Mammalian cones respond to light by closing a cGMP-gated channel via a cascade that includes a heterotrimeric G-protein, cone transducin, comprising G␣t2, G3 and G␥t2 subunits. The function of G␥ in this cascade has not been examined. Here, we investigate the role of G3 by assessing cone structure and function in G3-null mouse (Gnb3 Ϫ/Ϫ ). We found that G3 is required for the normal expression of its partners, because in the Gnb3 Ϫ/Ϫ cone outer segments, the levels of G␣t2 and G␥t2 are reduced by fourfold to sixfold, whereas other components of the cascade remain unaltered. Surprisingly, Gnb3Ϫ/Ϫ cones produce stable responses with normal kinetics and saturating response amplitudes similar to that of the wild-type, suggesting that cone phototransduction can function efficiently without a G subunit. However, light sensitivity was reduced by approximately fourfold in the knock-out cones. Because the reduction in sensitivity was similar in magnitude to the reduction in G␣t2 level in the cone outer segment, we conclude that activation of G␣t2 in Gnb3 Ϫ/Ϫ cones proceeds at a rate approximately proportional to its outer segment concentration, and that activation of phosphodiesterase and downstream cascade components is normal. These results suggest that the main role of G3 in cones is to establish optimal levels of transducin heteromer in the outer segment, thereby indirectly contributing to robust response properties.
The CALTROP program which is presented in this paper provides a test of the feasibility of representing a decision tree as a linear chromosome and applying a genetic algorithm to the optimisation of the decision tree with respect to the classification of test sets of example data. The unit of the genetic alphabet (the "ealtrop") is a 3-integer string corresponding to a subtree of the decision tree. The program offers a user a choice of mating strategies and mutation rates. Test runs with different data sets show that the decision trees produced by the CALTROP program usually compare favourably with those produced by the popular automatic induction algorithm, ID3.
Purpose: Although stereotactic body radiotherapy (SBRT) is effective in early-stage non-small cell lung cancer (NSCLC), approximately 10%-15% of patients will fail regionally and 20%-25% distantly. We evaluate a novel circulating tumor cell (CTC) assay as a prognostic marker for increased risk of recurrence following SBRT.Experimental Design: Ninety-two subjects (median age, 71 years) with T1a (64%), T1b (23%), or T2a (13%) stage I NSCLC treated with SBRT were prospectively enrolled. CTCs were enumerated by utilizing a GFP-expressing adenoviral probe that detects elevated telomerase activity in cancer cells. Samples were obtained before, during, and serially up to 24 months after treatment. SBRT was delivered to a median dose of 50 Gy (range, 40-60 Gy), mostly commonly in four to five fractions (92%).Results: Thirty-eight of 92 subjects (41%) had a positive CTC test prior to SBRT. A cutoff of ≥5 CTCs/mL before treatment defined favorable (n ¼ 78) and unfavorable (n ¼ 14) prognostic groups. Increased risk of nodal (P ¼ 0.04) and distant (P ¼ 0.03) failure was observed in the unfavorable group. Within 3 months following SBRT, CTCs continued to be detected in 10 of 35 (29%) subjects. Persistent detection of CTCs was associated with increased risk of distant failure (P ¼ 0.04) and trended toward increased regional (P ¼ 0.08) and local failure (P ¼ 0.16).Conclusions: Higher pretreatment CTCs and persistence of CTCs posttreatment is significantly associated with increased risk of recurrence outside the targeted treatment site. This suggests that CTC analysis may potentially identify patients at higher risk for regional or distant recurrences and who may benefit from either systemic therapy and/or timely locoregional salvage treatment.
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