References of "Willems, Luc"
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See detailPhysiological and bio-functional properties of gum arabic: a notable interest for certain human diseases
Eloundou Mballa, Pierre; Goffin, Dorothée ULg; Destain, Jacqueline ULg et al

in Biotechnologie, Agronomie, Société et Environnement = Biotechnology, Agronomy, Society and Environment [=BASE] (in press)

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See detailImprovement of malignant pleural mesothelioma immunotherapy by epigenetic modulators
Hamaïdia, Malik ULg; Staumont, Bernard ULg; DUYSINX, Bernard ULg et al

in Current Topics in Medicinal Chemistry (2016), 16

In the absence of a satisfactory treatment of malignant pleural mesothelioma (MPM), novel therapeutic strategies are urgently needed. Among these, immunotherapy offers a series of advantages such as tumor ... [more ▼]

In the absence of a satisfactory treatment of malignant pleural mesothelioma (MPM), novel therapeutic strategies are urgently needed. Among these, immunotherapy offers a series of advantages such as tumor specificity and good tolerability. Unfortunately, MPM immunotherapy is frequently limited by incomplete cell differentiation or feedback loop regulatory mechanisms. In this review, we describe different components of the innate immune system and discuss strategies to improve MPM immunotherapy by using epigenetic modulators. [less ▲]

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See detailRecent advances in BLV research
Barez, Pierre-Yves ULg; De Brogniez, Alix ULg; Carpentier, Alexandre ULg et al

in Viruses (2015), 7(11), 6080-6088

Different animal models have been proposed to investigate the mechanisms of HTLV-induced pathogenesis: rats, transgenic and NOD-SCID/γcnull (NOG) mice, rabbits, squirrel monkeys, baboons and macaques ... [more ▼]

Different animal models have been proposed to investigate the mechanisms of HTLV-induced pathogenesis: rats, transgenic and NOD-SCID/γcnull (NOG) mice, rabbits, squirrel monkeys, baboons and macaques. These systems indeed provide useful information but have intrinsic limitations such as lack of disease relevance, species specificity or inadequate immune response. Another strategy based on a comparative virology approach is to characterize a related pathogen and to speculate on possible shared mechanisms. In this perspective, bovine leukemia virus (BLV), another member of the deltaretrovirus genus, is evolutionary related to HTLV-1. BLV induces lymphoproliferative disorders in ruminants providing useful information on the mechanisms of viral persistence, genetic determinants of pathogenesis and potential novel therapies. [less ▲]

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See detailValproic acid improves second-line regimen of small cell lung carcinoma in preclinical models
Hubaux, Roland; Vandermeers, Fabian; Cosse, Jean-Philippe et al

in European Respiratory Society (2015), 1(2), 00028

With 5-year survival rates below 5%, small cell lung carcinoma (SCLC) has very poor prognosis and requires improved therapies. Despite an excellent overall response to first-line therapy, relapses are ... [more ▼]

With 5-year survival rates below 5%, small cell lung carcinoma (SCLC) has very poor prognosis and requires improved therapies. Despite an excellent overall response to first-line therapy, relapses are frequent and further treatments are disappointing. The goal of the study was to improve secondline therapy of SCLC. The effect of chemotherapeutic agents was evaluated in cell lines (apoptosis, reactive oxygen species, and RNA and protein expression) and in mouse models (tumour development). We demonstrate here that valproic acid, a histone deacetylase inhibitor, improves the efficacy of a second-line regimen (vindesine, doxorubicin and cyclophosphamide) in SCLC cells and in mouse models. Transcriptomic profiling integrating microRNA and mRNA data identifies key signalling pathways in the response of SCLC cells to valproic acid, opening new prospects for improved therapies. [less ▲]

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See detailVAC chemotherapy with valproic acid for refractory/relapsing small cell lung cancer: a phase II study
Berghmans, Thierry; Lafitte, Jean-Jacques; Scherpereel, Arnaud et al

in European Respiratory Society Open Research (2015), 1(2),

Salvage chemotherapy (CT) for relapsing or refractory small cell lung cancer (SCLC) remains disappointing. In vitro experiments showed that valproic acid increases apoptosis of SCLC cell lines exposed to ... [more ▼]

