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Institution

Research Triangle Park

NonprofitDurham, North Carolina, United States
About: Research Triangle Park is a nonprofit organization based out in Durham, North Carolina, United States. It is known for research contribution in the topics: Population & Environmental exposure. The organization has 24961 authors who have published 35800 publications receiving 1684504 citations. The organization is also known as: RTP.


Papers
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Journal ArticleDOI
TL;DR: In this article, the authors present a data base containing information relevant to the setting of Toxic Equivalency Factors (TEFs), and, based on the available information, to assess the relative potencies and to derive consensus TEFs for PCDDs, PCDFs and dioxin-like PCBs.

698 citations

Journal ArticleDOI
TL;DR: The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance.
Abstract: Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance. The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication. The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website ( www.ispor.org/TaskForces/EconomicPubGuidelines.asp ). We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in five years.

697 citations

Journal ArticleDOI
28 Apr 1996
TL;DR: Simulation results are compared to, and shown to be superior to, that of an intentional frequency offset system over a wide range of system parameters.
Abstract: Transmitter diversity wireless communication systems over Rayleigh fading channels using pilot symbol assisted modulation (PSAM) are studied. Unlike conventional transmitter diversity systems with PSAM that estimate the superimposed fading process, we are able to estimate each individual fading process corresponding to the multiple transmitters by using appropriately designed pilot symbol sequences. With such sequences, special coded modulation schemes can then be designed to access the diversity provided by the multiple transmitters without having to use an interleaver or expand the signal bandwidth. The code matrix notion is introduced for the coded modulation scheme, and its design criteria are also established. In addition to the reduction in receiver complexity, simulation results are compared to, and shown to be superior to, that of an intentional frequency offset system over a wide range of system parameters.

