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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 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 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 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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See detailInfusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease
Hannon, Muriel ULg; LECHANTEUR, Chantal ULg; Lucas, Sophie et al

in Transfusion (2014), 54(February), 353-363

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See detailVascular Endothelial Growth Factor-111 (VEGF-111) and tendon healing: preliminary results in a rat model of tendon injury
Kaux, Jean-François ULg; Janssen, Lauriane ULg; Drion, Pierre ULg et al

in Muscles, Ligaments and Tendons Journal (2014), 4(1 (eCollection 2014 Jan)), 25-28

Tendon lesions are among the most frequent musculoskeletal pathologies. Vascular endothelial growth factor (VEGF) is known to regulate angiogenesis. VEGF-111, a biologically active and proteolysis ... [more ▼]

Tendon lesions are among the most frequent musculoskeletal pathologies. Vascular endothelial growth factor (VEGF) is known to regulate angiogenesis. VEGF-111, a biologically active and proteolysis-resistant splice variant of this family, was recently identified. This study aimed at evaluating whether VEGF-111 could have a therapeutic interest in tendon pathologies. Surgical section of one Achilles tendon of rats was performed before a local injection of either saline or VEGF-111. After 5, 15 and 30 days, the Achilles tendons of 10 rats of both groups were sampled and submitted to a biomechanical tensile test. The force necessary to induce tendon rupture was greater for tendons of the VEGF-111 group (p<0.05) while the section areas of the tendons were similar. The mechanical stress was similar at 5 and 15 days in the both groups but was improved for the VEGF-111 group at day 30 (p <0.001). No difference was observed in the mRNA expression of collagen III, tenomodulin and MMP-9. In conclusion, we observed that a local injection of VEGF-111 improves the early phases of the healing process of rat tendons after a surgical section. Further confirmatory experimentations are needed to consolidate our results. [less ▲]

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See detailEccentric training improves tendon biomechanical properties: a rat model
Kaux, Jean-François ULg; Drion, Pierre ULg; Libertiaux, Vincent et al

in British Journal of Sports Medicine (2014, April), 48(7), 155

Background: Even if eccentric exercises appear favourable in primary prevention of tendons lesions and, especially, in secondary prevention after tendinopathy, the biomechanical changes to the tissue are ... [more ▼]

Background: Even if eccentric exercises appear favourable in primary prevention of tendons lesions and, especially, in secondary prevention after tendinopathy, the biomechanical changes to the tissue are not yet clear. Objective: We aimed to better define the biomechanical changes that affect healthy tendon after eccentric and concentric training. Design: Randomised controlled trial. Participants: Eighteen Sprague-Dawley rats of 2 months. Interventions: The six rats in the control group (U) were not subjected to physical exercise. The 12 remaining rats (6 in each group) ran on a treadmill set at a +15° incline for concentric training (C) or a -15° incline for eccentric training (E), at a speed of 17 m/min for 1 h, three times per week for 5 weeks. Main Outcome Measurements: The tricipital, patellar and Achilles tendons were subsequently removed to perform a traction test until rupture, and a histological analysis was performed. Results: There was a significant improvement in the rupture force of the patellar and tricipital tendons between the U and E groups. The tricipital tendons in the control group presented a significantly smaller cross-section than the E- and C-trained groups, but none between E and C groups. No significant difference was observed for the mechanical stress at rupture per surface unit between the three groups for all three tendons. However, a tendency towards improvement these values was observed between the trained and the U groups for the patellar tendon. Histological studies demonstrated the tendency of the development of a greater number of blood vessels and a larger quantity of collagen in the eccentric group. Conclusions: The mechanical properties of tendons in rats improve after specific training, especially following eccentric training. Our results partly explained how mechanical loading, especially in eccentric mode, could improve the tendon structure. [less ▲]

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See detailImmunomodulatory effects of Rapamycin in xenogeneic GVHD
Ehx, Grégory ULg; HANNON, Muriel ULg; DUBOIS, Sophie ULg et al

Poster (2014, January 27)

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See detailDUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase
Amand, Mathieu ULg; Erpicum, Charlotte ULg; BAJOU, Khalid ULg et al

Poster (2014, January 27)

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See detailCryopreservation of embryos : a way to reduce the number of housed animals and the genetic drift.
Remy, Benoît ULg; Ectors, Fabien ULg; Drion, Pierre ULg

Poster (2014, January 27)

The GIGA Mouse facility platform has recently improved its mouse line cryopreservation technique. The method of embryo cryopreservation by rapid cooling also called aseptic vitrification has been selected ... [more ▼]

The GIGA Mouse facility platform has recently improved its mouse line cryopreservation technique. The method of embryo cryopreservation by rapid cooling also called aseptic vitrification has been selected. Vitrification media, key steps and timing have been optimized and validated. After a first partial exposition of the embryos to cryoprotective solutions, they are immersed in a vitrifying mixture of penetrating and non-penetrating cryoprotectants for a short time. The straw containing the embryos is immediately sealed before to be plunged in LN2, resulting in a brutal solidification in which crystallization does not have time to occur. [less ▲]

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See detailGIGA ANIMAL CARE : Mice & Zebrafish Animal Facility and Transgenesis
Remy, Benoît ULg; Ectors, Fabien ULg; Winandy, Marie ULg et al

