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PubMed | University of Washington, Molecular Biomarkers., Medicinal Chemistry., Early Development Statistics and. and 2 more.
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2014

BACE, a -secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimers disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the -secretase pathway and a lowering of CNS amyloid- (A) levels. The interaction of the -secretase and -secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated A and soluble APP (sAPP), with increased newly generated sAPP. A stable isotope labeling kinetics experiment in NHPs was performed with a (13)C6-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPP, sAPP, and A in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPP, sAPP, and A were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPP and sAPP kinetics were similar, but both significantly slower than A. BACE inhibition resulted in decreased labeled sAPP and A in CSF, without observable changes in labeled CSF sAPP. ELISA concentrations of sAPP and A both decreased and sAPP increased. sAPP increased by ELISA, with no difference by labeled sAPP kinetics indicating increases in product may be due to APP shunting from the -secretase to the -secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.

News Article | November 3, 2016

New Rochelle, NY, November 3, 2016-Analysis of a single urine sample using a metabolomics-based screening approach can identify multiple different inborn errors of metabolism (IEMs), facilitating early disease detection and rapid initiation of treatment, as described in an article published in Genetic Testing and Molecular Biomarkers, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Genetic Testing and Molecular Biomarkers website until November 30, 2016. Adam Kennedy, Sarah Elsea, and coauthors from Metabolon, Inc. (Durham, NC) and Baylor College of Medicine (Houston, TX), present the automated IEM screening platform they have designed and implemented in the article entitled "Metabolomic Profiling of Human Urine as a Screen for Multiple Inborn Errors of Metabolism". Biochemical signatures have been identified in urine for more than 30 IEMs, which have traditionally been detected in various different bodily fluids including blood and cerebrospinal fluid. This study demonstrates the potential to detect numerous IEMs in a single urine sample using one metabolomics-based assay performed on an automated screening platform. "This is both transformative research and an economical and efficient way to provide precision medicine on a population-based scale," says Genetic Testing and Molecular Biomarkers Editor-in-Chief Garth D. Ehrlich, PhD, FAAAS, Center for Genomic Sciences and Center for Advanced Microbial Processing, Institute for Molecular Medicine and Infectious Disease, Drexel College of Medicine (Philadelphia, PA). Genetic Testing and Molecular Biomarkers is an authoritative peer-reviewed journal published 12 times per year online with open access options and in print that reports on all aspects of genetic testing, including molecular and biochemical based tests and varied clinical situations; ethical, legal, social, and economic aspects of genetic testing; and issues concerning effective genetic counseling. Tables of content and a free sample issue may be viewed on the Genetic Testing and Molecular Biomarkers website. Mary Ann Liebert, Inc., publishers is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Human Gene Therapy and OMICS: A Journal of Integrative Biology. Its biotechnology trade magazine, GEN (Genetic Engineering & Biotechnology News), was the first in its field and is today the industry's most widely read publication worldwide. A complete list of the firm's 80 journals, books, and newsmagazines is available on the Mary Ann Liebert, Inc., publishers website.

Previs S.F.,Molecular Biomarkers | McLaren D.G.,Molecular Biomarkers | Wang S.-P.,Molecular Biomarkers | Stout S.J.,Molecular Biomarkers | And 9 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Our ability to understand the pathogenesis of problems surrounding lipid accretion requires attention towards quantifying lipid kinetics. In addition, studies of metabolic flux should also help unravel mechanisms that lead to imbalances in inter-organ lipid trafficking which contribute to dyslipidemia and/or peripheral lipid accumulation (e.g. hepatic fat deposits). This review aims to outline the development and use of novel methods for studying lipid kinetics in vivo. Although our focus is directed towards some of the approaches that are currently reported in the literature, we include a discussion of the older literature in order to put "new" methods in better perspective and inform readers of valuable historical research. Presumably, future advances in understanding lipid dynamics will benefit from a careful consideration of the past efforts, where possible we have tried to identify seminal papers or those that provide clear data to emphasize essential points. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. © 2013 Elsevier B.V.

McAvoy T.,Lincoln Laboratory | Lassman M.E.,Lincoln Laboratory | Spellman D.S.,Molecular Biomarkers | Ke Z.,Molecular Biomarkers | And 6 more authors.
Clinical Chemistry | Year: 2014

BACKGROUND: Cerebrospinal fluid (CSF) tau is a common biomarker for Alzheimer disease (AD). Measurements of tau have historically been performed using immunoassays. Given the molecular diversity of tau in CSF, the selectivity of these immunoassays has often been questioned. Therefore, we aimed to develop an analytically sensitive and selective immunoaffinity liquid chromatography-tandem mass spectrometry (LCMS/ MS) (IA-MS) assay.METHODS: IA-MS sample analysis involved the additionof an internal standard, immunoaffinity purification of tau using a tau monoclonal antibody coupled to magnetic beads, trypsin digestion, andquantification of a surrogate tau peptide by LCMS/ MS using a Waters Trizaic nanoTile ultraperformanceLC microfluidic device. Further characterization of tau peptides was performed by full-scan MS using a Thermo Orbitrap LC-MS. CSF samples from a cohort of age-matched controls and patients withAD were analyzed by the IA-MS method as well as a commercially available immunoassay. RESULTS: The IA-MS assay had intra- and interassay imprecision values of 3.2% to 8.1% CV and 7.8% to18.9% C, respectively, a mean recovery of 106%, and a limit of quantification of 0.25 pmol/L and was able to quantify tau concentrations in all human specimens tested. The IA-MS assay showed a correlation of R2 = 0.950 against a total-tau immunoassay. In patients withAD, tau was increased approximately 2-fold. CONCLUSIONS: Combining immunoaffinity enrichment with microflow LC-MS/MS analysis is an effective approach for the development of a highly selective assay to measure total tau and, potentially, other posttranslationally modified forms of tau in CSF. ©2014 American Association for Clinical Chemistry.

News Article | November 16, 2016

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News Article | November 18, 2016

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