Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for !12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Over the last two decades, pancreatic islet transplantations have become a promising treatment for Type I diabetes. However, although providing a consistent and sustained exogenous insulin supply, there are a number of limitations hindering the widespread application of this approach. These include the lack of sufficient vasculature and allogeneic immune attacks after transplantation, which both contribute to poor cell survival rates. Here, these issues are addressed using a biofabrication approach. An alginate/gelatin‐based bioink formulation is optimized for islet and islet‐related cell encapsulation and 3D printing. In addition, a custom‐designed coaxial printer is developed for 3D printing of multicellular islet‐containing constructs. In this work, the ability to fabricate 3D constructs with precise control over the distribution of multiple cell types is demonstrated. In addition, it is shown that the viability of pancreatic islets is well maintained after the 3D printing process. Taken together, these results represent the first step toward an improved vehicle for islet transplantation and a potential novel strategy to treat Type I diabetes.

Phenoxodiol (2H-1-benzopyran-7-0,1, 3-[4-hydroxyphenyl], PXD) is a synthetic analogue of the naturally-occurring plant isoflavone and anticancer agent, genistein. PXD directly induces mitotic arrest and apoptosis in most cancer cells and is currently undergoing clinical trials, as a chemotherapeutic in ovarian and prostate cancers. We show here that PXD also exhibits potent antiangiogenic properties. Thus, it inhibited endothelial cell proliferation, migration and capillary tube formation and inhibited expression of the matrix metalloproteinase MMP-2, a major matrix degrading enzyme. Importantly, we demonstrate that PXD is functional in vivo since it inhibited the extent of capillary tube invasion in an in vivo model of angiogenesis. We show that phenoxodiol inhibits hallmarks of endothelial cell activation, namely TNF or IL-1 induced E-selectin and VCAM-1 expression and IL-8 secretion. However, PXD had no effect on unstimulated endothelial cells. We also describe that PXD inhibits the lipid kinase sphingosine kinase, which recently has been implicated in endothelial cell activation and angiogenesis as well as oncogenesis. Thus, our results suggest that PXD may be an effective anticancer drug targeting the two drivers of tumour growth -the proliferation of the tumour cells themselves and the angiogenic and inflammatory stimulation of the vasculature. ' 2005 Wiley-Liss, Inc.Key words: flavonoids; cancer; angiogenesis; sphingosine kinase It is now well recognised that successful tumour growth involves uncontrolled proliferation of tumour cells and a supply of necessary nutrients delivered through a network of newly formed blood vessels. The ability of the tumour cells to stimulate angiogenesis is viewed as the ''angiogenic switch'' 1-3 a state essential for the continued growth and expansion of the tumour mass. Thus, combination therapy using drugs directed towards inhibition of the tumour cells, combined with drugs directed against the expanding vasculature is now considered a strategic direction for anticancer chemotherapy. The naturally-occurring plant isoflavone, genestein, became of interest in this regard, because of its dual effects of direct antitumour activities (mitotic arrest and apoptosis) and antiangiogenesis. [4][5][6][7][8][9][10][11][12] However, genistein has not been considered for development as a chemotherapeutic because of its poor bio-availability and high rate of metabolism, and the fact that the potencies of its anticancer actions are relatively modest.The experimental anticancer drug, phenoxodiol (PXD), is a sterically-modified version of genistein, which has substantially improved bio-availability and lower rate of metabolism and increased antitumour potency. PXD is currently undergoing Phase II clinical studies for the treatment of hormone-refractory prostatic adenocarcinoma, recurrent ovarian cancer, renal carcinoma and cervical squamous cell carcinoma. Two known biological effects of PXD are mitotic arrest of tumour cells in G1 of the cell cycle as a result of p53-independent upregula...