This 6-month trial indicates that 80-mg soy-derived isoflavone supplementation did not improve performance on standard neuropsychological tests and overall quality of life in generally healthy Chinese postmenopausal women.

Mice with one thyroid hormone receptor (TR) alpha-1 allele encoding a dominant negative mutant receptor (TR alpha1(PV/+)) have persistently elevated serum T3 levels (1.9-fold above normal). They also have markedly increased hepatic type 1 iodothyronine deiodinase (D1) mRNA and enzyme activity (4- to 5-fold), whereas other hepatic T3-responsive genes, such as Spot14 and mitochondrial alpha-glycerol phosphate dehydrogenase (alpha-GPD), are only 0.7-fold and 1.7-fold that of wild-type littermates (TR alpha1+/+). To determine the cause of the disproportionate elevation of D1, TR alpha1+/+ and TR alpha1(PV/+) mice were rendered hypothyroid and then treated with T3. Hypothyroidism decreased hepatic D1, Spot14, and alpha-GPD mRNA to similar levels in TR alpha1+/+ and TR alpha1(PV/+) mice, whereas T3 administration caused an approximately 175-fold elevation of D1 mRNA but only a 3- to 6-fold increases in Spot14 and alpha-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 iodothyronine deiodinase activity was 3 times greater in the TR alpha1(PV/+) mice, and these mice had no T3-dependent induction of type 3 iodothyronine deiodinase. Thus, the marked responsiveness of hepatic D1 to T3 relative to other genes, such as Spot14 and alpha-GPD, explains the relatively large effect of the modest increase in serum T3 in the TR alpha1(PV/+) mice, and TR alpha plays a key role in T3-dependent positive and negative regulation of the deiodinases in the cerebral cortex.

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RAR␣ and one of four fusion partners: PML, PLZF, NPM, and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo, we generated transgenic mice with PLZF-RAR␣ and NPM-RAR␣. PLZF-RAR␣ transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM-RAR␣ transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RAR␣ transgenic mice, those from NPM-RAR␣ transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA concentrations of 0.01 M, 0.1 M, and 1.0 M for RAR␣-RXR␣, NPM-RAR␣, and PML-RAR␣, respectively, but not observed for PLZF-RAR␣ even in the presence of 10 M ATRA. We also determined the expression of the tissue factor gene in transgenic mice, which was detected only in bone marrow cells of mice expressing the fusion genes. These data clearly establish the leukemogenic role of PLZF-RAR␣ and NPM-RAR␣ and the importance of fusion receptor͞corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.Acute promyelocytic leukemia (APL) is characterized in most patients by accumulation of promyelocytes containing a specific chromosomal translocation t(15;17) and a unique sensitivity to all-trans-retinoic acid (ATRA) treatment (1, 2). There have been three variant translocations reported, including t(11;17)(q23;q21), t(5;17)(q32;q21), and t(11;17)(q13;q21). These chromosomal translocations invariably involve the RAR␣ (retinoic acid receptor ␣) gene on chromosome 17, and the PML