University of Arkansas for Medical Sciences

About: University of Arkansas for Medical Sciences is a education organization based out in Little Rock, Arkansas, United States. It is known for research contribution in the topics: Population & Health care. The organization has 14077 authors who have published 26012 publications receiving 973592 citations. The organization is also known as: UAMS.

Catalytic function of Drosophila melanogaster glutathione S-transferase DmGSTS1-1 (GST-2) in conjugation of lipid peroxidation end products.

Abstract: Drosophila melanogaster glutathione S-transferase DmGSTS1-1 (earlier designated as GST-2) is related to sigma class GSTs and was previously described as an indirect flight muscle-associated protein with no known catalytic properties. We now report that DmGSTS1-1 isolated from Drosophila or expressed in Escherichia coli is essentially inactive toward the commonly used synthetic substrate 1-chloro-2,4-dinitrobenzene (CDNB), but has relatively high glutathione-conjugating activity for 4-hydroxynonenal (4-HNE), an electrophilic aldehyde derived from lipid peroxidation. 4-HNE is thought to have signaling functions and, at higher concentrations, has been shown to be cytotoxic and involved in the etiology of various degenerative diseases. Drosophila strains carrying P-element insertions in the GstS1 gene have a reduced capacity for glutathione conjugation of 4-HNE. In flies with both, one, or none of the GstS1 alleles disrupted by P-element insertion, there is a linear correlation between DmGSTS1-1 protein content and 4-HNE-conjugating activity. This correlation indicates that in adult Drosophila 70 +/- 6% of the capacity to conjugate 4-HNE is attributable to DmGSTS1-1. The high abundance of DmGSTS1-1 (approximately 2% of the soluble protein in adult flies) and its previously reported localization in tissues that are either highly aerobic (indirect flight muscle) or especially sensitive to oxidative damage (neuronal tissue) suggest that the enzyme may have a protective role against deleterious effects of oxidative stress. Such function in insects would be analogous to that carried out in mammals by specialized alpha class glutathione S-transferases (e.g. GSTA4-4). The independent emergence of 4-HNE-conjugating activity in more than one branch of the glutathione S-transferase superfamily suggests that 4-HNE catabolism may be essential for aerobic life.

A comparison of batch effect removal methods for enhancement of prediction performance using MAQC-II microarray gene expression data

Abstract: Batch effects are the systematic non-biological differences between batches (groups) of samples in microarray experiments due to various causes such as differences in sample preparation and hybridization protocols. Previous work focused mainly on the development of methods for effective batch effects removal. However, their impact on cross-batch prediction performance, which is one of the most important goals in microarray-based applications, has not been addressed. This paper uses a broad selection of data sets from the Microarray Quality Control Phase II (MAQC-II) effort, generated on three microarray platforms with different causes of batch effects to assess the efficacy of their removal. Two data sets from cross-tissue and cross-platform experiments are also included. Of the 120 cases studied using Support vector machines (SVM) and K nearest neighbors (KNN) as classifiers and Matthews correlation coefficient (MCC) as performance metric, we find that Ratio-G, Ratio-A, EJLR, mean-centering and standardization methods perform better or equivalent to no batch effect removal in 89, 85, 83, 79 and 75% of the cases, respectively, suggesting that the application of these methods is generally advisable and ratio-based methods are preferred.

Clinical Outcomes in Antihypertensive Treatment of Type 2 Diabetes, Impaired Fasting Glucose Concentration, and Normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Abstract: Background Optimal first-step antihypertensive drug therapy in type 2 diabetes mellitus (DM) or impaired fasting glucose levels (IFG) is uncertain. We wished to determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor decreases clinical complications compared with treatment with a thiazide-type diuretic in DM, IFG, and normoglycemia (NG). Methods Active-controlled trial in 31 512 adults, 55 years or older, with hypertension and at least 1 other risk factor for coronary heart disease, stratified into DM (n = 13 101), IFG (n = 1399), and NG (n = 17 012) groups on the basis of national guidelines. Participants were randomly assigned to double-blind first-step treatment with chlorthalidone, 12.5 to 25 mg/d, amlodipine besylate, 2.5 to 10 mg/d, or lisinopril, 10 to 40 mg/d. We conducted an intention-to-treat analysis of fatal coronary heart disease or nonfatal myocardial infarction (primary outcome), total mortality, and other clinical complications. Results There was no significant difference in relative risk (RR) for the primary outcome in DM or NG participants assigned to amlodipine or lisinopril vs chlorthalidone or in IFG participants assigned to lisinopril vs chlorthalidone. A significantly higher RR (95% confidence interval) was noted for the primary outcome in IFG participants assigned to amlodipine vs chlorthalidone (1.73 [1.10-2.72]). Stroke was more common in NG participants assigned to lisinopril vs chlorthalidone (1.31 [1.10-1.57]). Heart failure was more common in DM and NG participants assigned to amlodipine (1.39 [1.22-1.59] and 1.30 [1.12-1.51], respectively) or lisinopril (1.15 [1.00-1.32] and 1.19 [1.02-1.39], respectively) vs chlorthalidone. Conclusion Our results provide no evidence of superiority for treatment with calcium channel blockers or angiotensin-converting enzyme inhibitors compared with a thiazide-type diuretic during first-step antihypertensive therapy in DM, IFG, or NG.

The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to beta1 integrin-dependent cell spreading.

Abstract: The ADAMs (a disintegrin and metalloprotease) family of proteins is involved in a variety of cellular interactions, including cell adhesion and ecto- domain shedding. Here we show that ADAM 12 binds to cell surface syndecans. Three forms of recombinant ADAM 12 were used in these experiments: the cys-teine-rich domain made in Escherichia coli (rADAM 12-cys), the disintegrin-like and cysteine-rich domain made in insect cells (rADAM 12-DC), and full-length human ADAM 12-S tagged with green fluorescent protein made in mammalian cells (rADAM 12-GFP). Mesenchymal cells specifically and in a dose-dependent manner attach to ADAM 12 via members of the syndecan family. After binding to syndecans, mesenchymal cells spread and form focal adhesions and actin stress fibers. Integrin β1 was responsible for cell spreading because function-blocking monoclonal antibodies completely inhibited cell spreading, and chondroblasts lacking β1 integrin attached but did not spread. These data suggest that mesenchymal cells use syndecans as the initial receptor for the ADAM 12 cysteine-rich domain–mediated cell adhesion, and then the β1 integrin to induce cell spreading. Interestingly, carcinoma cells attached but did not spread on ADAM 12. However, spreading could be efficiently induced by the addition of either 1 mM Mn2+ or the β1 integrin–activating monoclonal antibody 12G10, suggesting that in these carcinoma cells, the ADAM 12–syndecan complex fails to modulate the function of β1 integrin.

Cross-talk between Paracrine-Acting Cytokine and Chemokine Pathways Promotes Malignancy in Benign Human Prostatic Epithelium

Abstract: The present study explores the mechanisms by which human prostatic carcinoma-associated fibroblasts (CAF) induce tumorigenesis in initiated but nonmalignant human prostatic epithelial cells (BPH-1). CAF express elevated levels of both transforming growth factor-β1 (TGF-β1) and stromal cell–derived factor-1 (SDF-1/CXCL12). TGF-β inhibits the growth of BPH-1 cells in vitro, but was found to be necessary for the tumorigenic response to CAF. This counterintuitive result suggested that the TGF-β signaling system was involved in other processes relating to tumorigenesis. The SDF-1 receptor, CXCR4, is expressed at low levels in benign prostate tissue and in BPH-1 cells in culture. However, CXCR4 levels increase during prostate cancer progression. CXCR4 was found to be induced and localized to the cell membrane in BPH1 cells by CAF-conditioned medium and by CAF cells in tissue recombinants. TGF-β was both necessary and sufficient to allow the detection of membrane-localized CXCR4 in BPH1 cells. Suppression of epithelial cell CXCR4 expression abrogated the tumorigenic response to CAF. SDF-1, secreted by CAF, acts via the TGF-β–regulated CXCR4 to activate Akt in the epithelial cells. This mechanism elicits tumorigenesis and obviates the growth-inhibitory effects of TGF-β. Thus, tumor stroma can contribute to carcinogenesis through synergism between TGF-β, SDF-1, and CXCR4. These experiments suggest mechanisms by which TGF-β can shift its role from an inhibitor to a promoter of proliferation during tumor progression. Both the TGF-β and SDF-1 pathways are targets of drug discovery efforts; these data suggest potential benefits in the cotargeting of these pathways. [Cancer Res 2007;67(9):4244–53]