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See detailAzacytidine mitigates experimental sclerodermic graft-versus-host disease
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

in Journal of Hematology & Oncology (2016)

Background Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express the gene ... [more ▼]

Background Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express the gene of the transcription factor Foxp3 whose CNS2 region is heavily methylated in conventional CD4+ T cells (CD4+Tconvs) but demethylated in Tregs. Methods Here, we assessed the impact of azacytidine (AZA) on cGVHD in a well-established murine model of sclerodermic cGVHD (B10.D2 (H-2d) → BALB/cJ (H-2d)). Results The administration of AZA every 48 h from day +10 to day +30 at the dose of 0.5 mg/kg or 2 mg/kg mitigated chronic GVHD. Further, AZA-treated mice exhibited higher blood and thymic Treg frequencies on day +35, as well as higher demethylation levels of the Foxp3 enhancer and the IL-2 promoter in splenocytes at day +52. Interestingly, Tregs from AZA-treated mice expressed more frequently the activation marker CD103 on day +52. AZA-treated mice had also lower counts of CD4+Tconvs and CD8+ T cells from day +21 to day +35 after transplantation, as well as a lower proportion of CD4+Tconvs expressing the Ki67 antigen on day +21 demonstrating an anti-proliferating effect of the drug on T cells. Conclusions Our results indicate that AZA prevented sclerodermic cGVHD in a well-established murine model of cGVHD. These data might serve as the basis for a pilot study of AZA administration for cGVHD prevention in patients at high risk for cGVHD. [less ▲]

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See detailSepramesh and postoperative peritoneal adhesions in a rat model
Arung, Willy; Drion, Pierre ULg; DETRY, Olivier ULg

in Acta Chirurgica Belgica (2016), Online

Purpose: The present study aimed to investigate the safety and the anti-postoperative peritoneal adhesion (PPA) characteristics of SeprameshVR (Davol), a composite mesh made of polypropylene covered with ... [more ▼]

Purpose: The present study aimed to investigate the safety and the anti-postoperative peritoneal adhesion (PPA) characteristics of SeprameshVR (Davol), a composite mesh made of polypropylene covered with Seprafilm, when intraperitoneally placed in a rat model. Methods: Twenty male rats were randomized into a control group and a Sepramesh group. They underwent a primary surgical procedure aiming to induce a peritoneal injury in order to induce PPAs. In the Sepramesh group, the burnt peritoneum was covered with a 2-cm diameter disc of Sepramesh prosthesis. The mesh was fixed to the parietal peritoneum with four 3-0 absorbable stitches. PPAs were assessed during a second laparotomy 10 days later using quantitative and qualitative scoring systems. Results: There was no difference in terms of mean number of PPAs between both groups. All the rats from the control group developed PPAs. In the Sepramesh group, no adhesions were observed at the site of the injured peritoneum that had been covered with the Sepramesh prosthesis, but PPAs occurred at the extremities of the mesh, where there was close contact between polypropylene and viscera, or where the fixation sutures were placed. The severity and the type of adhesions were significantly higher in the control group. Conclusions: This study demonstrated that for the Sepramesh prostheses, the Seprafilm layer might be effective in PPA prevention, but damage caused by the section and fixation of Sepramesh should be limited in order to limit PPAs. [less ▲]

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See detail188Re and 68Ga radiolabeled Starch-Based Microparticles as potential theranostic radiopharmaceutical for Hepatocellular Carcinoma
Verger, Elise ULg; Drion, Pierre ULg; MEFFRE, Geneviève ULg et al

in Journal of Nuclear Medicine (The) (2016, May 01), 57(suppl. 2),

The SBMP as a unique vector is a promising theranostic agent for the SIRT of HCC.

