Human fibroblast growth factor 20 (FGF-20; CG53135-05): a novel cytoprotectant with radioprotective potential.

The aim was to evaluate the radioprotective properties of recombinant human fibroblast growth factor 20 (FGF-20; CG53135-05) in vitro and in vivo and to examine its effects on known cellular pathways of radioprotection. Relative transcript levels of the cyclooxygenase 2 (COX2), Mn-super oxide dismutase (SOD), CuZn-SOD, extracellular (EC)-SOD, nuclear respiratory factor 2 (Nrf2), glutathione peroxidase 1 (GPX1) and intestinal trefoil factor 3 (ITF3) genes, which are involved in radiation response pathways, were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) in NIH/3T3, IEC18, CCD-18Co, CCD-1070sk and human umbilical vein endothelial cells (HUVEC) cells exposed to FGF-20. Activation of the radioprotective signal transduction pathways initiating with the serine/threonine Akt kinase and the extracellular regulated kinase (ERK) were analysed. Levels of intracellular hydrogen peroxide and cytosolic redox potential were also measured in irradiated and unirradiated cells in the presence or absence of FGF-20. The effects of FGF-20 on cell survival in vitro following ionizing radiation were evaluated using clonogenic assays. To test the potential activity of FGF-20 as a radioprotectant in vivo, mice were administered a single dose of FGF-20 (4 mg kg(-1), intraperitoneally (i.p.) 1 day before lethal total-body irradiation and evaluated for survival. In vitro exposure to FGF-20 increased expression of the Nrf2 transcription factor and oxygen radical scavenging enzymes such as MnSOD, activated signal transduction pathways (ERK and Akt) and resulted in increased survival of irradiated cells in vitro. FGF-20 treatment also resulted in a concomitant reduction in intracellular levels of injurious reactive oxygen species (ROS) following acute ionizing irradiation. Finally, prophylactic administration of FGF-20 to mice before potentially lethal, whole-body X-irradiation led to significant increases in overall survival. FGF-20 reduced the lethal effects of acute ionizing radiation exposure in cells by up-regulating important signalling and free radical scavenging pathways. Survival-sparing effects of FGF-20 prophylaxis in acutely irradiated mice presumably are elicited by comparable mechanisms. These results indicate that FGF-20, has significant radioprotective attributes with potential applications in clinical and non-clinical exposure settings.

A quantitative genomic expression analysis platform for multiplexed in vitro prediction of drug action.

Genomic expression signatures provide high-content biomarkers of cellular physiology, including the diverse responses to therapeutic drugs. To recognize these signatures, we devised a method of biomarker evaluation called 'sampling over gene space' (SOGS) that imparts superior predictive performance to existing supervised classification algorithms. Applied to microarray data from drug-treated human cortical neuron 1A cell cultures, this method predicts whether individual compounds possess anticonvulsant, antihypertensive, cyclooxygenase inhibitor, or opioid action. Thus, stable cell lines can be suitable for expression signature-based screening of a diverse range of activities. A SOGS-based system also discriminates physiologically active from inactive compounds, identifies drugs with off-target side effects, and incorporates a quantitative method for assigning confidence to individual predictions that, at its most stringent, approaches 100% accuracy. The capacity to resolve multiple distinct drug activities while simultaneously discriminating inactive and potential false-positive compounds in a cell line presents a unified framework for streamlined chemical genomic drug discovery.

Growth and behavior of thyroid-deficient lizards (Sceloporus undulatus).

This study investigates thyroid control of growth and energy metabolism plus growth-dependent and growth-independent behavioral effects of thyroid manipulation in lizards. Experiments were done on surgically thyroidectomized (Tx) and sham-operated (Sh) yearling Sceloporus undulatus enclosed in their natural habitat. Lizards were placed in an outdoor enclosure in early August. Growth rate was measured and behavior was observed until mid-October. Subsequently, lizards were returned to the lab for measurements of plasma thyroxine (T4), standard metabolic rate (SMR), and running endurance. Thyroidectomy reduced plasma T4 from 4.3 +/- 0.56 ng/ml to undetectable levels (P = 0.006) and SMR by 44% (P less than 0.0001). Thyroid deficiency produced a threefold reduction in growth rate (Tx: 0.04 +/- 0.010 mm/day, n = 12 vs Sh: 0.11 +/- 0.006 mm/day, n = 11, P less than 0.0001). Growth rate was correlated with SMR among individuals (length-specific: r = 0.55, P = 0.027, n = 16), even after statistical removal of mass and treatment effects. The total volume of oxygen consumed for standard metabolism during the growth period, as estimated from allometric equations, was correlated with cumulative growth (R2 = 0.94, P = 0.013) and was significantly lower for thyroid-deficient lizards than for controls (P less than 0.0001). Distance moved in the field and running endurance on a treadmill both scaled on body mass (M0.98 +/- 0.418, P = 0.030 and M1.72 +/- 0.763, P = 0.040, respectively), indicating that larger lizards moved farther and had greater stamina than their smaller counterparts. Neither of these behavioral factors was affected directly by thyroid status. Thyroid-deficient lizards were active for a smaller percentage of the day than controls (Tx: 42.6 +/- 5.7%, n = 11 vs Sh: 57.4 +/- 3.2%, n = 12, P = 0.040), independent of differences in body size. On an interindividual basis, the frequency of activity was significantly correlated with SMR (r = 0.57, P = 0.020, n = 16) and growth rate (mass-specific: r = 0.47, P = 0.025, n = 23).