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See detailThe inside-out transobturator sling for the surgical treatment of post-radical prostatectomy urinary incontinence: Short term results of a prospective study
Waltregny, David ULg; Leruth, Julie ULg; de Leval, Jean ULg

in European Urology Supplements (2009), 4(8), 336

Introduction and Objective: To prospectively evaluate the short-term safety and efficacy of a new transobturator sling procedure for treating post-radical prostatectomy (RP) stress urinary incontinence ... [more ▼]

Introduction and Objective: To prospectively evaluate the short-term safety and efficacy of a new transobturator sling procedure for treating post-radical prostatectomy (RP) stress urinary incontinence (SUI). Methods: The sling technique uses specific instruments and a polypropylene mesh with 2 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. Inclusion criteria were clinically and urodynamically demonstrated SUI, positive bulbar compression test, and signed informed consent. Patients with detrusor overactivity were excluded. Baseline and followup 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 ≤ 2 and reduced by at least 50%. Complications were recorded. Results: From 04/2006 through 10/2008, 70 consecutive patients who fulfilled inclusion and exclusion criteria underwent the sling procedure using the same operative protocol. As of October 2008, 55 and 35 patients who consecutively underwent the sling procedure were expected to have a minimum followup of 6 months and 1 year, respectively. Preoperatively, 13 (24%), 25 (45%), and 17 (31%) patients were using 2, 3 to 5, and >5 pads/d, respectively. Nine and 6 patients had undergone prior surgery for SUI and/or previous pelvic irradiation, respectively. The sling procedure was preceded by an endoscopic urethrotomy in 5 (9%) patients. No perioperative complication was noted. Seven (13%) patients required suprapubic catheterization; normal voiding resumed in all 7 patients except 1 who underwent urinary diversion for radiation-induced complete anastomotic stricture. Six-month and 1-year minimum followup was available on 51 (93%) and 33 (94%) patients, respectively (Table 1). Of note, at 6 months, among the 17 patients with preoperative severe incontinence (> 5 pads/day), 9 (53%) patients were cured and 6 others (35%) were improved (1 pad/d). Overall, QoL was significantly enhanced and 85% 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. No sling was withdrawn or cut. Conclusions: The inside-out transobturator sling procedure appears to be safe and efficient at short term. [less ▲]

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See detailThe inside-out transobturator sling for the surgical treatment of post-radical prostatectomy urinary incontinence: Interim results of a prospective, observational study after a 1-year minimum follow-up
Waltregny, David ULg; Leruth, Julie ULg; de Leval, Jean ULg

in Neurourology and Urodynamics (2009), 28(7), 687-688

Hypothesis / aims of study The aim of this study was to prospectively evaluate the short-term safety and efficacy of the inside-out transobturator sling procedure for treating post-radical prostatectomy ... [more ▼]

