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See detailThe inside-out trans-obturator sling: a novel surgical technique for the treatment of male urinary incontinence
de Leval, Jean ULg; Waltregny, David ULg

in European Urology (2008), 54(5), 1051-65

OBJECTIVES: To describe a new sling procedure for treating stress urinary incontinence (SUI) after radical prostatectomy (RP) and prospectively evaluate its short-term safety and efficacy. METHODS: The ... [more ▼]

OBJECTIVES: To describe a new sling procedure for treating stress urinary incontinence (SUI) after radical prostatectomy (RP) and prospectively evaluate its short-term safety and efficacy. METHODS: The sling technique uses specific instruments and a polypropylene mesh with two arms that are passed inside to outside through the obturator foramens, pulled for compressing the bulbar urethra upward, and tied to each other across the midline. Patients with detrusor overactivity were excluded. Baseline and follow-up evaluations included uroflowmetry and continence and quality of life (QoL) questionnaires. Cure was defined by no pad use and improvement by a number of pads/d <or=2 and reduced by at least 50%. Complications were recorded. RESULTS: From April 2006 through February 2007, 20 consecutive patients suffering from post-RP SUI underwent the sling procedure using the same operative protocol. Preoperatively, 3 (15%), 11 (55%), and 6 (25%) patients were using 2, 3-5, and >5pads/d, respectively. The procedure was preceded by an endoscopic urethrotomy in four patients. No perioperative complication was noted; three patients required suprapubic catheterization. At 6 mo, nine (45%) patients were cured and eight others (40%) were improved (1pad/d). QoL was significantly enhanced and 80% of patients were moderately to completely satisfied with the procedure. Preoperative and postoperative maximum flow rate and postvoid residual values were not statistically different. No sling infection, urethra erosion, persistent pain, or neurologic complications were observed. CONCLUSIONS: The inside-out trans-obturator sling procedure appears to be safe and efficient at short term. Further studies are warranted to determine long-term outcome. [less ▲]

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See detailThe inside-out transobturator sling for the treatment of male urinary incontinence
de Leval, Jean ULg; Waltregny, David ULg

in Journal of Urology (The) (2008), 179(4), 123

Introduction and objective: <br />Sling procedures are currently re-emerging as an attractive alternative to the artificial urinary sphincter for the treatment of post-radical prostatectomy (RP) stress ... [more ▼]

Introduction and objective: <br />Sling procedures are currently re-emerging as an attractive alternative to the artificial urinary sphincter for the treatment of post-radical prostatectomy (RP) stress urinary incontinence (SUI), given that they are inexpensive, nonmechanical and allow for physiological voiding without significant obstruction. The aim of this study was to describe a novel transobturator sling procedure for treating post-RP SUI, and to prospectively evaluate its short-term safety and efficacy. <br /> <br />Methods: <br />The inside-out transobturator sling technique used specific instruments and a polypropylene mesh with 2 arms that were passed inside to outside through the obturator foramens, pulled for compressing the bulbar urethra upward, and then tied to each other across the midline. Perioperative dual channel urodynamic studies were repeated until tension on both arms of the mesh increased abdominal leak point pressure to approximately 100 cm H2O. The two mesh arms were then tied to each other for maintaining bulbar urethra compression. Patients with detrusor overactivity were excluded. Baseline and followup evaluations included uroflowmetry, and continence, quality of life (QoL), and satisfaction questionnaires. Cure was defined by no pad use and improvement by a number of pads/day ≤2 and reduced by at least 50%. Complications were recorded. The video also illustrates anatomic and physiopathologic differences between male and pelvis in relation with transobturator tapes. <br /> <br />Results: <br />From April 2006 through February 2007, 20 consecutive patients suffering from post-RP SUI underwent the sling procedure using the same operative protocol. Preoperatively, 3 (15%), 11 (55%), and 6 (25%) patients were using 2, 3 to 5, and more than 5 pads/day, respectively. The procedure was preceded by an endoscopic urethrotomy in 4 patients. No perioperative complication was noted; 3 patients required suprapubic catheterization. At 6 months, 9 (45%) patients were cured and 8 others (40%) were improved (1 pad/day). QoL was significantly enhanced and 80% patients were moderately to completely satisfied with the procedure. Preoperative and postoperative max flow rate and postvoid residual values were not statistically different. No sling infection, urethra erosion, persistent pain or neurological complication was observed. <br /> <br />Conclusions: <br />The inside-out transobturator sling procedure appears to be safe and efficient at short term. Further studies are warranted to determine long term outcome. [less ▲]

