Azacytidine Enhances Regulatory T-Cells In Vivo and Prevents Experimental Xenogeneic Graft-Versus-Host Disease
Ehx, Grégory ; Fransolet, Gilles ; de Leval, Laurence 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 ▲]Detailed reference viewed: 20 (9 ULg)
Diffuse large B-cell lymphoma of Waldeyer's ring has distinc clinicopathologic features: a GELA study.
de Leval, Laurence ; Bonnet, Christophe ; et al
in Annals of Oncology (2012), 23(12)
Background Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. Patients and methods We analyzed a cohort of 187 primary Waldeyer's ring ... [more ▼]
Background Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. Patients and methods We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. Results Most patients (92%) had stage I–II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). Conclusions WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart. [less ▲]Detailed reference viewed: 15 (2 ULg)
Surgical treatment of cardiovascular complications in patients with Marfan syndrome: a report of two cases and literature review.
BRULS, Samuel ; Radermecker, Marc ; et al
in Acta Chirurgica Belgica (2012), 112(3), 213-8
Cardiovascular disease is the main cause of morbidity and mortality in patients with Marfan syndrome. The most life threatening complication is aortic root aneurysms leading to aortic dissection or ... [more ▼]
Cardiovascular disease is the main cause of morbidity and mortality in patients with Marfan syndrome. The most life threatening complication is aortic root aneurysms leading to aortic dissection or rupture. It can be prevented by regular aortic follow-up and prophylactic aortic surgery. Modern aortic surgery has led to a substantial increase in the life expectancy of these patients. We report two cases of Marfan syndrome with cardiovascular complications. Their management is discussed according to the most recent literature. [less ▲]Detailed reference viewed: 35 (6 ULg)
Cardiac paraganglioma : diagnostic work up and review of the literature.
Sooknunden, Marvyn ; HAMOIR, Etienne ; de Leval, Laurence et al
in Acta Chirurgica Belgica (2012), 112Detailed reference viewed: 56 (3 ULg)
c-Maf expression in angioimmunoblastic T-cell lymphoma reflects follicular helper T-cell derivation rather than oncogenesis
Bisig, Bettina ; Thielen, Caroline ; HERENS, Christian et al
in Histopathology (2012), 60(2), 371-376Detailed reference viewed: 70 (14 ULg)
BM-573 INHIBITS THE EARLY ATHEROSCLEROTIC LESIONS IN APO-E DEFICIENT MICE BY BLOCKING TP RECEPTORS AND THROMBOXANE SYNTHASE
Cherdon, Céline ; ; Hanson, Julien et al
in Congress of the International Society of Thrombosis and Hemostasis- 57th Annual SSC Meeting (2011, July)
Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2() have recently ... [more ▼]
Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2() have recently received a lot of attention. This study aimed to investigate the effect of a dual thromboxane synthase inhibitor and thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB(2) synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF(2(). Our results show that a molecule combining receptor antagonism and thromboxane synthase inhibition is more efficient in delaying atherosclerosis in Apo E(-/-) mice than sole inhibition of TXA(2) formation. [less ▲]Detailed reference viewed: 75 (11 ULg)
Primary central nervous system lymphoma in a patient treated with Natalizumab.
Phan-Ba, Rémy ; Bisig, Bettina ; Deprez, Manuel et al
in Annals of Neurology (2011), 69(6), 1060-1Detailed reference viewed: 72 (15 ULg)
BM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase.
Cherdon, Céline ; ; Hanson, Julien et al
in Prostaglandins & Other Lipid Mediators (2011)
Le cas clinique du mois. A propos d'un cas de sequestration pulmonaire intralobaire diagnostique a l'age adulte.
Somja, Joan ; de Leval, Laurence ; Boniver, Jacques et al
in Revue Médicale de Liège (2011), 66(1), 7-12
Pulmonary sequestration is a rare congenital lung malformation characterized by an abnormal segment of bronchopulmonary tissue supplied by aberrant systemic arteries. Due to the non-specific ... [more ▼]
Pulmonary sequestration is a rare congenital lung malformation characterized by an abnormal segment of bronchopulmonary tissue supplied by aberrant systemic arteries. Due to the non-specific symptomatology, the diagnosis can be missed. Imaging is the cornerstone of the diagnosis. Complete surgical resection provides the definitive treatment. We report a case of pulmonary sequestration associated with an asymptomatic aspergillosis presenting during adulthood and describe briefly the epidemiology, embryology, histology, imaging and surgical treatment of this congenital abnormality. [less ▲]Detailed reference viewed: 19 (3 ULg)
Identification of stromal proteins overexpressed in nodular sclerosis Hodgkin lymphoma.
