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

Conference (2007)

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See detailAlpha-smooth muscle actin immunoreactivity in the human ileum: playing foul play?
Wedel, Theo; Waltregny, David ULg; Bogers, J. P. et al

Conference (2007)

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See detailDevelopment of urine-based DNA methylation assay for prostate cancer screening
Vener, T. I.; Derecho, C.; Varde, S. et al

Poster (2007)

Introduction: The best outcome for patients with prostate cancer (PCa) is seen for those treated at an early stage of the disease. A digital rectal examination (DRE) and the measurement of serum prostate ... [more ▼]

Introduction: The best outcome for patients with prostate cancer (PCa) is seen for those treated at an early stage of the disease. A digital rectal examination (DRE) and the measurement of serum prostate specific antigen (PSA) levels are the current standards for PCa early detection. However, serum PSA testing lacks both sensitivity and specificity, and core biopsies frequently fail to identify small foci of PCa. The availability of non-invasive diagnostic molecular tests that could allow for a more precise identification of malignant prostate cells in asymptomatic men would be of great clinical value to improve PCa diagnosis. Study design: 114 men scheduled to undergo a prostate biopsy were enrolled in the study. The biopsies were triggered either by an abnormally high PSA value or by suspicious findings on DRE. Patients with other known or suspected urinary malignancy were excluded from the study. Morning, post-prostate massage and post-biopsy urine samples were collected from all individuals. The main goals of this study were a) to determine if prostate massage can improve the prostate DNA quantity compared to urine collected in the morning or after biopsy, and b) to evaluate the methylation status of a gene panel in urine samples from subjects with cancer found in prostate biopsy tissue cores versus subjects without cancer. Methods: Gene promoter methylation is associated with prostate cancer and has been successfully used for the molecular detection of neoplasia in urine. We have developed real-time methylation specific PCR assays to define the methylation status of several genes. Results: Median age of the patients was 65 years (range 48-85). PCa was found in 51% of the patients. Histological diagnosis of the biopsies was compared to methylation results in urine from 102 samples (89% success rate due low DNA yields for 12 samples). The comparison between different urine sampling techniques showed that prostate massage is needed. The best results were obtained in post massage urine samples with a combination of GSTP1, p14, p16, RARβ2 and RASSF1A resulting in a sensitivity of 74% and a specificity of 75%. Future: A multiplex assay using the Cepheid SmartCycler™ II platform is under development. Further studies are in progress to validate the assay across multiple centers. [less ▲]

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See detailFeasibility of a urine-based DNA methylation assay for early detection of bladder cancer
Renard, Isabelle; Kelly, J.; Collette, Catherine et al

Poster (2007)

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See detailA chemical proteomics approach for the identification of accessible antigens expressed in human kidney cancer
Castronovo, Vincenzo ULg; Waltregny, David ULg; Kischel, Philippe ULg et al

in Molecular & Cellular Proteomics (2006), 5(11), 2083-2091

A promising avenue toward the development of more selective anticancer drugs consists in the targeted delivery of bioactive molecules to the tumor environment by means of binding molecules specific to ... [more ▼]

A promising avenue toward the development of more selective anticancer drugs consists in the targeted delivery of bioactive molecules to the tumor environment by means of binding molecules specific to tumor-associated markers. We have used a chemical proteomics approach based on the ex vivo perfusion and biotinylation of accessible structures within surgically resected human kidneys with tumor to gain information about accessible and abundant antigens that are overexpressed in human cancer. This procedure led to the selective labeling with biotin of vascular structures. Biotinylated proteins were purified on streptavidin resin and identified using mass spectrometric methodologies, revealing 637 proteins, 184 of which were only found in tumor specimens and 223 of which were only found in portions of normal kidneys. Immunohistochemical and PCR analysis confirmed that several of the putative cancer antigens identified in this study are indeed preferentially expressed in tumors. In conclusion, we have developed a methodology that allows the identification of accessible biomarkers in human tissues. The tumor-associated antigens identified in this study may be suitable targets for antibody-based anticancer therapies. The experimental approach described here should be applicable to other surgical specimens and to other pathologies as well as to the study of basic physiological and immunological processes. [less ▲]