Salvage chemotherapy (CT) for relapsing or refractory small cell lung cancer (SCLC) remains disappointing. In vitro experiments showed that valproic acid increases apoptosis of SCLC cell lines exposed to doxorubicin, vindesine and bis(2-chloroethyl)amine. The primary objective of this phase II study was to determine whether epigenetic modulation with valproic acid in addition to a doxorubicin, vindesine and cyclophosphamide (VAC) regimen improves 6-month progression-free survival (PFS). Patients with pathologically proven SCLC refractory to prior platinum derivatives and etoposide were eligible. After central registration, patients received VAC plus daily oral valproic acid. 64 patients were registered, of whom six were ineligible. Seven patients did not receive any CT, leaving 51 patients assessable for the primary end-point. The objective response rate was 19.6%. Median PFS was 2.8 months (95% CI 2.5–3.6 months) and 6-month PFS was 6%. Median survival time was 5.9 months (95% CI 4.7–7.5 months). Toxicity was mainly haematological, with 88% and 26% grade 3–4 neutropenia and thrombopenia, respectively. Despite an interesting response rate, the addition of valproic acid to VAC did not translate into adequate PFS in relapsing SCLC or SCLC refractory to platinum–etoposide. [less ▲]

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See detailModes of Human T Cell Leukemia Virus Type 1 Transmission, Replication and Persistence
Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg; Hamaïdia, Malik ULg et al

in Viruses (2015), 7

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes cancer (Adult T cell Leukemia, ATL) and a spectrum of inflammatory diseases (mainly HTLV-associated myelopathy—tropical spastic ... [more ▼]

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes cancer (Adult T cell Leukemia, ATL) and a spectrum of inflammatory diseases (mainly HTLV-associated myelopathy—tropical spastic paraparesis, HAM/TSP). Since virions are particularly unstable, HTLV-1 transmission primarily occurs by transfer of a cell carrying an integrated provirus. After transcription, the viral genomic RNA undergoes reverse transcription and integration into the chromosomal DNA of a cell from the newly infected host. The virus then replicates by either one of two modes: (i) an infectious cycle by virus budding and infection of new targets and (ii) mitotic division of cells harboring an integrated provirus. HTLV-1 replication initiates a series of mechanisms in the host including antiviral immunity and checkpoint control of cell proliferation. HTLV-1 has elaborated strategies to counteract these defense mechanisms allowing continuous persistence in humans. [less ▲]

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See detailN-Hydroxy-6-(5-Nitro- Naphtalimide)-Hexanamide Inhibits Lysine Deacetylation, Mitigates Angiogenesis and Reduces Tumor Growth
Shankar, T.V. Shiva; Sulka, B.; Hubert, P. et al

in Journal of Cancer Sciences (2015), 2(1),

In this report, we present a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human ... [more ▼]

In this report, we present a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish). Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA). Finally, ES8 also reduced tumor growth in mouse models of small cell lung cancer. Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies. [less ▲]

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See detailAPOBEC3 Interference during Replication of Viral Genomes
Willems, Luc ULg; Gillet, Nicolas ULg

in Viruses (2015)

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See detailCheckpoints modulation by the human T-lymphotropic virus type 1 (HTLV-1) Tax protein : towards new therapeutic approaches
Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg; Boxus, Mathieu et al

Poster (2015, May 13)

HTLV-1 infects approximately 15 million people worldwide and causes several diseases. This virus is responsible for the adult T-cell leukemia (ATL) and for a chronic neuropathology (TSP/HAM). There is ... [more ▼]

HTLV-1 infects approximately 15 million people worldwide and causes several diseases. This virus is responsible for the adult T-cell leukemia (ATL) and for a chronic neuropathology (TSP/HAM). There is currently no satisfactory treatment for these diseases. Among the proteins encoded by HTLV-1, Tax appears to play an important role in the mechanisms leading to pathogenicity. We are interested in the mechanisms of cell transformation by the Tax viral oncoprotein. In particular, we aim at understanding the interplay between Tax and the DNA damage response (DDR). We show that transient expression of Tax results in DNA damage, cell cycle arrest and activation of the DDR. In fibroblasts, cell cycle arrest occurs at the G1 and G2 phases depending on the p53 background. In contrast, HTLV-1 infected lymphocytes proliferate continuously and appear to be adapted to the checkpoints. This mechanism of checkpoint adaptation thus allows ongoing proliferation despite the presence of genomic lesions. Quantification of the rates of NHEJ and homologous recombination indicates that HTLV-1 infected cells require very efficient DNA repair for survival. Therefore, we propose a novel therapeutic approach based on the principle of synthetic lethality using inhibitors of DNA repair. [less ▲]

