It has been discovered that NAD.sup.+-dependent histone deacetylase SIRT6 is critical for suppression of PDAC by controlling the expression of Lin28b, which is a negative regulator of let-7 microRNA. Specifically, SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1, and IGF2BP3. This invention relates generally to agents and methods of reducing expression or activity of Lin28b to treat (aggressive) PDAC in a subject.

The present invention provides a method of diagnosing endometriosis and/or infertility in a subject, comprising: a) obtaining a sample from the subject; b) detecting a level of expression of a SIRT1 gene and/or protein in the sample; c) detecting a level of expression of a BCL6 gene and/or protein in the sample; d) comparing the level of expression detected in (b) with the level of expression of a SIRT1 gene and/or protein in a sample obtained from a control subject or a population of control subjects; e) comparing the level of expression detected in (c) with the level of expression of a BCL6 gene and/or protein in a sample obtained from a control subject or a population of control subjects; and f) diagnosing the subject as having infertility when the subject has a level of expression of the SIRT1 gene and/or protein greater than the level of expression of the SIRT1 gene and/or protein of the control subject or population of control subjects and also has a level of expression of the BCL6 gene and/or protein that is greater than the level of expression of the BCL6 gene and/or protein of the control subject or population of control subjects.

The present invention provides workflows for the discovery of nonallosteric sirtuin activation compounds. Workflows enable drug discovery of novel sirtuin activating compounds with prescribed effects on the binding in pockets near the active site interacting with flexible protein degrees of freedom around the active site. Novel kinetic models are used to confirm hit compounds and to improve their properties.

The instant invention provides workflows for the design and characterization of mechanism-based sirtuin modulating compounds, including new or improved sirtuin activating compounds. Workflows for the design of mechanism-based sirtuin activating compounds are provided, based on conditions that must be satisfied by activators if they are to exploit the common catalytic mechanism of all sirtuin enzymes and hence increase catalytic efficiency for any sirtuin and any substrate.

The present invention provides methods to improve the sensitivity of detecting glycosylamines released from glycoconjugates, such as glycoproteins or glycopeptides, by enzymatic digestion when labeling them with amine-reactive dyes.

A composition having the following structure:

##STR00001## wherein: R.sup.1 is OH, ester group, ether group, amine, thiol, thioether, halide, or a group containing an alkynyl or azido functionality; R.sup.2 is H, OH, ester group, ether group, amine, thiol, thioether, halide, or a group containing an alkynyl or azido functionality; R.sup.3 is a group containing a reactive functionality capable of covalent binding to a thiol or amine; and R.sup.4 is H, OH, ester group, ether group, amine, thiol, thioether, halide, or a group containing an alkynyl or azido functionality; wherein one of R.sup.1, R.sup.2 and R.sup.4 is a group containing an alkynyl or azido functionality. Also disclosed is a method for profiling changes in BSH enzyme activity by attaching active BSH enzymes in a sample to the probe shown above, attaching a tag to the probe, and detecting the active BSH enzymes to obtain an activity profile.

The present invention relates generally to glutaminase inhibitors of Formula I, Formula II, or Formula III, as well as pharmaceutical compounds containing them and methods of their use.

The instant invention provides workflows for the design and characterization of mechanism-based sirtuin modulating compounds, including new or improved sirtuin activating compounds. Workflows for the design of mechanism-based sirtuin activating compounds are provided, based on conditions that must be satisfied by activators if they are to exploit the common catalytic mechanism of all sirtuin enzymes and hence increase catalytic efficiency for any sirtuin and any substrate.

Disclosed herein are methods of using an immobilized substrate, immobilized ligand, and a fusion protein of an enzyme for the substrate and a receptor for the ligand, where the immobilized substrate can react to form an immobilized product that has a different mass than the immobilized substrate, and using this transformation to indirectly determine the binding of the receptor and the ligand. These methods can be used for high-throughput screening for possible modulators (e.g., inhibitors or activators) of the ligand-receptor interaction.

The present invention relates to a labeled glutaminase (GLS) protein comprising a GLS protein and a fluorescent reporter group attached to the GLS protein, wherein the fluorescent reporter group is attached to the GLS protein within the glutaminase domain pfam04960 of GLS. The present invention also relates to isolated glutaminase protein mutants. Also disclosed is a method of screening for compounds that allosterically bind to a glutaminase protein. The present invention also relates to a method of identifying compounds that inhibit or stabilize tetramer formation of glutaminase protein. The present invention further relates to a screening kit for compounds that inhibit or stabilize tetramer formation.