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Scott D Patterson

Publications and source records attributed to Scott D Patterson.

12 recordsLinked to original sources
PubMed2006

Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist.

OBJECTIVE: Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)delta expression. In parallel, PPARdelta agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models. METHODS AND RESULTS: Healthy volunteers were allocated placebo (n=6) or PPARdelta agonist (GW501516) at 2.5 mg (n=9) or 10 mg (n=9), orally, once-daily for 2 weeks while hospitalized and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (P=0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (P=0.02). HDLc was enhanced in both treatment groups (2.5 mg P=0.004, 10 mg P<0.001) when compared with the decrease in the placebo group (-11.5+/-1.6%, P=0.002). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addition to a 2-fold increase in ABCA1 (P=0.002). However, LpL expression remained unchanged. CONCLUSIONS: This is the first report of a PPARdelta agonist administered to man. In this small study, GW501516 significantly influenced HDLc and TGs in healthy volunteers. Enhanced in vivo serum fat clearance, and the first demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression, suggests peripheral fat utilization and lipidation as potential mechanisms toward these HDL:TG effects.

ATP Binding Cassette Transporter 1↗
PubMed2006

Guidelines for the next 10 years of proteomics.

In the last ten years, the field of proteomics has expanded at a rapid rate. A range of exciting new technology has been developed and enthusiastically applied to an enormous variety of biological questions. However, the degree of stringency required in proteomic data generation and analysis appears to have been underestimated. As a result, there are likely to be numerous published findings that are of questionable quality, requiring further confirmation and/or validation. This manuscript outlines a number of key issues in proteomic research, including those associated with experimental design, differential display and biomarker discovery, protein identification and analytical incompleteness. In an effort to set a standard that reflects current thinking on the necessary and desirable characteristics of publishable manuscripts in the field, a minimal set of guidelines for proteomics research is then described. These guidelines will serve as a set of criteria which editors of PROTEOMICS will use for assessment of future submissions to the Journal.

Biomarkers↗
PubMed2006

A strategic view on the use of pharmacodynamic biomarkers in early clinical drug development.

Early-phase clinical trials have traditionally focused on the safety, tolerability and pharmacokinetic properties of a therapeutic candidate, while questions regarding efficacy have been left unanswered until phase II clinical development. Although an understanding of all of these parameters is unarguably essential to the successful development of a drug candidate, this information is insufficient. Biomarkers are increasingly being used in early drug development to allow for the exploration of pharmacodynamic effects of targeted therapeutics before clinical signs and symptoms are evaluated. The trend of using pharmacodynamic biomarkers will continue and, ultimately, may enable these biomarkers to be used routinely to demonstrate the impact of a compound on the treatment of a disease, and to aid in the selection of therapeutic doses and regimens based on accurate measures of human physiological responses. Biomarkers are also beginning to be used to determine those patients who are most likely to respond to a therapeutic, and thereby improve treatment outcomes while avoiding the administration of a drug to individuals who are unlikely to benefit. This article describes a strategy that is being used to achieve these aims for biomarkers, and discusses how biomarkers can be used to identify information that can be applied back into to the drug discovery process.

Biomarkers↗
PubMed2005

Informatics for protein identification by mass spectrometry.

High throughput protein analysis (i.e., proteomics) first became possible when sensitive peptide mass mapping techniques were developed, thereby allowing for the possibility of identifying and cataloging most 2D gel electrophoresis spots. Shortly thereafter a few groups pioneered the idea of identifying proteins by using peptide tandem mass spectra to search protein sequence databases. Hence, it became possible to identify proteins from very complex mixtures. One drawback to these latter techniques is that it is not entirely straightforward to make matches using tandem mass spectra of peptides that are modified or have sequences that differ slightly from what is present in the sequence database that is being searched. This has been part of the motivation behind automated de novo sequencing programs that attempt to derive a peptide sequence regardless of its presence in a sequence database. The sequence candidates thus generated are then subjected to homology-based database search programs (e.g., BLAST or FASTA). These homology search programs, however, were not developed with mass spectrometry in mind, and it became necessary to make minor modifications such that mass spectrometric ambiguities can be taken into account when comparing query and database sequences. Finally, this review will discuss the important issue of validating protein identifications. All of the search programs will produce a top ranked answer; however, only the credulous are willing to accept them carte blanche.

