Phenotype phenotypic response

An alternative approach involves testing of new drug entities on whole-cell systems and measuring effects on integrated cellular pathways. Favorable phenotypic responses are identified with this approach that may better produce alteration of multicomponent disease processes. 

As well as complex biological targets, complex chemical targets (drugs with multiple activity, prodrugs) can be used to produce therapeutically useful phenotypic responses. 

The role of an immune response to intestinal bacteria in the development of UC may not be as strong a contributing factor as it is in CD. The potential role of environmental factors in the development of UC implies that the immune response is directed against an unknown antigen. The findings that development and severity of UC are reduced in patients who smoke, or in those with appendectomies, may support the theory that these factors may somehow modify either the genetic component or phenotypic response to immunologic stimuli.11,13... 

Antiproliferative assay, flow cytometry studies, in vivo activities and biomarkers determination represent key tools for profiling the phenotypic response to molecular or pharmacologic perturbation at cellular or tissue levels the study enables therapeutic response irrespective of target activity of topi and taken together, these results suggest that there is a strong potential for edotecarin in clinical [36, 37] development for treatment of human tumors. 

Apoptosis is one of a number of phenotypic responses that may occur as a result of a signal transduction pathways occurring in the cell. Clustering of cellular receptors is a commonly observed first step in the mechanism of signal transduction pathways to result in apoptosis. Receptor-clustered cytoplasmic domains trigger... 

Stanford CM, Morcuende JA, Brand RA. Proliferative and phenotypic responses of bonelike cells to mechanical deformation. J Orthop Res. 1995 13 664-670. 

More recent efforts now indicate that this activity is far more complex than the targeting of this single event, as different phenotypic responses readily occur across a panel of cell lines. While at this time it is difficult to determine if this discovery provides a drug target, it has become clear that development of systems that target intermediate filaments and their cytokeratin structures offers a new realm for small molecule discovery. 

Lors, C., Mossmann, J. R. Barbe, P. (2004). Phenotypic responses of the soil bacterial... 

III) The correlation between the observed molecular changes in the genome (SNPs) and the phenotypic response (resistance) is as high as possible. A sound survey should be conducted to determine whether different mechanisms of resistance exist and how... 

Elevated peripheral eosinophil counts in asthmatics have correlated with decreases in specific airway conductance, forced expiratory volume (FEVi), maximum mid-expiratory flow rate (Horn et al., 1975), bronchial hyperreactivity (BHR) to histamine (H Taylor and Luksza, 1987) and clinical severity scores (Aas Bousquet et al., 1990). When circulating eosinophils were isolated fi om asymptomatic asthmatics, a large proportion of cells (35%) was recovered with centrifugal density less than 1.082 gml compared to normal subjects (10% Frick et al., 1989). Alteration of centrifugal density of eosinophils is one of the phenotypic responses to cellular activation (Hansel et al., 1990 Fukuda and Makino, 1992). Not only is the number of cells increased in asthma, circulating eosinophils may be activated intravascularly as well. 

Progression of a KMO inhibitor into an HD clinical trial will require evidence that the inhibition of the enzyme in vitro safely translates to both the anticipated modulation of tryptophan metabolites in vivo in the brain as well as positive phenotypical responses within relevant transgenic mouse models. 

In other words, what we should use instead, rather than the two-degree-of-freedom test, is a one-degree-of-freedom test based on the linear contrast only. Similar arguments could be made for the other two pairs of contrasts. The first member of the pair is probably more interesting than the second. This raises the issue whether the particular contrast chosen is the best. This depends, of course on the true relationship between genotype and phenotypic response. We investigate the implication of this is the next section. 

Associated with each of the three schemes of contrasts one can calculate the variance of the resulting estimates. Figure 25.6 gives the factor by which a /N would have to be multiplied to obtain the variance for each of the three ordinary least-squares estimators of phenotypic response. A fourth universal contrast has been added. This does not correspond to any least-squares solution, except the linear one when p (a) = 0.5. It is, however, universally unbiased for any of the three models of inheritance being considered here dominant, recessive, additive (linear). This is because it uses the contrast (—1, 1) and hence does not use the heterozygous group at all. In fact, it is... 

Figure 25.6 Variances of four possible estimators of phenotypic response. The graph shows the factor by which <7 jN must be multiplied to obtain the variance of the given contrast.

The phenolic compounds shown to reduce aflatoxin production in response to oxidative stress have potential as tools to investigate functional elucidation of the genes involved but this is limited by the absence of a practical gene transformation system. In the absence of a direct approach with A flavus, use can be made of the yeast Saccharomyces cerevisiae, for which numerous stress response pathways have been characterized [34]. Selected 5. cerevisiae strains, including mutants with single gene deletions, have been used as a model to evaluate phenotypic response to oxidative stress induced by H2O2 [35]. 

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