A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member April, Inhibits Tumor Cell Growth

A proliferation-inducing ligand (APRIL) is a ligand of the tumor necrosis factor (TNF) family that stimulates tumor cell growth in vitro and in vivo. Expression of APRIL is highly upregulated in many tumors including colon and prostate carcinomas. Here we identify B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI), two predicted members of the TNF receptor family, as receptors for APRIL. APRIL binds BCMA with higher affinity than TACI. A soluble form of BCMA, which inhibits the proliferative activity of APRIL in vitro, decreases tumor cell proliferation in nude mice. Growth of HT29 colon carcinoma cells is blocked when mice are treated once per week with the soluble receptor. These results suggest an important role for APRIL in tumorigenesis and point towards a novel anticancer strategy

Two Adjacent Trimeric Fas Ligands Are Required for Fas Signaling and Formation of a Death-Inducing Signaling Complex

The membrane-bound form of Fas ligand (FasL) signals apoptosis in target cells through engagement of the death receptor Fas, whereas the proteolytically processed, soluble form of FasL does not induce cell death. However, soluble FasL can be rendered active upon cross-linking. Since the minimal extent of oligomerization of FasL that exerts cytotoxicity is unknown, we engineered hexameric proteins containing two trimers of FasL within the same molecule. This was achieved by fusing FasL to the Fc portion of immunoglobulin G1 or to the collagen domain of ACRP30/adiponectin. Trimeric FasL and hexameric FasL both bound to Fas, but only the hexameric forms were highly cytotoxic and competent to signal apoptosis via formation of a death-inducing signaling complex. Three sequential early events in Fas-mediated apoptosis could be dissected, namely, receptor binding, receptor activation, and recruitment of intracellular signaling molecules, each of which occurred independently of the subsequent one. These results demonstrate that the limited oligomerization of FasL, and most likely of some other tumor necrosis factor family ligands such as CD40L, is required for triggering of the signaling pathways

Rapid Occurrence of Chronic Kidney Disease in Patients Experiencing Reversible Acute Kidney Injury after Cardiac Surgery

International audienceBackground: There is recent evidence to show that patients suffering from acute kidney injury are at increased risk of devel-oping chronic kidney disease despite the fact that surviving tubular epithelial cells have the capacity to fully regenerate renal tubules and restore renal function within days or weeks. The aim of the study was to investigate the impact of acute kidney injury on de novo chronic kidney disease.Methods: The authors conducted a retrospective population-based cohort study of patients initially free from chronic kidney disease who were scheduled for elective cardiac surgery with cardiopulmonary bypass and who developed an episode of acute kidney injury from which they recovered. The study was conducted at two French university hospitals between 2005 and 2015. These individuals were matched with patients without acute kidney injury according to a propensity score for develop-ing acute kidney injury.Results: Among the 4,791 patients meeting the authors’ inclusion criteria, 1,375 (29%) developed acute kidney injury and 685 fully recovered. Propensity score matching was used to balance the distribution of covariates between acute kidney injury and non- acute kidney injury control patients. Matching was possible for 597 cases. During follow-up, 34 (5.7%) had reached a diagnosis of chronic kidney disease as opposed to 17 (2.8%) in the control population (hazard ratio, 2.3; bootstrapping 95% CI, 1.9 to 2.6).Conclusions: The authors’ data consolidate the recent paradigm shift, reporting acute kidney injury asa strong risk factor for the rapid development of chronic kidney disease

Conversion to belatacept after lung transplantation: Report of 10 cases

Background Calcineurin inhibitors (CNIs) remain the cornerstone of maintenance immunosuppression (IS) after lung transplantation (LTx), although CNI-related life-threatening toxic effects may occur. Belatacept, a novel immunosuppressant that blocks a T-cell co-stimulation pathway, is a non-nephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, there are only a few reports of belatacept conversion as a CNI-free or CNI-sparing IS treatment. Methods We reviewed a series of 10 LTx recipients with conversion to a CNI-free belatacept IS regimen within the first year post-LTx (n = 7) or a belatacept/low-dose CNI combination after the first year (n = 3). Results Use of belatacept was triggered by severe renal failure in 9 patients and under-IS with previous other IS-related toxicities in 1 patient. Mean estimated glomerular filtration rate after starting belatacept significantly improved at 6 months after initiation and at the last-follow-up (p = 0.006, and p = 0.002 respectively). The incidence of recurrent and/or severe acute cellular rejection (ACR) episodes was high in patients with CNI-free belatacept-based IS (n = 4/7). Chronic graft allograft dysfunction developed in 2 of 9 recipients under belatacept IS. Belatacept was stopped in 6 patients because of recurrent/severe ACR (n = 3), recurrent opportunistic infections (n = 1), center modified policy (n = 1), or other cause (n = 1). Conclusion Early conversion to CNI-free belatacept-based IS improved renal function in this series but was counterbalanced by a high incidence of recurrent ACR, including life-threatening episodes. Other studies are needed to better determine the indications for its use after LTx, possibly with lower immunological risk IS regimens, such as CNI-sparing belatacept

Ni malades, ni en bonne santé

Les pratiques médicales s'élargissent continuellement autour de la définition de nouveaux risques : la définition de nouvelles maladies, le dépistage génétique, l'identification de comportements néfastes, la découverte de nouveaux risques dans l'environnement viennent placer les individus à l’intersection de la santé et de la maladie. Plus les recherches cliniques et épidémiologiques sont poussées et plus elles révèlent aux individus des failles potentielles dans leur état de santé. En outre, les scanners, IRM, et autres examens plus ou moins invasifs révèlent que le corps n’est pas entièrement parfait. Les médecins et chercheurs confrontés à ces résultats doivent communiquer autour de ces nouveaux risques, sans que ne soient toujours posées les limites de ces révélations, ni leurs conséquences en termes de santé pour les individus et les populations. Ce numéro spécial se propose d’analyser les conséquences de cette prolifération des risques qui obscurcissent, décalent, brouillent les frontières entre la santé et la maladie. On s’intéressera également à l’émergence de nouvelles pratiques, oscillant entre une « médecine sur mesure » susceptible de soigner les individus dans leur singularité et des dispositifs de surveillance soulignant les contradictions entre normes préventives et attentes sociales

Acteurs et action

Ancré dans le champ des didactiques de l’histoire et de la géographie, l’ouvrage analyse les situations d’enseignement-apprentissage par le prisme de l’action didactique. Il cherche à cerner les processus en jeu lorsque les professeurs proposent aux élèves des situations empreintes d’un certain degré d’incertitude, afin que ces derniers appréhendent la situation d’incertitude qui est celle des acteurs du monde. La première partie éclaire l’action didactique à partir de l’appropriation par les élèves de situations qui leur sont proposées sur le mode de la rupture avec les fonctionnements classiques en histoire et en géographie. Centrée sur les professeurs, la deuxième partie en donne l’image d’acteurs incertains, loin de celle de meneurs qui se joueraient aisément des contraintes. Et parmi ces incertitudes, celles qui sont produites par les élèves se révèlent les plus délicates à gérer, soulignant ainsi l’indissociable relation entre enseignement et apprentissage. La troisième partie souligne les difficultés à faire construire en géographie l’idée que les individus puissent être appréhendés comme des acteurs de la société dans laquelle ils vivent, alors même que l’usage du terme d’acteur s’est fortement répandu dans cet enseignement. Articulant études de cas et synthèses, l’ouvrage engage à développer les recherches en didactiques de l’histoire et de la géographie, du côté des conditions de possibilité d’une prise de distance des acteurs, professeurs et élèves, avec les cultures disciplinaires scolaires