Quantifying the limits of CAR T-cell delivery in mice and men

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

Reconfigurable hardware implementation of a phase-correlation stereoalgorithm

This paper describes the implementation of a stereo-vision system using Field Programmable Gate Arrays (FPGAs). Reconfigurable hardware, including FPGAs, is an attractive platform for implementing vision algorithms due to its ability to exploit parallelism often found in these algorithms, and due to the speed with which applications can be developed as compared to hardware. The system outputs 8-bit, subpixel disparity estimates for 256× 360 pixel images at 30,fps. A local-weighted phase correlation algorithm for stereo disparity [Fleet, D. J.: {Int. Conf. Syst. Man Cybernetics 1:48–54 (1994)] is implemented. Despite the complexity of performing correlations on multiscale, multiorientation phase data, the system runs as much as 300 times faster in hardware than its software implementation. This paper describes the hardware platform used, the algorithm, and the issues encountered during its hardware implementation. Of particular interest is the implementation of multiscale, steerable filters, which are widely used in computer vision algorithms. Several trade-offs (reducing the number of filter orientations from three to two, using fixed-point computation, changing the location of one localized low-pass filter, and using L1 instead of L2 norms) were required to both fit the design into the available hardware and to achieve video-rate processing. Finally, results from the system are given both for synthetic data sets as well as several standard stereo-pair test images.     

The Emotional Dog Gets Mistaken for a Possum.

H. D. Saltzstein and T. Kasachkoff (2004) (see record 2004-21519-004) critique the social intuitionist model (J. Haidt, 2001) (see record 2001-18918-008), but the model they critique is a stripped-down version that should be called the "possum" model. They make 3 charges about the possum model that are not true about the social intuitionist model: that it includes no role for reasoning, that it reduces social influence to compliance, and that it does not take a developmental perspective. After a defense of the honor of the social intuitionist model, this article raises 2 areas of legitimate dispute: the scope and nature of moral reasoning and the usefulness of appealing to innate ideas, rather than to learning and reasoning, as the origin of moral knowledge. This article presents 3 clusters of innate moral intuitions, related to sympathy, hierarchy, and reciprocity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Experimental evidence of a relationship between monomer plasma residence time and carboxyl group retention in acrylic acid plasma polymers

Decreasing carboxyl retention in deposits from the glow region of an acrylic acid plasma was measured by X-ray photoelectron spectroscopy and chemical derivatisation as the collection distance from the monomer vapour inlet was increased. Volatilisation of plasma polymerised acrylic acid was detected after trifluoroethanol derivatisation; this is correlated with evaporation of low molecular weight components observed previously.     

Efficiency improvements in US office equipment: Expected policy impacts and uncertainties

We create a business as usual scenario for office equipment electricity use from industry forecasts of equipment sales, surveys of equipment densities by building type, measured data on wattage and usage by equipment type and projected lifetimes for equipment. We then calculate electricity used by building type and equipment type for Energy Star and advanced scenarios and explore the sensitivity of these results to variations in key input parameters. According to our analysis, the Energy Star programme will save the US almost US$1 billion annually starting in the year 2000, with minimal expenditure of public funds.     

GaN and AlGaN high-voltage rectifiers grown by metal-organic chemical-vapor deposition

In this paper, we report the study of the electrical characteristics of GaN and AlGaN vertical p-i-n junctions and Schottky rectifiers grown on both sapphire and SiC substrates by metal-organic chemical-vapor deposition. For GaN p-i-n rectifiers grown on SiC with a relatively thin “i” region of 2 μm, a breakdown voltage over 400 V, and forward voltage as low as 4.5 V at 100 A/cm² are exhibited for a 60-μm-diameter device. A GaN Schottky diode with a 2-μm-thick undoped layer exhibits a blocking voltage in excess of ∼230 V at a reverse-leakage current density below 1 mA/cm², and a forward-voltage drop of 3.5 V at a current density of 100 A/cm². It has been found that with the same device structure and process approach, the leakage current of a device grown on a SiC substrate is much lower than a device grown on a sapphire substrate. The use of Mg ion implantation for p-guard rings as planar-edge terminations in mesageometry GaN Schottky rectifiers has also been studied.     

Specification,Verification and Prototyping of an Optimized Compiler

This paper generalizes an algebraic method for the design of a correct compiler to tackle specification and verification of an optimized compiler. The main optimization issues of concern here include the use of existing contents of registers where possible and the identification of common expressions. A register table is introduced in the compiling specification predicates to map each register to an expression whose value is held by it. We define different kinds of predicates to specify compilation of programs, expressions and Boolean tests. A set of theorems relating to these predicates, acting as a correct compiling specification, are presented and an example proof within the refinement algebra of the programming language is given. Based on these theorems, a prototype compiler in Prolog is produced.