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See detailMicroparticules à base d’amidon radiomarquées au 188Re et 68Ga comme agent théranostique pour la radiothérapie interne sélective du carcinome hépatocellulaire
Verger, Elise ULg; Drion, Pierre ULg; MEFFRE, Geneviève ULg et al

in 2es Journées Francophones de Médecine Nucléaire (2016, May), 40(3), 182

Les microparticules SBMP, en étant capable d'être radiomarquées rapidement, de manière reproductible, sous forme de kits prêt-à-l‘emploi, par du 188Re et du 68Ga, se révèlent être un outil théranostique ... [more ▼]

Les microparticules SBMP, en étant capable d'être radiomarquées rapidement, de manière reproductible, sous forme de kits prêt-à-l‘emploi, par du 188Re et du 68Ga, se révèlent être un outil théranostique prometteur pour le traitement du carcinome hépatocellulaire. [less ▲]

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See detailAzacytidine Enhances Regulatory T-Cells In Vivo and Prevents Experimental Xenogeneic Graft-Versus-Host Disease
Ehx, Grégory ULg; Fransolet, Gilles ULg; de Leval, Laurence ULg et al

in Biology of Blood and Marrow Transplantation (2016, March), 22(3), 393

Background. The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 ... [more ▼]

Background. The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Tregs). Objective. We investigated the impact of AZA on xenogeneic graft-versus-host disease (xGVHD) in a humanized murine model of transplantation, and described the impact of the drug on human T cells in vivo. Methods. In order to induce xGVHD, human peripheral blood mononuclear cells (huPBMC) were administered intravenously in NOD-scid IL-2Rγnull (NSG) mice. Results. AZA successfully improved both survival (p<0.0001) and xGVHD scores (p<0.0001). Further, AZA significantly decreased human T-cell proliferation as well as INF-γ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA administration significantly increased the function, proliferation and frequency of Tregs through demethylation of FOXP3i1 and higher secretion of IL-2 by conventional T cells due to IL2 gene promoter site 1 demethylation. Interestingly, among AZA-treated mice surviving the acute phase of xGVHD, there was an inverse correlation between the presence of Tregs and signs of chronic GVHD. Finally, Tregs harvested from the spleen of AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Conclusion. These findings emphasize a potential role for AZA as prevention or treatment of GVHD and other autoimmune diseases. [less ▲]

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See detailMultimodality imaging assessment of the deleterious role of the intraluminal thrombus on the growth of abdominal aortic aneurysm in a rat model
NCHIMI LONGANG, Alain ULg; Courtois, Audrey ULg; EL HACHEMI, Mounia ULg et al

in European Radiology (2016), 26

Objectives To evaluate imaging changes occurring in a rat model of elastase-induced abdominal aortic aneurysm (AAA), with emphasis on the intraluminal thrombus (ILT) occurrence. Methods The post-induction ... [more ▼]

Objectives To evaluate imaging changes occurring in a rat model of elastase-induced abdominal aortic aneurysm (AAA), with emphasis on the intraluminal thrombus (ILT) occurrence. Methods The post-induction growth of the AAA diameter was characterized using ultrasound in 22 rats. ILT was reported on 13 rats that underwent 14 magnetic resonance imaging (MRI) 2-18 days post-surgery, and on 10 rats that underwent 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET)/microcomputed tomography examinations 2-27 days post-surgery. Logistic regressions were used to establish the evolution with time of AAA length, diameter, ILT thickness, volume, stratification, MRI and FDG PET signalling properties, and histological assessment of inflammatory infiltrates. Results All of the following significantly increased with time post-induction (p < 0.001): AAA length, AAA diameter, ILT maximal thickness, ILT volume, ILT iron content and related MRI signalling changes, quantitative uptake on FDG PET, and the magnitude of inflammatory infiltrates on histology. However, the aneurysm growth peak followed occurrence of ILT approximately 6 days after elastase infusion. Conclusion Our model emphasizes that occurrence of ILT precedes AAA peak growth. Aneurysm growth is associated with increasing levels of iron, signalling properties changes in both MRI and FDG PET, relating to its biological activities. [less ▲]

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See detailL'Azacytidine comme traitement de la maladie du greffon contre l'hôte de type chronique sclérodermique expérimentale.
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

Conference (2015, November 19)

Introduction: Graft-versus-host disease (GVHD) has remained a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) for the last decades. Following unmanipulated peripheral-blood ... [more ▼]

