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.     

Sulfated zirconia catalysts: Are Brønsted acid sites the source of the activity?

The thermal decomposition products of pyridinium sulfate differ from those of pyridinium sulfate supported on zirconia which in turn differs from that of pyridine adsorbed on a sulfated zirconia. Unsupported pyridinium sulfate decomposes to produce pyridine and sulfuric acid, and these subsequently react to produce oxides of carbon and sulfur. Zirconia that is sulfated and then exposed to pyridine does not release detectable amount of pyridine during heating in an inert gas; rather the pyridine undergoes oxidation reduction reactions simultaneously to release CO₂ and sulfur compounds. Pyridinium sulfate supported on zirconia decomposes upon heating to release pyridine and sulfuric acid, which reacts with the zirconia. The desorption of pyridine in one case and only CO₂/SO_x in the other case suggests that sulfated zirconia does not contain Brønsted acidity that can form pyridinium sulfate.     

iSAX: disk-aware mining and indexing of massive time series datasets

Current research in indexing and mining time series data has produced many interesting algorithms and representations. However, the algorithms and the size of data considered have generally not been representative of the increasingly massive datasets encountered in science, engineering, and business domains. In this work, we introduce a novel multi-resolution symbolic representation which can be used to index datasets which are several orders of magnitude larger than anything else considered in the literature. To demonstrate the utility of this representation, we constructed a simple tree-based index structure which facilitates fast exact search and orders of magnitude faster, approximate search. For example, with a database of one-hundred million time series, the approximate search can retrieve high quality nearest neighbors in slightly over a second, whereas a sequential scan would take tens of minutes. Our experimental evaluation demonstrates that our representation allows index performance to scale well with increasing dataset sizes. Additionally, we provide analysis concerning parameter sensitivity, approximate search effectiveness, and lower bound comparisons between time series representations in a bit constrained environment. We further show how to exploit the combination of both exact and approximate search as sub-routines in data mining algorithms, allowing for the exact mining of truly massive real world datasets, containing tens of millions of time series.     

Dimensionality Reduction for Fast Similarity Search in Large Time Series Databases

The problem of similarity search in large time series databases has attracted much attention recently. It is a non-trivial problem because of the inherent high dimensionality of the data. The most promising solutions involve first performing dimensionality reduction on the data, and then indexing the reduced data with a spatial access method. Three major dimensionality reduction techniques have been proposed: Singular Value Decomposition (SVD), the Discrete Fourier transform (DFT), and more recently the Discrete Wavelet Transform (DWT). In this work we introduce a new dimensionality reduction technique which we call Piecewise Aggregate Approximation (PAA). We theoretically and empirically compare it to the other techniques and demonstrate its superiority. In addition to being competitive with or faster than the other methods, our approach has numerous other advantages. It is simple to understand and to implement, it allows more flexible distance measures, including weighted Euclidean queries, and the index can be built in linear time. Received 16 May 2000 / Revised 18 December 2000 / Accepted in revised form 2 January 2001     

Total System Reliability: Integrated Model for Growth and Test Termination

Reliability demonstration testing is not the most efficient method of assuring product reliability prior to shipment. It is costly, time consuming and has inherent technical and social limitations. The dilemma facing the reliability and quality engineer is whether to continue demonstration testing and risk shipping a product late or ship the product and risk warranty and field service returns. Either option can cause the company to lose significant market share and profit. This paper sets out to solve this dilemma by meeting both the time to market constraints and the product reliability goals. The weaknesses of existing reliability demonstration techniques are explored and a comprehensive methodology is introduced involving controlled development processes, stress testing, root cause determination and process change feedback mechanisms. All prototype products are manufactured on the final volume process line resulting in the early identification and correction of process‐related problems. Testing commences on the first available prototypes with system stress/robust testing being employed to stimulate failures, determine their root cause and correct them. Reliability growth modelling assesses the ongoing improvements occurring in reliability during the development cycle, while a statistical stopping rule is used to determine the optimal product release time without risking product warranty. The approach is applicable to systems incorporating both hardware and software elements. The methodology has been validated on three development projects of telecommunication systems comprising hardware and software. In addition to enhancing team behaviour and performance, the development times have been reduced by 14% and the ramp‐up time to full worldwide product shipments has been reduced by 50%. Copyright © 2005 John Wiley & Sons, Ltd.     

Transitioning Towards Creativity and Innovation Measurement in SMEs

The aim of this paper is to explore the transition from traditional measures to creativity and innovation measures within a number of small to medium‐sized enterprises (SMEs) case studies. The need for increased competitiveness has created an impetus for increased creativity and innovation in SMEs. However, the measures associated with the process of creativity and innovation in organisations sometimes do not follow cause‐and‐effect rationale, reflecting non‐linear behaviour. A multiple SME‐based case research methodology is used to explore the transitioning effects from traditional to more creativity and innovation based measures. The cases were part of a longitudinal creativity and innovation intervention programme, which combined taught modules and Critical Action Learning networks over a two‐year period. These networks involved sub‐groups applying critical theory‐based study to the learning they had received in the modules. The findings reveal that the transition dynamics include a complex mix of cause and effect rationale, phenomenology, incremental change, radical change, quantitative, qualitative and linear and complex contrasts and comparisons. Thus, managers must facilitate an eclectic approach to creativity and innovation measures.     

