CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts

CD44 is a marker of tumour-initiating cells and is upregulated in invasive breast carcinoma; however, its role in the cancer progression is unknown. Here, we show that antibody-mediated CD44-targeting in human breast cancer xenografts (HBCx) significantly reduces tumour growth and that this effect is associated to induction of growth-inhibiting factors. Moreover, treatment with this antibody prevents tumour relapse after chemotherapy-induced remission in a basal-like HBCx

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Rôle de ERK1/2 et des cytokines dans la différenciation des cellules leucémiques monoblastiques par des anticorps monoclonaux Antic-CD44

PARIS7-Bibliothèque centrale (751132105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Mise en évidence du rôle de la protéine p27-kip1 dans l'inhibition de la prolifération des cellules leucémiques myéloïdes par des anticorps monoclonaux anti-CD44

Dans les leucémies aiguës myéloïdes (LAM), la prolifération extensive des cellules souches et progéniteurs leucémiques génère des blastes incapables de se différencier. Nous avons montré que l'activation du CD44 par des anticorps spécifiques provoque la différenciation terminale des blastes, suggérant la possibilité de dévelppper unt thérapie différenciatrice CD44-ciblée des LAM. J'ai montré que l'activation du CD44 induit aussi la différenciation terminale de plusieurs lignées leucémiques en inhibe leur prolifération. J'ai montré que l'activation de CD44 stabilise l'inhibiteur du cycle cellulaire P27-Kip1 (p27), qui s'accumule dans les cellules LAM (lignées et cultures primaires). En utilisant des vecteurs antisens, j'ai montré que p27 est indispensable à l'action antiproliférative du CD44, p27 étant un puissant suppresseur de tumeur et sa quantité élevée étant un facteur de bon pronostic, ces résultats sont en faveur du développement d'une thérapie CD44-ciblée des LAM.Acute myeloid leukemia (AML) is sustained by extensive proliferation of leukemic stem and progenitor cells generating leukemic blasts with defective differentiation. Our laboratory showed that CD44 activation with specific antibodies induces terminal differentiation of primary AML blasts, suggesting the possibility of developping a CD44-targeted differentiation therapy in AML. I showed that CD44 activation induces terminal differentiation of several myeloid leukemia cell lines and, moreover, inhibits their proliferation. Furthermore, I showed that CD44 activation stabilizes the cyclin-dependent kinase inhibitor p27-Kip1 (p27), in both cell lines and primary blasts. By transfection experiments with a p27 antisense vector, I demonstrated that p27 is essential for the antiproliferative activity of CD44. Since p27 is a potent tumor suppressor and that its high expression is a factor of good prognosis in AML, these results provide new basis for developing CD44-targeted therapy in AML.PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Inheritance of susceptibility to the myeloproliferative sarcoma virus: effect of the Fv-2 locus and evidence for a myeloproliferative sarcoma virus resistance locus.

Myeloproliferative sarcoma virus (MPSV) causes a generalized stem cell leukemia with erythroid and myeloid hyperplasia in adult mice. MPSV also transforms fibroblasts. Mice congenic for the Fv-2 locus showed marked differences in susceptibility to MPSV according to the Fv-2 genotype. MPSV was injected into C57BL/6 Fvs and C57BL/6 Fv-2r mice congenic except for the Fv-2 locus. C57BL/6 mice with the Fvs genotype were much more susceptible to MPSV than were those with the Fvr genotype. Both DDD Fv-2r mice congenic with DDD Fv-2s mice except for the Fv-2 locus and DDD Fv-2s mice, however, were sensitive to spleen focus formation by MPSV. These data indicate that at least one additional resistance locus to MPSV is present in C57BL/6 mice but not in DDD mice. Both the Fv-2 locus and the putative MSPV resistance locus (loci) Mpsvr appear to be epistatic to either of the sensitivity loci. Fibroblast focus formation by MPSV was obtained well in C57BL/6 Fv-2r and C57BL/6 Fvs fibroblasts, indicating that the genes for MPSV resistance (Fv-2r and Mpsvr) were not operating in fibroblast cells. A model is proposed which may account for the differences in response of genetically different mice to MPSV and Friend spleen focus-forming virus