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.     

Liquid crystalline polymers as additives to enhance the device properties of low molecular mass liquid crystals

Magnetic and electric fields have been used to determine the splay (k₁₁) and bend (k₃₃) elastic constants in a series of polymer/monomer liquid crystal solutions using the well known Freedericksz transition technique. Measurements have been carried out as a function of concentration and temperature. The polymer used was a smectogenic polysiloxane side chain liquid crystal with both cyanobiphenyl and benzoate ester side groups. The monomeric solvent was the nematogen 4-n-pentyl-4′-cyanobiphenyl. All of the solutions studied were nematogenic up to a concentration of 40% w/w. It has been shown that k₁₁, k₃₃ and $\text{k}{}_{33}\text{k}{}_{11}$ all decrease with increasing polymer concentration and that at high enough concentrations $\text{k}{}_{33}\text{k}{}_{11}$ tends to become independent of temperature. The implications of these results are discussed in terms of the performance of the most common liquid crystal display, i.e. the twisted nematic device.     

A study of the static and dynamic properties of side-chain liquid crystalline polymers in low molar mass mesogens

The static and dynamic properties of solutions of a side chain polysiloxane liquid crystal polymer have been studied in a cyanobiphenyl nematic host as a function of concentration and temperature. Refractive index measurements were carried out on aligned samples and the data used to determine the macroscopic order parameter, S, using Haller's method. Photon correlation spectroscopy has been used to measure ($\text{k}{}_{22}\text{γ}{}_1$) for the pure nematic solvent and the solutions. From these measurements it appears that the static properties vary slowly and linearly with increasing polymer concentration whilst the dynamic or viscoelastic properties change markedly. This change has been attributed to γ₁, the twist viscosity, and the results have been discussed in terms of the function of the siloxane polymer backbone.     

New pseudoternary line code for high-speed twisted pair data links

Regulated mark inversion (RMI) is a new pseudoternary line code which minimises high-frequency spectral components in a similar way to the FDDI TP-PMD MLT3 code, and yet also has a bounded running digital sum. The code has significantly lower DC content than standard MLT3, and a lower high-frequency content than run-length-limited MLT3 codes     

Optics clustered to output unique solutions: a multi-laser facility for combined single molecule and ensemble microscopy

Optics clustered to output unique solutions (OCTOPUS) is a microscopy platform that combines single molecule and ensemble imaging methodologies. A novel aspect of OCTOPUS is its laser excitation system, which consists of a central core of interlocked continuous wave and pulsed laser sources, launched into optical fibres and linked via laser combiners. Fibres are plugged into wall-mounted patch panels that reach microscopy end-stations in adjacent rooms. This allows multiple tailor-made combinations of laser colours and time characteristics to be shared by different end-stations minimising the need for laser duplications. This setup brings significant benefits in terms of cost effectiveness, ease of operation, and user safety. The modular nature of OCTOPUS also facilitates the addition of new techniques as required, allowing the use of existing lasers in new microscopes while retaining the ability to run the established parts of the facility. To date, techniques interlinked are multi-photon/multicolour confocal fluorescence lifetime imaging for several modalities of fluorescence resonance energy transfer (FRET) and time-resolved anisotropy, total internal reflection fluorescence, single molecule imaging of single pair FRET, single molecule fluorescence polarisation, particle tracking, and optical tweezers. Here, we use a well-studied system, the epidermal growth factor receptor network, to illustrate how OCTOPUS can aid in the investigation of complex biological phenomena.     

Simulation of wave propagation in three-dimensional random media

Quantitative error analyses for the simulation of wave propagation in three-dimensional random media, when narrow angular scattering is assumed, are presented for plane-wave and spherical-wave geometry. This includes the errors that result from finite grid size, finite simulation dimensions, and the separation of the two-dimensional screens along the propagation direction. Simple error scalings are determined for power-law spectra of the random refractive indices of the media. The effects of a finite inner scale are also considered. The spatial spectra of the intensity errors are calculated and compared with the spatial spectra of intensity. The numerical requirements for a simulation of given accuracy are determined for realizations of the field. The numerical requirements for accurate estimation of higher moments of the field are less stringent.     

Surgical management of total anomalous pulmonary venous drainage: impact of coexisting cardiac anomalies

BACKGROUND: Recent reports have cited improving results for surgical management of isolated total anomalous pulmonary venous drainage. Complex cases (with other cardiac anomalies) are less frequently reported and are associated with higher mortality. METHODS: Retrospective review identified 170 consecutive patients treated for total anomalous pulmonary venous drainage from 1982 to 1996: 44 cases were "complex" (with significant associated cardiac lesions) and 126 cases were "simple." RESULTS: Operative mortality for simple cases decreased from 26% to 8%, and mortality for complex cases remained constant at 52%. Age, size, and the presence of atrial isomerism were univariate predictors of mortality. Multivariable analysis identified only univentricular hearts and associated cardiac lesions as predictors of operative mortality. Pulmonary artery (n = 16) and arteriopulmonary (n = 7) shunting strategies for complex cases resulted in less than 30% long-term survival. CONCLUSIONS: Despite improvement in survival for simple cases, management of total anomalous pulmonary venous drainage with single-ventricle hearts or other associated cardiac lesions remains problematic.     

Ultra‐fast‐switching flexoelectric liquid‐crystal display with high contrast

Abstract— The flexoelectro‐optic effect provides a fast‐switching mechanism (0.01–0.1 msec), suitable for use in field‐sequential‐color full‐motion‐video displays. An in‐plane electric field is applied to a short‐pitch chiral nematic liquid crystal aligned in the uniform standing helix (or Grandjean) texture. The switching mechanism is experimentally demonstrated in a single‐pixel test cell, and the display performance is investigated as a function of device parameters. A contrast ratio of 2000:1 is predicted.