Introduction: Graft-versus-host disease (GVHD) has remained a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) for the last decades. Following unmanipulated peripheral-blood stem cell transplantation, 60% of the patients experience chronic GVHD while approximately 15% of them develop a sclerodermic form of chronic GVHD characterized by multiple organ fibrosis and loss of skin elasticity. Regulatory T cells (Tregs) play a pivotal protective role in the pathogenesis of chronic GVHD by inhibiting alloreactive conventional T cells (Tconvs). Several studies have shown that hypomethylating agents such as azacytidine (Aza) can demethylate the master transcription factor of Treg (Forkhead box protein 3 factor, FoxP3), thus promoting Treg differentiation from Tconvs. This work investigates the impact of Aza in a classical murine model of sclerodermic chronic GVHD (B10.D2  BALB/cJ). Methods: In vitro analyses have been performed to determine the impact of Aza on collagen production. NIH-3T3 fibroblastic cells were plated and stimulated with 50 ng of PDGF or 10 ng of TGF-beta. Cells were then cultured with various concentrations of Aza for 48 hours. After culture, cells were stained with Sirius Red before quantification of collagen amount by absorbance at 490 nm. For in vivo experiments, lethally irradiated (7 Gy) BALB/cJ recipient mice were injected with 107 bone marrow cells + 7.107splenocytes from B10.D2 donor mice to induce scl-cGVHD. Recipients were injected with either 0,5 or 2 mg/kg of Aza every 48 hours from day 10 to 30 following transplantation. GVHD was scored using a five criteria scale (weight loss, activity, fibrosis, hair loss and mice posture; 0-1-2 points/criteria). Mice were sacrificed at a score of 8/10 (or > 20% weight loss) or at day 52 after transplantation (end of experiment). Results: Concerning in vitro analyses, results suggest a decreased production of collagen at higher concentration of Aza with both stimulations (seen by a gradual diminution of absorbance). For in vivo experiments, mice treated with Aza 0.5 mg/kg (n = 14) or 2 mg/kg (n = 25) had significant lower clinical scores of GVHD compared to control ones (n = 23) after treatment. FACS analysis showed a higher proportion of Treg among CD4+ T cells in the blood of Aza 2 mg/kg mice than in control mice at day 35 following transplantation (P = 0.047), as well as a higher percentage of Tregs expressing the KI67 proliferative marker on the same time point (P = 0.0005). Finally, analyses of the cellular blood components with Cell-dyn demonstrated that Aza 2 mg/kg treated mice were significantly lymphopenic as compared to control mice at day 35 after transplantation (P = 0.05). Conclusion : Aza prevented sclerodermic GVHD in this classical murine model of chronic GVHD. [less ▲]

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See detailPlasma riche en plaquettes pour le traitements de lésions tendineuses
Kaux, Jean-François ULg; Drion, Pierre ULg; Croisier, Jean-Louis ULg et al

in Journal de Réadaptation Médicale (2015), 35(3), 181-191

Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to ... [more ▼]

Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. Materials and method: Articles in French and English, published between 1 January 2012 and 30 September 2014 dealing with PRP and tendons were searched for using the Medline and Scopus data bases. Results: Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, 5 addressed lateral epicondylitis, 2 addressed rotator cuff tendinopathies, 10 dealt with patellar tendinopathies and 3 looked at Achilles tendinopathies. Conclusions: The majority of pre-clinical studies show that PRP stimulates the tendon's healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed. [less ▲]

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See detailPreovulatory follicle diameter, growth rate and time of ovulation during induced oestrus using a CIDR® in trypanotolerant female Bos taurus N'Dama cattle.
Okouyi, M'foumou W'otari Marcel; Drion, Pierre ULg; Hanzen, Christian ULg

in Tropical Animal Health and Production (2015), 47

The aim of this study was to assess the dose (300 to 600 IU) effects of equine Chorionic Gonadotropin (eCG) on the preovulatory follicle diameter, growth rate, and time of ovulation characterized by ... [more ▼]

