Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL–AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL–AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (ß5i) and LMP2 (ß1i) sites of the immunoproteasome, and LU-102, inhibitor of proteasome ß2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL

Kinetic studies of CO2 methanation over a Ni/γ-Al2O3 catalyst using a batch reactor

The methanation of CO2 was investigated over a wide range of partial pressures of products and reactants using a gradientless, spinning-basket reactor operated in batch mode. The rate and selectivity of CO2 methanation, using a 12 wt% Ni/γ–Al2O3 catalyst, were explored at temperatures 453–483 K and pressures up to 20 bar. The rate was found to increase with increasing partial pressures of H2 and CO2 when the partial pressures of these reactants were low; however, the rate of reaction was found to be insensitive to changes in the partial pressures of H2 and CO2 when their partial pressures were high. A convenient method of determining the effect of H2O on the rate of reaction was also developed using the batch reactor and the inhibitory effect of H2O on CO2 methanation was quantified. The kinetic measurements were compared with a mathematical model of the reactor, in which different kinetic expressions were explored. The kinetics of the reaction were found to be consistent with a mechanism in which adsorbed CO2 dissociated to adsorbed CO and O on the surface of the catalyst with the rate-limiting step being the subsequent dissociation of adsorbed CO

Thermodynamic analysis of methanation of palm empty fruit bunch (PEFB) pyrolysis oil with and without in situ CO2 sorption

Thermodynamic equilibrium analysis for conversion of palm empty fruit bunch (PEFB) bio-oil to methane using low-temperature steam reforming (LTSR) process was conducted by assuming either isothermal or adiabatic condition, with and without sorption enhancement (SE-LTSR), with CaO(S) or Ca(OH)2(S) as CO2 sorbent. Temperatures of 300-800 K, molar steam to carbon (S/C) ratios of 0.3-7.0, pressures of 1-30 atm and molar calcium to carbon ratios (Ca:C) of 0.3-1.0 were simulated. For reasons of process simplicity, the best conditions for CH4 production were observed for the adiabatic LTSR process without sorption at S/C between 2.5 and 3 (compared to the stoichiometric S/C of 0.375), inlet temperature above 450 K, resulting in reformer temperature of 582 K, where close to the theoretical maximum CH4 yield of 38 wt % of the simulated dry PEFB oil was obtained, resulting in a reformate consisting of 44.5 vol % CH4, 42.7 vol % CO2 and 12.7 vol % H2 and requiring only moderate heating mainly to partially preheat the reactants. Temperatures and S/C below these resulted in high risk of carbon by-product

Biomassevergasung Laborversuche zur Pyrolyse- und Crackstufe und Simulation eines neuen Biomassevergasungskonzeptes

Diplomarbeit im an der Brandenburgischen Technischen Universität Cottbus, Lehrstuhl Prozeßsystemtechnik. Angefertigt am Fraunhofer-Institut für Solare Energiesysteme -ISE-, Abteilung Energietechnik, Freiburg

Synthetic natural gas from wood: Reactions of ethylene in fluidised bed methanation

The synthesis step in the production of synthetic natural gas from wood, i.e. the methanation, was investigated by systematic experiments with commercial nickel catalyst in a micro-fluidised bed reactor. Ethylene in the feed is always converted completely; dominantly serial reactions of ethylene to ethane and further to methane under isothermal fluidised bed methanation conditions could be shown. Lower temperatures favour the production of the intermediate ethane while high temperatures cause the formation of carbon depositions and carbon whiskers. Applying optimal operation conditions, the hydrogenation of the unsaturated olefin not only avoids the deposition of carbon or coke, but also leads to an increase of the higher heating value (HHV) of the produced (raw) SNG. © 2013 Elsevier B.V. All rights reserved

Assessment of a catalytic plate reactor with in-situ sampling capabilities by means of CFD modeling and experiments

A catalytic plate reactor with a small movable sampling capillary enables us to gather a significantly larger set of kinetic data for the parameter estimation than using a typical steady-state packed-bed reactor with end-of-pipe measurement. In this study, a reactive three-dimensional CFD model developed with catalyticFOAM is validated by experimental axial gas species concentration profiles and then used to investigate the flow dynamics and study the effect of the immersed capillary for various operating conditions for the CO2 methanation reaction over Ni/Al2O3 catalyst. The results confirmed that the presence of the capillary (diameter 0.5 mm, continuous vs. open-ended) inside the rectangular channel (5 × 40 × 100 mm), the position of the orifice (diameter 0.25 mm), and the suction (2 to 8 ml/min) did not affect the quality of the kinetic data collected. For the current design of the reactor inlet, the flow fully develops within the first 10–25 mm of the reactor domain depending on the total flow rate (100 to 300 mlN/min). Hence, up to 90% of the reactor's length can be used for in-situ measurements. This work demonstrates that our channel reactor is very suitable for collecting kinetic data, especially for fast and exothermic heterogeneous catalyzed reactions, with a high spatial resolution for gas composition and catalyst surface temperature