; Waltregny, David ; et al
in Proteome Science (2011), 9(1), 63
ABSTRACT: Hodgkin lymphoma (HL) represents a category of lymphoid neoplasms with unique features, notably the usual scarcity of tumour cells in involved tissues. The most common subtype of classical HL ... [more ▼]
ABSTRACT: Hodgkin lymphoma (HL) represents a category of lymphoid neoplasms with unique features, notably the usual scarcity of tumour cells in involved tissues. The most common subtype of classical HL, nodular sclerosis HL, characteristically comprises abundant fibrous tissue stroma. Little information is available about the protein composition of the stromal environment from HL. Moreover, the identification of valid protein targets, specifically and abundantly expressed in HL, would be of utmost importance for targeted therapies and imaging, yet the biomarkers must necessarily be accessible from the bloodstream. To characterize HL stroma and to identify potentially accessible proteins, we used a chemical proteomic approach, consisting in the labelling of accessible proteins and their subsequent purification and identification by mass spectrometry. We performed an analysis of potentially accessible proteins in lymph node biopsies from HL and reactive lymphoid tissues, and in total, more than 1400 proteins were identified in 7 samples. We have identified several extracellular matrix proteins overexpressed in HL, such as versican, fibulin-1, periostin, and other proteins such as S100-A8. These proteins were validated by immunohistochemistry on a larger series of biopsy samples, and bear the potential to become targets for antibody-based anti-cancer therapies. [less ▲]Detailed reference viewed: 102 (15 ULg)
CHIC cells: a novel ALK+ cell line derived from a relapsed anaplastic large cell lymphoma
Thielen, Caroline ; Bisig, Bettina ; Gofflot, Stéphanie et al
in British Journal of Haematology (2011), 152
Since the initial description of anaplastic large cell lymphoma (ALCL) as a proliferation of large CD30+ lymphoid cells, the morphological spectrum of ALCL positive for anaplastic lymphoma kinase (ALCL ... [more ▼]
Since the initial description of anaplastic large cell lymphoma (ALCL) as a proliferation of large CD30+ lymphoid cells, the morphological spectrum of ALCL positive for anaplastic lymphoma kinase (ALCL, ALK+) has expanded, and beyond the common pattern most frequently encountered, several variants have been identified, including the lymphohistiocytic and the small cell patterns (Swerdlow et al, 2008). Only ten ALK+ ALCL cell lines are currently available, and most were derived from tumours demonstrating the common type morphology (Drexler & MacLeod, 2004). We have established a novel cell line (CHIC) from the cerebrospinal fluid of a 32-year-old man with relapsing/refractory ALK+ ALCL with a t(2;5)(p23;q35) translocation whose initial tumour exhibited lymphohistiocytic features. This cell line is now made available to the scientific community. In addition to multiple in vitro applications, the tumourigenic capacity of these cells represents a useful property for in vivo drug testing. [less ▲]Detailed reference viewed: 57 (22 ULg)
Non complicated large complex tear in an aneurysmal Marfan ascending aorta.
Brüls, Samuel ; Radermacher, Vincent ; de Leval, Laurence et al
in Annals of Thoracic Surgery (2010), 89(5), 1674Detailed reference viewed: 71 (28 ULg)
Le cas clinique du mois. La triade "classique" de présentation de certains cancers bronchiolo-alvéolaires mucineux.
; de Leval, Laurence ; et al
in Revue Médicale de Liège (2010), 65(11), 611-4
The case of a 59-year-old female complaining of cough of recent onset, abundant salty expectoration and lung condensation is presented. This "triad" constitutes a rare but nearly pathognomonic ... [more ▼]
The case of a 59-year-old female complaining of cough of recent onset, abundant salty expectoration and lung condensation is presented. This "triad" constitutes a rare but nearly pathognomonic presentation of mucinous bronchioloalveolar carcinoma (BAC) of the lung. [less ▲]Detailed reference viewed: 102 (5 ULg)
Diverse phenotypic profile of uterine tumors resembling ovarian sex cord tumors: an immunohistochemical study of 12 cases.