Amino Acid Sequence↗
PubMed2004

Proteomic analysis of interchromatin granule clusters.

A variety of proteins involved in gene expression have been localized within mammalian cell nuclei in a speckled distribution that predominantly corresponds to interchromatin granule clusters (IGCs). We have applied a mass spectrometry strategy to identify the protein composition of this nuclear organelle purified from mouse liver nuclei. Using this approach, we have identified 146 proteins, many of which had already been shown to be localized to IGCs, or their functions are common to other already identified IGC proteins. In addition, we identified 32 proteins for which only sequence information is available and thus these represent novel IGC protein candidates. We find that 54% of the identified IGC proteins have known functions in pre-mRNA splicing. In combination with proteins involved in other steps of pre-mRNA processing, 81% of the identified IGC proteins are associated with RNA metabolism. In addition, proteins involved in transcription, as well as several other cellular functions, have been identified in the IGC fraction. However, the predominance of pre-mRNA processing factors supports the proposed role of IGCs as assembly, modification, and/or storage sites for proteins involved in pre-mRNA processing.

Animals↗
PubMed2004

Quantitation of phosphopeptides using affinity chromatography and stable isotope labeling.

Reversible phosphorylation of proteins represents an important component of cellular signaling pathways. The isolation of phosphoproteins in complex mixtures and the determination of the level of phosphorylation have been and remain a major challenge. It has prompted the development of several strategies, including immobilized metal affinity capture to enrich for phosphorylated peptides. An improved methodology was published (Ficarro, et al., Nature Biotechnology 2002, 20, 301-305) that showed increased selectivity through esterification of amino acid side chain carboxylic groups of enzymatically digested peptides. This method was applied for relative quantitation of phosphopeptides in conjunction with the use of stable isotope labeling. The merits and limits of the approach are discussed and its application to the analysis of the effects of serum starvation on in vitro cultured human lung cells is presented.

Amino Acid Sequence↗
PubMed2003

Proteomics: the first decade and beyond.

Proteomics is the systematic study of the many and diverse properties of proteins in a parallel manner with the aim of providing detailed descriptions of the structure, function and control of biological systems in health and disease. Advances in methods and technologies have catalyzed an expansion of the scope of biological studies from the reductionist biochemical analysis of single proteins to proteome-wide measurements. Proteomics and other complementary analysis methods are essential components of the emerging 'systems biology' approach that seeks to comprehensively describe biological systems through integration of diverse types of data and, in the future, to ultimately allow computational simulations of complex biological systems.

Amino Acid Sequence↗
PubMed2002

Proteomics: drug target discovery on an industrial scale.

The discovery of targets that are sufficiently robust to yield marketable therapeutics is an enormous challenge. Through the years, several approaches have been used with varying degrees of success. These include target-independent screening of tumor-derived cell lines (disease-dependent), reductionist approaches to identifying crucial elements of disease-affected pathways, disease-independent screening of homologs of previously drugged targets, disease-dependent 'global' examination of gene transcript levels, and disease-dependent global examination of protein expression levels. These endeavors have been enabled by several major advancements in technology, most recently, the sequencing of the human genome. This review identifies the technical issues to be addressed for industrial-scale protein-based discovery in the identification of targets for therapeutic (or diagnostic) intervention. Such approaches aim to direct discovery in a way that increases the probability of robust target identification, and decreases the probability of failure owing to variable expression in this emerging field.

Algorithms↗
PubMed2002

Enabling parallel protein analysis through mass spectrometry.

The targets of the majority of drugs on the market and in development are proteins, and the efficient analysis of these molecules is critical to defining targets for better therapeutic intervention. Mass spectrometry is currently the key technology for parallel protein analysis (also referred to as proteomics). In this review we will describe recent advances in mass spectrometry instrumentation, methods and applications that are likely to impact drug discovery.

Animals↗