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See detailHistone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis
Mottet, Denis ULg; Bellahcene, Akeila ULg; Pirotte, Sophie ULg et al

in Circulation Research (2007), 101(12), 1237-1246

Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the ... [more ▼]

Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the development of blood vessels. Using small interfering RNAs, we observed that HDAC7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis. Among several factors known to be involved in angiogenesis, platelet-derived growth factor-B (PDGF-B) and its receptor (PDGFR-beta) were the most upregulated genes following HDAC7 silencing. We demonstrated that their increased expression induced by HDAC7 silencing was partially responsible for the inhibition of endothelial cell migration. In addition, we have also shown that treatment of endothelial cells with phorbol 12-myristate 13-acetate resulted in the exportation of HDAC7 out of the nucleus through a protein kinase C/protein kinase D activation pathway and induced, similarly to HDAC7 silencing, an increase in PDGF-B expression, as well as a partial inhibition of endothelial cell migration. Collectively, these data identified HDAC7 as a key modulator of endothelial cell migration and hence angiogenesis, at least in part, by regulating PDGF-B/PDGFR-beta gene expression. Because angiogenesis is required for tumor progression, HDAC7 may represent a rational target for therapeutic intervention against cancer. [less ▲]

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See detailHistone deacetylase HDAC7 as a key regulator of the angiogenic process
Mottet, Denis; Bellahcene, Akeila ULg; Waltregny, David ULg et al

Poster (2006, January 20)

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha-actin and is essential for smooth muscle cell contractility
Waltregny, David ULg; Glenisson, Wendy; Tran, Syv Li et al

in FASEB Journal (2005), 19(8), 966-968

Although originally characterized as nuclear enzymes controlling the stability of nucleosomes, histone deacetylases (HDACs) may also exert their activity within the cytosol. Recently, we have demonstrated ... [more ▼]

Although originally characterized as nuclear enzymes controlling the stability of nucleosomes, histone deacetylases (HDACs) may also exert their activity within the cytosol. Recently, we have demonstrated that HDAC8, a class I HDAC, is a novel, prominently cytosolic marker of smooth muscle differentiation. As HDAC8 displays a striking stress fiber-like pattern of distribution and is coexpressed in vivo with smooth muscle alpha-actin (alpha-SMA) and smooth muscle myosin heavy chain, we have explored the possible participation of this HDAC in smooth muscle cytoskeleton regulation. Cell fractionation assays performed with primary human smooth muscle cells (HSMCs) showed that HDAC8, in contrast to HDAC1 and HDAC3, was enriched in cytoskeleton-bound protein fractions and insoluble cell pellets, suggesting an association of HDAC8 with the cystoskeleton. Coimmunoprecipitation experiments using HSMCs, NIH-3T3 cells, and human prostate tissue lysates further demonstrated that HDAC8 associates with alpha-SMA but not with beta-actin. HDAC8 silencing through RNA interference strongly reduced the capacity of HSMCs to contract collagen lattices. Mock transfections had no effect on HSMC contractily, and transfections with small interfering RNAs (siRNAs) specific for HDAC6, a cytosolic HDAC that functions as an alpha-tubulin deacetylase, resulted in a weak contraction inhibition. Although mock- and HDAC6 siRNA-transfected HSMCs showed no noticeable morphological changes, HDAC8 siRNA-transfected HSMCs displayed a size reduction with diminished cell spreading after replating. Altogether, our findings indicate that HDAC8 associates with the smooth muscle actin cytoskeleton and may regulate the contractile capacity of smooth muscle cells. [less ▲]

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha–actin and is essential for smooth muscle cell contractility
Glénisson, Wendy; Waltregny, David ULg; Tran, Syv Li et al

Conference (2006)

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha–actin and is essential for smooth muscle cell contractility
Glénisson, Wendy; Waltregny, David ULg; Tran, Syv Li et al

Conference (2005)

