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.     

把DAC的输出从单端模式转换到差分模式的电路

高速DAC,比如模拟器件(AnalogDevices)公司的AD9776/78/79TxDAC系列,能提供差分输出,但对于低端交流电应用或高精度电平设置应用,配备差分转换电路的单端电流输出DAC提供了一种新颖的方法来生成差分波形控制功能。图1中的基本电路组合了电流输出DAC(即IC1,如8位AD5424D A C)和一个单端至差分运算放大级IC2、IC3A、IC3B——来产生要求的输出。对于双电源应用,可选择DAC的单极工作模式来达到DAC的最优性能。DAC利用单一运算放大器提供了双象限倍增或单极输出电压摆动。DAC的输出需要缓冲器,这是因为对施加到DAC输入端的代…     

An efficient nonlinear circuit simulation technique

This paper proposes a novel method for the analysis and simulation of integrated circuits (ICs) with the potential to greatly shorten the IC design cycle. The circuits are assumed to be subjected to input signals that have widely separated rates of variation, e.g., in communication systems, an RF carrier modulated by a low-frequency information signal. The proposed technique involves two stages. Initially, a particular order result for the circuit response is obtained using a multiresolution collocation scheme involving cubic spline wavelet decomposition. A more accurate solution is then obtained by adding another layer to the wavelet series approximation. However, the novel technique presented here enables the reuse of results acquired in the first stage to obtain the second-stage result. Therefore, vast gains in efficiency are obtained. Furthermore, a nonlinear model-order reduction technique can readily be used in both stages making the calculations even more efficient. Results will highlight the efficacy of the proposed approach     

Expression of type 2 11beta-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life

In adult life, the type 2 isozyme of 11beta-hydroxysteroid dehydrogenase (11betaHSD2) protects the mineralocorticoid receptor (MR) from glucocorticoid by inactivating cortisol to cortisone. 11betaHSD2 activity has been reported in human fetal tissues, where glucocorticoids may impair fetal growth yet are also required for normal fetal development. Using digoxigenin-labeled complementary ribonucleic acid (RNA) probes and an in-house 11betaHSD2 antiserum, we have analyzed the expression of 11betaHSD2, MR, and glucocorticoid receptor (GR) in human fetal tissues of gestational age 6-17 weeks (n=15). 11BetaHSD2 expression was absent at gestational age 6+ weeks, but was expressed in abundance in many fetal tissues between 8-12 weeks. At this time, 11betaHSD2 colocalized with GR messenger RNA (mRNA) expression in metanephros, gut, muscle, spinal cord and dorsal root ganglia, periderm, sex chords of testis, and adrenal. In particular within fetal kidney, intense expression of 11betaHSD2 and GR mRNA was observed over Bowman's capsule and the vascular tufts of developing glomeruli as they migrated from the surface of the kidney to the inner cortex. Only lung and adrenal medullary rests demonstrated high levels of GR mRNA but low levels of 11betaHSD2. 11BetaHSD2 mRNA and immunoreactivity staining patterns were similar, with the exception of the fetal adrenal, where mRNA was localized to the outer definitive zone but immunoreactivity was localized to the inner fetal zone. Colocalization of 11betaHSD2 (and GR mRNA) with MR mRNA was observed principally within epithelial cells of collecting ducts, particularly after 16 weeks gestation when the pattern of distribution of 11betaHSD2 became more adult in nature. High levels of MR mRNA were observed within developing bone. The data indicate that 11betaHSD2 in fetal life principally modulates ligand access to the GR in most fetal tissues, notably glomeruli and tubules in the developing kidney, testis, and periderm, and this may be have ramifications for fetal sodium homeostasis and differentiation. The development of tissues previously shown to have a critical requirement for glucocorticoids, such as lung and adrenal medulla, is facilitated by the expression of GR mRNA, but not 11betaHSD2. The expression of MR mRNA in high abundance in bone suggests a role for corticosteroids in human bone development, and the low/absent expression of 11betaHSD2 at this site suggests that it is functionally acting as a GR.     

Asymptotic solvers for second-order differential equation systems with multiple frequencies

In this paper, an asymptotic expansion is constructed to solve second-order differential equation systems with highly oscillatory forcing terms involving multiple frequencies. An asymptotic expansion is derived in inverse of powers of the oscillatory parameter and its truncation results in a very effective method of dicretizing the differential equation system in question. Numerical experiments illustrate the effectiveness of the asymptotic method in contrast to the standard Runge–Kutta method.     

