Abstract: Disclosed herein are methods of using 3-amino-4-(4-(4 (dimethylcarbamoyl) phenyl)-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide or deuterated analogues thereof for treating cancers and pharmaceutical compositions comprising the same.

Abstract: Disclosed herein are quinoline-based compounds and method for inhibiting CDK8 or CDK19 for the intervention in diseases, disorders, and conditions. The quinoline-based composition comprise substituents at quinoline ring positions 4 and 6, wherein the substituent at position 4 is selected from a substituted or unsubstituted arylalkylamine or a substituted or unsubstituted arylhetrocyclylamine. Pharmaceutical compositions comprising the substituted qunioline compositions, methods of inhibiting CDK8 or CDK19, and methods of treating CDK8/19-associated diseases, disorders, or conditions are also disclosed.

Abstract: Disclosed herein are quinoline-based compounds and method for inhibiting CDK8 or CDK19 for the intervention in diseases, disorders, and conditions. The quinoline-based composition comprise substituents at quinoline ring positions 4 and 6, wherein the substituent at position 4 is selected from a substituted or unsubstituted arylalkylamine or a substituted or unsubstituted arylhetrocyclylamine. Pharmaceutical compositions comprising the substituted quinoline compositions, methods of inhibiting CDK8 or CDK19, and methods of treating CDK8/19-associated diseases, disorders, or conditions are also disclosed.

Abstract: Disclosed herein are quinoline-based compounds and method for inhibiting CDK8 or CDK19 for the intervention in diseases, disorders, and conditions. The quinoline-based composition comprise substituents at quinoline ring positions 4 and 6, wherein the substituent at position 4 is selected from a substituted or unsubstituted arylalkylamine or a substituted or unsubstituted arylhetrocyclylamine. Pharmaceutical compositions comprising the substituted qunioline compositions, methods of inhibiting CDK8 or CDK19, and methods of treating CDK8/19-associated diseases, disorders, or conditions are also disclosed.

Abstract: The invention provides a method for treating prostate cancer in a subject comprising administering to the subject an effective amount of a selective inhibitor of one or more of CDK8 and CDK19. In some embodiments the inhibitor inhibits CDK19. In some embodiments, the inhibitor inhibits CDK8 at a Kd of lower than 200 nM and/or inhibits CDK19 at a Kd of lower than 100 nM. In some embodiments, the prostate cancer is androgen independent. In some embodiments, the prostate cancer is androgen independent due to one or more of androgen receptor gene amplification, androgen receptor gene mutation, ligand-independent transactivation of androgen receptor and activation of intracellular androgen synthesis. In some embodiments, the inhibitor inhibits increased activity of NF-?B. In some embodiments, the inhibitor does not inhibit increased basal levels of NF-?B. In some embodiments, inhibition of one or more genes by AR is not inhibited.

Abstract: The invention provides a method for treating prostate cancer in a subject comprising administering to the subject an effective amount of a selective inhibitor of one or more of CDK8 and CDK19. In some embodiments the inhibitor inhibits CDK19. In some embodiments, the inhibitor inhibits CDK8 at a Kd of lower than 200 nM and/or inhibits CDK19 at a Kd of lower than 100 nM. In some embodiments, the prostate cancer is androgen independent. In some embodiments, the prostate cancer is androgen independent due to one or more of androgen receptor gene amplification, androgen receptor gene mutation, ligand-independent transactivation of androgen receptor and activation of intracellular androgen synthesis. In some embodiments, the inhibitor inhibits increased activity of NF-?B. In some embodiments, the inhibitor does not inhibit increased basal levels of NF-?B. In some embodiments, inhibition of one or more genes by AR is not inhibited.

Abstract: The invention relates to the inhibition of the Cyclin-Dependent Kinase Inhibitor (CDKI) pathway. More particularly, the invention relates to methods for inhibiting increases in MAPT expression induced by the CDKI pathway for studies of and intervention in senescence-related and other CDKI-related diseases.

Abstract: The invention relates to the inhibition of the Cyclin-Dependent Kinase Inhibitor (CDKI) pathway. More particularly, the invention relates to methods for inhibiting the CDKI pathway for studies of and intervention in senescence-related and other CDKI-related diseases.

Abstract: The invention relates to the induction of senescence in neoplastic cells. More particularly, the invention relates to the use of small molecule compounds to mediate such induction of senescence. The invention provides methods for identifying such compounds, and methods for using the compounds.

Abstract: The present invention provides mutant P-glycoprotein polypeptides that confer increased resistance to certain chemotherapeutic drugs relative to wild-type P-glycoprotein or P-glycoprotein having a glycine to valine substitution at position 185, and nucleic acid molecules encoding the same. The invention also provides antibodies that specifically bind mutant P-glycoproteins. The invention further provides methods for the diagnosis and treatment of conditions associated with P-glycoprotein-mediated multidrug resistance.