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See detailHistone deacetylase inhibitor trichostatin A sustains sodium pervanadate-induced NF-kappa B activation by delaying IkappaBalpha mRNA resynthesis : comparison with tumor necrosis factor alpha
Horion, Julie ULg; Gloire, Geoffrey ULg; El Mjiyad, Nadia et al

in Journal of Biological Chemistry (2007), 282(21), 15383

NF-kappaB is a crucial transcription factor tightly regulated by protein interactions and post-translational modifications, like phosphorylation and acetylation. A previous study has shown that ... [more ▼]

NF-kappaB is a crucial transcription factor tightly regulated by protein interactions and post-translational modifications, like phosphorylation and acetylation. A previous study has shown that trichostatin A (TSA), a histone deacetylase inhibitor, potentiates tumor necrosis factor (TNF) alpha-elicited NF-kappaB activation and delays IkappaBalpha cytoplasmic reappearance. Here, we demonstrated that TSA also prolongs NF-kappaB activation when induced by the insulino-mimetic pervanadate (PV), a tyrosine phosphatase inhibitor that initiates an atypical NF-kappaB signaling. This extension is similarly correlated with delayed IkappaBalpha cytoplasmic reappearance. However, whereas TSA causes a prolonged IKK activity when addedtoTNFalpha, it does notwhenaddedtoPV.Instead, quantitative reverse transcriptase-PCR revealed a decrease of ikappabalphamRNAlevel after TSA addition to PV stimulation. This synthesis deficit of the inhibitor could explain the sustained NF-kappaB residence in the nucleus. In vivo analysis by chromatin immunoprecipitation assays uncovered that, forPVinduction but not forTNFalpha, the presence of TSA provokes several impairments on the ikappabalphapromoter: (i) diminution of RNA Pol II recruitment; (ii) reduced acetylation and phosphorylation of histone H3-Lys14 and -Ser10, respectively; (iii) decreased presence of phosphorylated p65-Ser536; and (iv) reduction of IKKalphabinding. The recruitment of these proteins on the icam-1 promoter, another NF-kappaB-regulated gene, is not equally affected, suggesting a promoter specificity of PV with TSA stimulation. Taken together, these data suggest that TSA acts differently depending on the NF-kappaB pathway and the targeted promoter in question. This indicates that one overall histone deacetylase role is to inhibit NF-kappaB activation by molecular mechanisms specific of the stimulus and the promoter. [less ▲]

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See detailHistone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients.
Lezin, Agnes; Gillet, Nicolas ULg; Olindo, Stephane et al

in Blood (2007), 110(10), 3722-8

Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated ... [more ▼]

Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches that focus on reducing either cell proliferation, viral replication, or tissue invasion are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/as no. NCT00519181. [less ▲]

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See detailHistone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling
Deroanne, Christophe ULg; Bonjean, Karine; Servotte, Sandrine et al

in Oncogene (2002), 21(3), 427-436

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to ... [more ▼]

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-positive capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relationship, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not observed in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling. [less ▲]

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See detailHistone deacetylases: anti-angiogenic targets in cancer therapy.
Mottet, Denis ULg; Castronovo, Vincenzo ULg

in Current Cancer Drug Targets (2010), 10(8), 898-913

Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost ... [more ▼]

Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost 40 years, this concept has inspired generations of researchers to identify anti-angiogenic molecules that could be used therapeutically to stop blood vessels formation and starve tumors of nutrients and oxygen. Tumor angiogenesis requires complex cellular and molecular interactions between endothelial and cancer cells. In response to external stimuli such as hypoxia, cancer cells secrete pro-angiogenic factors into the extracellular matrix that activate the surrounding endothelial cells to proliferate, migrate and form new blood vessels. So, vascularization of malignant lesions depends on the expression of specific genes in both endothelial and tumor cells and accumulating evidences shows that several members of the histone deacetylase (HDAC) family play key roles in the regulation of these genes. Indeed, numerous in vitro and in vivo studies demonstrated that inhibitors of HDAC modulate angiogenic gene expression in both endothelial and cancer cells and disturb the delicate and complex balance between the collective action of pro-angiogenic factors and angiogenesis inhibitors. Thus, HDAC are currently recognized as promising targets for the development of anti-cancer drugs. This review is an effort to present and discuss the role, functions and mechanisms of action of HDAC during tumor-driven angiogenesis as well as a brief summary of the clinical status of the main HDAC inhibitors (HDACi) currently under development in cancer therapy. [less ▲]

