Abstract: The present invention relates to novel diagnostic, prognostic, predictive and pharmacodynamic properties with regard to amyotrophic lateral sclerosis (ALS) and/or Parkinson's disease (PD) with and without dementia components. The methods described herein will prove very useful in the development of diagnostic as well as treatment strategies for patients with amyotrophic lateral sclerosis (ALS) and/or Parkinson's disease (PD).

Abstract: The invention disclosed herein describes a novel therapeutic target for motoneuron diseases (altered dynamics of microtubules and microtubule-mediated axonal transport of cargo molecules in neurons), with or without dementia, and in dementia; methods for measuring the state of activity of this therapeutic target in subjects with established, incipient, or potential motoneuron disease, with or without dementia, and in dementia; the discovery of drug agents that modulate neuronal microtubule dynamics in living subjects with motoneuron diseases; the discovery that administration of such agents, alone or in combinations, can improve MT-mediated transport of cargo molecules along and through axons; the discovery that such modulation of altered microtubule dynamics and improvement in MT-transport of molecules along axons can provide marked neuroprotective therapy for living subjects with motoneuron diseases, including delay in symptoms and prolongation of survival; and the discovery that monitoring of microtubule-m

Abstract: The proliferation and activation of microglia is emerging as an important etiologic factor and target for therapeutic intervention in several CNS diseases, including Alzheimer's disease and multiple sclerosis. Here, we have discovered that retinoic acids dramatically inhibit microglial proliferation in an in vivo model including the widely-used animal model of multiple sclerosis, the experimental autoimmune encephalomyelitis (EAE) mouse model.

Abstract: The present invention relates to biochemical methods for determining reverse cholesterol transport. Specifically, the rates of the two arms of reverse cholesterol transport (HDL or first arm and post-HDL or second arm) are obtained by measuring the flow of unlabeled cholesterol from tissues into plasma HDL and from plasma HDL to bile acids.

Abstract: The present invention relates to biochemical methods for assessing metabolic fitness and/or aerobic demands of a living system. Specifically, the rate of synthesis and turnover of the molecular components of mitochondrial mass are used to determine the aerobic capacity and/or aerobic demand of tissues or living organisms. The direct measurement of metabolic fitness and/or aerobic demand by this means can be used as an index of the efficacy of an exercise training program or other therapeutic intervention; as a medical risk factor for predicting the risk of cardiovascular disease, diabetes, death or other health outcome; or as an aid to pharmaceutical companies for drug discovery in the area of metabolic fitness, deconditioning, and oxidative biology.

Abstract: The invention disclosed herein describes a novel therapeutic target for motoneuron diseases (altered dynamics of microtubules in neurons); a method for measuring the state of activity of this therapeutic target in subjects with established, incipient, or potential motoneuron disease; the discovery of drug agents that modulate neuronal microtubule dynamics in living subjects with motoneuron diseases; the discovery that administration of such agents, alone or in combinations, can provide marked neuroprotective therapy for living subjects with motoneuron diseases including delay in symptoms and prolongation of survival; and the discovery that monitoring of neuronal microtubule dynamics in subjects with motoneuron diseases, in response to therapeutic interventions, allows diagnostic monitoring for optimization of therapeutic regimen and strategy for individual subjects or for drug trials.

Abstract: Provided are methods for determining concurrently with a simple, minimally invasive test, the adequacy of pancreatic beta-cell compensation and/or the presence of tissue insulin resistance in a subject human or an experimental animal. The methods allow for the determination of a subject's or experimental animal's susceptibility to developing type 2 diabetes mellitus (DM2) or to progression to more advanced forms of DM2.

Abstract: The present invention relates to biochemical methods for determining reverse cholesterol transport (RCT). Specifically, the three components of RCT (efflux, plasma, and excretion) are measured in vivo by administering an isotope-labeled cholesterol or cholesterol-related molecule or cholesterol-related complex, and then measuring the dilution or appearance of isotopes in the various cholesterol or cholesterol-related molecules or cholesterol-related complexes, as well as recovery in sterol end-products, that are part of RCT. A parameter of Global RCT flux, representing for the first time in living organisms that combined rate of cholesterol efflux from tissues into blood and excretion from blood out of the body, is generated. Such methods find use in drug discovery and development, diagnosis and prognosis of atherosclerosis and other blood vessel diseases and conditions, the selection of proper doses for treating disease, and selecting subjects for therapies targeting RCT flux.

Abstract: The invention relates to techniques for measuring and comparing relative molecular flux rates of different biological molecules by administering isotope-labeled water to one or more tissues or individuals and comparing the molecular flux rates of two or more biological molecules, including biological molecules in different chemical classes. The methods find use in several applications including diagnosing, prognosing, or monitoring a disease, disorder, or condition, the in vivo high-throughput screening of chemical entities and biological factors for therapeutic effects in various disease models, and the in vivo high-throughput screening of chemical entities and biological factors for toxic effects.

Abstract: Provided herein are methods for measuring protein biosynthesis by using 2H2O or radioactive 3H2O and applicable uses thereof.

