of B cells during HBeAg seroconversion and an active regulation of B cell signalling in the liver.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2020
Adriaensen, Wim; Cuypers, Bart; Cordero, Carlota F; Mengasha, Bewketu; Blesson, Séverine; Cnops, Lieselotte; Kaye, Paul M; Alves, Fabiana; Diro, Ermias; van Griensven, Johan
Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV Journal Article
In: EBioMedicine, vol. 55, 2020, ISSN: 2352-3964.
@article{Adriaensen2020,
title = {Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV},
author = {Wim Adriaensen and Bart Cuypers and Carlota F Cordero and Bewketu Mengasha and S\'{e}verine Blesson and Lieselotte Cnops and Paul M Kaye and Fabiana Alves and Ermias Diro and Johan van Griensven},
url = {https://doi.org/10.1016/j.ebiom.2020.102748},
doi = {10.1016/j.ebiom.2020.102748},
issn = {2352-3964},
year = {2020},
date = {2020-05-01},
journal = {EBioMedicine},
volume = {55},
publisher = {Elsevier},
abstract = {BackgroundVisceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients during treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2018
Krivoshiev, Boris V; Beemster, Gerrit T S; Sprangers, Katrien; Cuypers, Bart; Laukens, Kris; Blust, Ronny; Husson, Steven J
Toxicogenomics of the flame retardant tris (2-butoxyethyl) phosphate in HepG2 cells using RNA-seq Journal Article
In: Toxicology in Vitro, vol. 46, pp. 178 - 188, 2018, ISSN: 0887-2333.
@article{KRIVOSHIEV2018178,
title = {Toxicogenomics of the flame retardant tris (2-butoxyethyl) phosphate in HepG2 cells using RNA-seq},
author = {Boris V Krivoshiev and Gerrit T S Beemster and Katrien Sprangers and Bart Cuypers and Kris Laukens and Ronny Blust and Steven J Husson},
url = {http://www.sciencedirect.com/science/article/pii/S0887233317303089},
doi = {https://doi.org/10.1016/j.tiv.2017.10.011},
issn = {0887-2333},
year = {2018},
date = {2018-01-01},
journal = {Toxicology in Vitro},
volume = {46},
pages = {178 - 188},
abstract = {Tris (2-butoxyethyl) phosphate (TBOEP) is a compound produced at high volume that is used as both a flame retardant and a plasticizer. It is persistent and bioaccumulative, yet little is known of its toxicological modes of action. Such insight may aid risk assessment in a weight-of-evidence approach supplementing current testing strategies. We used an RNA sequencing approach as an unbiased and sensitive tool to explore potential negative health effects of sub-cytotoxic concentrations of TBOEP on the transcriptome of the human liver hepatocellular carcinoma cell line, HepG2, with the lowest concentration used potentially holding relevance to human physiological levels. Over-representation and gene set enrichment analysis corresponded well and revealed that TBOEP treatments resulted in an upregulation of genes involved in protein and energy metabolism, along with DNA replication. Such increases in cell and macromolecule metabolism could explain the increase in mitochondrial activity at lower TBOEP concentrations. In addition, TBOEP affected a wide variety of biological processes, the most notable one being the general stress response, wound healing. Finally, TBOEP showed effects on steroid hormone biosynthesis and activation, regulation, and potentiation of immune responses, in agreement with other studies. As such, this study is the first study investigating genome-wide changes in gene transcription in response to TBOEP in human cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cuypers, Bart
A systems biology approach for a comprehensive understanding of molecular adaptation in** Leishmania donovani PhD Thesis
University of Antwerp, 2018.
@phdthesis{cuypers2018systems,
title = {A systems biology approach for a comprehensive understanding of molecular adaptation in** Leishmania donovani},
author = {Bart Cuypers},
year = {2018},
date = {2018-01-01},
school = {University of Antwerp},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Dumetz, F; Cuypers, B; Imamura, H; Zander, D; DtextquoterightHaenens, E; Maes, I; Domagalska, M A; Clos, J; Dujardin, J -C; Muylder, G De
Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent Journal Article
In: mSphere, vol. 3, no. 2, 2018.