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See detailHistone Deacetylases: Target Enzymes for Cancer Therapy
Mottet, Denis ULg; Castronovo, Vincenzo ULg

in Clinical & Experimental Metastasis (2007)

Epigenic regulation of gene transcription has recently been the subject of a fast growing interest particularly in the field of cancer. Enzymatic acetylation and deacetylation of the epsilon-amino groups ... [more ▼]

Epigenic regulation of gene transcription has recently been the subject of a fast growing interest particularly in the field of cancer. Enzymatic acetylation and deacetylation of the epsilon-amino groups of lysine residues from nucleosomal histones, represents major molecular epigenic mechanisms controlling gene expression. Histone deacetylases (HDACs) and histone acetyl transferases (HAT) represent the two families of enzymes in charge of the control of the level of acetylation of the histone tails. By removing the acetyl groups that abrogate the positive charge of the lysine residues that maintain the histone tails attached to DNA, HDACs repress transcription. In mammals, these latter enzymes form three groups of related enzymes based on their sequence homology and are classified as HDACs I, II and III. Global inhibition of the HDACs I and II groups results in cell growth arrest and apoptosis of cancer cells and alters tumor growth in in vivo experimental models. Their surprisingly low general toxicity and their impressive efficiency in preclinical cancer models has led to consider HDAC inhibitors as very promising new anticancer pharmacological agents. In this review, we attempt to give a comprehensive overview of the role and the involvement of HDAC in carcinogenesis as well as the current progress on the development of HDAC general and specific inhibitors as new cancer therapies. [less ▲]

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See detailLes histones desacetylases : nouvelles cibles pour les therapies anti-cancereuses.
Mottet, Denis ULg; Castronovo, Vincenzo ULg

in Medecine Sciences : M/S (2008), 24(8-9), 742-6

Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred ... [more ▼]

Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred different genes in cancer development. Today, the model has evolved: it has been demonstrated that malignancies can be initiated not only through genetic alterations but also through epigenetic deregulations. By altering the expression of gene involved in cell regulation, epigenetic alterations, such as histone acetylation, play a key role in the initiation and progression of neoplasm. It has been shown that an imbalance between the acelylated and deacetylated status of chromatin is significantly involved in the acquisition of a malignant phenotype. Thus, the modulation of the histone acetylation level by histone deacetylase (HDAC) inhibitors could lead to a genetic re-programmation in cancer cells that would favor apoptosis and prevent proliferation. The potential therapeutic value of several HDAC inhibitors for cancer patients has been evaluated in clinical assays with very promising outcome. Indeed, the first inhibitors available for patients has been recently approved for cancer patients tracing the way for a new class of promising anti-cancer therapy modalities. [less ▲]

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See detailHistopathological comparison of two mouse-adapted influenza A strains in mice.
Garigliany, Mutien-Marie ULg; Habyarimana, Adélite; Cornet, Anne et al

Conference (2008, October)

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See detailHistopathological diagnosis of a type vii mucopolysaccharidosis after pregnancy termination.
Delbecque, Katty ULg; Gaillez, Stephanie ULg; Schaaps, Jean-Pierre ULg

in Fetal & Pediatric Pathology (2009), 28(1), 1-8

Type VII mucopolysaccharidosis is a very rare recessive lysosomal storage disease. We diagnosed a type VII MPS in a case of severe fetal hydrops after pregnancy termination at 23 weeks of gestation. The ... [more ▼]

Type VII mucopolysaccharidosis is a very rare recessive lysosomal storage disease. We diagnosed a type VII MPS in a case of severe fetal hydrops after pregnancy termination at 23 weeks of gestation. The diagnosis was suspected on histopathological examination by the presence of foam cells in many viscera and foamy placental Hofbauer cells. Enzyme assay on cultured amniotic cells showed a markedly deficient beta-glucuronidase activity, thus confirming the diagnosis. This report shows the importance of a precise necropsy diagnosis in nonimmune hydrops because of putative implications for genetic counseling and prenatal diagnosis in subsequent pregnancies. [less ▲]

