Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Herein we report results of a phase I/II trial to evaluate the safety and activity of autologous T-cells engineered to express an affinity-enhanced T-cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4×109 engineered T cells two days after autologous stem cell transplant (ASCT). Infusions were well-tolerated without clinically apparent cytokine release syndrome, despite high IL-6 levels. Engineered T-cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, consistent with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression free survival of 19.1 months. NY-ESO-1/LAGE-1 TCR-engineered T-cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.

Purpose:Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity.Methods:A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease–causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies.Results:Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay.Conclusion:The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.Genet Med 19 4, 430–438.

Dynamic soaring harvests energy from a spatiotemporal wind gradient, allowing albatrosses to glide over vast distances. However, its use is challenging to demonstrate empirically and has yet to be confirmed in other seabirds. Here, we investigate how flap-gliding Manx shearwaters optimize their flight for dynamic soaring. We do so by deriving a new metric, the horizontal wind effectiveness, that quantifies how effectively flight harvests energy from a shear layer. We evaluate this metric empirically for fine-scale trajectories reconstructed from bird-borne video data using a simplified flight dynamics model. We find that the birds’ undulations are phased with their horizontal turning to optimize energy harvesting. We also assess the opportunity for energy harvesting in long-range, GPS-logged foraging trajectories and find that Manx shearwaters optimize their flight to increase the opportunity for dynamic soaring during favorable wind conditions. Our results show how small-scale dynamic soaring affects large-scale Manx shearwater distribution at sea.

Background: Remaining physically active is important to maintain functional ability and reduce the incidence of co-morbidities in people with Multiple Sclerosis. The aim of this review was to evaluate the effectiveness of interventions on physical activity or sedentary behaviour in people with Multiple Sclerosis. Methods: A systematic search was conducted in May 2018 of the following databases: Web of Science Core Collections, Embase and Medline. Included studies were randomised controlled trials involving people with Multiple Sclerosis who completed an intervention, compared to any comparator. Outcomes included subjective or objective measures of physical activity or sedentary behaviour. Quality assessment was performed using the Physiotherapy Evidence Database scale. Results: Twenty-five trials were included covering 1697 participants, the majority of which had mild-moderate disability (average Physiotherapy Evidence Database score 6.2±1.5). Experimental interventions included exercise prescription (n=5), behaviour change interventions (n=10), combined exercise and behaviour change techniques (n=7) and education (n=3). Generally, subjective but not objective physical activity improved in those with mild-moderate disability. Insufficient data existed on the effectiveness on sedentary behaviour. Conclusion: A discrepancy seems to exists between the effectiveness of physical activity interventions in people with Multiple Sclerosis depending on whether physical activity was assessed objectively or subjectively, with the latter indicating effects.Effects on sedentary behaviour remain to be elucidated.

SignificanceProcellariiform seabirds homing from distant foraging locations present a natural situation in which the homing route can become obstructed by islands or peninsulas because birds will not travel long distances over land. By measuring initial orientation from Global Positioning System (GPS) tracks during homing, we found that the Manx shearwater fails to encode such obstacles while homing, implying a navigation system that encodes the direction of home rather than a learned route. Nonetheless, shearwaters timed their journeys home, implying that their navigational system provides them with information about both direction and distance home, providing evidence that for routine, yet long-distance navigation, seabirds probably ascertain homeward direction by comparing their current position and the location of home with 2 or more intersecting field gradients.