de Leval, Laurence ; ; Waltregny, David et al
in American Journal of Surgical Pathology (2010), 34(12), 1749-61
BACKGROUND: Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare neoplasms thought to be of putative endometrial stromal origin and solely composed of sex cord elements. Our study aimed ... [more ▼]
BACKGROUND: Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare neoplasms thought to be of putative endometrial stromal origin and solely composed of sex cord elements. Our study aimed to delineate the immunophenotype of these tumors and to verify whether their morphology reflects true sex cord-like differentiation. DESIGN: Representative paraffin blocks from 12 UTROSCTs were selected after confirmation of the diagnosis. Cords and/or trabeculae were seen in all tumors, whereas tubules, diffuse areas, and a retiform pattern were present in 9, 6, and 2 cases, respectively. Tumors were stained for sex cord (inhibin, calretinin, WT1, and melan-A), epithelial (KL1 and epithelial membrane antigen), and smooth muscle markers (smooth muscle actin, desmin, smooth muscle myosin heavy chain, h-caldesmon, and histone deacetylase-8), CD10, HMB45, S100, and CD117. Intensity and percentage of staining were recorded. RESULTS: Six out of 12 tumors were positive for sex cord markers (inhibin 3 of 12, calretinin 4 of 12, WT1 4 of 12, and melan-A 3 of 11) with 4 tumors coexpressing more than one marker. Half of the UTROSCTs showed positivity for KL1, with 2 tumors coexpressing epithelial membrane antigen. All but one tumor expressed one or more smooth muscle markers, with smooth muscle actin, desmin and histone deacetylase-8 being most commonly expressed. CD10 was positive in 6 of 12 tumors, CD117 in 4 of 12, and S100 in 2 of 11 tumors, whereas HMB45 was negative in 11 tumors tested. CONCLUSIONS: UTROSCTs have a diverse immunohistochemical profile often coexpressing sex cord, epithelial, and smooth muscle markers. The expression of smooth muscle markers in these tumors does not imply a smooth muscle origin as endometrial and sex cord stromal tumors are not infrequently positive for these markers. Positivity for sex cord markers supports a true sex cord/steroid phenotype. Although the immunohistochemical profile of these tumors overlaps with that of endometrial stromal tumors with sex cord-like differentiation as well as ovarian sex cord stromal tumors, the origin of UTROSCT remains uncertain. [less ▲]Detailed reference viewed: 27 (0 ULg)
Pneumopathies organisées: à propos de 3 cas
; Frusch, Nicolas ; Louis, Renaud et al
in Revue Médicale de Liège (2010), 65(10), 549-55
Infiltrative lung lesions are not always linked to infectious processes or cancers. An interesting entity, the OP (Organizing Pneumonia) or COP (Cryptogenic Organizing Pneumonia)--formerly BOOP ... [more ▼]
Infiltrative lung lesions are not always linked to infectious processes or cancers. An interesting entity, the OP (Organizing Pneumonia) or COP (Cryptogenic Organizing Pneumonia)--formerly BOOP (Bronchiolitis Obliterans Organizing Pneumonia)--is discussed through observations repor. ted in this article. We provide some keys to allow the astute observer to target this often curable disease. [less ▲]Detailed reference viewed: 58 (3 ULg)
Hyperacute graft rejection during heart transplantation for giant cell myocarditis: A case report.
; Delbecque, Katty ; Defraigne, Jean-Olivier et al
in Pathology - Research & Practice (2010), 15(206), 411-4
We report the case of a patient with giant cell myocarditis who was bridged to transplantation with mechanical circulatory support and developed a fatal perioperative hyperacute rejection. The patient had ... [more ▼]
We report the case of a patient with giant cell myocarditis who was bridged to transplantation with mechanical circulatory support and developed a fatal perioperative hyperacute rejection. The patient had received abundant transfusions that had raised her anti-HLA antibody titers. The cross-match test was positive. No pre-transplantation immunosuppressive therapy had been administered given concomitant infection. The severity and acuteness of the rejection in this case likely reflect the combined effect of preformed anti-HLA antibodies in the context of an active organ-specific immune process at the time of transplantation. This case raises the questions of the need for intensive immunosuppressive therapy before transplantation in giant cell myocarditis and of the management of patients with positive cross-match in the context of a giant cell myocarditis. [less ▲]Detailed reference viewed: 39 (9 ULg)
Identification and Validation of the Methylated TWIST1 and NID2 Genes through Real-Time Methylation-Specific Polymerase Chain Reaction Assays for the Noninvasive Detection of Primary Bladder Cancer in Urine Samples.
