NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16 + and granzyme B + NK cells, and higher frequency of TIM-3 + and HLA-DR + NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells

New insight in understanding the contribution of SGLT1 in cardiac glucose uptake: evidence for a truncated form in mice and humans.

Although sodium-glucose co-transporter 1 (SGLT1) has been identified as one of the major SGLT isoforms expressed in the heart, its exact role remains elusive. Evidences using phlorizin, the most common inhibitor of SGLTs, suggested its role in glucose transport. However, phlorizin could also affect classical facilitated diffusion via glucose transporters (GLUTs), bringing into question the relevance of SGLT1 in overall cardiac glucose uptake. Accordingly, we assessed the contribution of SGLT1 in cardiac glucose uptake using the SGLT1 knock-out mouse model, which lacks exon 1. Glucose uptake was similar in cardiomyocytes isolated from SGLT1 knock-out (KO) and control littermate (WT) mice, either under basal state, insulin, or hyperglycemia. Similarly, in vivo basal and insulin-stimulated cardiac glucose transport measured by micro-PET scan technology did not differ between WT and KO mice. Micromolar concentrations of phlorizin had no impact on glucose uptake in either isolated WT or KO-derived cardiomyocytes. However, higher concentrations (1mM) completely inhibited insulin-stimulated glucose transport without affecting insulin signaling nor GLUT4 translocation, independently from cardiomyocyte genotype. Interestingly, we discover that mouse and human hearts expressed a shorter slc5a1 transcript, leading to SGLT1 protein lacking transmembrane domains and residues involved in glucose and sodium bindings. In conclusion, cardiac SGLT1 does not contribute to overall glucose uptake, probably due to the expression of slc5a1 transcript variant. The inhibitory effect of phlorizin on cardiac glucose uptake is SGLT1-independent and can be explained by GLUT transporter inhibition. These data open new perspectives in understanding the role of SGLT1 in the heart

NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16+and granzyme B+NK cells, and higher frequency of TIM-3+and HLA-DR+NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells

Arbitrage et conciliation dans l'Islam médiéval et moderne

La justice en Islam est souvent associée au personnage du cadi, juge nommé par le pouvoir. L’État n’eut cependant jamais le monopole de la résolution des conflits. L’arbitre et le médiateur proposaient deux alternatives possibles, fondées sur le consensus des parties. Tandis que le premier, doté d’un rôle décisionnel, pouvait rendre une sentence généralement considérée comme exécutoire, le second orchestrait un processus de négociation se concluant par un accord à l’amiable. Face à des modes d’adjudication visant à déterminer un vainqueur et un perdant, la conciliation était tenue en haute estime par les juristes comme par les justiciables. La recherche d’un moyen terme permettait non seulement à chacun des adversaires de garder la face, mais servait aussi à préserver l’apparence d’une communauté musulmane unie. Les dix contributions à ce dossier thématique explorent le fonctionnement de l’arbitrage et de la conciliation dans divers contextes, maghrébins et moyen-orientaux, depuis l’apparition de l’Islam jusqu’à la fin du xviiie siècle. Dans le cadre de litiges aux fondements juridiques, ces deux procédés pouvaient soit offrir une alternative à la justice du pouvoir, soit s’y articuler pour assouplir la prise de décision et l’adapter aux réalités sociales. Au-delà de cette complexe articulation entre institutions judiciaires officielles et privées, la conciliation fut aussi un outil essentiel de gestion des rivalités politiques, tout particulièrement dans le milieu de la cour. L’image idéale de consensus associée aux procédures de conciliation ne doit cependant pas occulter des stratégies peu avouables par les acteurs eux-mêmes. C’est que la transaction permettait, aussi, de contourner la loi islamique, parfois au détriment de l’équité. Cette livraison de la Remmm invite ainsi à une lecture dynamique des conflits et de leurs résolutions en rapport avec leurs contextes historiques