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Dynamic contrast-enhanced magnetic resonance imaging (DE-MRI) of the tumor blood pool is used to study tumor tissue perfusion. The results are then analyzed using percolation models. Percolation cluster geometry is depicted using the wash-in component of MRI contrast signal intensity. Fractal characteristics are determined for each two-dimensional cluster. The invasion percolation model is used to describe the evolution of the tumor perfusion front. Although tumor perfusion can be depicted rigorously only in three dimensions, two-dimensional cases are used to validate the methodology. It is concluded that the blood perfusion in a two-dimensional tumor vessel network has a fractal structure and that the evolution of the perfusion front can be characterized using invasion percolation. For all the cases studied, the front starts to grow from the periphery of the tumor (where the feeding vessel was assumed to lie) and continues to grow toward the center of the tumor, accounting for the well-documented perfused periphery and necrotic core of the tumor tissue.

Estrogens are thought to regulate female reproductive functions by altering gene transcription in target organs primarily via the nuclear estrogen receptor-[Alpha] (ER-[Alpha]). By using ER-[Alpha] 'knock-out' (ERKO) mice, we demonstrate herein that a catecholestrogen, 4-hydroxyestradiol-17[Beta] (4-OH-[E.sub.2]), and an environmental estrogen, chlordecone (kepone), up-regulate the uterine expression of an estrogen-responsive gene, lactoferrin (LF), independent of ER-[Alpha]. A primary estrogen, estradiol-17[Beta] ([E.sub.2]), did not induce this LF response. An estrogen receptor antagonist, ICI-182,780, or [E.sub.2] failed to inhibit uterine LF gene expression induced by 4-OH-[E.sub.2] or kepone in ERKO mice, which suggests that this estrogen signaling pathway is independent of both ER-[Alpha] and the recently cloned ER-[Beta].4-OH-[E.sub.2], but not [E.sub.2], also stimulated increases in uterine water imbibition and macromolecule uptake in ovariectomized ERKO mice. The results strongly imply the presence of a distinct estrogen-signaling pathway in the mouse uterus that mediates the effects of both physiological and environmental estrogens. This estrogen response pathway will have profound implications for our understanding of the physiology and pathophysiology of female sex steroid hormone actions in target organs.

In the mouse, the process of implantation is initiated by the attachment reaction between the blastocyst trophectoderm and uterine luminal epithelium that occurs at 2200-2300 h on day 4 (day 1 = vaginal plug) of pregnancy. Several members of the EGF family are considered important in embryo-uterine interactions during implantation. This investigation demonstrates that the expression of two additions to the family, betacellulin and epiregulin, are exquisitely restricted to the mouse uterine luminal epithelium and underlying stroma adjacent to the implanting blastocyst. These genes are not expressed during progesterone-maintained delayed implantation, but are rapidly switched on in the uterus surrounding the implanting blastocyst following termination of the delay by estrogen. These results provide evidence that expression of betacellulin and epiregulin in the uterus requires the presence of an active blastocyst and suggest an involvement of these growth factors in the process of implantation. Key Words: betacellulin; epiregulin; uterus; implantation; mouse.