Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model.

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials

Resource Slack, Innovation Ambidexterity, and Quality Performance: Knowledge Heterogeneity Perspective

Abstract. Resource slack and innovation ambidexterity can both be represented and connected conceptually with heterogeneous knowledge structure. Hypothesizing with the logic of knowledge heterogeneity, the present study empirically examined ambidexterity’s mediation effect in the relationship between two forms of resource slacks (i.e., human and financial resources) and product quality. Companies in Taiwanese manufacturing industry were located based on the random inspection conducted by the Department of Budget, Accounting and Statistics of the Government in 2011, and surveyed. Our findings demonstrated that slack resource is only an indirect factor for product quality evaluated by internal developers and producers (i.e. development and delivery processes) and external customers (product-specific quality). Specifically, first, different resource slacks influence differently on ambidexterity; second, both exploration and exploitation positively influence quality of innovation; third, ambidexterity plays a significant mediator’s role that may strategically alter the relationship between slack and quality. Research has paid increasing attention to ambidexterity (i.e., exploration and exploitation) in organizational innovation. Mostly, however, focus on the influencing factors leading to possible ambidextrous design or implementation of innovation. Few have examined ambidexterity’s effects on specific dimensions of innovation as outcomes.Keywords. Resource slacks, Ambidexterity, Quality, Knowledge heterogeneity.JEL. M10; M11; M14

Magnetic Resonance Fingerprinting of the Pediatric Brain

Magnetic resonance fingerprinting (MRF) is increasingly being used to evaluate brain development and differentiate normal and pathologic tissues in children. MRF can provide reliable and accurate intrinsic tissue properties, such as T1 and T2 relaxation times. MRF is a powerful tool in evaluating brain disease in pediatric population. MRF is a new quantitative MR imaging technique for rapid and simultaneous quantification of multiple tissue properties

A Shallow Ritz Method for Elliptic Problems with Singular Sources

In this paper, a shallow Ritz-type neural network for solving elliptic equations with delta function singular sources on an interface is developed. There are three novel features in the present work; namely, (i) the delta function singularity is naturally removed, (ii) level set function is introduced as a feature input, (iii) it is completely shallow, comprising only one hidden layer. We first introduce the energy functional of the problem and then transform the contribution of singular sources to a regular surface integral along the interface. In such a way, the delta function singularity can be naturally removed without introducing a discrete one that is commonly used in traditional regularization methods, such as the well-known immersed boundary method. The original problem is then reformulated as a minimization problem. We propose a shallow Ritz-type neural network with one hidden layer to approximate the global minimizer of the energy functional. As a result, the network is trained by minimizing the loss function that is a discrete version of the energy. In addition, we include the level set function of the interface as a feature input of the network and find that it significantly improves the training efficiency and accuracy. We perform a series of numerical tests to show the accuracy of the present method and its capability for problems in irregular domains and higher dimensions

Poly[bis­(μ2-4,4′-bipyridine)­bis­(3-nitro­benzoato)nickel(II)]

The crystal structure of the title complex, [Ni(C7H4NO4)2(C10H8N2)2]n, exhibits a two-dimensional network, which is built up from slightly distorted NiN4O2 polyhedra (2 symmetry), bipyridine ligands, and carboxyl­ate anions. The NiII atoms are six-coordinated by two O atoms of two monodentate carboxyl­ate anions and four N atoms from bipyridine ligands and are connected into layers by the 4,4′-bipyridine ligands