Abstract: The invention provides methods and reagents for identifying mammalian genes necessary for tumor cell growth as targets for developing drugs that inhibit expression of said genes and inhibit tumor cell growth thereby.

Abstract: This invention identifies tumor senescence genes induced by treatment with cytotoxic agents. The invention provides reagents and methods for identifying compounds that induce expression of these cellular genes and produce cellular senescence, particularly senescence in tumor cells. The invention also provides reagents that are recombinant mammalian cells containing recombinant expression constructs that express a reporter gene under the transcriptional control of a promoter for a gene the expression of which is modulated in senescent cells, and methods for using such cells to identify compounds that modulate expression of these cellular genes.

Abstract: The invention relates to the induction of tumor cell growth arrest. More particularly, the invention relates to the use of retinoic acid receptor (RAR) agonists and antagonists to mediate such growth arrest. The invention provides methods for using RAR-modulating compounds to induce growth arrest, methods for identifying such RAR-modulating compounds, and RAR-modulating compounds identified by such latter methods.

Abstract: The invention relates to methods for high-throughput screening for compounds that modulate cell growth or promoter activity. The invention provides the use of cell lines with properly regulated promoter-reporter expression, suitable for high-throughput screening. More particularly, the invention relates to such screening to identify compounds that affect cell growth and/or that modulate the effect of cell cycle arrest on the function of a promoter that is responsive to cell cycle inhibition.

Abstract: This invention identifies growth-inhibitory genes induced by retinoids. The invention provides reagents and methods for identifying compounds other than retinoids that induce expression of these cellular genes. The invention also provides reagents that are recombinant mammalian cells containing recombinant expression constructs that express a reporter gene under the transcriptional control of a promoter for a gene that is regulated by retinoids, and methods for using such cells to identify compounds other than retinoids that modulate expression of these cellular genes.

Abstract: This invention provides methods and reagents for identifying genes involved in cell cycle progression, growth promotion, modulation of apoptosis, cellular senescence and aging, and methods for identifying compounds that inhibit or potentiate cellular senescence.

Abstract: The present invention provides mutant P-glycoprotein polypeptides that confer increased resistance to certain chemotherapeutic drugs relative to wild-type P-glycoprotein or P-glycoprotein having a glycine to valine substitution at position 185, and nucleic acid molecules encoding the same. The invention also provides antibodies that specifically bind mutant P-glycoproteins. The invention further provides methods for the diagnosis and treatment of conditions associated with P-glycoprotein-mediated multidrug resistance.

Abstract: The present invention provides a method of classifying an unclassified live poliovirus vaccine as having an acceptable or unacceptable level of neurovirulence, comprising, prior to vaccine administration, the steps of: a) selectively amplifying a region of an unclassified poliovirus vaccine genome containing a nucleotide position predictive for increased neurovirulence using selectively mismatched primers, whereby a restriction endonuclease site in the selectively amplified region is created by introducing a site-specific mutation into the amplified region; b) digesting an amount of the amplified region with a restriction endonuclease that specifically cleaves the amplified sequences in revertant viruses which contain a reversion at the nucleotide position predictive for increased neurovirulence; c) digesting an amount of the amplified region with a restriction endonuclease that specifically cleaves the amplified sequences in nonrevertant viruses which contain the nucleotide position predictive for increased

Abstract: The present invention comprises the method of evaluation of the safety of live attenuated vaccines based on detection and measurement of the incidence of genetic changes associated with reversion to virulence in vaccine microorganisms. The method based on PCR and restriction enzyme analysis was developed and used for determination of the proportion of mutants contributing to neurovirulence of type 3 live oral poliovirus vaccine. The correlation between the neurovirulence of OPV lots revealed by the monkey test and the abundance of mutant virus containing cytidine in the position 472 was discovered. The amount of these mutants increases upon passages of the virus in cell cultures at a rate dependent on the cell type, cultivation conditions and the seed virus stock.

Abstract: A novel method for detecting and isolating DNA sequences commonly held by different DNA preparations or repeated or amplified within a complex genome has been provided. The DNA preparations of interest are digested with the same restriction enzyme and a portion of at least one preparation is labeled with .sup.32 P. The labeled and unlabeled DNA preparations are combined and electrophoresed in an agarose gel. Following electrophoresis, the DNA is denatured in situ and allowed to reanneal within the gel so that homologous DNA sequences present within restriction fragments of the same size can reanneal. After reannealing, unhybridized single-stranded DNA is digested in situ followed by detection of the reannealed DNA by autoradiography. When labeled and unlabeled DNAs are derived from different DNA preparations, only the restriction fragments commonly held by these two preparations are detected.