@article{Dumetze00548-17,
title = {Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent},
author = {F Dumetz and B Cuypers and H Imamura and D Zander and E D{textquoteright}Haenens and I Maes and M A Domagalska and J Clos and J -C Dujardin and G De Muylder},
editor = {Margaret Phillips},
url = {https://msphere.asm.org/content/3/2/e00548-17},
doi = {10.1128/mSphere.00548-17},
year = {2018},
date = {2018-01-01},
journal = {mSphere},
volume = {3},
number = {2},
publisher = {American Society for Microbiology Journals},
abstract = {Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL). Now abandoned in the Indian subcontinent (ISC) because of Leishmania donovani resistance, this drug offers a unique model for understanding drug resistance dynamics. In a previous phylogenomic study, we found two distinct populations of L. donovani: the core group (CG) in the Gangetic plains and ISC1 in the Nepalese highlands. Sb resistance was only encountered within the CG, and a series of potential markers were identified. Here, we analyzed the development of resistance to trivalent antimonials (SbIII) upon experimental selection in ISC1 and CG strains. We observed that (i) baseline SbIII susceptibility of parasites was higher in ISC1 than in the CG, (ii) time to SbIII resistance was higher for ISC1 parasites than for CG strains, and (iii) untargeted genomic and metabolomic analyses revealed molecular changes along the selection process: these were more numerous in ISC1 than in the CG. Altogether these observations led to the hypothesis that CG parasites are preadapted to SbIII resistance. This hypothesis was experimentally confirmed by showing that only wild-type CG strains could survive a direct exposure to the maximal concentration of SbIII. The main driver of this preadaptation was shown to be MRPA, a gene involved in SbIII sequestration and amplified in an intrachromosomal amplicon in all CG strains characterized so far. This amplicon emerged around 1850 in the CG, well before the implementation of antimonials for VL chemotherapy, and we discuss here several hypotheses of selective pressure that could have accompanied its emergence.IMPORTANCE The textquotedblleftantibiotic resistance crisistextquotedblright is a major challenge for scientists and medical professionals. This steady rise in drug-resistant pathogens also extends to parasitic diseases, with antimony being the first anti-Leishmania drug that fell in the Indian subcontinent (ISC). Leishmaniasis is a major but neglected infectious disease with limited therapeutic options. Therefore, understanding how parasites became resistant to antimonials is of commanding importance. In this study, we experimentally characterized the dynamics of this resistance acquisition and show for the first time that some Leishmania populations of the ISC were preadapted to antimony resistance, likely driven by environmental factors or by drugs used in the 19th century.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2017
Cuypers, Bart; Domagalska, Malgorzata A; Meysman, Pieter; de Muylder, Géraldine; Vanaerschot, Manu; Imamura, Hideo; Dumetz, Franck; Verdonckt, Thomas Wolf; Myler, Peter J; Ramasamy, Gowthaman; Laukens, Kris; Dujardin, Jean-Claude
Multiplexed Spliced-Leader Sequencing: A high-throughput, selective method for RNA-seq in Trypanosomatids Journal Article
In: Scientific Reports, vol. 7, no. 1, pp. 3725, 2017, ISSN: 2045-2322.
@article{Cuypers2017,
title = {Multiplexed Spliced-Leader Sequencing: A high-throughput, selective method for RNA-seq in Trypanosomatids},
author = {Bart Cuypers and Malgorzata A Domagalska and Pieter Meysman and G\'{e}raldine de Muylder and Manu Vanaerschot and Hideo Imamura and Franck Dumetz and Thomas Wolf Verdonckt and Peter J Myler and Gowthaman Ramasamy and Kris Laukens and Jean-Claude Dujardin},
url = {https://doi.org/10.1038/s41598-017-03987-0},
doi = {10.1038/s41598-017-03987-0},
issn = {2045-2322},
year = {2017},
date = {2017-06-16},
journal = {Scientific Reports},
volume = {7},
number = {1},
pages = {3725},
abstract = {High throughput sequencing techniques are poorly adapted for in vivo studies of parasites, which require prior in vitro culturing and purification. Trypanosomatids, a group of kinetoplastid protozoans, possess a distinctive feature in their transcriptional mechanism whereby a specific Spliced Leader (SL) sequence is added to the 5textasciiacutexend of each mRNA by trans-splicing. This allows to discriminate Trypansomatid RNA from mammalian RNA and forms the basis of our new multiplexed protocol for high-throughput, selective RNA-sequencing called SL-seq. We provided a proof-of-concept of SL-seq in Leishmania donovani, the main causative agent of visceral leishmaniasis in humans, and successfully applied the method to sequence Leishmania mRNA directly from infected macrophages and from highly diluted mixes with human RNA. mRNA profiles obtained with SL-seq corresponded largely to those obtained from conventional poly-A tail purification methods, indicating both enumerate the same mRNA pool. However, SL-seq offers additional advantages, including lower sequencing depth requirements, fast and simple library prep and high resolution splice site detection. SL-seq is therefore ideal for fast and massive parallel sequencing of parasite transcriptomes directly from host tissues. Since SLs are also present in Nematodes, Cnidaria and primitive chordates, this method could also have high potential for transcriptomics studies in other organisms.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dumetz, F; Imamura, H; Sanders, M; Seblova, V; Myskova, J; Pescher, P; Vanaerschot, M; Meehan, C J; Cuypers, B; Muylder, G De; Späth, G F; Bussotti, G; Vermeesch, J R; Berriman, M; Cotton, J A; Volf, P; Dujardin, J C; Domagalska, M A
In: mBio, vol. 8, no. 3, 2017.