The effect of fertilizer nitrogen input to grass-clover swards and calving date on the productivity of pasture-based dairy production

The objective of this systems-scale study was to investigate grazing season timeframes on pasture and milk production and on milk processability of dairy systems with compact spring-calving dairy cows grazing white clover (Trifolium repens L.) based grassland. Fifty-four primiparous and multiparous Holstein-Friesian dairy cows were used in a one-factor study with 3 systems (n = 18) and repeated over 2 yr (2008/09 and 2009/10). The 3 systems were: early spring calving with annual fertilizer N input of 100 kg·ha^?1 applied in spring (ES100N; 2.1 cows·ha^?1; grazing February to November), early spring calving without fertilizer N (ES0N; 1.6 cows·ha^?1; grazing February to November) and late spring calving without fertilizer N (LS0N; 1.53 cows·ha^?1; grazing April to January). Annual pasture production was affected by an interaction between grazing system and year: Mean annual pasture yields for 2008 and 2009 were ES100N; 10.35 and 9.88, ES0N; 8.88 and 8.63, LS0N; 9.18 and 10.31 t of dry matter (DM)·ha^?1 (SEM 0.39). LS0N had higher pasture DM yield in 2009 due to higher clover DM production and biological N fixation compared with the other systems. Clover stolon and root mass in the following February was correlated with stolon and root mass in the previous November with 64% of stolon mass present on LS0N in February (R² = 0.84). There were no detectable differences in per-lactation milk yield (6,335 kg·cow^?1), fat, protein and lactose yields (271, 226, 297 kg·cow^?1, respectively), cow liveweight (585 kg) or body condition score (3.02). Although winter grazing favored subsequent clover DM production, biological N fixation and pasture DM production, delaying calving date in spring and extending lactation into the following winter led to inefficient use of this pasture by the grazing herd and lowered the quality of late-lactation milk for processing purposes. Hence, a mean calving date in mid- to late-February is recommended for zero-fertilizer N input clover-based grassland.     

Growth of InGaN HBTs by MOCVD

The design and growth of GaN/InGaN heterojunction bipolar transistors (HBTs) by metalorganic chemical vapor deposition (MOCVD) are studied. Atomic-force microscopy (AFM) images of p⁺InGaN base layers (∼100 nm) deposited under various growth conditions indicate that the optimal growth temperature is limited to the range between 810 and 830°C due to a trade-off between surface roughness and indium incorporation. At these temperatures, the growth pressure must be kept above 300 Torr in order to keep surface pit density under control. An InGaN graded-composition emitter is adopted in order to reduce the number of V-shaped defects, which appear at the interface between GaN emitter and InGaN base and render an abrupt emitter-base heterojunction nearly impossible. However, the device performance is severely limited by the high p-type base contact resistance due to surface etching damage, which resulted from the emitter mesa etch.     

Endometriosis and the neoplastic process

Endometriosis is a frequent disorder that commonly presents with infertility and pelvic pain. Although the precise aetiology of endometriosis is unclear, it is generally considered to involve multiple genetic, environmental, immunological, angiogenic and endocrine processes. Genetic factors have been implicated in endometriosis but the susceptibility genes remain largely unknown. Although endometriosis is a benign disorder, recent studies of endometriosis suggest endometriosis could be viewed as a neoplastic process. Evidence to support this hypothesis includes the increased susceptibility to develop ovarian clear-cell and endometrioid cancers in the presence of endometriosis, and molecular similarities between endometriosis and cancer. In this article we discuss (i) the evidence suggesting that endometriosis might be viewed as a neoplastic process, and (ii) the implications of this hypothesis for elucidating the pathogenesis of endometriosis and developing novel methods of diagnostic classification and individualised treatments.     

Multiple Sliding and Rolling Contact Dynamics for a Flexible Rotor/Magnetic Bearing System

Active magnetic bearings (AMBs) offer contact-free and frictionless support of rotating machinery. However, because of their limited force capacity, they have to incorporate retainer bearings to protect the rotor and stator laminations against high-amplitude vibration levels. Efficient modeling of contact dynamics is important for the design of adaptive controllers to prevent contact. If, however, contact does occur, it is necessary to recover the rotor position with minimum damage and without shutting down the system. This paper utilizes constrained Lagrangian equations of motion to develop a computationally efficient method to model contact dynamics. The method does not require a direct physical modeling of contact forces, although the contact forces are automatically evaluated from the constraint conditions, and it can be applied to multicontact cases. Furthermore, the technique is capable of detecting and simulating the destructive backward whirl rolling motion. A model reduction technique is introduced to improve the computational efficiency. This is demonstrated by comparing numerical predictions with experimental results, obtained for a 2-m-long flexible rotor supported by two magnetic bearings