; ; et al
in European urology (2010)
BACKGROUND: Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers. OBJECTIVE: To determine whether a panel of methylated genes would have the ... [more ▼]
BACKGROUND: Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers. OBJECTIVE: To determine whether a panel of methylated genes would have the potential to identify primary bladder cancer (BCa) in voided urine samples. DESIGN, SETTING, AND PARTICIPANTS: A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls. MEASUREMENTS: A urine sample was classified as valid when >/=10 copies of the gene encoding ss-actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared. RESULTS AND LIMITATIONS: MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively. CONCLUSIONS: Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (>/=90%) sensitive and specific, noninvasive approach for detecting primary BCa. TRIAL REGISTRATION: BlCa-001 study - EudraCt 2006-003303-40. [less ▲]Detailed reference viewed: 100 (6 ULg)
The use of an adapted model allows contributing to the “Reduction” of mice used in experimental protocols: the case of the apoE–deficient (apo E-/-) mice in a model of atherosclerosis control
Cherdon, Céline ; ; de Leval, Laurence et al
Poster (2009, December 01)
Atherosclerosis is a chronic vascular disease whose development is influenced by several mediators 1. Among them, the prostanoids large family lipids generated from the metabolism of arachidonic acid by ... [more ▼]
Atherosclerosis is a chronic vascular disease whose development is influenced by several mediators 1. Among them, the prostanoids large family lipids generated from the metabolism of arachidonic acid by the action of COX includes various types of PGs and thromboxane. Thromboxane A2 and PGI2 are present in abnormally elevated concentration in atherosclerosis 2-3. To exert its effects TXA2 and its precursor PGH2 act at a specific receptor termed TP receptor 4. As a result, TXA2 synthase inhibitors and TP antagonists have been developed to reduce and to prevent TXA2 production and actions, respectively. The present study was undertaken in order to investigate whether BM-573, an original sulfonylurea derivate synthesized in our lab 5, and aspirin would be effective in preventing the progression of atherosclerosis in an apo E deficient mouse model. [less ▲]Detailed reference viewed: 60 (14 ULg)
Le bm-573, un antagoniste original du récepteur au thromboxane a2, réduit le développement des lésions athéromateuses chez des souris déficientes en apolipoprotéine e (apo e-/-) contrairement a l’aspirine.
Cherdon, Céline ; ; Ooms, Annie et al
(2009, May 28)
Afin d’examiner l'efficacité de l’aspirine et du BM-573 dans l'athérogenèse, des souris apo E-/- femelles ont été traitées durant 10 et 20 semaines avec le BM-573 (10mg/kg/j), l’aspirine (30mg/kg/j) ou un ... [more ▼]
Afin d’examiner l'efficacité de l’aspirine et du BM-573 dans l'athérogenèse, des souris apo E-/- femelles ont été traitées durant 10 et 20 semaines avec le BM-573 (10mg/kg/j), l’aspirine (30mg/kg/j) ou un placébo. Au cours de cette expérience, aucune modification du poids corporel ou de la cholestérolémie n’a été observée. Par contre, le traitement des animaux par le BM-573, a eu pour effet de diminuer les lésions athéromateuses de manière significative tandis que l’aspirine a été sans effet sur ce paramètre. Ces données ont été confirmées par des analyses histopathologiques et biochimiques. Ces résultats confirment que l'antagonisme sélectif des récepteurs TP associé à une inhibition de la thromboxane synthétase réduit significativement les lésions athéromateuses chez les souris apo E-/-. Le BM-573 est, par conséquent, un agent thérapeutique potentiel pour la prévention de l'athérosclérose. [less ▲]Detailed reference viewed: 51 (12 ULg)
Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes.
Robert, Isabelle ; Aussems, Marie ; Keutgens, Aurore et al
in Oncogene (2009), 28(13), 1626-1638
Constitutive nuclear factor (NF)-kappaB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-kappaB inhibitory molecules such ... [more ▼]
Constitutive nuclear factor (NF)-kappaB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-kappaB inhibitory molecules such as IkappaBalpha or p100. Hut-78, a truncated form of p100, constitutively generates p52 and contributes to the development of T-cell lymphomas but the molecular mechanism underlying this oncogenic potential remains unclear. We show here that MMP9 gene expression is induced through the alternative NF-kappaB-activating pathway in fibroblasts and also on Hut-78 or p52 overexpression in fibroblasts as well as in lymphoma cells. p52 is critical for Hut-78-mediated MMP9 gene induction as a Hut-78 mutant as well as other truncated NF-kappaB2 proteins that are not processed into p52 failed to induce the expression of this metalloproteinase. Conversely, MMP9 gene expression is impaired in p52-depleted HUT-78 cells. Interestingly, MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IkappaBalpha promoter, and the H3K4 trimethyltransferase activity recruited on the MMP9 promoter is impaired in p52-depleted HUT-78 cells. Moreover, MLL1 and MLL2 are associated with Hut-78 in a native chromatin-enriched extract. Thus, we identified a molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-kappaB-dependent gene induces its expression and potentially the invasive potential of lymphoma cells harbouring constitutive activity of the alternative NF-kappaB-activating pathway. [less ▲]Detailed reference viewed: 143 (42 ULg)