@article{Dumetze00599-17,
title = {Modulation of Aneuploidy in Leishmania donovani during Adaptation to Different In Vitro and In Vivo Environments and Its Impact on Gene Expression},
author = {F Dumetz and H Imamura and M Sanders and V Seblova and J Myskova and P Pescher and M Vanaerschot and C J Meehan and B Cuypers and G De Muylder and G F Sp\"{a}th and G Bussotti and J R Vermeesch and M Berriman and J A Cotton and P Volf and J C Dujardin and M A Domagalska},
editor = {Keith Gull},
url = {https://mbio.asm.org/content/8/3/e00599-17},
doi = {10.1128/mBio.00599-17},
year = {2017},
date = {2017-01-01},
journal = {mBio},
volume = {8},
number = {3},
publisher = {American Society for Microbiology},
abstract = {Aneuploidy is usually deleterious in multicellular organisms but appears to be tolerated and potentially beneficial in unicellular organisms, including pathogens. Leishmania, a major protozoan parasite, is emerging as a new model for aneuploidy, since in vitro-cultivated strains are highly aneuploid, with interstrain diversity and intrastrain mosaicism. The alternation of two life stages in different environments (extracellular promastigotes and intracellular amastigotes) offers a unique opportunity to study the impact of environment on aneuploidy and gene expression. We sequenced the whole genomes and transcriptomes of Leishmania donovani strains throughout their adaptation to in vivo conditions mimicking natural vertebrate and invertebrate host environments. The nucleotide sequences were almost unchanged within a strain, in contrast to highly variable aneuploidy. Although high in promastigotes in vitro, aneuploidy dropped significantly in hamster amastigotes, in a progressive and strain-specific manner, accompanied by the emergence of new polysomies. After a passage through a sand fly, smaller yet consistent karyotype changes were detected. Changes in chromosome copy numbers were correlated with the corresponding transcript levels, but additional aneuploidy-independent regulation of gene expression was observed. This affected stage-specific gene expression, downregulation of the entire chromosome 31, and upregulation of gene arrays on chromosomes 5 and 8. Aneuploidy changes in Leishmania are probably adaptive and exploited to modulate the dosage and expression of specific genes; they are well tolerated, but additional mechanisms may exist to regulate the transcript levels of other genes located on aneuploid chromosomes. Our model should allow studies of the impact of aneuploidy on molecular adaptations and cellular fitness.IMPORTANCE Aneuploidy is usually detrimental in multicellular organisms, but in several microorganisms, it can be tolerated and even beneficial. Leishmania\textemdasha protozoan parasite that kills more than 30,000 people each year\textemdashis emerging as a new model for aneuploidy studies, as unexpectedly high levels of aneuploidy are found in clinical isolates. Leishmania lacks classical regulation of transcription at initiation through promoters, so aneuploidy could represent a major adaptive strategy of this parasite to modulate gene dosage in response to stressful environments. For the first time, we document the dynamics of aneuploidy throughout the life cycle of the parasite, in vitro and in vivo. We show its adaptive impact on transcription and its interaction with regulation. Besides offering a new model for aneuploidy studies, we show that further genomic studies should be done directly in clinical samples without parasite isolation and that adequate methods should be developed for this.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}