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See detailActivation of the thromboxane A2 pathway in human prostate cancer correlates with tumor Gleason score and pathologic stage
Dassesse, Thibaut; de Leval, Xavier; de Leval, Laurence ULg et al

in European Urology (2006), 50(5), 1021-311031

OBJECTIVE: We investigated the potential involvement of the thromboxane A(2) (TXA(2)) pathway in human prostate cancer (PCa). METHODS: Expression of cyclooxygenase-2 (COX-2), TXA(2) synthase (TXS), and ... [more ▼]

OBJECTIVE: We investigated the potential involvement of the thromboxane A(2) (TXA(2)) pathway in human prostate cancer (PCa). METHODS: Expression of cyclooxygenase-2 (COX-2), TXA(2) synthase (TXS), and TXA(2) receptors (TPRs), the main actors of the TXA(2) pathway, was analyzed on serial tissue sections from 46 human PCa specimens. RESULTS: The expression levels of COX-2, TXS, and TPRs were significantly higher in malignant than in corresponding nontumoral prostatic epithelial cells. Increased immunoreactivity for these antigens was also observed in high-grade prostate intraepithelial neoplasia (HGPIN) glands. COX-2, TXS, and TPR proteins usually displayed a coordinated overexpression pattern in PCa lesions, as assessed in serial tissue sections. Increased levels of these proteins in the tumors were all significantly associated with higher Gleason scores and pathologic stages. CONCLUSIONS: Proteins specifically involved in the TXA(2) pathway are up-regulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation. Our study is the first to examine simultaneously all key proteins involved in this pathway including TXA(2) receptors and results suggest that the TXA(2) pathway may be a potential target for PCa prevention/therapy. [less ▲]

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See detailEvaluation of original dual thromboxane A2 modulators as antiangiogenic agents
de Leval, Xavier; Dassesse, Thibaut; Dogné, Jean-Michel ULg et al

in Journal of Pharmacology and Experimental Therapeutics (The) (2006), 318(3), 1057-1067

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A ... [more ▼]

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A(2) (TXA(2)) inhibitors derived from torasemide, a marketed loop diuretic with TXA(2) antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA(2) receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA(2) receptor agonist, and inhibited platelet TXA(2) synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA(2) inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor ( VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 mu M. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca2+ pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA(2) pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11- dideoxy- 9,11- methanoepoxyprostaglandin F 2) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl] urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2p- toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA(2) inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration. [less ▲]

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See detailNovel smooth muscle markers reveal abnormalities of the intestinal musculature in severe colorectal motility disorders
Wedel, Thilo; Van Eys, Guillaume; Waltregny, David ULg et al

in Neurogastroenterology and Motility (2006), 18(7), 526-538

Histopathological studies of gastrointestinal motility disorders have mainly focused on enteric nerves and interstitial cells of Cajal, but rarely considered the enteric musculature. Here we used both ... [more ▼]

Histopathological studies of gastrointestinal motility disorders have mainly focused on enteric nerves and interstitial cells of Cajal, but rarely considered the enteric musculature. Here we used both classical and novel smooth muscle markers and transmission electron microscopy (TEM) to investigate muscular alterations in severe colorectal motility disorders. Full-thickness specimens from Hirschsprung's disease, idiopathic megacolon, slow-transit constipation and controls were stained with haematoxylin/eosin (HE) and Masson's trichrome (MT), incubated with antibodies against smooth muscle alpha-actin (alpha-SMA), smooth muscle myosin heavy chain (SMMHC), smoothelin (SM) and histone deacetylase 8 (HDAC8) and processed for TEM. Control specimens exhibited homogeneous immunoreactivity for all antibodies. Diseased specimens showed normal smooth muscle morphology by HE and MT. While anti-alpha-SMA staining was generally normal, immunoreactivity for SMMHC, HDAC8 and/or SM was either absent or focally lacking in Hirschsprung's disease (80%), idiopathic megacolon (75%) and slow-transit constipation (70%). Ultrastructurally, clusters of myocytes with noticeably decreased myofilaments were observed in all diseases. SMMHC and the novel smooth muscle markers SM and HDAC8 often display striking abnormalities linked to the smooth muscle contractile apparatus unnoticed by both routine stainings and alpha-SMA, suggesting specific defects of smooth muscle cells involved in the pathogenesis of gastrointestinal motility disorders. [less ▲]

