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.     

Re-entrant activity and its control in a model of mammalian ventricular tissue

We characterize the meander of re-entrant excitation in a model of a sheet of mammalian ventricular tissue, and its control by resonant drift under feedback driven stimulation. The Oxsoft equations for excitability in a guinea pig single ventricular cell were incorporated in a two dimensional reaction-diffusion system to model homogeneous, isotropic tissue with a plane wave conduction velocity of 0.35 m s-1. Re-entrant spiral wave solutions have a spatially extended transient motion (linear core) that settles down into rotation with an irregular period of 100-110 ms around an irregular, multi-lobed spiky core. In anisotropic tissue this would appear as a linear conduction block. The typical velocity of drift of the spiral wave induced by low amplitude resonant forcing is 0.4 cm s-1.     

把DAC的输出从单端模式转换到差分模式的电路

高速DAC,比如模拟器件(AnalogDevices)公司的AD9776/78/79TxDAC系列,能提供差分输出,但对于低端交流电应用或高精度电平设置应用,配备差分转换电路的单端电流输出DAC提供了一种新颖的方法来生成差分波形控制功能。图1中的基本电路组合了电流输出DAC(即IC1,如8位AD5424D A C)和一个单端至差分运算放大级IC2、IC3A、IC3B——来产生要求的输出。对于双电源应用,可选择DAC的单极工作模式来达到DAC的最优性能。DAC利用单一运算放大器提供了双象限倍增或单极输出电压摆动。DAC的输出需要缓冲器,这是因为对施加到DAC输入端的代…     

Virulence of Aspergillus fumigatus double mutants lacking restriction and an alkaline protease in a low-dose model of invasive pulmonary aspergillosis

To investigate the pathogenicity of Aspergillus fumigatus mutants lacking putative virulence factors, we have developed a new murine model of invasive pulmonary aspergillosis based on neutropenia, the major factor predisposing patients to this infection. Mice were treated with cyclophosphamide and inoculated by the intranasal route with 5 x 10(3) conidia, a significant reduction from inoculum levels used in previous models. Evidence for the production of the extracellular alkaline protease (Alp) in lung tissue was obtained by using a fungal transformant harboring an alp::lacZ reporter gene fusion. The pathogenicities of single mutant strains lacking either Alp or the ribotoxin restrictocin and of a double mutant strain lacking both proteins were assessed in this infection model. There were no significant differences between the mutant and the wild-type strains in terms of mortality or histological-features. Inoculations with mixtures of conidia showed that the double mutant strain is slightly less virulent than the wild-type strain. We conclude that Alp and restrictocin are not important virulence determinants in pulmonary infection.     

Intergranular stresses in ZIRCALOY-2

The development of the understanding of the intergranular stresses in ZIRCALOY-2 is reviewed. Neutron diffraction measurements of the intergranular strains were made on rod-textured material and highly textured plate. The elastoplastic self-consistent (EPSC) model provides a sound theoretical foundation for our understanding of the behavior. The strain response of ZIRCALOY-2 to applied tensile stress is well described for two very different textures with the same slip and hardening parameters. It is almost certain that tensile twinning is the explanation for the response to compressive stress and rolling that is, as yet, incompletely understood. This article is based on a presentation made in the symposium entitled “Defect Properties and Mechanical Behavior of HCP Metals and Alloys” at the TMS Annual Meeting, February 11–15, 2001, in New Orleans, Louisiana, under the auspices of the following ASM committees: Materials Science Critical Technology Sector, Structural Materials Division, Electronic, Magnetic & Photonic Materials Division, Chemistry & Physics of Materials Committee, Joint Nuclear Materials Committee, and Titanium Committee.     

A model of personality test item response dissimulation.