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See detailHistopathological pattern and humoral immune response to a crude exo-antigen and purified keratinase of Microsporum canis in symptomatic and asymptomatic infected cats.
Mignon, Bernard ULg; Coignoul, Freddy ULg; Leclipteux, T. et al

in Medical Mycology (1999), 37(1), 1-9

In order to understand better the mechanisms involved in the diverse clinical patterns in Microsporum canis-infected cats, the histopathological features were compared in symptomatic and asymptomatic ... [more ▼]

In order to understand better the mechanisms involved in the diverse clinical patterns in Microsporum canis-infected cats, the histopathological features were compared in symptomatic and asymptomatic infected cats. Additionally, the IgG immune response to a crude exo-antigen and purified keratinase of M. canis was studied by ELISA in cats of various clinical and mycological status. Acute and subacute perifolliculitis and folliculitis occurred more frequently in symptomatic than asymptomatic cats. The latter usually displayed signs of chronic inflammation and a marked infiltration of superficial dermis by mast cells, which would suggest that these animals present similarities to chronically dermatophytic humans or animals. When using a crude M. canis antigen, all infected cats were shown to have significantly higher levels of specific IgG when compared to culture negative and mechanical carrier-cats. In these non-infected animals, specific IgG was more frequently detected in adults than in young animals. No difference in anti-crude antigen specific IgG was observed between symptomatic and asymptomatic infected cats, indicating that the presence of IgG is probably unrelated to the clinical status of cats. Anti-keratinase specific IgG was only detected in one of the infected cats. [less ▲]

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See detailThe histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man
Syrjä, P; Heikkilä, HP; Lilja-Maula, L et al

in Journal of Comparative Pathology (2013), 149(2-3), 303-313

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See detailHistoplasmose africiaine à Histoplasma duboisii (Histoplasma capsulatum var. duboisii): quatorze cas congolais observés en 10 ans (1981-1990)
Carme, Bernard; Hayette, Marie-Pierre ULg; Itoua Ngaporo, A. et al

in Journal de Mycologie Médicale (1993), 3

Fourteen cases of histoplasmosis due to Histoplasma duboisii seen in Congo from 1981 through 1990, are reported: the average age of the patients was 25 years (the youngest being 1,5 y and the oldest 50y ... [more ▼]

Fourteen cases of histoplasmosis due to Histoplasma duboisii seen in Congo from 1981 through 1990, are reported: the average age of the patients was 25 years (the youngest being 1,5 y and the oldest 50y), the M/F ratio was 2,5; most of the patients (10/14) live in a rural area. there was a rather constant frequency of one to three cases per annum from 1981 through 1990. The fisrt congolese AIDS-associated systemic histoplasmosis duboisii case was observed in 1990. Lymph node involvment and mucocutaneous lesions were the most frequent clinical manifestations. In all cases, the disgnosis was established by histological examination. When performed, direct microscopy was always positive (11/11). Isolation of H. duboisii in culture was successful in 7 out of 9 attempts. Two cases of systemic infection were rapidly fatal but a good clinical response was obtained in the other cases wih amphotericin B, which due to intolerance, was replaced by ketoconazole in 2 patients. [less ▲]

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See detailHistoria de la Acromegalia y del Gigantismo
Beckers, Albert ULg

Scientific conference (2013, April)

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See detailHistorical changes in carbon dioxide (CO2) and dimethyl sulphide (DMS) emissions in the eutrophied Southern North Sea
Gypens, N.; Borges, Alberto ULg; Lancelot, C.

Conference (2012, April 22)

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See detailHistorical formation and student understanding of mathematics
Schneider, Marguerite ULg

in Fauvel, J.; van Maanen, J. (Eds.) History of Mathematics Education (2000)

Detailed reference viewed: 30 (5 ULg)