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See detailIdentification of new accessible tumor antigens in human colon cancer by ex vivo protein biotinylation and comparative mass spectrometry analysis.
Conrotto, Paolo; Roesli, Cristof; Rybak, Jascha et al

in International Journal of Cancer = Journal International du Cancer (2008), 123(12), 2856-2864

One of the most promising new strategies for the development of efficacious cancer therapies relies on the targeted delivery of biopharmaceutical to the tumor environment by the use of selective and ... [more ▼]

One of the most promising new strategies for the development of efficacious cancer therapies relies on the targeted delivery of biopharmaceutical to the tumor environment by the use of selective and specific antibodies. The identification of accessible perivascular proteins selectively overexpressed in cancer tissue may facilitate the development of antibody-based biopharmaceutical administration. This approach is potentially highly selective and specific, combining the presence of tumor biomarkers readily accessible from the blood vessels and the high rate of angiogenesis characteristic of cancer tissues. We performed ex vivo perfusions of surgically resected human colon cancer using a reactive ester derivative of biotin, thus achieving a selective covalent modification of accessible proteins in vascular structures and stroma. After extraction and purification, biotinylated proteins were digested and the resulting peptides submitted to a comparative mass spectrometry-based proteomic analysis, revealing quantitative differences between normal and cancer colon. Sixty-seven of the total 367 proteins identified were found to be preferentially expressed at the tumor site. We generated human monoclonal antibodies against 2 potential tumor targets, NGAL and GW112, and we proved their selective expression in cancer colon and not or barely in healthy tissues. This article presents the first proteomic analysis of human colorectal cancer structures readily accessible from the tumor vasculature, revealing the overexpression of novel tumor antigens which may serve as selective targets for antibody-based imaging and therapeutic biomolecular strategies. (c) 2008 Wiley-Liss, Inc. [less ▲]

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See detailIdentification and characterization of new blood-accessible colorectal cancer biomarkers
Conrotto, Paolo; Roesli, Christoph; Rybak, J. et al

Conference (2008)

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See detailContribution of glycoproteomics in the search for accessible biomarkers in human lymphoma
Kischel, Philippe; Greffe, Yannick; Waltregny, David ULg et al

Scientific conference (2008)

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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 detailIdentification of accessible human cancer biomarkers using ex vivo chemical proteomic strategies
Kischel, Philippe ULg; Waltregny, David ULg; Castronovo, Vincenzo ULg

in Expert Review of Proteomics (2007), 4(6), 727-739

One promising avenue towards the development of more selective, better anticancer drugs lies in the targeted delivery of bioactive compounds to the tumor environment by means of binding molecules specific ... [more ▼]

One promising avenue towards the development of more selective, better anticancer drugs lies in the targeted delivery of bioactive compounds to the tumor environment by means of binding molecules specific for tumor-associated biomarkers. Eligibility of such markers for therapeutic ideally use three criteria: accessibility from the bloodstream; expression at sufficient level, and no (or much lower) expression in normal tissues. Most current discovery strategies (such as biomarker searching into body fluids) provide no clue as to whether proteins of interest are accessible, in human tissues, to suitable high-affinity ligands, such as systemically delivered monoclonal antibodies. To address this limitation, our group recently developed two methodologies based on chemical proteomic modifications, enabling the discovery of proteins accessible from the bloodstream and the extracellular space in human pathological tissues. In this review, we will discuss the potential benefits of these methodologies for the fast discovery of therapeutically valuable biomarkers. [less ▲]

