Multinuclear NMR as a tool for studying local order and dynamics in CH3NH3PbX3 (X = Cl, Br, I) hybrid perovskites

International audienceWe report on Pb, Br, N, H, C and H NMR experiments for studying the local order and dynamics in hybrid perovskite lattices. Pb NMR experiments conducted at room temperature on a series of MAPbX compounds (MA = CHNH; X = Cl, Br and I) showed that the isotropic Pb NMR shift is strongly dependent on the nature of the halogen ions. Therefore Pb NMR appears to be a very promising tool for the characterisation of local order in mixed halogen hybrid perovskites. Pb NMR on MAPbBrI served as a proof of concept. Proton, C and N NMR experiments confirmed the results previously reported in the literature. Low temperature deuterium NMR measurements, down to 25 K, were carried out to investigate the structural phase transitions of MAPbBr. Spectral lineshapes allow following the successive phase transitions of MAPbBr. Finally, quadrupolar NMR lineshapes recorded in the orthorhombic phase were compared with simulated spectra, using DFT calculated electric field gradients (EFG). Computed data do not take into account any temperature effect. Thus, the discrepancy between the calculated and experimental EFG evidences the fact that MA cations are still subject to significant dynamics, even at 25 K

The multiple myeloma bone eco-system and its relation to oncogenesis

International audiencePure lytic bone lesions are the hallmark of myeloma (MM). MM is the only hematological malignancy associated with lytic bone lesions and the mechanisms of bone destruction are well documented both at the cellular and molecular levels. An uncoupling bone process characterizes MM, with stimulation of bone resorption and inhibition of bone formation. The capacity of MM cells to directly or indirectly inhibit bone formation is specific of MM, although many carcinomas have the capacity to stimulate bone resorption, directly or indirectly in a similar way to MM. Few MM do not develop bone lesions, while true sclerotic MM remain exceptional. Inhibition of bone formation is the major event explaining the transition from MGUS to overt MM. It is now well documented that bone cells regulate MM cell growth, osteoclast stimulating MM cell growth and osteoblasts inhibiting it. Progression of MM from MGUS is characterized by the selection of MM clones able to inhibit osteoblasts, favoring tumor growth. These data underline the interest of new treatments able to regenerate bone

Mcl-1L cleavage is involved in TRAIL-R1– and TRAIL-R2–mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells

International audienceWe evaluated the ability of 2 human mAbsdirected against TRAILR1 (HGS-ETR1)and TRAILR2 (HGS-ETR2) to kill humanmyeloma cells. HGS-ETR1 and HGS-ETR2mAbs killed 15 and 9 human myeloma celllines (HMCLs; n22), respectively. IL-6,the major survival and growth factor forthese HMCLs, did not prevent their kill-ing. Killing induced by either HGS-ETR1or HGS-ETR2 was correlated with thecleavage of Mcl-1L, a major molecule formyeloma survival. Mcl-1L cleavage andanti-TRAILR HMCL killing were depen-dent on caspase activation. Kinetic stud-ies showed that Mcl-1L cleavage oc-curred very early (less than 1 hour) andbecame drastic once caspase 3 was acti-vated. Our data showed that both theextrinsic (caspase 8, Bid) and the intrin-sic (caspase 9) pathways are activated byanti–TRAIL mAb. Finally, we showed thatthe HGS-ETR1 and, to a lesser extent, theHGS-ETR2 mAbs were able to induce thekilling of primary myeloma cells. Of note,HGS-ETR1 mAb was able to induce thedeath of medullary and extramedullarymyeloma cells collected from patients atrelapse. Taken together, our data clearlyencourage clinical trials of anti–TRAILR1mAb in multiple myeloma, especially forpatients whose disease is in relapse, atthe time of drug resistance

Single versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma

BACKGROUND. We conducted a randomized trial of the treatment of multiple myeloma with high-dose chemotherapy followed by either one or two successive autologous stem-cell transplantations. METHODS. At the time of diagnosis, 399 previously untreated patients under the age of 60 years were randomly assigned to receive a single or double transplant. RESULTS. A complete or a very good partial response was achieved by 42 percent of patients in the single-transplant group and 50 percent of patients in the double-transplant group (P=0.10). The probability of surviving event-free for seven years after the diagnosis was 10 percent in the single-transplant group and 20 percent in the double-transplant group (P=0.03). The estimated overall seven-year survival rate was 21 percent in the single-transplant group and 42 percent in the double-transplant group (P=0.01). Among patients who did not have a very good partial response within three months after one transplantation, the probability of surviving seven years was 11 percent in the single-transplant group and 43 percent in the double-transplant group (P<0.001). Four factors were significantly related to survival: base-line serum levels of beta 2-microglobulin (P<0.01) and lactate dehydrogenase (P<0.01), age (P<0.05), and treatment group (P<0.01). CONCLUSIONS. As compared with a single autologous stem-cell transplantation after high-dose chemotherapy, double transplantation improves overall survival among patients with myeloma, especially those who do not have a very good partial response after undergoing one transplantation