Data-driven computer simulation of human cancer cell.

Using the Diagrammatic Cell Language trade mark, Gene Network Sciences (GNS) has created a network model of interconnected signal transduction pathways and gene expression networks that control human cell proliferation and apoptosis. It includes receptor activation and mitogenic signaling, initiation of cell cycle, and passage of checkpoints and apoptosis. Time-course experiments measuring mRNA abundance and protein activity are conducted on Caco-2 and HCT 116 colon cell lines. These data were used to constrain unknown regulatory interactions and kinetic parameters via sensitivity analysis and parameter optimization methods contained in the DigitalCell computer simulation platform. FACS, RNA knockdown, cell growth, and apoptosis data are also used to constrain the model and to identify unknown pathways, and cross talk between known pathways will also be discussed. Using the cell simulation, GNS tested the efficacy of various drug targets and performed validation experiments to test computer simulation predictions. The simulation is a powerful tool that can in principle incorporate patient-specific data on the DNA, RNA, and protein levels for assessing efficacy of therapeutics in specific patient populations and can greatly impact success of a given therapeutic strategy.

Development of an evolutionarily novel structure: fibroblast growth factor expression in the carapacial ridge of turtle embryos.

The turtle shell, an evolutionarily novel structure, contains a bony exoskeleton that includes a dorsal carapace and a ventral plastron. The development of the carapace is dependent on the carapacial ridge (CR), a bulge in the dorsal flank that contains an ectodermal structure analogous to the apical ectodermal ridge (AER) of the developing limb (Burke. 1989a. J Morphol 199:363-378; Burke. 1989b. Fortschr Zool 35:206-209). Although the CR is thought to mediate the initiation and outgrowth of the carapace, the mechanisms of shell development have not been studied on the molecular level. Here, we present data suggesting that carapace formation is initiated by co-opting genes that had other functions in the ancestral embryo, specifically those of limb outgrowth. However, there is divergence in the signaling repertoire from that involved in limb initiation and outgrowth. In situ hybridizations with antisense riboprobes derived from Trionyx spiniferous fibroblast growth factor-10 (tfgf10) and Trachemys scripta (T. scripta) fibroblast-growth factor 8 (tfgf8) cDNAs were performed on sections of early T. scripta embryos (< 30 days). Expression of tfgf10 was localized to the mesenchyme subjacent to the ectoderm of the CR. In the chick limb bud, FGF10 is known to be expressed in the early limb-forming mesenchyme and is capable of inducing FGF8 in the AER to initiate the outgrowth of the limb bud. Although the expression of tfgf8 was found in the AER of the developing turtle limb, it was not seen in the CR. Thus, the initiation of the carapace is in agreement with FGF10 expression in the CR, but FGF8 does not appear to have a role in mediating early carapace outgrowth.

The effect of changes in arterial CO2 tension on plasma lidocaine concentration.

The authors studied the effect of changes in arterial carbon dioxide tension on plasma lidocaine concentrations during a constant lidocaine infusion in eight healthy volunteers. With a PaCO2 of 41.4 +/- 0.9 mmHg (mean +/- SE), total plasma lidocaine concentrations were 3.97 +/- 0.20 microgram X ml-1. There was no significant change associated with hypercarbia (PaCO2 = 55.7 +/- 1.5 mmHg, lidocaine = 3.93 +/- 0.18 microgram X ml-1) or hypocarbia (PaCO2 = 19.5 +/- 1.4 mmHg, lidocaine = 4.29 +/- 0.25 microgram X ml-1), despite the known effects of changes in CO2 tension on hepatic blood flow and lidocaine protein binding. During hypercarbia, plasma lidocaine binding decreases while total plasma lidocaine remains essentially constant; therefore, increased CO2 tensions could cause toxicity if total lidocaine concentrations were in the high therapeutic range (5 micrograms X ml-1). Four subjects experienced transient symptoms of mild lidocaine toxicity during acute increases in carbon dioxide tension.

Evaluation of the Ohmeda 3700 pulse oximeter: steady-state and transient response characteristics.

The authors determined the accuracy of the Ohmeda 3700 (version J) pulse oximeter in healthy volunteers rendered hypoxic (SaO2 from 60-98%) by breathing mixtures of O2 in N2. When equipped with an ear probe, the pulse oximeter reading (y) reliably predicted arterial saturation (x) under steady-state conditions (y = 1.05x - 4.66, r = 0.98) as well as when oxygen saturation was rapidly decreasing (y = 1.05x - 6.38, r = 0.96). Conversely, when equipped with a finger probe, the oximeter tended to significantly underestimate steady-state arterial saturation (y = 1.21x - 19.1, r = 0.98, P less than 0.001). In response to this information, the manufacturer modified the oximeter's software (version XJ1), resulting in improved agreement between oximeter readings and arterial values (y = 0.96x + 4.59, r = 0.99). Despite the close correlation between steady-state oximeter readings and arterial saturation, the 99% prediction limits for both the ear and finger probes (version XJ1) were +/- 8%. Finger probe readings did not reliably reflect radial arterial oxygenation during rapid desaturation (y = 0.55x + 45.2, r = 0.78). This may be related to the time required to "arterialize" the blood in the finger; during acute resaturation, we found that the ear- to finger-probe delay was 24.0 +/- 2.3 s (means +/- SE, P less than 0.001).