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.     

Quantitative mass spectrometry for colorectal cancer proteomics

This review documents the uses of quantitative MS applied to colorectal cancer (CRC) proteomics for biomarker discovery and molecular pathway profiling. Investigators are adopting various labeling and label-free MS approaches to quantitate differential protein levels in cells, tumors, and plasma/serum. We comprehensively review recent uses of this technology to examine mouse models of CRC, CRC cell lines, their secretomes and subcellular fractions, CRC tumors, CRC patient plasma/serum, and stool samples. For biomarker discovery these approaches are uncovering proteins with potential diagnostic and prognostic utility, while in vitro cell culture experiments are characterizing proteomic and phosphoproteomic responses to disrupted signaling pathways due to mutations or to inhibition of drugable enzymes.     

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.     

The development of multiple reaction monitoring assays for liver-derived plasma proteins

There is wide interpatient variability in toxicity to chemotherapeutic drugs and a lack of routine clinical tests for prospectively identifying patients at risk of developing toxicity from chemotherapy. An empirically driven MS strategy has been developed to monitor liver-derived plasma proteins as potential biomarkers of early toxicity. Multiple reaction monitoring (MRM) has been used to assess 46 candidate peptides from 18 liver-derived proteins. Following an iterative process of assay design, optimisation and assessment we selected 29 MRM assays (median CV 4.6%, range 1.2-11.6%) and monitored changes in levels of plasma proteins from a small number of colorectal cancer (CRC) patients undergoing chemotherapy. We demonstrated MRM assay robustness, and show that patients undergo minor elevation in plasma proteins when profiled on Day 3 of the chemotherapeutic regime. The MRM assays were in general agreement with 2-D DIGE-based quantitation from the same patient samples. The data supports the application of MRM-based methods as facile, highly reproducible, medium-throughput techniques that warrant expanded investigation for clinical utility in identifying patients at risk of developing chemotoxicity.     

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.     

Factors controlling volatile organic compounds in dwellings in Melbourne,Australia

This study characterized indoor volatile organic compounds (VOCs) and investigated the effects of the dwelling characteristics, building materials, occupant activities, and environmental conditions on indoor VOC concentrations in 40 dwellings located in Melbourne, Australia, in 2008 and 2009. A total of 97 VOCs were identified. Nine VOCs, n‐butane, 2‐methylbutane, toluene, formaldehyde, acetaldehyde, d‐limonene, ethanol, 2‐propanol, and acetic acid, accounted for 68% of the sum of all VOCs. The median indoor concentrations of all VOCs were greater than those measured outdoors. The occupant density was positively associated with indoor VOC concentrations via occupant activities, including respiration and combustion. Terpenes were associated with the use of household cleaning and laundry products. A petroleum‐like indoor VOC signature of alkanes and aromatics was associated with the proximity of major roads. The indoor VOC concentrations were negatively correlated (P < 0.05) with ventilation. Levels of VOCs in these Australian dwellings were lower than those from previous studies in North America and Europe, probably due to a combination of an ongoing temporal decrease in indoor VOC concentrations and the leakier nature of Australian dwellings.     

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.     

Nonlinear \boldsymbol{\mathcal{H}}_{\boldsymbol\infty} Control of UAVs for Collision Avoidance in Gusty Environments

This paper proposes a nonlinear $\mathcal{H}_{\infty}$ controller for stabilization of velocities, attitudes and angular rates of a fixed-wing unmanned aerial vehicle (UAV) in a windy environment. The suggested controller aims to achieve a steady-state flight condition in the presence of wind gusts such that the host UAV can be maneuvered to avoid collision with other UAVs during cruise flight with safety guarantees. This paper begins with building a proper model capturing flight aerodynamics of UAVs. Then a nonlinear controller is developed with gust attenuation and rapid response properties. Simulations are conducted for the Shadow UAV to verify performance of the proposed controller. Comparative studies with the proportional-integral-derivative (PID) controllers demonstrate that the proposed controller exhibits great performance improvement in a gusty environment, making it suitable for integration into the design of flight control systems for cruise flight of UAVs.     

Supporting exact indexing of arbitrarily rotated shapes and periodic time series under Euclidean and warping distance measures

Shape matching and indexing is important topic in its own right, and is a fundamental subroutine in most shape data mining algorithms. Given the ubiquity of shape, shape matching is an important problem with applications in domains as diverse as biometrics, industry, medicine, zoology and anthropology. The distance/similarity measure for used for shape matching must be invariant to many distortions, including scale, offset, noise, articulation, partial occlusion, etc. Most of these distortions are relatively easy to handle, either in the representation of the data or in the similarity measure used. However, rotation invariance is noted in the literature as being an especially difficult challenge. Current approaches typically try to achieve rotation invariance in the representation of the data, at the expense of discrimination ability, or in the distance measure, at the expense of efficiency. In this work, we show that we can take the slow but accurate approaches and dramatically speed them up. On real world problems our technique can take current approaches and make them four orders of magnitude faster without false dismissals. Moreover, our technique can be used with any of the dozens of existing shape representations and with all the most popular distance measures including Euclidean distance, dynamic time warping and Longest Common Subsequence. We further show that our indexing technique can be used to index star light curves, an important type of astronomical data, without modification. Reproducible Research Statement: All datasets and images used in this work are freely available at .