Poster (2014, January 27)

In fundamental research, animal models allow to place molecular and cellular observations back into their physiological context. In applied research, these models still remain a mandatory step to evaluate ... [more ▼]

In fundamental research, animal models allow to place molecular and cellular observations back into their physiological context. In applied research, these models still remain a mandatory step to evaluate the efficiency and the toxicity of potential treatments, before going to clinical trials. Mouse and Zebrafish (Danio rerio) are two very interesting models because of a short live cycle and a high prolificacy. They require a limited space. Their genome is well known and shows a high homology with the human. Many tools are available to produce transgenic mice or zebrafishes. Many tests are validated using both these species. [less ▲]

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See detailDevice-based controlled local delivery of anastrozol into peritoneal cavity: in vitro and in vivo evaluation
Krier, Fabrice ULg; Riva, Raphaël ULg; Defrère, Sylvie et al

in Journal of Drug Delivery Science and Technology [=JDDST] (2014), 24(2), 198-204

Local treatment using drug loaded implants allows decreasing seric concentrations of the active ingredient with the purpose of limiting side effects and reaching perfect observance. Nowadays, some ... [more ▼]

Local treatment using drug loaded implants allows decreasing seric concentrations of the active ingredient with the purpose of limiting side effects and reaching perfect observance. Nowadays, some diseases are already treated with implants, but generally, by subcutaneous or intra vaginal implantation. In this work, a new implant device dedicated to the intra-peritoneal cavity was developed. For this purpose, a core-membrane polymer implant was selected. We propose an original method to determine the most appropriate membrane to control the release based on the use of Franz cells. The ability of the implant to release a constant quantity of an active ingredient will be assessed by testing implants in vitro. Finally, intra peritoneal cavity and subcutaneous in vivo implantation has been achieved in order to confirm the controlled and local release of the active ingredient. [less ▲]

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See detailDUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase
Amand, Mathieu ULg; Erpicum, Charlotte ULg; BAJOU, Khalid ULg et al

in Molecular Cancer (2014)

Background DUSP3 phosphatase, also known as Vaccinia-H1 Related (VHR) phosphatase, encoded by DUSP3/Dusp3 gene, is a relatively small member of the dual-specificity protein phosphatases. In vitro studies ... [more ▼]

Background DUSP3 phosphatase, also known as Vaccinia-H1 Related (VHR) phosphatase, encoded by DUSP3/Dusp3 gene, is a relatively small member of the dual-specificity protein phosphatases. In vitro studies showed that DUSP3 is a negative regulator of ERK and JNK pathways in several cell lines. On the other hand, DUSP3 is implicated in human cancer. It has been alternatively described as having tumor suppressive and oncogenic properties. Thus, the available data suggest that DUSP3 plays complex and contradictory roles in tumorigenesis that could be cell type-dependent. Since most of these studies were performed using recombinant proteins or in cell-transfection based assays, the physiological function of DUSP3 has remained elusive. Results Using immunohistochemistry on human cervical sections, we observed a strong expression of DUSP3 in endothelial cells (EC) suggesting a contribution for this phosphatase to EC functions. DUSP3 downregulation, using RNA interference, in human EC reduced significantly in vitro tube formation on Matrigel and spheroid angiogenic sprouting. However, this defect was not associated with an altered phosphorylation of the documented in vitro DUSP3 substrates, ERK1/2, JNK1/2 and EGFR but was associated with an increased PKC phosphorylation. To investigate the physiological function of DUSP3, we generated Dusp3-deficient mice by homologous recombination. The obtained DUSP3-/- mice were healthy, fertile, with no spontaneous phenotype and no vascular defect. However, DUSP3 deficiency prevented neo-vascularization of transplanted b-FGF containing Matrigel and LLC xenograft tumors as evidenced by hemoglobin (Hb) and FITC-dextran quantifications. Furthermore, we found that DUSP3 is required for b-FGF-induced microvessel outgrowth in the aortic ring assay. Conclusions All together, our data identify DUSP3 as a new important player in angiogenesis. [less ▲]

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See detailEstablishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation
Binsfeld, Marilène ULg; Beguin, Yves ULg; Belle, Ludovic et al

in PLoS ONE (2014), (doi:10.1371), 113764

Background: Multiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic ... [more ▼]

Background: Multiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT) has remained controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice (previously injected with the MOPC315.BM myeloma cell line), based on a chronic graft-versus-host disease (GvHD) murine model. Methods and results: Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received 30 days later an allogeneic (B10.D2 donor) or autologous (Balb/cJ donor) transplantation by intravenous administration of bone marrow cells and splenocytes. We observed a graft-versus-myeloma effect in 94% of the allogeneic transplanted mice, as luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma evolution. Lower serum paraprotein levels and myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect, while allogeneic mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggest the involvement of effector memory CD4 and CD8 T cells in the GvM effect. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR V spectratyping analysis identified V families within CD4 and CD8 T cells which were associated with both GvM effects and GVHD, whereas other V families within CD4 T cells were associated exclusively with either GvM or GvHD responses. Conclusions: We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first immunocompetent murine model which is based on a MM model closely resembling human MM disease (bone marrow tropism, ...) and using allo-SCT after the disease establishment, as a curative treatment [less ▲]

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