Abstract: This invention provides methods for determining drug specificity, therapeutic index and effective doses for individual patients. According to the methods of the invention, graded levels of drug are applied to a biological sample or a patient. A plurality of cellular constituents are measured to determine the activity of the drug on a target pathway and at least one off-target pathway. A drug specificity is determined by comparing the target and off target activities of the drug. A therapeutic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the target pathway. A toxic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the off target pathway. Therapeutic index is the ratio of the toxic concentration over therapeutic concentration. Methods are also provided to determine an effective dose of a drug for a patient by measuring the activity of the drug on the particular patient.

Abstract: The present invention provides methods for monitoring disease states in a subject, as well as methods for monitoring the levels of effect of therapies upon a subject having one or more disease states. The methods involve: (i) measuring abundances of cellular constituents in a cell from a subject so that a diagnostic profile is obtained, (ii) measuring abundances of cellular constituents in a cell of one or more analogous subjects so that perturbation response profiles are obtained which correlate to a particular disease or therapy, and (iii) determining the interpolated perturbation response profile or profiles which best fit the diagnostic profile according to some objective measure.

Abstract: The present invention provides methods for enhanced detection of biological response patterns. In one embodiment of the invention, genes are grouped into basis genesets according to the co-regulation of their expression. Expression of individual genes within a geneset is indicated with a single gene expression value for the geneset by a projection process. The expression values of genesets, rather than the expression of individual genes are then used as the basis for comparison and detection of biological responses with greatly enhanced sensitivity.

Abstract: The present invention relates to genes in Saccharomyces cerevisiae which are essential for germination and proliferation of S. cerevisiae and using the identified genes or their encoded proteins as targets for highly specific antifungal agents, insecticides, herbicides and anti-proliferation drugs. The present invention provides antisense molecules and ribozymes comprising sequences complementary to the sequences of mRNAs of essential genes that function to inhibit the essential genes. The present invention also provides neutralizing antibodies to proteins encoded by essential genes that bind to and inactivate the essential gene products. The present invention further provides pharmaceutical compositions for treating fungal and proliferative diseases, as well as methods of treatment of fungal and proliferative diseases.

Abstract: The present invention relates to genes in Saccharomyces cerevisiae which are essential for germination and proliferation of S. cerevisiae and using the identified genes or their encoded proteins as targets for highly specific antifungal agents, insecticides, herbicides and anti-proliferation drugs. The present invention provides antisense molecules and ribozymes comprising sequences complementary to the sequences of mRNAs of essential genes that function to inhibit the essential genes. The present invention also provides neutralizing antibodies to proteins encoded by essential genes that bind to and inactivate the essential gene products. The present invention further provides pharmaceutical compositions for treating fungal and proliferative diseases, as well as methods of treatment of fungal and proliferative diseases.

Abstract: The present invention provides methods for distinguishing the fractions of polynucleotide sequences which hybridize to any given probe, including probes on microarrays such as those described herein. In particular, the present invention enables users to identify the fraction of sequences which are perfectly complementary to a probe, thereby correcting for effects of cross hybridization in a hybridization assay. The methods of the invention work by monitoring the kinetics of dissociation of sequences from the probe so that a resulting “dissociation curve” may be compared to a combination of the individual “dissociation profiles” for each sequence which hybridizes. In alternative embodiments, the invention also provides computer systems for performing the present methods, as well as databases of the dissociation profiles.

Abstract: This invention relates to methods and systems for characterizing the actions of drugs in cells. In particular, the invention provides methods for determining the presence of a number of primary targets through which a drug, drug candidate, or other compound of interest acts on a cell. Thus, the invention also relates to methods for drug development based on the disclosed methods for determining the presence of a number of primary targets of a drug. The methods of the invention involve: (i) measuring responses of cellular constituents to graded exposures of the cell to a drug of interest; (ii) identifying an "inflection concentration" of the drug for each cellular constituent measured; and (iii) identifying "expression sets" of cellular constituents from the distribution of the inflection drug concentrations. Each expression set corresponds to a particular primary target of the drug.

Abstract: The present invention provides methods and systems for testing and confirming how well a network model represents a biological pathway in a biological system. The network model comprises a network of logical operators relating input cellular constituents (e.g., mRNA or protein abundances) to output classes of cellular constituents, which are affected by the pathway in the biological system. The methods of this invention provide, first, for choosing complete and efficient experiments for testing the network model which compare relative changes in the biological system in response to perturbations of the network.

Abstract: The present invention provides methods for identifying and representing the biological pathways of drug action on a cell by: (i) measuring responses of cellular constituents to graded exposures of the cell to a drug of interest; (ii) measuring the responses of cellular constituents to perturbations in one or more biological pathways of the cell; and (iii) scaling a combination of the measured pathway responses to fit the measured drug responses best according to an objective measure. In alternative embodiments, the present invention also provides for assessing the significance of the identified representation and for verifying that the identified pathways are actual pathway of drug action. In various embodiments, the effects on the cell can be determined by measuring gene expression, protein abundances, protein activities, or a combination of such measurements.