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See detailInside out transobturator vaginal tape for the treatment of female stress urinary incontinence: Interim results of a prospective study after a 1-year minimum followup
Waltregny, David ULg; Reul, Olivier ULg; Mathantu, Balombi et al

in Journal of Urology (The) (2006), 175(6), 2191-2195

Purpose: We analyzed the results of a prospective, observational trial designed to assess the safety and efficacy of the TVT-O procedure for female SUI. Materials and Methods: Preoperative and ... [more ▼]

Purpose: We analyzed the results of a prospective, observational trial designed to assess the safety and efficacy of the TVT-O procedure for female SUI. Materials and Methods: Preoperative and postoperative evaluations included physical examination, and urinary symptom and quality of life scale questionnaires. Results: Between March 2003 and December 2004, 253 patients with clinical and urodynamic diagnoses of SUI who fulfilled inclusion and exclusion criteria were enrolled in the trial and underwent the TVT-O procedure. No significant intraoperative complications were observed. One-year minimum followup was available on 99 of the initial 102 patients, of whom 16 had undergone concomitant pelvic organ prolapse surgical treatment. The SUI complete cure rate was 91%. No patient had vaginal or urethral erosion. Four patients required tape release or section. Frequency and urge symptoms improved after the operation (p < 0.001). The severity of obstructive symptoms slightly increased postoperatively in the group of patients who did not undergo associated pelvic organ prolapse treatment (p < 0.05), while maximum flow rates somewhat decreased (p < 0.001) and post-void residual urine volumes somewhat increased (p < 0.005). Most patients reported a significant decrease in incontinence severity and improvement in quality of life (p < 0.0001). Conclusions: The results of this study, which suggest that the TVT-O procedure is a safe and efficient surgical treatment for female SUI, warrant further comparative evaluation of this procedure with retropubic and outside in transobturator approaches in appropriately designed, prospective, randomized trials. [less ▲]

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See detailPrognostic value of PSA nadir < or =4 ng/ml within 4 months of high-dose radiotherapy for locally advanced prostate cancer
Nickers, Philippe ULg; Albert, Adelin ULg; Waltregny, David ULg et al

in International Journal of Radiation, Oncology, Biology, Physics (2006), 65(1), 73-77

PURPOSE: To investigate early prostate-specific antigen (PSA) kinetics after high radiation doses of 85 Gy on locally advanced prostate cancer. METHODS AND MATERIALS: A total of 201 patients were ... [more ▼]

PURPOSE: To investigate early prostate-specific antigen (PSA) kinetics after high radiation doses of 85 Gy on locally advanced prostate cancer. METHODS AND MATERIALS: A total of 201 patients were prospectively and consecutively treated with external beam radiotherapy and a brachytherapy boost. Of the 201 patients, 104 received concomitant hormonal therapy on the decision of the referring urologist and were excluded, yielding a study population of 97 patients. The first posttreatment PSA analysis was performed not earlier than 1 month after treatment completion but within the first 4 months, and then every 4 months. Analysis of PSA kinetics included the PSA nadir (nPSA) at values of < or =4 ng/mL to < or =0.5 ng/mL. The nPSA at < or =4 ng/mL within 4 months (nPSA < or =4/4m) was the variable of interest. RESULTS: We established highly significant associations between an nPSA of < or =1 and < or =0.5 ng/mL and the nPSA < or =4/4m (p <0.0001). A hazard ratio of 0.33 (95% Confidence Interval (CI), 0.12-0.91) underlined the lower risk of recurrence related to nPSA < or =4/4m achievement (p = 0.033). Using time-dependent covariate models for patients who did not reach an nPSA < or =4/4m, an nPSA of < or =1 ng/mL remained without prognostic significance (p = 0.06). However, for patients who reached an nPSA < or =4/4m, an nPSA of < or =1 ng/mL did significantly improve the prognosis (p <0.001), but much later after treatment. The same analysis was repeated for nPSA < or =0.5 ng/mL with similar conclusions as when nPSA < or =4/4m was obtained (p <0.01). CONCLUSION: The nPSA < or =4/4m has been demonstrated to be a significant predictor of biochemical no evidence of disease after high radiation doses of 85 Gy. Its major advantage is that it was available earlier than the other nadirs. [less ▲]