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See detailRegulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase
Ahuja, Nidhi; Schwer, Bjoern; Carobbio, Stefania et al

in Journal of Biological Chemistry (2007), 282(46),

Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and ... [more ▼]

Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulin degrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin-expressing beta cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion. [less ▲]

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See detailFunctional and profiling studies prove that prostate cancer upregulated neuroblastoma thymosin beta is the true human homologue of rat thymosin beta 15
Dhaese, S.; Jonckheere, V.; Goethals, M. et al

in FEBS Letters (2007), 581(25), 4809-4815

A peptide with a sequence identical to rat thymosin beta(Tb)15 was reported to be upregulated in human prostate cancer. However, in this report we provide evidence that TbNB, initially identified in human ... [more ▼]

A peptide with a sequence identical to rat thymosin beta(Tb)15 was reported to be upregulated in human prostate cancer. However, in this report we provide evidence that TbNB, initially identified in human neuroblastoma, is the only Tb isoform upregulated in human prostate cancer and that the Tb15 sequence is not present herein. In addition, we demonstrate that human TbNB has a higher affinity for actin in comparison to Tb4 and promotes cell migration. In combination, this experimentally validates TbNB as functional homologue of rat Tb15 in the human organism and clarifies the current composition of the human Tb family. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. [less ▲]

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See detailHistone deacetylase 4 is required for TGF beta 1-induced myofibroblastic differentiation
Glenisson, Wendy; Castronovo, Vincenzo ULg; Waltregny, David ULg

in Biochimica et Biophysica Acta-Molecular Cell Research (2007), 1773(10), 1572-1582

Transforming Growth Factor beta 1 (TGF beta 1) is a crucial cytokine triggering myofibroblastic (MF) differentiation, a process involved in tissue healing as well as in pathologic conditions such as ... [more ▼]

Transforming Growth Factor beta 1 (TGF beta 1) is a crucial cytokine triggering myofibroblastic (MF) differentiation, a process involved in tissue healing as well as in pathologic conditions such as fibrosis and cancer. Together with cell shape modifications, TGF beta 1-mediated differentiation of fibroblasts into myofibroblasts is characteristically associated with the neo-expression of smooth muscle alpha-actin (alpha-SMA), a cytoskeletal protein that enhances their contractile activity. Several cellular differentiation programs have been linked to epigenetic regulation of gene expression, including gene methylation and historic acetylation. Herein, we sought to investigate the role of histone deacetylases (HDAC) in TGF beta 1-induced MY differentiation. We found that TSA, a global inhibitor of class I and class II HDACs, prevented alpha-SMA transcript and protein expression and morphological changes mediated by TGF beta 1 in cultured human skin fibroblasts. In order to identify the HDAC(s) participating in MF differentiation, the impact of specific HDAC silencing (HDAC1 through HDAC8) using RNA interference was investigated in fibroblasts exposed to TGF beta 1. Among the eight HDACs tested, silencing of HDAC4, HDAC6, and HDAC8 expression impaired TGF beta 1-induced alpha-SMA expression. HDAC4 silencing most efficiently abrogated alpha-SMA expression and also prevented TGF beta 1-mediated morphological changes. Forced down-regulation of HDAC4 stimulated the expression of 5'-TG-3'-Interacting Factor (TGIF) and TGIF2 homeoproteins, two known endogenous repressors of the TGF beta signaling pathway, but not of the inhibitory Smad7. Collectively, these data suggest that HDAC4 is an essential epigenetic regulator of MF differentiation and unveil HDAC4 as a potential target for treating MF-related disorders. (C) 2007 Published by Elsevier B.V. [less ▲]

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See detailIdentification of specific reachable molecular targets in human breast cancer using a versatile ex vivo proteomic method
Castronovo, Vincenzo ULg; Kischel, Philippe ULg; Guillonneau, Francois et al

in Proteomics (2007), 7(8), 1188-1196

Targeting of tumoral tissues is one of the most promising approaches to improve both the efficacy and safety of anticancer treatments. The identification of valid targets, including proteins specifically ... [more ▼]