Proposes and empirically evaluates a general model of faking on self-report personality test items. The model predicts that differential test item response latencies should be faster for schema-congruent test answers than for noncongruent responses. Thus, individuals faking good should take relatively longer to endorse socially undesirable test item content than desirable test item content. Conversely, individuals faking bad should endorse socially desirable test item content relatively slower than undesirable test item content. Support for the model was found to generalize across personality inventories and across populations of university students and maximum security prisoners. Conflicting results from previous research are viewed in terms of the model. Further testing of the model's generality and practical relevance is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The distribution of brominated long-chain fatty acids in sponge and symbiont cell types from the tropical marine spongeAmphimedon terpenensis

The tropical marine spongeAmphimedon terpenensis (family Niphatidae, order Haplosclerida) has previously been shown to possess unusual lipids, including unusual fatty acids. The biosynthetic origin of these fatty acids is of interest as the sponge supports a significant population of eubacterial and cyanobacterial symbionts. The total fatty acid composition of the sponge was analyzed by gas chromatography/mass spectrometry of the methyl esters. Among the most abundant of the fatty acids in intact tissue were 16∶0, 18∶0 and 3,7,11,15-tetramethylhexadecanoic (phytanic) acid. In addition, three brominated fatty acids, (5E,9Z)-6-bromo-5,9-tetracosadienoic acid (24∶2Br), (5E,9Z)-6-bromo-5,9-pentacosadienoic acid (25∶2Br) and (5E,9Z)-6-bromo-5,9-hexacosadienoic acid (26∶2Br) were also present. The three brominated fatty acids, together with phytanic acid, were isolated from both ectosomoal (superficial) and choanosomal (internal) regions of the sponge. Analysis of extracts prepared from sponge/symbiont cells, partitioned by density gradient centrifugation on Ficoll, indicated that phytanic acid and the three brominated fatty acids were associated with sponge cells only. Further, a fatty acid methyl ester sample from intact tissue ofA. terpenensis was partitioned according to phospholipid class, and the brominated fatty acids were shown to be associated with the phosphatidylserine and phosphatidylethanolamine fractions that are commonly present in marine sponge lipids. The phosphatidylcholine and phosphatidylglycerol fractions were rich in the relatively shorter chain fatty acids (16∶0 and 18∶0). The association of brominated long-chain fatty acids (LCFA) with sponge cells has been confirmed. The findings allow comment on the use of fatty acid profiles in chemotaxonomy and permit further interpretation of LCFA biosynthetic pathways in sponges. The assignment of the sponge studied, which is currently placed asA. terpenensis, is being supported to some extent, but the species is unusual in having C₂₅ fatty acids as the major constituent in this group. Other factors, such as season or microenvironmental conditions, may influence observed fatty acid composition which tends to reduce the usefulness of fatty acid profiles as markers in sponge chemotaxonomy.     

Enhancing the construct validity of differential response latencies for personality test items.

Evaluated the effects of increasing scale reliability and of priming dimensional activation on the construct validity of personality test item differential response latencies. 93 undergraduates were computer-administered items from the 3 lengthened scales of the Personality Research Form. Findings show that differential response latencies can demonstrate remarkably strong evidence for their construct validity. In addition, the priming of personality traits may enhance the construct validity of their corresponding differential response latencies. Results support a model of test item responding where differential item response latencies reflect the interaction of an individual's schema with test item content. (French abstract) (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Disguise and the structured self-report assessment of psychopathology: I. An analogue investigation.

Explored the utility of disguise in structured self-report assessments of psychopathology in 3 experiments with 370 university students. Exp I used items from the Basic Personality Inventory (BPI); Exp II used the BPI, the Desirability scale of the Personality Research Form—Form E, and 4 criterion measures; and Exp III used 2 of the criterion measures and the BPI. Data indicate that under normal test-taking circumstances, the use of disguised test items was not advantageous. This relationship, however, was moderated by a number of dimensional parameters. When faking response sets in terms of desirability was induced, the use of disguised test item content was not useful. Data are interpreted in terms of the various strategies of test construction underlying the assessment of psychopathology. Results support a rational strategy of test construction emphasizing the use of relevant test item content. It is concluded that, in structured self-report assessments, the most valid results may be obtained through the use of direct questions with cooperative test respondents. (43 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)