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.     

Real-time organic aerosol chemical speciation in the indoor environment using extractive electrospray ionization mass spectrometry

Understanding the sources and composition of organic aerosol (OA) in indoor environments requires rapid measurements, since many emissions and processes have short timescales. However, real-time molecular-level OA measurements have not been reported indoors. Here, we present quantitative measurements, at a time resolution of five seconds, of molecular ions corresponding to diverse aerosol-phase species, by applying extractive electrospray ionization mass spectrometry (EESI-MS) to indoor air analysis for the first time, as part of the highly instrumented HOMEChem field study. We demonstrate how the complex spectra of EESI-MS are screened in order to extract chemical information and investigate the possibility of interference from gas-phase semivolatile species. During experiments that simulated the Thanksgiving US holiday meal preparation, EESI-MS quantified multiple species, including fatty acids, carbohydrates, siloxanes, and phthalates. Intercomparisons with Aerosol Mass Spectrometer (AMS) and Scanning Mobility Particle Sizer suggest that EESI-MS quantified a large fraction of OA. Comparisons with FIGAERO-CIMS shows similar signal levels and good correlation, with a range of 100 for the relative sensitivities. Comparisons with SV-TAG for phthalates and with SV-TAG and AMS for total siloxanes also show strong correlation. EESI-MS observations can be used with gas-phase measurements to identify co-emitted gas- and aerosol-phase species, and this is demonstrated using complementary gas-phase PTR-MS observations.     

Lateral ion implant straggle and mask proximity effect

Lateral scattering of retrograde well implants is shown to have an effect on the threshold voltage of nearby devices. The threshold voltage of both NMOSFETs and PMOSFETs increases in magnitude for conventional retrograde wells, but for triple-well isolated NMOSFETs the threshold voltage decreases for narrow devices near the edge of the well. Electrical data, SIMS, and SUPREM4 simulations are shown that elucidate the phenomenon.     

The pharmacokinetics and protein-binding of fusidic acid in patients with severe renal failure requiring either haemodialysis or continuous ambulatory peritoneal dialysis

Antibiotic treatment options for Burkholderia cepacia infection are limited because of high intrinsic resistance. The problem is complicated by development of cross-resistance between antibiotics of different classes. We isolated antibiotic-resistant mutants by stepwise exposure to chloramphenicol (Chlor) and to trimethoprim/sulphamethoxazole (T/S) for four B. cepacia strains: ATCC13945, Per (clinical isolate), Cas and D4 (environmental isolates). Chlor(r) mutants did not produce chloramphenicol acetyl-transferase. Cross-resistance, defined as greater than four-fold increase in MIC by microtitre dilution method, was consistently seen in both types of mutants. For chloramphenicol-resistant (Chlor[r]) and trimethoprim/sulphamethoxazole-resistant (Tr/Sr) mutants of B. cepacia ATCC13945 and Cas, no MIC change was seen for piperacillin, ceftazidime, rifampicin, gentamicin, tobramycin, polymyxin B or azithromycin. B. cepacia-Per and -D4 mutants showed cross-resistance to ceftazidime and to piperacillin. Comparison of outer membrane protein (OMP) profiles of B. cepacia and their mutants by SDS-PAGE revealed Tr/Sr) mutants to be deficient in a major OMP (molecular weight 39-47 kDa). Tr/Sr mutants also expressed additional OMPs not found in wild type strains at 75-77 kDa for B. cepacia-ATCC13945 and -Cas, and 20-21 kDa in B. cepacia-D4 and -Per. No OMP changes occurred in Chlor(r) mutants. Lipopolysaccharide (LPS) profiles of each type of mutant showed new high and low molecular weight LPS bands. Cross-resistance seems to be mediated by alterations in porin and LPS for Tr/Sr mutants, but only by LPS in Chlor(r) mutants.     

Academic faculty practices: issues for viability in competitive managed care markets

This study compares the perspectives of eighteen managed care executives and twenty-four faculty practice executives on critical policy issues related to the managed care marketplace. Market sites studied in 1994 included four major metropolitan areas: Minneapolis-St. Paul, Los Angeles, Philadelphia, and Atlanta. These markets were selected as being representative of communities with descending degrees of managed care involvement, but with significant market activity. Study participants from both managed care systems and faculty practices examined five policy issues: (1) the importance of including academic medical centers in current and future health care plans for marketing purposes; (2) the provision of clinical services that are unique to the academic medical center, that is, unavailable elsewhere in the community; (3) the degree of financial supplement that employers might pay for including an academic medical center; (4) future restructuring of organizations to sustain the educational mission of academic faculty within a viable delivery system; (5) satisfaction of managed care providers with graduates of academic medical centers, as measured by the clinical skills of graduate physicians. The study findings showed little support among managed care plans for paying supplements to include faculty practices in a health care network. Most study participants from managed care systems and academic faculty practices identified limited competencies that are unique to academic centers. Moreover, managed care organizations were only willing to undertake limited restructuring at best to include faculty practices within their networks. General concern about the preparation of resident physicians (especially those in primary care disciplines) for practice within contemporary managed care organizations existed among managed care informants. The results of the study indicate that as traditional funding sources for medical education are reduced, schools require greater integration with managed care plans to enable academic medical centers and their faculties to continue promoting clinical enterprise.     

The CD40-CD154 system in anti-infective host defense

Research in the past few years has documented significant advances in our understanding of the CD40-CD40 ligand (CD154) system in diverse immune functions. This system influences many T cell mediated inflammatory immune responses and effector functions, unmasking a previously unexpected role for CD40-CD154 in cell mediated immunity. Manipulation of CD154 in animal models of infection by the use of CD154-deficient mice or anti-CD154 antibodies has shown the importance of this system in the initiation of the inflammatory response, in the activation of antigen-presenting cells and in resistance to infections.     

Tuning of MST neurons to spiral motions

Cells in the dorsal division of the medial superior temporal area (MSTd) have large receptive fields and respond to expansion/contraction, rotation, and translation motions. These same motions are generated as we move through the environment, leading investigators to suggest that area MSTd analyzes the optical flow. One influential idea suggests that navigation is achieved by decomposing the optical flow into the separate and discrete channels mentioned above, that is, expansion/contraction, rotation, and translation. We directly tested whether MSTd neurons perform such a decomposition by examining whether there are cells that are preferentially tuned to intermediate spiral motions, which combine both expansion/contraction and rotation components. The finding that many cells in MSTd are preferentially selective for spiral motions indicates that this simple three-channel decomposition hypothesis for MSTd does not appear to be correct. Instead, there is a continuum of patterns to which MSTd cells are selective. In addition, we find that MSTd cells maintain their selectivity when stimuli are moved to different locations in their large receptive fields. This position invariance indicates that MSTd cells selective for expansion cannot give precise information about the retinal location of the focus of expansion. Thus, individual MSTd neurons cannot code, in a precise fashion, the direction of heading by using the location of the focus of expansion. The only way this navigational information could be accurately derived from MSTd is through the use of a coarse, population encoding. Positional invariance and selectivity for a wide array of stimuli suggest that MSTd neurons encode patterns of motion per se, regardless of whether these motions are generated by moving objects or by motion induced by observer locomotion.