A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability

Gemtuzumab ozogamicin (GO, Mylotarg) is a targeted therapeutic agent in which an anti-CD33 antibody is chemically coupled to a highly cytotoxic calicheamicin derivative through a hydrolysable linker. GO has improved the treatment outcome for a subgroup of acute myeloid leukemia (AML) patients, but its use is associated with severe myelosuppression and hepatotoxicity. Here, we report on a novel anti-leukemia agent, designated scFvCD33:sTRAIL, in which an anti-CD33 single chain fragment of variable regions (scFv) antibody fragment is genetically linked to soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). Normal CD33-positive monocytes were fully resistant to prolonged treatment with scFvCD33: sTRAIL, whereas treatment with GO resulted in substantial cytotoxicity. The activity of scFvCD33: sTRAIL towards AML cells was up to 30-fold higher than GO. The CD33-restricted anti-leukemia activity of scFvCD33: sTRAIL remained stable during prolonged storage at 37 degrees C, whereas GO showed a rapid increase in CD33-independent cytotoxicity. Moreover, scFvCD33: sTRAIL showed potent anti-leukemia activity towards CD33+ CML cells when treatment was combined with the Bcr-Abl tyrosine kinase inhibitor, Gleevec. Importantly, ex vivo treatment of patient-derived CD33+ AML tumor cells with scFvCD33: sTRAIL resulted in potent apoptosis induction that was enhanced by valproic acid, mitoxantrone and 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG). Taken together, scFvCD33: sTRAIL is superior to GO in terms of tumor selectivity, activity and stability, warranting its further development for the treatment of CD33-positive leukemias. Leukemia (2009) 23, 1389-1397; doi:10.1038/leu.2009.34; published online 5 March 200

Cox-Rower Architecture for Fast Parallel Montgomery Multiplication

Abstract. This paper proposes a fast parallel Montgomery multiplication algorithm based on Residue Number Systems (RNS). It is easy to construct a fast modular exponentiation by applying the algorithm repeatedly. To realize an efficient RNS Montgomery multiplication, the main contribution of this paper is to provide a new RNS base extension algorithm. Cox-Rower Architecture described in this paper is a hardware suitable for the RNS Montgomery multiplication. In this architecture, a base extension algorithm is executed in parallel by plural Rower units controlled by a Cox unit. Each Rower unit is a single-precision modular multiplier-and-accumulator, whereas Cox unit is typically a 7 bit adder. Although the main body of the algorithm processes numbers in an RNS form, efficient procedures to transform RNS to or from a radix representation are also provided. The exponentiation algorithm can, thus, be adapted to an existing standard radix interface of RSA cryptosystem.

Measurements of low-mode asymmetries in the areal density of laser-direct-drive deuterium-tritium cryogenic implosions on OMEGA using neutron spectroscopy

Areal density is one of the key parameters that determines the confinement time in inertial confinement fusion experiments, and low-mode asymmetries in the compressed fuel are detrimental to the implosion performance. The energy spectra from the scattering of the primary deuterium–tritium (DT) neutrons off the compressed cold fuel assembly are used to investigate low-mode nonuniformities in direct-drive cryogenic DT implosions at the Omega Laser Facility. For spherically symmetric implosions, the shape of the energy spectrum is primarily determined by the elastic and inelastic scattering cross sections for both neutron-deuterium and neutron-tritium kinematic interactions. Two highly collimated lines of sight, which are positioned at nearly orthogonal locations around the OMEGA target chamber, record the neutron time-of-flight signal in the current mode. An evolutionary algorithm is being used to extract a model-independent energy spectrum of the scattered neutrons from the experimental neutron time-of-flight data and is used to infer the modal spatial variations (l = 1) in the areal density. Experimental observations of the low-mode variations of the cold-fuel assembly (ρL0 + ρL1) show good agreement with a recently developed model, indicating a departure from the spherical symmetry of the compressed DT fuel assembly. Another key signature that has been observed in the presence of a low-mode variation is the broadening of the kinematic end-point due to the anisotropy of the dense fuel conditions