The aim of this study was to assess the dose (300 to 600 IU) effects of equine Chorionic Gonadotropin (eCG) on the preovulatory follicle diameter, growth rate, and time of ovulation characterized by echography. The eCG was injected at the end (D0) of the 7-day treatment with a controlled internal device release (CIDR) and a PGF2a being injected 2 days before the removal of the CIDR (D-2). The 120 female N'Dama cattle were distributed into five experimental groups. The control group (n = 26) was treated with physiological saline at the removal of the CIDR®, while the animals in the four treated groups received, respectively, 300 IU (n = 25), 400 IU (n = 24), 500 IU (n = 22) and 600 IU (n = 23) of eCG (Folligon®). Follicle growth rate (FGR) was significantly (P < 0.05) higher in animals treated using eCG (1.0 ± 0.4mm/day) than in the control group (0.9 ± 0.4mm/day). The diameter of the preovulatory follicle was significantly higher (P < 0.05) in the animals treated with 300 IU (10.1 ± 1.4mm) than in untreated animals (9.3 ± 1.2mm). Follicle growth rate was significantly higher (P<0.05) inn the animals treated with 300 IU (10,1 ± 1,4 mm) than in the control group (0.9±0,4 mm/day). The average interval between the time of eCG injection and ovulation was similar in the non-treated (83.7 ± 14.4 h) and treated animals (79.7 ± 11.9). Treated animals sowed a significant increase in the percentga of ovulation (94,7 %) compared to 73,1 %) (P<0.01). Use of eCG combined contributed towards synchronising the time of ovulation between 72 to 96 hours, which would facilitate the use of systematic insemination. [less ▲]

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See detailHigh-dose oral intake of serotonin induces valvular heart disease in rabbits.
Lancellotti, Patrizio ULg; NCHIMI LONGANG, Alain ULg; Hego, Alexandre ULg et al

in International Journal of Cardiology (2015), 197

Carcinoid tumors are rare neuroendocrine malignancies, often originating from enterochromaffin cells in the gastrointestinal tract. They can secrete serotonin (5-hydroxytryptamine, 5-HT), which is largely ... [more ▼]

Carcinoid tumors are rare neuroendocrine malignancies, often originating from enterochromaffin cells in the gastrointestinal tract. They can secrete serotonin (5-hydroxytryptamine, 5-HT), which is largely inactivated by the liver. Carcinoid heart disease occurs when tumor cells metastasize to the liver, as the vasoactive substances produced are able to reach the systemic circulation via the hepatic vein, causing deposition of fibrous tissue on the endocardial surfaces of the heart. It is predominantly manifested by right-sided valvular heart disease (VHD). Scavenging enzymes in the pulmonary endothelium may explain why left-sided cardiac involvement is unusual. The severity of cardiac damage is correlated with the plasmatic levels of serotonin, but the lowspecificity of serotonin for cardiac damage suggests that serotonin may be necessary but not sufficient to induce cardiac lesions. Therefore, other factors combined with serotonin might be required to induce VHD. However, recent animal studies confirmed the development of carcinoid-like valvular deposits in rats after 3 months of daily subcutaneous/intraperitoneal serotonin injections to avoid the liver first-pass clearance.Whether oral administration of serotonin can also induce VHD is unknown. We hypothesized that long-term oral serotonin overload in rabbits can lead to VHD, mimicking serotonin-induced lesions of carcinoid heart disease. We demonstrate, for the first time that high dose long-term oral administration of serotonin can lead to VHD in rabbits. [less ▲]

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See detailImpact of biomaterial physical characteristics on bone regeneration: Comparison of three hydroxyapatites
LAMBERT, France ULg; Bacevic, Miljana ULg; Schupbach, P et al

Poster (2015, June 03)

Bone regeneration biomaterials with identical chemical compositions are frequently considered by clinicians as similar. However, the clinical performance of regenerative biomaterial may be influenced by ... [more ▼]

Bone regeneration biomaterials with identical chemical compositions are frequently considered by clinicians as similar. However, the clinical performance of regenerative biomaterial may be influenced by other parameters such as topographical properties. [less ▲]

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See detailTendinopathies and platelet-rich plasma (PRP): from pre-clinical experiments to therapeutic use
KAUX, Jean-François ULg; Drion, Pierre ULg; Croisier, Jean-Louis ULg et al

in Journal of Stem Cell & Regenerative Medicine (2015), 11(1), 7-17

Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to ... [more ▼]

Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. Materials and method: Articles in French and English, published between 1 January 2012 and 31 December 2014 dealing with PRP and tendons were searched for using the Medline and Scopus data bases. Results: Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, five addressed lateral epicondylitis, two addressed rotator cuff tendinopathies, ten dealt with patellar tendinopathies and three looked at Achilles tendinopathies. Conclusions: The majority of pre-clinical studies show that PRP stimulates the tendon's healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed. [less ▲]

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See detailDUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis
Musumeci, Lucia ULg; Kuijpers, Marijke; Gilio, Karen et al

in Circulation (2015), 131(7), 656-68

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet ... [more ▼]

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) have emerged as critical regulators of platelet function. Methods and Results This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of PLCγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen and CLEC-2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. Conclusions DUSP3 plays a selective and essential role in collagen- and CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug. [less ▲]

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See detailAzacytidine prevents experimental sclerodermic chronic graft-versus-host disease
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

Poster (2015, January 30)

Introduction: Graft-versus-host disease (GVHD) remains one major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Following unmanipulated peripheral-blood stem cell ... [more ▼]

Introduction: Graft-versus-host disease (GVHD) remains one major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Following unmanipulated peripheral-blood stem cell transplantation, 60% of the patients experience chronic GVHD while approximately 15% of them develop a sclerodermic form of chronic GVHD characterized by multiple organ fibrosis and loss of skin elasticity. Regulatory T cells (Tregs) play a pivotal role in the pathology of chronic GVHD by inhibiting alloreactive conventional T cells. Several studies have shown the hypomethylating agent Azacytidine (Aza) can demethylate the master transcription factor of Treg (Forkhead box protein 3 factor, FoxP3), thus promoting Treg differentiation of conventional T cells. This work investigates the impact of Aza in a classical murine model of sclerodermic chronic GVHD (B10.D2  BALB/cJ). Methods: Lethally irradiated BALB/cJ recipient mice were injected with 107 bone marrow cells + 7.107splenocytes from B10.D2 donor mice. Recipients were treated with subcutaneous injections of Aza at the dose of 0,5 or 2 mg/kg every two days from day 10 to 30 following transplantation. Mice GVHD was evaluated with five criteria (weight loss, activity, fibrosis, hair loss and mice posture; 0-1-2 points/criteria). Mice were sacrificed at a score of 8/10 (or > 20% weight loss). Results: Mice treated with Aza 0.5 mg/kg (n = 14) or 2 mg/kg (n = 17) had significant lower clinical scores compared to control ones (n = 15) after treatment. FACS analysis showed a higher proportion of Treg among CD4+ T cells in the blood of Aza 2 mg/kg mice than in control mice (P = 0.047), as well as a higher percentage of Tregs expressing the KI67 proliferative marker on the same day (P = 0.0005). Finally, analyses of the cellular blood components with Cell-dyn demonstrated that Aza 2 mg/kg treated mice were significantly lymphopenic as compared to control mice (P = 0.05). Conclusion : Aza prevented sclerodermic GVHD in this classical murine model of chronic GVHD. [less ▲]

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See detailAsporin Is a Fibroblast-Derived TGF-beta1 Inhibitor and a Tumor Suppressor Associated with Good Prognosis in Breast Cancer.
Maris, Pamela; Blomme, Arnaud; Palacios, Ana Perez et al

in PLoS medicine (2015), 12(9), 1001871

BACKGROUND: Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-beta1 has been identified as a key ... [more ▼]

BACKGROUND: Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-beta1 has been identified as a key driving force behind metastatic breast cancer, with promising therapeutic implications. METHODS AND FINDINGS: Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1beta, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-beta1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort. CONCLUSIONS: Our data show that asporin is a stroma-derived inhibitor of TGF-beta1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy. [less ▲]

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See detailOleuropein or rutin consumption decreases the spontaneous development of osteoarthritis in the Hartley guinea pig.
Horcajada, M.-N.; Sanchez, Christelle ULg; Membrez Scalfo et al

in Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society (2015), 23(1), 94-102