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See detailInteraction of HTLV-1 Tax with minichromosome maintenance proteins modulates viral transcription
Barez, Pierre-Yves ULg; Carpentier, Alexandre ULg; Boxus, Mathieu et al

Poster (2015, May 13)

First human retrovirus discovered, HTLV-1 infects approximately twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases that include adult T-cell leukemia (ATL) and a ... [more ▼]

First human retrovirus discovered, HTLV-1 infects approximately twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases that include adult T-cell leukemia (ATL) and a neurodegenerative disorder called HAM/TSP (Human associated myelopathy/ Tropical spastic paraparesis). We are interested in the mechanisms of transformation by the viral Tax oncoprotein. We previously showed that Tax interacts with the minichromosome maintenance MCM2-7 helicase and affects host cell replication (Boxus et al, 2012 Blood 119:151). In this project, we focused on the role of the MCM2-7 complex in transcription. We first show by chromatin immunoprecipitation that the MCM2-7 is recruited onto the 5'-LTR promoter. The 5’-LTR does however not act as a DNA replication origin. In contrast, MCM2-7 activates viral transcription as revealed by luciferase reporter assays. Interaction between Tax and MCM2-7 also affect expression of cellular genes. Together, our data thus demonstrate that the viral promoter is not a replication origin and that interaction between Tax and MCM2-7 is involved in the viral transcription. [less ▲]

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See detailHighlights on CRISPR-Cas 9: from bacteria to eukaryotic cells
Barez, Pierre-Yves ULg; Hamaïdia, Malik ULg; Willems, Luc ULg

Conference (2015, April 24)

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See detailReprogramming of replication origin firing and checkpoint adaptation in adult T-cell leukemia
Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg; Boxus, Mathieu et al

Conference (2015, February 11)

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most common are the ... [more ▼]

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most common are the adult T-cell leukemia (ATL) and a neurodegenerative disorder called HAM/TSP (Human associated myelopathy/ Tropical spastic paraparesis). A key parameter of HTLV-1 pathogenesis is faster replication of provirus-carrying lymphocytes allowing clonal expansion of infected cell populations. The virally-encoded Tax oncoprotein plays an essential role in this process by interacting with DNA replication origins and accelerating S phase progression. By reprogramming the timing of origin firing, Tax also creates a replicative stress leading to DNA double strand breaks. This mechanism further triggers the DNA damage response (DDR) that induces cell cycle arrest and initiates either apoptosis or senescence. However, HTLV-1 infected cells have developed strategies to interfere with the DDR and are adapted to checkpoint control. These cells are thus able to proliferate despite occurrence of DNA damage. Based on these observations, we now propose a novel therapeutic approach based on the principle of synthetic lethality. [less ▲]

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See detailCheckpoints modulation by the human T-lymphotropic virus type 1 (HTLV-1) Tax protein : towards new therapeutic approaches
Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg; Boxus, Mathieu et al

Poster (2015, February 11)

HTLV-1 infects approximately 20 million people worldwide and causes several diseases. This virus is responsible for the adult T-cell leukemia (ATL) and for a chronic neuropathology (TSP/HAM). There is ... [more ▼]

HTLV-1 infects approximately 20 million people worldwide and causes several diseases. This virus is responsible for the adult T-cell leukemia (ATL) and for a chronic neuropathology (TSP/HAM). There is currently no satisfactory treatment for these diseases. Among the proteins encoded by HTLV-1, Tax appears to play an important role in the mechanisms leading to pathogenicity. We are interested in the mechanisms of cell transformation by HTLV-1 and more particularly in the interplay between the viral Tax oncoprotein and the DNA damage response (DDR). We demonstrate that transient expression of Tax results in DNA damage, cell cycle arrest and activation of the ATM-Chk2-p53 axis of the DDR. In fibroblasts, cell cycle arrest occurs at the G1 and G2 phases depending on the p53 background. Despite Tax expression hampers cell cycle progression, neither pro-apoptotic nor pro-senescent effects are observed. In contrast, HTLV-1 infected lymphocytes proliferate continuously and appear to be adapted to the checkpoints. This mechanism allows infected lymphocytes to proliferate despite the presence of genomic lesions. Those cells might thus rely on effective DNA repair mechanisms. Indeed, we show that Tax expressing cells activate the error free repair mechanism homologous recombination (HR). Inhibition of ATM, involved in DDR and DNA repair by HR, impedes Tax-mediated cellular transformation. Depending on these observations, we propose a novel therapeutic approach based on the principle of synthetic lethality. [less ▲]