Abstract: The methods described herein enable the evaluation of compounds on subjects to assess their therapeutic efficacy or toxic effects. The target of analysis is the underlying biochemical process or processes (i.e., metabolic process) thought to be involved in disease pathogenesis. Molecular flux rates within the one or more biochemical processes serve as biomarkers and are quantitated and compared with the molecular flux rates (i.e., biomarker) from control subjects (i.e., subjects not exposed to the compounds). Any change in the biomarker in the subject relative to the biomarker in the control subject provides the necessary information to evaluate therapeutic efficacy of an administered drug or a toxic effect and to develop the compound further if desired. In one aspect of the invention, stable isotope-labeled substrate molecules are administered to a subject and the label is incorporated into targeted molecules in a manner that reveals molecular flux rates through one or more metabolic pathways of interest.

Abstract: The present invention relates to methods for measuring the proliferation and destruction rates of cells by measuring deoxyribonucleic acid (DNA) synthesis. In particular, the methods utilize non-radioactive stable isotope labels to endogenously label DNA synthesized through the de novo nucleotide synthesis pathway in a cell. The amount of label incorporated in the DNA is measured as an indication of cellular proliferation. Such methods do not involve radioactivity or potentially toxic metabolites, and are suitable for use both in vitro and in vivo. Therefore, the invention is useful for measuring cellular proliferation in humans for the diagnosis of a variety of disease conditions in which cellular proliferation is involved.

Abstract: The methods of the present invention allow for the measurement of ribonucleotide reductase (RR) activity, an important enzyme in the de novo DNA synthesis pathway. Ribonucleotide reductase converts all four ribonucleotides to their deoxy form and is a rate-controlling step in this pathway. Biosynthetic pathways of deoxyribonucleotides (dN) have received considerable attention in the context of anti-proliferative chemotherapy. Inhibitors of various steps in dN biosynthesis, including inhibitors of RR are among the most useful chemotherapeutic agents in cancer, viral infections, and other therapeutic uses. DNA synthesis from the dN salvage pathway is also an important component to DNA replication. The relative contributions from RR vs. salvage pathways are critical to the actions and effectiveness of chemotherapeutic agents that act on nucleoside metabolic pathways. Until now, however, it has not been possible to study these metabolic processes in vivo.

Abstract: The present invention relates to biochemical methods for determining reverse cholesterol transport. Specifically, the rates of the two arms of reverse cholesterol transport (HDL or first arm and post-HDL or second arm) are obtained by measuring the flow of unlabeled cholesterol from tissues into plasma HDL and from plasma HDL to bile acids.

Abstract: The methods of the present invention allow for the non-invasive or minimally invasive isolation of epithelial cells or their biochemical contents from excreta after in vivo isotopic labeling. Once isolated, the labeled epithelial cells or their labeled biochemical contents find use as kinetic biomarkers of diseases of epithelial tissues including epithelial cancers and epithelial proliferative disorders such as psoriasis and benign prostate hyperplasia.

Abstract: The invention provides methods useful for establishing timing or spatial location of a biosynthetic event in a living organism, without disrupting the event of interest and without disrupting the living organism. A temporal or spatial gradient of an isotopically labeled biochemical precursor is created, which serves to isotopically fingerprint (i.e., definitively mark) when or where biosynthesis occurs. The methods of the invention are broadly applicable to a variety of medical, public health, and diagnostic applications, as well as for establishing sequences of biochemical events that occur within a living organism.

Abstract: The invention enables high-throughput screening of compounds in living systems to detect unanticipated or unintended biological actions. The invention also allows for screening, detection, and confirmation of new indications for approved drugs. Screening and detection of toxic effects of compounds also can be achieved by using the methods of the invention. The methods comprise administering isotope-labeled substrates to a living system so that the label is incorporated into molecules in a manner that reveals flux rates through metabolic pathways thought to be involved in a disease. Comparisons between living systems exposed to compounds and living systems not so exposed reveals the effects of the compounds on the flux rates through the metabolic pathways. Combinations or mixtures of compounds can be systematically screened to detect unanticipated or unintended biological actions, including synergistic actions, in the same manner.

Abstract: Provided herein are methods for measuring protein biosynthesis by using 2H2O or radioactive 3H2O and applicable uses thereof.

Abstract: The present invention relates to methods for measuring the proliferation and destruction rates of cells by measuring deoxyribonucleic acid (DNA) synthesis and/or destruction. In particular, the methods utilize non-radioactive stable isotope labels to endogenously label DNA synthesized through the de novo nucleotide synthesis pathway in a cell. The amount of label incorporated in the DNA is measured as an indication of cellular proliferation. The decay of labeled DNA over time is measured as an indication of cellular destruction. Such methods do not involve radioactivity or potentially toxic metabolites, and are suitable for use both in vitro and in vivo. Therefore, the invention is useful for measuring cellular proliferation or cellular destruction rates in humans for the diagnosis, prevention, or management of a variety of disease conditions in which cellular proliferation or cellular destruction is involved.

Abstract: The invention relates to techniques for measuring and comparing relative molecular flux rates of different biological molecules by administering isotope-labeled water to one or more tissues or individuals and comparing the molecular flux rates of two or more biological molecules, including biological molecules in different chemical classes. The methods find use in several applications including diagnosing, prognosing, or monitoring a disease, disorder, or condition, the in vivo high-throughput screening of chemical entities and biological factors for therapeutic effects in various disease models, and the in vivo high-throughput screening of chemical entities and biological factors for toxic effects.