Targeting of tumoral tissues is one of the most promising approaches to improve both the efficacy and safety of anticancer treatments. The identification of valid targets, including proteins specifically and abundantly expressed in cancer lesions, is of utmost importance. Despite state-of-the-art technologies, the discovery of cancer-associated target proteins still faces the limitation, in human tissues, of antigen accessibility to suitable high-affinity ligands such as human mAb bound to bioactive molecules. Terminal perfusion of tumor-bearing mice or ex vivo perfusion of human cancer-bearing organs with a reactive biotin ester solution has successfully led to the identification of novel accessible biomarkers. This methodology is however restricted to perfusable organs, and excludes most of the tissues of interest to targeted therapies, e.g. primary breast cancer and metastases. Herein, we report on the development of a new chemical proteomic method that bypasses the perfusion step and thus offers the potential to identify accessible molecular targets in virtually all types of animal and human tissues. We have validated our new procedure by identifying biomarkers selectively expressed in human breast carcinoma. Overall, this powerful technology may lay the ground not only for custom-made therapies in cancer, but also for the development of therapies that need to be selectively delivered in a specific tissue. [less ▲]

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See detailBone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor
Stabile, Helena; Mitola, Stefania; Moroni, Emanuela et al

in Blood (2007), 109(5), 1834-1840

Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly ... [more ▼]

Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly thought to affect different processes during growth, differentiation, and development by heterodimerizing various BMPs. Here, we identify Drm/gremlin as a novel proangiogenic factor expressed by endothelium. Indeed, Drm/gremlin was purified to homogeneity from the conditioned medium of transformed endothelial cells using an endothelial-cell sprouting assay to follow protein isolation. Accordingly, recombinant Drm/gremlin stimulates endothelial-cell migration and invasion in fibrin and collagen gels, binds with high affinity to various endothelial cell types, and triggers tyrosine phosphorylation of intracellular signaling proteins. Also, Drm/gremlin induces neovascularization in the chick embryo chorioallantoic membrane. BMP4 does not affect Drm/gremlin interaction with endothelium, and both molecules exert a proangiogenic activity in vitro and in vivo when administered alone or in combination. Finally, Drm/gremlin is produced by the stroma of human tumor xenografts in nude mice, and it is highly expressed in endothelial cells of human lung tumor vasculature when compared with nonneoplastic lung. Our observations point to a novel, previously unrecognized capacity of Drm/gremlin to interact directly with target endothelial cells and to modulate angiogenesis. [less ▲]

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See detailActualités therapeutiques en urologie. Le TVT-O, nouvelle technique mini-invasive pour le traitement de l'incontinence urinaire d'effort féminine, développements et expérience clinique
de Leval, Jean ULg; Bonnet, Pierre ULg; Waltregny, David ULg

in Revue Médicale de Liège (2007), 62 Spec No

Tension-free sub-urethral tapes have revolutionized the surgical treatment of female stress urinary incontinence for the past decade. The inside-out transobturator approach, developed in our Institution 5 ... [more ▼]

Tension-free sub-urethral tapes have revolutionized the surgical treatment of female stress urinary incontinence for the past decade. The inside-out transobturator approach, developed in our Institution 5 years ago, is currently being utilized worldwide. The technique is simple and reproducible and the incidence of complications is minimized. Stress urinary incontinence cure rates of almost 90% are achieved after a 3-year minimum follow up. These good results have been confirmed in the international literature. [less ▲]

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See detailStudy of the role of histone deacetylases in myofibroblastic differenciation
Glénisson, Wendy; Waltregny, David ULg; Castronovo, Vincenzo ULg

Scientific conference (2007)

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See detailRegulation by androgens of the expression of the EGF receptor family members in prostate cancer cells
Pignon, Jean-Christophe; Delacroix, Laurence; Nolens, Grégory et al

Conference (2007)

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