694 citations

Journal ArticleDOI
TL;DR: It is demonstrated that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase, which defines a novel mechanism for feedback repression of bile acid biosynthesis.
Abstract: The catabolism of cholesterol to bile acids represents a major pathway for the elimination of this potentially pathogenic sterol fromthe body. Bile acids subserve a number of important physiological functions, including the solubilization of cholesterol, fat soluble vitamins, and other lipids in the intestine (Vlahcevic et al. 1994, 1996). In addition, bile acids contribute to the generation of bile flow and promote the secretion of lipids, notably phosphatidylcholine and cholesterol, fromthe canalicular membrane into the bile canaliculus. However, because of their intrinsic toxicity, intracellular levels of bile acids must be tightly regulated, which is largely accomplished by transcriptional regulation of genes encoding proteins involved in bile acid biosynthesis, transport, and metabolism. The conversion of cholesterol to the primary bile acids, cholic acid and chenodeoxycholic acid (CDCA), involves at least 14 distinct enzymes and is accomplished via 2 pathways (Bjorkhem 1985; Russell and Setchell 1992). The first and rate-limiting step in the neutral (classic) pathway of bile acid biosynthesis is catalyzed by cholesterol 7 α-hydroxylase (CYP7A1; Bjorkhem 1985; Russell and Setchell 1992; Chiang 1998). Expression of the gene encoding CYP7A1 is known to be suppressed by a number of factors including insulin, protein kinase C activators, cytokines such as tumor necrosis factor α (TNF-α), steroid hormones, and, importantly, bile acids (for review, see Chiang 1998). The bile acid-dependent feedback repression of CYP7A1 is important in preventing a potentially harmful expansion of the bile acid pool. A number of studies have focused on characterizing the molecular mechanisms by which bile acids suppress CYP7A1 expression, and it is now apparent that multiple, redundant pathways exist (Stravitz et al. 1995; Antes et al. 2000; Goodwin et al. 2000; Lu et al. 2000; Miyake et al. 2000; De Fabiani et al. 2001; Kerr et al. 2002; Wang et al. 2002). Notably, these signaling cascades converge on a common bile acid responsive element (BARE) in the CYP7A1 promoter (Chiang and Stroup 1994; Stroup et al. 1997). This element is highly conserved across species and is a well-documented binding site for members of the nuclear receptor superfamily of ligand activated transcription factors, including liver receptor homolog-1 (LRH-1, NR5A2) and hepatocyte nuclear factor 4α (HNF-4α, NR2A1; Crestani et al. 1998; Nitta et al. 1999; Lu et al. 2000; Stroup and Chiang 2000; De Fabiani et al. 2001; Chiang 2002). The farnesoid X receptor (FXR; NR1H4) is a bile acid-activated transcription factor that also belongs to the nuclear receptor family (Makishima et al. 1999; Parks et al. 1999; Wang et al. 1999). FXR binds DNA as an obligate heterodimer with the retinoid X receptors (RXRs; Forman et al. 1995; Seol et al. 1995). The FXR/RXR heterodimer typically binds to an inverted repeat of the hexanucleotide motif AGG/TTCA separated by a single nucleotide, a so-called IR-1 (Forman et al. 1995; Seol et al. 1995). FXR is known to be expressed in tissues that are exposed to bile acids, including liver, intestine, gallbladder (C. Housset, pers. comm.), kidney, and adrenal gland (Forman et al. 1995; Seol et al. 1995). In liver, the biological consequences of FXR activation have recently become increasingly clear. Upon activation, FXR initiates transcription of a cohort of genes that function to decrease the concentration of bile acids within the hepatocyte. Specifically, FXR induces the expression of ATP-binding cassette (ABC) transporters bile salt export pump (BSEP; ABCB11; Sinal et al. 2000; Ananthanarayanan et al. 2001; Plass et al. 2002), multidrug resistance protein 3 (MDR3, ABCB4; B. Goodwin and S.A. Jones, unpubl.), and multidrug resistance-associated protein 2 (MRP2; ABCC2; Kast et al. 2002). These transporters function to transport bile acids and bile constituents fromthe hepatocytes into the bile. In addition, activation of FXR by both naturally occurring (CDCA) and synthetic ligands leads to the repression of two important genes in the bile acid biosynthetic pathway, namely CYP7A1 and CYP8B1, which encodes oxysterol 12α hydroxylase (Goodwin et al. 2000; Lu et al. 2000; Sinal et al. 2000; del Castillo-Olivares and Gil 2001; Zhang and Chiang 2001). The FXR-dependent suppression of CYP7A1 is mediated by the transcriptional repressor short heterodimer partner-1 (SHP; NR0B2), an atypical nuclear receptor that lacks a DNA-binding domain (Goodwin et al. 2000; Lu et al. 2000). Thus, activation of FXR results in increased expression of the SHP gene. In turn, SHP interacts with LRH-1, a known positive regulator of CYP7A1 (discussed above) and represses its transcriptional activity. Elegant studies performed in mice harboring a disrupted SHP gene confirmthe importance of the FXR–SHP–LRH-1 cascade in suppression of CYP7A1, however, they also demonstrate the existence of additional SHP-independent pathways, possibly involving the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (Kerr et al. 2002; Wang et al. 2002). In this study, we describe the discovery of a novel FXR-dependent signaling cascade for the suppression of CYP7A1. We show that FXR directly regulates expression of FGF-19, a member of the fibroblast growth factor (FGF) family of signaling molecules (Nishimura et al. 1999; Xie et al. 1999). The FGFs bind the extracellular domain of their cognate cell surface receptor (FGFR) and induce receptor dimerization and tyrosine kinase phosphorylation, which, in turn, leads to the activation of a number of intracellular pathways (Goldfarb 2001; Ornitz and Itoh 2001). For many years, it has been understood that the FGFs regulate cell growth, differentiation, and morphogenesis, however, it is now apparent that some of these proteins are also important components of specific homeostatic pathways (Yu et al. 2000; Shimada et al. 2001; Tomlinson et al. 2002). We demonstrate that FGF-19, acting as an FXR-induced signaling molecule, represses expression of the CYP7A1 gene. Our findings define a novel regulatory pathway for the suppression of bile acid biosynthesis.

694 citations

Journal ArticleDOI
TL;DR: This minireview focused on direct evidence for the generation of free radicals in intact animals following acute Cd overload and discussed the association of ROS in chronic Cd toxicity and carcinogenesis.

689 citations


Authors

Showing all 25006 results

NameH-indexPapersCitations
Douglas G. Altman2531001680344
Lewis C. Cantley196748169037
Ronald Klein1941305149140
Daniel J. Jacob16265676530
Christopher P. Cannon1511118108906
James B. Meigs147574115899
Lawrence Corey14677378105
Jeremy K. Nicholson14177380275
Paul M. Matthews14061788802
Herbert Y. Meltzer137114881371
Charles J. Yeo13667276424
Benjamin F. Cravatt13166661932
Timothy R. Billiar13183866133
Peter Brown12990868853
King K. Holmes12460656192
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202317
202277
2021988
20201,001
20191,035
20181,051