Hypothesis / aims of study The aim of this study was to prospectively evaluate the short-term safety and efficacy of the inside-out transobturator sling procedure for treating post-radical prostatectomy (RP) stress urinary incontinence (SUI). Study design, materials and methods The sling technique uses specific instruments and a polypropylene mesh with 2 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. Intra-operative urodynamic evaluation is performed to record the urethral pressure profile (UPP) and to measure the abdominal leak point pressure (ALPP) and maximal urethral pressure (MUP) before and after sling tensioning. Urodynamic measurements are repeated until tension on both arms of the mesh increases ALPP to approximately 100 cm H2O. In case of associated urethral stenosis, classic endoscopic urethrotomy is performed first. Inclusion criteria were clinically and urodynamically demonstrated SUI, positive bulbar compression test, and signed informed consent. Patients with detrusor overactivity or active urinary infection were excluded. Baseline evaluation included detailed history, physical examination with a bulbar urethra compression test, urine analysis, multichannel urodynamics, administration of self-questionnaires assessing urinary continence (questions 1 through 3 of the urinary section of the UCLA-PCI-SF questionnaire (1)) and quality of life (QoL) (Ditrovie questionnaire (2)), flexible urethrocystoscopy, and urethrocystography. The degree of incontinence was arbitrarily categorized as mild (1–2 pads/day), moderate (3–5 pads/day) or severe (>5 pads/day), as previously described (3). Follow-up evaluation at 1, 6, 12 months, and yearly thereafter included physical examination, uroflowmetry with PVR measurement, and administration of the self-questionnaires assessing urinary continence and QoL. All patients were also asked to self-evaluate their satisfaction with the treatment. Cure was defined by no pad use and improvement by a number of pads/day ≤ 2 and reduced by at least 50%. Peri- and post-operative complications were recorded. Results From April 2006 through March 2009, 95 consecutive patients who fulfilled inclusion and exclusion criteria underwent the sling procedure using the same operative protocol. As of March 2009, 58 patients who consecutively underwent the sling procedure were expected to have a minimum follow-up of 1 year. Mean age of the patients was 67.6 ± 6.5 years (range 52-79). Mean body mass index was 27.0 ± 3.6 (range 21.3 – 39.0). Of the 58 patients, 9 (16%) patients had undergone prior surgery for SUI: bulking agent injection in 5 patients, prior sling implantation in 1 patient and artificial urinary sphincter (AUS) implantation in 4 patients. A previous urethrotomy or urethral dilatation for urethral stenosis had been performed in 8 (14%) patients and 8 (14%) patients had had pelvic irradiation. Preoperatively, 14 (24%), 26 (45%), and 18 (31%) patients were using 2 (mild SUI), 3 to 5 (moderate SUI), and >5 pads/day (severe SUI), respectively. The sling procedure was performed under general and spinal anesthesia in 22 (38%) and 36 (62%) patients, respectively, and was preceded by an endoscopic urethrotomy in 5 (9%) patients. Penile prostheses were implanted concomitantly to the sling in 2 patients. Before sling tensioning, mean MUP and ALPP were 40 ± 21 cm H2O (range 5-101) and 45 ± 22 cm H2O (range 10-100). After sling tensioning, mean MUP and ALPP were 89 ± 24 cm H2O (range 44-141) and 109 ± 26 cm H2O (range 60-165). Mean increase in MUP and ALPP between post- and pre-tensioning of the sling was 49 ± 29 cm H2O (range 1-125) and 64 ± 32 cm H2O (range 20-135), respectively. Mean operative time was 65 ± 18 minutes. No intra-operative complication was noted. Seven (12%) patients required suprapubic catheterization; normal voiding resumed in all 7 patients except 1 who underwent urinary diversion for complete radiation-induced anastomotic stenosis. Mild perineal hematoma not requiring therapy was observed in 6 patients. Six-month and 1-year minimum follow-up was available on 54 (93%) and 56 (96%) of the 58 patients, respectively (Table 1). Two patients were completely lost to follow-up after the 1-month visit. At this 1-month visit, one patient was cured while the other was improved. Table 1. Postoperative pad usage Follow-up 6-month visit 1-year visit Preoperative SUI severity / Outcome Mild to moderate SUI (≤5 pads/d) Severe SUI (> 5 pads/d) Entire cohort (≥ 2 pads/d) Mild to moderate SUI (≤ 5 pads/d) Severe SUI (> 5 pads/d) Entire cohort (≥ 2 pads/d) Cure 22 (55.0%) 9 (50.0%) 31 (53.5%) 23 (57.5%) 8 (44.5%) 31 (53.5%) Improvement 13 (32.5%) 5 (27.8%) 18 (31.0%) 14 (35.0%) 6 (33.3%) 20 (34.4%) Failure 1 (2.5%) 4 (22.2%) 5 (8.6%) 1 (2.5%) 4 (22.2%) 5 (8.6%) Data not available 4 (10.0%) 0 (0.0%) 4 (6.9%) 2 (5.0%) 0 (0.0%) 2 (3.5%) Of note, at 12 months, among the 18 patients with preoperative severe incontinence, 8 (44.5%) were cured and 6 (35%) others were improved. In addition, SUI cure/improvement rates appeared to be similar at the 6 and 12 months time points. The 3 failures included one patient who had undergone post-RP radiation therapy. This man later developed a complete urethral anastomotic closure and underwent cystectomy with transileal ureterostomy 9 months after the sling procedure. The two other failed patients had a vesico-urethral anastomotic stricture before sling implantation. Both patients were implanted with an AUS after the sling procedure. After cutting the mesh arms laterally to the bulb, the AUS cuff was placed without difficulty around the bulbar urethra. The 4th failed patient had undergone previous radiation therapy and had a bulbar urethral stenosis. He is now wearing penile collectors. The 5th patient had a vesico-urethral stenosis that underwent urethrotomy just before the sling implantation. The patient has been offered the placement of an artificial urinary sphincter. Preoperative and postoperative max flow rate and postvoid residual values were not different (Table 2). Overall, QoL was substantially enhanced and 85% patients were satisfied with the procedure. Table 2. Postoperative evolution of QoL scores and voiding parameters QoL and voiding parameters Baseline (mean ± SD [range]) 6-month visit (mean ± SD [range]) 1-year visit (mean ± SD [range]) Ditrovie QoL scores (scale from 10 [best] to 50 [worst]) 32 ± 7 (17-50) 16 ± 8 (10-40) 17 ± 8 (10-42) Max flow rate (mL/sec) 20 ± 9 (6-46) 18 ± 9 (6-44) 17 ± 10 (4-51) Post void residual (mL) 17 ± 32 (0-160) 21 ± 51 (0-243) 6 ± 21 (0-87) No sling infection, urethra erosion, persistent pain or neurological complication was observed. No sling was withdrawn or cut. Interpretation of results The inside-out transobturator sling was associated with a minimal risk of intra- and post-operative complications. Postoperative SUI cure/improvement rates were found to remain stable over a 1-year period. The sling procedure appeared to be efficient at short term even in the group of patients with severe SUI before surgery. The sling procedure does not compromise concomitant penile prostheses or subsequent AUS implantation. Longer follow-up times are required to determine the long-term efficacy of this sling procedure. Concluding message The one-year results of this prospective study suggest that the inside-out transobturator sling is a safe and efficient surgical procedure at short term for the treatment of post-RP SUI. [less ▲]

