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.     

Extended donor criteria: use of cardiac allografts after carbon monoxide poisoning

BACKGROUND: An increasing demand for cardiac allografts for the treatment of end-stage cardiac failure has led to a shift in the traditional views about donor criteria. The use of allografts exposed to high concentrations of carbon monoxide is still under discussion. The current literature on this topic is contradictory. We describe our experience with orthotopic cardiac transplantation, using cardiac allografts after carbon monoxide poisoning. METHODS: Between March 13, 1989 and August 1, 1996, 770 orthotopic heart transplantations were performed in our center. Within this period, we accepted five cardiac allografts from brain-dead, carbon monoxide-poisoned donors. Donor history showed carbon monoxide intoxication in all cases. At the time of organ explantation, donor hemodynamic parameters were feeble in all patients. RESULTS: The postoperative course was uneventful in three of the five recipients. The overall 3-year survival rate in this small group is 40%. Induction therapy or rescue therapy with mono/polyclonal antibodies was not necessary. Myocardial right-ventricular biopsies did not show any specific signs of carbon monoxide poisoning. CONCLUSIONS: In our opinion, cardiac allografts from donors exposed to carbon monoxide can be transplanted successfully in infants and adults, if there are no signs of severe hemodynamic dysfunction in the presence of a normal central venous pressure and low-dose support with catecholamines and there are no electrocardiographic changes in combination with elevated transaminase. With extended donor criteria, the hearts of carbon monoxide-poisoned victims could increase the number of suitable organs and lower the death rate of patients on the United Network for Organ Sharing and Eurotransplant International Foundation waiting lists.     

Effect of shigella enterotoxin 1 (ShET1) on rabbit intestine in vitro and in vivo

The purpose of this study was to identify the optimal knot construction for interrupted dermal sutures. A synthetic braided absorbable suture, sizes 3-0 and 5-0, was selected for this evaluation. With reproducible mechanical performance tests, we determined that the construction of secure knots without ears required one additional throw as compared with secure knots with 3-mm ears. The direction of applied tension did not alter knot security, with the exception of granny knots, which required an extra throw when tension was applied parallel to the suture loop. Because interrupted dermal knot construction is accomplished without knot ears and with an applied tension parallel to the wound, one additional throw must be added to the knot to ensure knot security.     

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.