Gene expression profile in the post-menarchal macaque breast by microarray. (A) Venn diagram showing number of genes that changed with time (i.e. between 7-12 months to 18-24 months after menarche) in the control (CL) and soy group (SOY), based on unadjusted P-values from a paired t-test in each diet group. (B) The list of top-10 genes that showed significant difference by dietary treatment using empirical Bayes statistics. (C) The top-10 significantly enriched KEGG pathways in CL and SOY groups across time. FC = fold-change; FDR=false discovery rate.

PDF file - 65K, Composition of diets used to assess the effect of high-soy diet on the breast of female cynomolgus macaque across pubertal transition.

Representative photomicrographs of ERα staining in a transitional duct from a prepubertal animal (A); ERα staining in post-pubertal, differentiated lobuloalveolar tissue (B); ERβ staining in prepubertal transitional duct (C ); and ERβ staining in mature lobuloalveolar tissue (D). Bar = 50 microns.

1A. Cynomolgus macaque and human primer probe sets used to generate custom Taqman-based assay for qRT-PCR 1B. Applied Biosystems (ABI) Taqman gene expression assays used in qRT-PCR.

PDF file - 1MB, Hemizygous deletion of MAP3K7 in human prostatic tumorigenic cell lines.

Immunolocalization of Steroidogenic Enzymes in the Mammary Gland.

PDF file - 1MB, Complete lineage differentiation of shControl cells in vivo.

PDF file - 77K, Primer-probe sets for target genes evaluated by qRT-PCR.

PDF file - 6K, Primer sequences for detecting expression of the 5 genes within the consensus deletion regions in WFU3 cells.

Cynomolgus macaque primer sets (forward, F; reverse, R; and sequencing, S) for pyrosequencing assay.

PDF file - 115K, Bone mineral content (BMC) and bone mineral density (BMD) in the female cynomolgus macaque fed a soy or casein lactalbumin (CL) diet during pubertal development as measured by DEXA.

PDF file - 115K, Epithelial cell proliferation in the mammary tissue of cynomolgus macaque was not affected by soy treatment across pubertal transition.

Serum isoflavonoid concentrations across the pubertal transition. Levels of circulating total isoflavonoids (genistein + daidzein + equol) were significantly higher in soy-fed monkeys. Values represent LSMs for n=11-17 monkeys/group (bars = SEM). Significant main effects and interactions are indicated in the panel.

PDF file - 1MB, Suppression of Tak1 promotes scatter growth of shTak1 PrP/SCs.

PDF file - 139K, Expression of Tak1 is progressively lost with increasing Gleason grade both within each cancer and across cancers.

Abstract More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and c-jun-NH2-kinase activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer. Cancer Res; 72(11); 2833–43. ©2012 AACR.

PDF file - 949K, Expression of Tak1 Is Correlated with High Grade of Tumor in Human Prostate.

Executive functions including behavioral response inhibition mature after puberty, in tandem with structural changes in the prefrontal cortex. Little is known about how activity of prefrontal neurons relates to this profound cognitive development. To examine this, we tracked neuronal responses of the prefrontal cortex in monkeys as they transitioned from puberty into adulthood and compared activity at different developmental stages. Performance of the antisaccade task greatly improved in this period. Among neural mechanisms that could facilitate it, reduction of stimulus-driven activity, increased saccadic activity, or enhanced representation of the opposing goal location, only the latter was evident in adulthood. Greatly accentuated in adults, this neural correlate of vector inversion may be a prerequisite to the formation of a motor plan to look away from the stimulus. Our results suggest that the prefrontal mechanisms that underlie mature performance on the antisaccade task are more strongly associated with forming an alternative plan of action than with suppressing the neural impact of the prepotent stimulus.

Heart disease is an increasingly recognized, serious late effect of radiation exposure, most notably among breast cancer and Hodgkin's disease survivors, as well as the Hiroshima and Nagasaki atomic bomb survivors. The purpose of this study was to evaluate the late effects of total-body irradiation (TBI) on cardiac morphology, function and selected circulating biomarkers in a well-established nonhuman primate model. For this study we used male rhesus macaques that were exposed to a single total-body dose of ionizing gamma radiation (6.5–8.4 Gy) 5.6–9.7 years earlier at ages ranging from ∼3–10 years old and a cohort of nonirradiated controls. Transthoracic echocardiography was performed annually for 3 years on 20 irradiated and 11 control animals. Myocardium was examined grossly and histologically, and myocardial fibrosis/collagen was assessed microscopically and by morphometric analysis of Masson's trichrome-stained sections. Serum/plasma from 27 irradiated and 13 control animals was evaluated for circulating biomarkers of cardiac damage [N-terminal pro B-type natriuretic protein (nt-proBNP) and troponin-I], inflammation (CRP, IL-6, MCP-1, sICAM) and microbial translocation [LPS-binding protein (LBP) and sCD14]. A higher prevalence of histological myocardial fibrosis was observed in the hearts obtained from the irradiated animals (9/14) relative to controls (0/3) (P = 0.04, χ2). Echocardiographically determined left ventricular end diastolic and systolic diameters were significantly smaller in irradiated animals (repeated measures ANOVA, P < 0.001 and P < 0.008, respectively). Histomorphometric analysis of trichrome-stained sections of heart tissue demonstrated ∼14.9 ± 1.4% (mean ± SEM) of myocardial area staining for collagen in irradiated animals compared to 9.1 ± 0.9 % in control animals. Circulating levels of MCP-1 and LBP were significantly higher in irradiated animals (P < 0.05). A high incidence of diabetes in the irradiated animals was associated with higher plasma triglyceride and lower HDLc but did not appear to be associated with cardiovascular phenotypes. These results demonstrate that single total-body doses of 6.5–8.4 Gy produced long-term effects including a high incidence of myocardial fibrosis, reduced left ventricular diameter and elevated systemic inflammation. Additional prospective studies are required to define the time course and mechanisms underlying radiation-induced heart disease in this model.