Acute kidney injury (AKI) is a major clinical problem associated with high morbidity and mortality. Likely due to its complex pathophysiology, therapies with a single pharmacological agent have generally failed to improve outcomes. In contrast, stem cell-based interventions utilize these cells' ability to simultaneously target multiple pathophysiological components of AKI and thus represent a promising new tool for the treatment of AKI. The aims of the this study were to investigate the long-term outcome and safety of treatment with autologous and allogeneic mesenchymal stem cells (MSCs) after AKI and the role of vascular endothelial growth factor (VEGF) as one of the principal paracrine mediators of renoprotection of MSCs. MSC administration after AKI was not associated with adverse events and proved to be renoprotective in animals with severe renal failure. Identical doses of autologous MSC were more effective than allogeneic. At 3 months, MSCs were not engrafted in any tissues except in the bone marrow in 50% of animals given the highest allogeneic cell dose. There was no long-term fi brotic response in the kidneys attributable to MSC therapy, and animals with severe AKI were protected from development of fi brotic lesions after AKI. Furthermore, this study establishes VEGF as a critical factor mediating renal recovery. VEGF knockdown by small-interfering RNA reduced effectiveness of MSCs signifi cantly and decreased survival. In summary, our results show that both autologous and allogeneic MSC are safe and effective in AKI, and importantly, reduce late renal fi brosis and loss of renal function in surviving animals and that VEGF is a critical factor in renoprotection by MSCs. Together, we posit that these data provide further justifi cation for the conduct of clinical trails in which AKI is treated with MSC.

Smooth muscle cell (SMC) proliferation is thought to play a major role in vascular restenosis after angioplasty and is a serious complication of the procedure. Developing antisense (AS) oligonucleotides as therapeutics is attractive because of the potentially high specificity of binding to their targets, and several investigators have reported inhibition of SMC proliferation in vitro and in vivo by using AS strategies. We report here the results of our experiments on vascular SMCs using AS oligonucleotides directed toward c-myb and c-myc. We found that significant inhibition of SMC proliferation occurred with these specific AS sequences but that this inhibition was clearly not via a hybridizationdependent AS mechanism. Rather, inhibition was due to the presence of four contiguous guanosine residues in the oligonucleotide sequence. This was demonstrated in vitro in primary cultures of SMCs and in arteries ex vivo. The ex vivo model developed here provides a rapid and effective system in which to screen potential oligonucleotide drugs for restenosis. We have further explored the sequence requirements of this non-AS effect and determined that phosphorothioate oligonucleotides containing at least two sets of three or four consecutive guanosine residues inhibit SMC proliferation in vitro and ex vivo. These results suggest that previous AS data obtained using these and similar, contiguous guanosinecontaining AS sequences be reevaluated and that there may be an additional class of nucleic acid compounds that have potential as antirestenosis therapeutics.A great deal of interest has been focused on the potential for developing human therapeutics based on antisense (AS) phosphorothioate oligonucleotide (oligo) strategies. The elegant specificity of Watson-Crick base pairing between the AS oligo and the target mRNA or gene could form the basis for a highly specific and effective drug. AS oligo drugs could be designed to eliminate the expression of, in principle, any cellular protein (1). Recently, several groups have identified restenosis as a candidate for this type of therapeutic intervention (2-7).Restenosis, the reclosure of coronary arteries after angioplasty, limits the long-term benefits of this nonsurgical intervention. It is estimated that of the -400,000 procedures performed in the United States this year to open atherosclerotic arteries, 30-50% will restenose (reclose) within 6 months (8). Excessive proliferation of smooth muscle cells (SMCs) is thought to be a major contributing factor to restenosis and one viable strategy for intervention is the inhibition of this proliferative response (9).Using oligos complementary to c-myb and c-myc, a number of investigators have reported AS inhibition of SMC proliferThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. ation in vitro (5, 7, 10-14) and inhibition of restenosis in two different animal models (2,...

The incidence of prostate cancer (PCa) within Asian population used to be much lower than in the Western population; however, in recent years the incidence and mortality rate of PCa in some Asian countries have grown rapidly. This collaborative report summarized the latest epidemiology information, risk factors, and racial differences in PCa diagnosis, current status and new trends in surgery management and novel agents for castration-resistant prostate cancer. We believe such information would be helpful in clinical decision making for urologists and oncologists, health-care ministries and medical researchers.

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