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See detailUse of histone deacetylase 8 (HDAC8), a new marker of smooth muscle differentiation, in the classification of mesenchymal tumors of the uterus
de Leval, Laurence ULg; Waltregny, David ULg; Boniver, Jacques ULg et al

in American Journal of Surgical Pathology (2006), 30(3), 319-327

Uterine smooth muscle tumors (SMTs) are usually recognized on the basis of their routine morphologic features; however, their distinction from endometrial stromal tumors (ESTs), the second most common ... [more ▼]

Uterine smooth muscle tumors (SMTs) are usually recognized on the basis of their routine morphologic features; however, their distinction from endometrial stromal tumors (ESTs), the second most common mesenchymal tumor of the uterus, is sometimes problematic. Histone deacetylases (HDACs) were originally identified as nuclear enzymes regulating histone acetylation. We have recently shown that in normal human tissues, HDAC8 is exclusively expressed in the cytoplasm of cells showing smooth muscle differentiation. In this study, we examined HDAC8 expression in SMTs and ESTs of the uterus to determine whether HDAC8 may be a useful diagnostic tool in the classification of problematic uterine mesenchymal tumors. HDAC8 immunohistochemical staining was performed in 15 leiomyomas (LMs), 9 highly cellular leiomyomas (HCLs), 8 epithelioid SMTs, 13 leiomyosarcomas (LMSs), and 17 ESTs, including 3 with sex-cord differentiation and 5 with smooth muscle differentiation. All tumors were also stained for other smooth muscle markers (desmin, h-caldesmon, smooth muscle actin [SMA], smooth muscle myosin heavy chain) and for CD 10. All LMs had moderate to strong expression of all smooth muscle markers. HDAC8 was detected in 8 of 9 HCLs and in all epithelioid SMTs (8 of 8); however, it was weak in 4 epithelioid SMTs. In contrast, desmin, h-caldesmon and smooth muscle myosin were positive in only 2 of 8, 1 of 8 and 4 of 8 epithelioid SMTs, respectively. All smooth muscle markers had similar frequency of staining in LMSs; however, HDAC8 showed overall moderate intensity compared with other smooth muscle markers, which showed stronger staining. HDAC8, h-caldesmon, and smooth muscle myosin did not stain conventional areas of ESTs or ESTs with sex-cord differentiation, whereas SMA and desmin were positive in those areas in 4 of 12 and 3 of 12 ESTs, respectively. Areas of smooth muscle differentiation in ESTs were positive for HDAC8 in all cases, but they were less constantly positive for the other smooth muscle markers. CD10 was expressed in most ESTs (14 of 17), but it was also positive in 15 of 45 SMTs. In conclusion: 1) HDAC8 seems to be a specific marker of SM differentiation because conventional ESTs and ESTs with sex-cord differentiation are negative for HDAC8, whereas areas of smooth muscle differentiation in these tumors are consistently positive; 2) HDAC8 gives similar results to those obtained with desmin, h-caldesmon, and smooth muscle myosin in both LMs and LMSs, although the staining for HDAC8 in LMSs tends to be less intense; 3) HDAC8 may be a more sensitive marker than desmin and h-caldesmon in epithelioid SMTs. Thus, HDAC8 detection may be useful in helping the differential diagnosis of uterine mesenchymal tumors. [less ▲]

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