A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostate cancer (PCa), and loss of DAB2IP expression is frequently detected in metastatic PCa. However, the functional role of DAB2IP in PCa remains unknown. Here, we show that the loss of DAB2IP expression initiates epithelial-to-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in both human normal prostate epithelial and prostate carcinoma cells as well as in clinical prostate-cancer specimens. Conversely, restoring DAB2IP in metastatic PCa cells reversed EMT. In DAB2IP knockout mice, prostate epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human prostate xenograft-mouse model, we observed that knocking down endogenous DAB2IP in human carcinoma cells led to the development of multiple lymph node and distant organ metastases. Moreover, we showed that DAB2IP functions as a scaffold protein in regulating EMT by modulating nuclear β-catenin/Tcell factor activity. These results show the mechanism of DAB2IP in EMT and suggest that assessment of DAB2IP may provide a prognostic biomarker and potential therapeutic target for PCa metastasis. P rostate cancer (PCa) has surpassed lung cancer as the leading cancer among American men (1). In the absence of metastasis, prostate cancer is largely a treatable disease. Thus, early diagnosis of patients who will develop PCa metastasis could reduce the mortality and morbidity associated with this disease. The development of metastasis depends on the migration and invasion of cancer cells from the primary tumor into the surrounding tissue. To acquire such invasive abilities, carcinoma cells may acquire unique phenotypic changes such as epithelial-tomesenchymal transition (EMT). EMT is a highly conserved cellular process that allows polarized, generally immotile epithelial cells to convert to motile mesenchymal-appearing cells. This process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting carcinoma invasion and metastasis (2-4). During EMT, three major changes occur: (i) morphological changes from a cobblestone-like monolayer of epithelial cells to dispersed, spindle-shaped mesenchymal cells with migratory protrusions; (ii) changes of differentiation markers from cell-cell junction proteins and cytokeratin intermediate filaments to vimentin filaments and fibronectin; and (iii) acquisition of invasiveness through the extracellular matrix (4). Decreased E-cadherin expression or gain of vimentin expression is closely correlated with various indices of PCa progression, including grade, local invasiveness, dissemination into the blood, and tumor relapse after radiotherapy (5-8).A recent study using genome-wide association data reveals that a single nucleotide polymorphism probe located in the first intron of DAB2IP gene associates with the risk of aggressive PCa (9). The functional role of DAB2IP in PCa is poor...

Stroke is the second most common cause of death worldwide and is the complication of hypertension that is most directly linked to blood pressure. Hypertension affects nearly 30% of the world's population; therefore, reducing blood pressure is key for the prevention of stroke. Unlike the established role of hypertension as a risk factor for stroke, the prognostic importance of blood pressure in determining outcome after acute stroke is unclear. The acute hypertensive response occurs in more than 50% of all patients with acute stroke and is associated with poor prognosis. The relation between the outcome of acute stroke and blood pressure is U-shaped, with the best outcome at systolic blood-pressure levels ranging from about 140 to 180 mm Hg. The evidence that decreasing blood pressure in hypertensive patients with acute ischaemic or haemorrhagic stroke improves prognosis needs further confirmation. Whether raising blood pressure to improve perfusion of ischaemic brain areas is beneficial remains even more uncertain. Present guidelines for the management of blood pressure in patients with acute stroke are not evidence-based, but results from ongoing trials might provide more informed recommendations for the future.

Abstract-Activation of type-1 dopamine receptors (DRD1) reduces renal sodium reabsorption. In a family-based random sample of 611 untreated whites (women, 45.0%; mean age, 38.6 years), we measured blood pressure (BP). We used the endogenous lithium clearance to assess fractional sodium excretion (FE Na ) and proximal (RNa prox ) and distal (RNa dist ) tubular sodium reabsorption. We investigated multivariate-adjusted associations with the DRD1 promoter (AϪ48G, GϪ94A, and CϪ800T) and GRK4 (Ala142Val Key Words: blood pressure Ⅲ clinical genetics Ⅲ dopamine receptor gene Ⅲ GRK4 Ⅲ lithium clearance Ⅲ population science Ⅲ tubular transport D opamine reduces sodium reabsorption in the proximal renal tubules via activation of dopamine type-1 (DRD1) receptors, which leads to inhibition of sodium transporters, including the Na,H-exchanger and Na,K-ATPase. 1 The DRD1 promoter harbors several single-nucleotide polymorphisms (SNPs), 2 which influence the expression of the gene. Dopamine exerts its actions via G protein-coupled receptors, which in turn are under control of G protein-coupled receptor kinases (GRKs). 1 Amino-acid changing polymorphisms in one particular member of this family, GRK4, cause hyperphosphorylation, desensitization, and internalization of the DRD1 receptor and enhance the expression of the angiotensin II type-1 receptor. 1 The genes encoding DRD1 and GRK4 localize to chromosomes 5q35.1 3 and 4p16.3, 4 respectively. The GRK4 gene locus is embedded in a cluster on chromosome 4p16, which is associated with hypertension 5,6 and also includes ␣-adducin (ADD1). To our knowledge, there are no studies showing significant genome-wide linkage of hypertension with the DRD1 locus, although a genome-scan meta-analysis 7 identified 5q as a suggestive region.Measuring the clearance of endogenous lithium provides a way of estimating sodium handling in the proximal and postproximal nephron. 8,9 Expressing the renal clearance of endogenous lithium as a fraction of creatinine clearance provides a measure of tubular sodium reabsorption that is standardized for the glomerular filtration rate. 8,9 The fractional excretion of lithium (FE Li ) is a noninvasive marker of proximal tubular sodium handling and the proportion of sodium escaping reabsorption in the proximal segment of the nephron. FE Li also allows the calculation of the fractional distal reabsorption of sodium (RNa dist ). To our knowledge, no prior study addressed the possible association of these renal