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See detailThe TVT-obturator surgical procedure for the treatment of female stress urinary incontinence: a clinical update.
Waltregny, David ULg; De Leval, Jean ULg

in International Urogynecology Journal & Pelvic Floor Dysfunction (2009), 20(3), 337-48

Six years ago, the inside-out transobturator tape TVT-O procedure was developed for the surgical treatment of female stress urinary incontinence (SUI) with the aim of minimizing the risk of urethra and ... [more ▼]

Six years ago, the inside-out transobturator tape TVT-O procedure was developed for the surgical treatment of female stress urinary incontinence (SUI) with the aim of minimizing the risk of urethra and bladder injuries and ensuring minimal tissue dissection. Initial feasibility and efficacy studies suggested that the TVT-O procedure is associated with high SUI cure rates and low morbidity at short term. A recent analysis of medium-term results indicated that the TVT-O procedure is efficient, with maintenance, after a 3-year minimum follow-up, of cure rates comparing favorably with those reported for TVT. No late complications were observed. As of July 2008, more than 35 clinical papers, including ten randomized trials and two national registries, have been published on the outcome of the TVT-O surgery. Results from these studies have confirmed that the TVT-O procedure is safe and as efficient as the TVT procedure, at least in the short/medium term. [less ▲]

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See detailTVT-O for the Treatment of Female Stress Urinary Incontinence: Results of a Prospective Study after a 3-Year Minimum Follow-Up
Waltregny, David ULg; Gaspar, Yves; Hamida, Wissem et al

in European Urology (2008), 53(2), 401-8

OBJECTIVES: Medium-term results of transobturator tapes for the treatment of female stress urinary incontinence (SUI) are largely unknown. We analyzed the 3-yr results of a prospective, observational ... [more ▼]

OBJECTIVES: Medium-term results of transobturator tapes for the treatment of female stress urinary incontinence (SUI) are largely unknown. We analyzed the 3-yr results of a prospective, observational study designed to evaluate the safety and efficacy of the TVT-O procedure. METHODS: Preoperative and postoperative evaluations included physical examination, uroflowmetry and postvoid residual (PVR) measurement, and urinary symptoms and quality of life (QoL) questionnaires. Data were compared by means of the Wilcoxon matched pairs test. RESULTS: Between March 2003 and December 2003, 102 consecutive patients with clinical and urodynamic diagnoses of SUI who fulfilled inclusion and exclusion criteria underwent the TVT-O procedure; the latter was associated with pelvic organ prolapse treatment in 16 patients (15.7%). Three-year minimum follow-up (median, 40 mo) was available for 91 patients (89.2%). No erosion or persistent pain was noted. Four patients required tape release or section. Disappearance and improvement of SUI were observed in 88.4% and 9.3% of the patients, respectively. These cure rates were similar to those obtained 1 yr after the operation (p=0.55). Frequency and urge symptoms were improved at 3 yr (p<0.005). Whereas maximum flow rates were somewhat decreased (p=0.01), the severity of obstructive symptoms and PVR volumes were not statistically different (p=0.11 and p=0.32, respectively). Incontinence severity and QoL scale scores were largely better than preoperative ones (p<0.001) and did not differ from those reported at 1 yr (p=0.15 and p=0.08, respectively). CONCLUSIONS: The TVT-O procedure is a safe and efficient treatment of female SUI, with maintenance of high cure rates after a 3-yr minimum follow-up. [less ▲]

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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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