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The ideas and findings in this report should not be construed as an official DoD position. It is published in the interest of scientific and technical information exchange. Use of any trademarks in this report is not intended in any way to infringe on the rights of the trademark holder. Internal use. Permission to reproduce this document and to prepare(More)
English- and Spanish-learning infants were tested for perception of 2 synthetic speech contrasts differing in voice onset time. The 2 pairs were chosen so that they were native to either Spanish or English. Using the Visually Reinforced Infant Speech Discrimination (VRISD) paradigm, 6--8-month-old infants were taught to respond to a change in auditory(More)
A visually reinforced infant speech discrimination (VRISD) paradigm is described and evaluated. Infants at two ages were tested with the new paradigm on the following speech contrasts: [sa] vs [va], [sa] vs [fa], [sa] VS [za], [as] vs [a:s], vs [a:z], [at] vs [a:d], [a:t] vs [a:d], [at] vs [a:t], [fa] vs [thetaa]and [fi] vs [thetai]. The data reported are(More)
The ideas and findings in this report should not be construed as an official DoD position. It is published in the interest of scientific and technical information exchange. Use of any trademarks in this report is not intended in any way to infringe on the rights of the trademark holder. Internal use. Permission to reproduce this document and to prepare(More)
A new in vitro model has been developed for investigating extravascular diffusion of therapeutic agents in tumour tissue. V79-171b or EMT6/Ak cells are grown on porous Teflon support membranes and submerged in a large reservoir of medium, to give diffusion-limited 'multicellular membranes' (MMs) c. 200 microm in thickness. MMs are histologically similar to(More)
In common with other bioreductive drugs, metabolic reduction is required for activation of the benzotriazine-di-N-oxide tirapazamine (TPZ) in hypoxic regions of tumors. This same metabolism also consumes the drug as it diffuses, impeding its penetration into hypoxic tissue. In this study, we develop a pharmacokinetic (PK)/pharmacodynamic (PD) model for TPZ(More)
Prodrug activation gene therapy is a developing approach to cancer treatment, whereby prodrug-activating enzymes are expressed in tumour cells. After administration of a non-toxic prodrug, its conversion to cytotoxic metabolites directly kills tumour cells expressing the activating enzyme, whereas the local spread of activated metabolites can kill nearby(More)
Activation of prodrugs in tumors (e.g., by bioreduction in hypoxic zones) has the potential to generate active metabolites that can diffuse within the tumor microenvironment. Such "bystander effects" may offset spatial heterogeneity in prodrug activation but the relative importance of this effect is not understood. Here, we quantify the contribution of(More)
Hypoxia is a prevalent feature of many tumors contributing to disease progression and treatment resistance, and therefore constitutes an attractive therapeutic target. Several hypoxia-activated prodrugs (HAP) have been developed, including the phase III candidate TH-302 (evofosfamide) and the preclinical agent SN30000, which is an optimized analogue of the(More)