OBJECTIVE: To assess the potential protective effects of three polyphenols oleuropein, rutin and curcumin, on joint ageing and osteoarthritis (OA) development. DESIGN: Sixty 4-week-old Dunkin-Hartley ... [more ▼]

OBJECTIVE: To assess the potential protective effects of three polyphenols oleuropein, rutin and curcumin, on joint ageing and osteoarthritis (OA) development. DESIGN: Sixty 4-week-old Dunkin-Hartley guinea pigs were randomized into four groups and received daily during 31 weeks either standard guinea pig diet (control group) or a standard guinea pig diet enriched with oleuropein (0.025%), rutin (0.5%) or rutin/curcumin (0.5%/0.25%) association. Biomarkers of OA (Coll2-1, Coll2-1NO2, Fib3-1, Fib3-2, ARGS), as well as inflammation (PGE2) were quantified in the serum. Histological assessments of knee cartilage and synovial membrane were performed at week 4 (five young reference guinea pigs) and week 35. RESULTS: At week 35, guinea pigs in the control group spontaneously developed significant cartilage lesions with mild synovial inflammation. The histological scores of cartilage lesions and synovitis were well correlated with the increased level of serum biomarkers. Histologically, all treatments significantly reduced the cartilage degradation score (P < 0.01), but only oleuropein significantly decreased the synovial histological score (P < 0.05) and serum PGE2 levels (P < 0.01) compared to the control group. Coll2-1 was decreased by rutin and the combination of rutin/curcumin, Fib3-1 and Fib3-2 were only decreased by the rutin/curcumin mixture, while Coll2-1NO2 was significantly decreased by all treatments (P < 0.05). CONCLUSION: Oleuropein and rutin +/- curcumin significantly slowed down the progression of spontaneous OA lesions in guinea pigs. While no additive effect was seen in the curcumin + rutin group, the differential effects of oleuropein and rutin on inflammatory and cartilage catabolic markers suggest an interesting combination for future studies in OA protection. [less ▲]

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See detailSex Differences in Abdominal Aortic Aneurysm: the Role of Sex Hormones.
Makrygiannis, Georgios ULg; Courtois, Audrey ULg; Drion, Pierre ULg et al

in Annals of vascular surgery (2014), 28(8), 1946-1958

Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in males, whereas women have a greater risk of rupture and more frequently ... [more ▼]

Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in males, whereas women have a greater risk of rupture and more frequently have concomitant thoracic aortic aneurysms. Moreover, women are diagnosed with AAA about 10 years later and seem to be protected by female sex hormones. In this MEDLINE-based review of literature we examined human and animal, in vivo and in vitro studies, to further deepen our understanding of the sexual dimorphism of AAA. We focus on the role of sex hormones during the formation and growth of AAA. Endogenous estrogens and exogenous 17beta-estradiol were found to exert favorable actions protecting from AAA in animal models, whereas exogenous hormone replacement therapy in humans had inconclusive results. Androgens, known to have detrimental effects in the vasculature, in sufficient levels maintain the integrity of the aortic wall through their anabolic actions and act differentially in males and females, whereas lower levels of testosterone have been associated with AAA in humans. In conclusion, sex differences remain an important area of AAA research, but further studies especially in humans are needed. Furthermore, differential molecular mechanisms of sex hormones constitute a potential therapeutic target for AAA. [less ▲]

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See detailPlasma riche en plaquettes et lésions tendineuses
KAUX, Jean-François ULg; Drion, Pierre ULg; Croisier, Jean-Louis ULg et al

in Revue Médicale de Liège (2014), 69(Synthèse 2014), 72-77

Platelets contain growth factors released during their degranulation following activation. These growth factors promote tissue remodeling, wound healing and angiogenesis. Currently, the clinical effect of ... [more ▼]

Platelets contain growth factors released during their degranulation following activation. These growth factors promote tissue remodeling, wound healing and angiogenesis. Currently, the clinical effect of Platelet-Rich Plasma (PRP) is still discussed or even controversial. Our researches have evaluated the effectiveness of PRP on the healing of animal tendons and human suffering from chronic jumper's knee. [less ▲]

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