| Records |
Author  |
Cheung, C.; Akiyama, T.E.; Ward, J.M.; Nicol, C.J.; Feigenbaum, L.; Vinson, C.; Gonzalez, F.J. |
| Title |
Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha |
Type |
Journal Article |
| Year |
2004 |
Publication |
Cancer research |
Abbreviated Journal |
Cancer Res |
| Volume |
64 |
Issue |
11 |
Pages |
3849-3854 |
| Keywords |
Animals; Anticholesteremic Agents/pharmacology; Carcinogens/pharmacology; Cell Division; DNA Replication/drug effects; Fatty Acids/metabolism; Hepatocytes/cytology/drug effects/metabolism/*physiology; Humans; Mice; Mice, Transgenic; Oxidation-Reduction; Peroxisome Proliferators/pharmacology; Pyrimidines/pharmacology; Receptors, Cytoplasmic and Nuclear/genetics/*physiology; Species Specificity; Transcription Factors/genetics/*physiology |
| Abstract |
Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators. |
| Address |
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA |
| Corporate Author |
|
Thesis |
|
| Publisher |
|
Place of Publication |
|
Editor |
|
| Language |
English |
Summary Language |
|
Original Title |
|
| Series Editor |
|
Series Title |
|
Abbreviated Series Title |
|
| Series Volume |
|
Series Issue |
|
Edition |
|
| ISSN |
0008-5472 |
ISBN |
|
Medium |
|
| Area |
|
Expedition |
|
Conference |
|
| Notes |
PMID:15172993 |
Approved |
no |
| Call Number |
refbase @ user @ |
Serial |
74 |
| Permanent link to this record |
| |
|
| |
| Author |
Mantel, N. |
| Title |
The Detection of Disease Clustering and a Generalized Regression Approach |
Type |
Journal Article |
| Year |
1967 |
Publication |
Cancer Res |
Abbreviated Journal |
Cancer Res |
| Volume |
27 |
Issue |
2_Part_1 |
Pages |
209-220 |
| Keywords |
|
| Abstract |
The problem of identifying subtle time-space clustering of disease, as may be occurring in leukemia, is described and reviewed. Published approaches, generally associated with studies of leukemia, not dependent on knowledge of the underlying population for their validity, are directed towards identifying clustering by establishing a relationship between the temporal and the spatial separations for the n(n – 1)/2 possible pairs which can be formed from the n observed cases of disease. Here it is proposed that statistical power can be improved by applying a reciprocal transform to these separations. While a permutational approach can give valid probability levels for any observed association, for reasons of practicability, it is suggested that the observed association be tested relative to its permutational variance. Formulas and computational procedures for doing so are given. While the distance measures between points represent symmetric relationships subject to mathematical and geometric regularities, the variance formula developed is appropriate for arbitrary relationships. Simplified procedures are given for the case of symmetric and skew-symmetric relationships. The general procedure is indicated as being potentially useful in other situations as, for example, the study of interpersonal relationships. Viewing the procedure as a regression approach, the possibility for extending it to nonlinear and multivariate situations is suggested. Other aspects of the problem and of the procedure developed are discussed. Similarly, pure temporal clustering can be identified by a study of incidence rates in periods of widespread epidemics. In point of fact, many epidemics of communicable diseases are somewhat local in nature and so these do actually constitute temporal-spatial clusters. For leukemia and similar diseases in which cases seem to arise substantially at random rather than as clear-cut epidemics, it is necessary to devise sensitive and efficient procedures for detecting any nonrandom component of disease occurrence. Various ingenious procedures which statisticians have developed for the detection of disease clustering are reviewed here. These procedures can be generalized so as to increase their statistical validity and efficiency. The technic to be given below for imparting statistical validity to the procedures already in vogue can be viewed as a generalized form of regression with possible useful application to problems arising in quite different contexts. N1 - |
| Address |
|
| Corporate Author |
|
Thesis |
|
| Publisher |
|
Place of Publication |
|
Editor |
|
| Language |
|
Summary Language |
|
Original Title |
|
| Series Editor |
|
Series Title |
|
Abbreviated Series Title |
|
| Series Volume |
|
Series Issue |
|
Edition |
|
| ISSN |
|
ISBN |
|
Medium |
|
| Area |
|
Expedition |
|
Conference |
|
| Notes |
|
Approved |
no |
| Call Number |
Equine Behaviour @ team @ |
Serial |
5034 |
| Permanent link to this record |