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See detailRisk of emergence of a hyperpathogenic bovine leukemia virus by mutation of a single envelope N-linked glycosylation site
De Brogniez, Alix ULg; Bouzar, Amel-Baya; Jacques, Jean-Rock ULg et al

Poster (2015, February 11)

- Introduction : Pathogens have co-evolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is ... [more ▼]

- Introduction : Pathogens have co-evolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) system in which lymphoproliferative disorders develop in ruminants after latency periods of several years. Infection of sheep and cattle with BLV is a model system for the related human T-lymphotropic virus type 1 (HTLV-1) responsible for Adult T-cell Leukemia (ATL). - Aims : The goal of this work is to investigate the role of N-glycans of the viral envelope protein during viral replication and pathogenesis. - Methods and results : Using glycosylation inhibitors and lectins, we showed that N-glycosylation is involved in viral infection (i.e. cell-to-cell fusion). Using reverse genetics of an infectious molecular provirus, we next demonstrated that a particular N-linked envelope glycosylation site (N230) limits viral replication and pathogenicity in vitro and in vivo. We have thus generated a viral mutant that is more pathogenic than the wild type strain. - Conclusions : To our knowledge, this is the first time that a hyperpathogenic BLV has been identified. This unexpected observation has important consequences in terms of disease control and managing. Indeed, during evolution, pathogens and their hosts should achieve an equilibrium allowing the coexistence of the two species. Occurrence of this particular mutation may thus represent a potential threat associated with emergence of hyperpathogenic BLV strains and possibly of new variants of the related HTLV-1. [less ▲]

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See detailReprogramming of replication origin firing and checkpoint adaptation in adult T-cell leukemia
Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg; Boxus, Mathieu et al

Conference (2015, February 03)

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most common are the ... [more ▼]

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most common are the adult T-cell leukemia (ATL) and a neurodegenerative disorder called HAM/TSP (Human associated myelopathy/ Tropical spastic paraparesis). A key parameter of HTLV-1 pathogenesis is faster replication of provirus-carrying lymphocytes allowing clonal expansion of infected cell populations. The virally-encoded Tax oncoprotein plays an essential role in this process by interacting with DNA replication origins and accelerating S phase progression. By reprogramming the timing of origin firing, Tax also creates a replicative stress leading to DNA double strand breaks. This mechanism further triggers the DNA damage response (DDR) that induces cell cycle arrest and initiates either apoptosis or senescence. However, HTLV-1 infected cells have developed strategies to interfere with the DDR and are adapted to checkpoint control. These cells are thus able to proliferate despite occurrence of DNA damage. Based on these observations, we now propose a novel therapeutic approach based on the principle of synthetic lethality. [less ▲]

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See detailProspective validation obtained in a similar group of patients and with similar high throughput biological tests failed to confirm signatures for prediction of response to chemotherapy and survival in advanced NSCLC: a prospective study from the European Lung Cancer Working Party
Berghmans, Thierry; Ameye, Lieveke; Lafitte, Jean-Jacques et al

in Frontiers in Oncology (2015), 4

Cisplatin doublets are standard 1st line treatment for advanced non-small cell lung cancer (NSCLC), without accurate predictor for response and survival, but important toxicity. Our aimswere to identify ... [more ▼]

Cisplatin doublets are standard 1st line treatment for advanced non-small cell lung cancer (NSCLC), without accurate predictor for response and survival, but important toxicity. Our aimswere to identify predictive (for response) and prognostic (for survival) biological signatures in patients with NSCLC using messenger RNAs (mRNA) and miRNA expression. [less ▲]

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