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.     

Retroviral display of antibody fragments; interdomain spacing strongly influences vector infectivity

Five different single-chain antibody fragments (scFv) against human cell-surface antigens were displayed on murine ecotropic retroviral vectors by fusing them to the Moloney SU envelope glycoprotein. The spacing between the scFv and the SU glycoprotein was varied by fusing the scFv to residue +7 or to residue +1 of Moloney SU and by inserting linker sequences of different lengths between the domains. All of the chimeric envelopes were efficiently incorporated into vector particles and could bind to human cells through their displayed antibody fragments, but did not infect them. The spacing between the scFvs and the SU glycoproteins had no significant effect on the efficiency of envelope expression or viral incorporation and did not affect the binding properties of the chimeric envelopes, nor did it influence the efficiency of targeted gene delivery to human cells by scFv-displaying vectors. However, on murine fibroblasts the infectivity of vectors incorporating the chimeric envelopes was strongly influenced by the length of the interdomain spacer. The titers were very low when the single-chain antibodies were fused through a tripeptide linker to SU residue +7 and were greatly enhanced (up to 10(5)-fold) when they were fused to SU residue +1 through a heptapeptide linker. These results point to the importance of steric interactions between the domains of chimeric envelope glycoproteins and may have implications for retroviral vector design for human gene therapy.     

Grain size effects on cyclic fatigue and crack-growth resistance behaviour of partially stabilized zirconia

Cyclic fatigue crack growth and crack-resistance behaviour was studied in partially stabilized zirconia (PSZ) with three different cubic-phase grain sizes following sub-eutectoid heat treatments. Raman spectroscopy was used to determine the extent of phase transformation around the cracks for both cyclic and monotonic loading conditions. All tests were on long, through thickness cracks using compact-tension specimens. Predictions of crack-tip shielding were made following determination of toughening parameters using crackresistance data. It was found that the dominant factors affecting cyclic fatigue-crack growth were the level of crack-tip shielding, as a result of phase transformation, and the intrinsic toughness of the material. Grain size did not appear to significantly affect fatigue crack-growth behaviour.     

Service Science

This paper is a first exploration of the relationship between service science and Grid computing. Service science is the study of value co-creation interactions among entities, known as service systems. Within the emerging service science community, service is often defined as the application of competences (resources) for the benefit of another. Grid computing is the study of resource sharing among entities, known as virtual organizations, which solve complex business, societal, scientific, and engineering problems. Within the Grid computing community, service is sometimes defined as protocols plus behavior. Both Grid computing and service science are connecting academic, industry, government, and volunteer sector collaborators on a range of projects including eScience, healthcare, environmental sustainability, and more. This paper compares and contrasts the notions of resource, entity, service, interaction, and success criteria for the two areas of study. In conclusion, new areas for collaborative inquiry are proposed.     

A functional correspondence between call-by-need evaluators and lazy abstract machines

We bridge the gap between compositional evaluators and abstract machines for the lambda-calculus, using closure conversion, transformation into continuation-passing style, and defunctionalization of continuations. This article is a followup of our article at PPDP 2003, where we consider call by name and call by value. Here, however, we consider call by need.We derive a lazy abstract machine from an ordinary call-by-need evaluator that threads a heap of updatable cells. In this resulting abstract machine, the continuation fragment for updating a heap cell naturally appears as an ‘update marker’, an implementation technique that was invented for the Three Instruction Machine and subsequently used to construct lazy variants of Krivine's abstract machine. Tuning the evaluator leads to other implementation techniques such as unboxed values. The correctness of the resulting abstract machines is a corollary of the correctness of the original evaluators and of the program transformations used in the derivation.     

Photocatalysis in the visible range of sub-stoichiometric anatase films prepared by MOCVD

Anatase phase of titanium oxide is the most promising photocatalyst material for organic pollutant degradation. However, due to its large band gap energy (3.2 eV) it is not viable to use sunlight as an energy source for the photocatalysis activation, and so, ultraviolet (UV) radiation below the wavelength of 380 nm is required.This paper focuses on the experimental demonstration of the reduction of this large band gap energy by inducing defects in the anatase structure under the form of oxygen sub-stoichiometry. TiO₂ thin films were prepared in a metal organic chemical vapour deposition (MOCVD) reactor. The samples stoichiometry was measured by the Rutherford backscattering spectrometry (RBS) technique. Optical characterisation was also performed and the photodegradation activity in the visible range was tested using nonylphenol, which is one of the most harmful pollutants present in waste waters.     

The application of marginal voltage measurements to detect and locate defects in digital microcircuits

A new method of testing digital integrated circuits is described which is based upon a measurement of the minimum values of supply voltage (marginal voltages) which are necessary to just maintain the correct logical operation of a circuit during a functional test. The special test equipment is described and results are given to show how the technique can be used to identify circuits which are defective and yet satisfy all the manufacturer's normal acceptance measurements. For example, it has been found that up to 10% of the TTL components examined yield anomalous marginal voltage results attributable to the effects of internal defects.It is also shown how marginal voltage measurements can be used with a lightspot scanning technique to provide a simple method of locating the defects in anomalous circuits. The basic principles of the technique are explained by considering the operation of a simple manually scanned system. Finally, three examples of the defects found in some TTL circuits are given in order to illustrate the practical application of the technique and to demonstrate the correlation between defects and anomalous marginal voltages.