New integer linear programming approaches for course timetabling

The most complete form of academic timetabling problem is the population and course timetabling problem. In this problem, there may be multiple classes of each subject, and the decision on which students are to constitute each class is made in concert with the decision on the timetable for each class. In order to solve this problem, it is normally simplified or decomposed in some fashion. One simplification commonly used in practice is known as blocking: it is assumed that the classes can be partitioned into sets of classes (or blocks) that will be timetabled in parallel. This restricts clashing to occur only between classes in the same block, and essentially removes the timetabling aspect of the problem, which can be carried out once the blocks are constituted and the classes populated. The problem of constituting the blocks and populating the classes, known as the course blocking and population problem, is nevertheless a challenging problem, and provides the focus of this paper. We demonstrate, using data provided by a local high school, that integer linear programming approaches can solve the problem in a matter of seconds. Key features include remodelling to remove symmetry caused by students with identical subject selection, and the observation that in practice, only integrality of the block composition variables needs to be enforced; the class population aspects of the model have strong integrality properties.     

Business process management with the user requirements notation

A number of recent initiatives in both academia and industry have sought to achieve improvements in e-businesses through the utilization of Business Process Management (BPM) methodologies and tools. However there are still some inadequacies that need to be addressed when it comes to achieving alignment between business goals and business processes. The User Requirements Notation (URN), recently standardized by ITU-T, has some unique features and capabilities beyond what is available in other notations that can help address alignment issues. In this paper, a URN-based framework and its supporting toolset are introduced which provide business process monitoring and performance management capabilities integrated across the BPM lifecycle. The framework extends the URN notation with Key Performance Indicators (KPIs) and other concepts to measure and align processes and goals. An example process for controlling access to a healthcare data warehouse is used to illustrate and evaluate the framework. Early results indicate the feasibility of the approach.     

Hidden Markov models for the stimulus-response relationships of multistate neural systems

Given recent experimental results suggesting that neural circuits may evolve through multiple firing states, we develop a framework for estimating state-dependent neural response properties from spike train data. We modify the traditional hidden Markov model (HMM) framework to incorporate stimulus-driven, non-Poisson point-process observations. For maximal flexibility, we allow external, time-varying stimuli and the neurons' own spike histories to drive both the spiking behavior in each state and the transitioning behavior between states. We employ an appropriately modified expectation-maximization algorithm to estimate the model parameters. The expectation step is solved by the standard forward-backward algorithm for HMMs. The maximization step reduces to a set of separable concave optimization problems if the model is restricted slightly. We first test our algorithm on simulated data and are able to fully recover the parameters used to generate the data and accurately recapitulate the sequence of hidden states. We then apply our algorithm to a recently published data set in which the observed neuronal ensembles displayed multistate behavior and show that inclusion of spike history information significantly improves the fit of the model. Additionally, we show that a simple reformulation of the state space of the underlying Markov chain allows us to implement a hybrid half-multistate, half-histogram model that may be more appropriate for capturing the complexity of certain data sets than either a simple HMM or a simple peristimulus time histogram model alone.     

Selecting critical patterns based on local geometrical and statistical information

Pattern selection methods have been traditionally developed with a dependency on a specific classifier. In contrast, this paper presents a method that selects critical patterns deemed to carry essential information applicable to train those types of classifiers which require spatial information of the training data set. Critical patterns include those edge patterns that define the boundary and those border patterns that separate classes. The proposed method selects patterns from a new perspective, primarily based on their location in input space. It determines class edge patterns with the assistance of the approximated tangent hyperplane of a class surface. It also identifies border patterns between classes using local probability. The proposed method is evaluated on benchmark problems using popular classifiers, including multilayer perceptrons, radial basis functions, support vector machines, and nearest neighbors. The proposed approach is also compared with four state-of-the-art approaches and it is shown to provide similar but more consistent accuracy from a reduced data set. Experimental results demonstrate that it selects patterns sufficient to represent class boundary and to preserve the decision surface.     

On Bounded Leg Shortest Paths Problems

Let V be a set of points in a d-dimensional l _p -metric space. Let s,t∈V and let L be a real number. An L-bounded leg path from s to t is an ordered set of points which connects s to t such that the leg between any two consecutive points in the set has length of at most L. The minimal path among all these paths is the L-bounded leg shortest path from s to t. In the s–t Bounded Leg Shortest Path (stBLSP) problem we are given two points s and t and a real number L, and are required to compute an L-bounded leg shortest path from s to t. In the All-Pairs Bounded Leg Shortest Path (apBLSP) problem we are required to build a data structure that, given any two query points from V and a real number L, outputs the length of the L-bounded leg shortest path (a distance query) or the path itself (a path query). In this paper we obtain the following results: