SULFs in human neoplasia: implication as progression and prognosis factors

<p>Abstract</p> <p>Background</p> <p>The sulfation pattern of heparan sulfate chains influences signaling events mediated by heparan sulfate proteoglycans located on cell surface. SULF1 and SULF2 are two endosulfatases able to cleave specific 6-O sulfate groups within the heparan chains. Their action can modulate signaling processes, many of which with key relevance for cancer development and expansion. SULF1 has been associated with tumor suppressor effects in various models of cancer, whereas SULF2 dysregulation was in relation with protumorigenic actions. However, other observations argue for contradictory effects of these sulfatases in cancer, suggesting the complexity of their action in the tumor microenvironment.</p> <p>Methods</p> <p>We compared the expression of the genes encoding SULF1, SULF2 and heparan sulfate proteoglycans in a large panel of cancer samples to their normal tissue counterparts using publicly available gene expression data, including the data obtained from two cohorts of newly-diagnosed multiple myeloma patients, the Oncomine Cancer Microarray database, the Amazonia data base and the ITTACA database. We also analysed prognosis data in relation with these databases.</p> <p>Results</p> <p>We demonstrated that <it>SULF2 </it>expression in primary multiple myeloma cells was associated with a poor prognosis in two independent large cohorts of patients. It remained an independent predictor when considered together with conventional multiple myeloma prognosis factors. Besides, we observed an over-representation of <it>SULF2 </it>gene expression in skin cancer, colorectal carcinoma, testicular teratoma and liver cancer compared to their normal tissue counterpart. We found that <it>SULF2 </it>was significantly over-expressed in high grade uveal melanoma compared to low grade and in patients presenting colorectal carcinoma compared to benign colon adenoma.</p> <p>We observed that, in addition to previous observations, <it>SULF1 </it>gene expression was increased in T prolymphocytic leukemia, acute myeloid leukemia and in renal carcinoma compared to corresponding normal tissues. Furthermore, we found that high <it>SULF1 </it>expression was associated with a poor prognosis in lung adenocarcinoma.</p> <p>Finally, <it>SULF1 </it>and <it>SULF2 </it>were simultaneously overexpressed in 6 cancer types: brain, breast, head and neck, renal, skin and testicular cancers.</p> <p>Conclusions</p> <p><it>SULF1 </it>and <it>SULF2 </it>are overexpressed in various human cancer types and can be associated to progression and prognosis. Targeting SULF1 and/or SULF2 could be interesting strategies to develop novel cancer therapies.</p

Design of a prospective observational study on the effectiveness and real-world usage of recombinant factor VIII Fc (rFVIIIFc) compared with conventional products in haemophilia A: The A-SURE study

Introduction: Haemophilia A is a rare bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. This is treated with factor VIII, conventionally using products with a half-life of 8-12 hours typically administered every 2-3 days. Recombinant FVIII Fc (rFVIIIFc) represents a new generation of products with an extended half-life allowing higher FVIII levels and longer dosing interval. The efficacy and safety of rFVIIIFc have been established in clinical studies and several years of postmarketing use. However, there remains a need to compare treatment outcome with conventional products in routine clinical use. Methods and analysis: A-SURE is an ongoing, non-interventional European study with the primary objective to compare the clinical effectiveness of rFVIIIFc with conventional factor products used for haemophilia A prophylaxis. Data covering a 24-month prospective period and a 12-month retrospective period will be collected. Three primary endpoints: bleeding rate, injection frequency and factor consumption will be used to evaluate treatment outcomes. Enrolment of 175 patients on rFVIIIFc and 175 on conventional products is planned. All eligible patients from participating centres will be invited to participate. Visits and treatments follow routine clinical practice. Bias will be reduced by patient matching for age at baseline and the last weekly prophylaxis dose of a conventional product prior to baseline. Propensity scores will be calculated based on prognostic factors and potential confounders assessed at baseline and adjusted for in the estimation of the treatment effect. Ethics and dissemination: Study approval was obtained by local independent ethics committees and/or authorities, and informed consent from patients or their legal representative is a requirement for participation. Names of ethical committees and approval numbers are provided as supplementary information. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences.This work was fully funded by Swedish Orphan Biovitrum AB (publ

Expression Map of the Human Exome in CD34+ Cells and Blood Cells: Increased Alternative Splicing in Cell Motility and Immune Response Genes

International audienceBACKGROUND: Hematopoietic cells are endowed with very specific biological functions, including cell motility and immune response. These specific functions are dramatically altered during hematopoietic cell differentiation, whereby undifferentiated hematopoietic stem and progenitor cells (HSPC) residing in bone marrow differentiate into platelets, red blood cells and immune cells that exit into the blood stream and eventually move into lymphoid organs or inflamed tissues. The contribution of alternative splicing (AS) to these functions has long been minimized due to incomplete knowledge on AS events in hematopoietic cells. PRINCIPAL FINDINGS: Using Human Exon ST 1.0 microarrays, the entire exome expression profile of immature CD34+ HSPC and mature whole blood cells was mapped, compared to a collection of solid tissues and made freely available as an online exome expression atlas (Amazonia Exon! : http://amazonia.transcriptome.eu/exon.php). At a whole transcript level, HSPC strongly expressed EREG and the pluripotency marker DPPA4. Using a differential splicing index scheme (dsi), a list of 849 transcripts differentially expressed between hematopoietic cells and solid tissues was computed, that included NEDD9 and CD74. Some of these genes also underwent alternative splicing events during hematopoietic differentiation, such as INPP4B, PTPLA or COMMD6, with varied contribution of CD3+ T cells, CD19+ B cells, CD14+ or CD15+ myelomonocytic populations. Strikingly, these genes were significantly enriched for genes involved in cell motility, cell adhesion, response to wounding and immune processes. CONCLUSION: The relevance and the precision provided by this exon expression map highlights the contribution of alternative splicing to key feature of blood cells differentiation and function

Exploration des variations physiologiques du facteur XI pendant la grossesse

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Évaluation de la pratique sportive chez les patients hémophiles (étude des bénéfices et des risques associés)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Contrôle immunologique et immunogénicité des cellules tumorales dans le myélome multiple

Le myélome multiple (MM) est une néoplasie B caractérisée par l accumulation d un clone plasmocytaire dans la moelle osseuse, pour laquelle des stratégies d immunothérapie peuvent être développées. La chimiothérapie intensive supportée par une autogreffe de cellules souches hématopoïétiques (CSH) est un traitement majeur du MM. Nous avons qualifié et quantifié les lymphocytes T, en particulier les lymphocytes T régulateurs, mobilisés avec les CSH par cyclophosphamide et G-GSF. Par ailleurs, le transfert des gènes CD80 et 4-1BBL dans des lignées de MM les rend capables de stimuler des lymphocytes T CD8 autologues cytolytiques, dirigés contre des antigènes tumoraux partagés. Nous avons identifié 24 gènes de la famille cancer-testis exprimés chez au moins 5% des patients atteints de MM, au moyen de puces à ADN pangénomiques. Parmi ces gènes; 6 sont de mauvais pronostic. Ces travaux permettront de concevoir des protocoles cliniques d immunothérapie efficaces et originaux dans le MMMONTPELLIER-BU Pharmacie (341722105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Exploration des variations physiologiques du facteur XI pendant la grossesse

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Prise en charge pluridisciplinaire de la pose de prothèse de cheville chez les patients atteints de maladie hémorragique grave

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Les déficits constitutionnels en facteur VII de la coagulation (approche clinique, biologique et moléculaire)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUP (751062107) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF