Low oxygenation of islets contributes to cellular death and dysfunction during preparation of islets for transplantation, as well as posttransplantation. Interventions at these different steps to ensure adequate oxygenation have the potential to improve the results of clinical islet transplantation.
Pancreatic islet transplantation is presently almost exclusively performed using the intraportal route for transplantation into the liver. However, islets at this site are poorly revascularized and, when also considering the poor long-term results of clinical islet transplantation, there has in recent years emerged an increased interest to evaluate alternative sites for islet transplantation. Striated muscle is easily accessible and has for decades been used for autotransplantation of parathyroid glands. Moreover, it is almost the only tissue in the adult where physiological angiogenesis occurs. The present study tested the hypothesis that striated muscle would provide good conditions for revascularization and oxygenation of transplanted islets. Because we previously have observed similar revascularization of islets implanted to the renal subcapsular site and intraportally into the liver, islets grafted to the kidney were for simplicity besides native islets used for comparison. Islets grafted into muscle were found to have three times more blood vessels than corresponding islets at the renal subcapsular site at 2 month follow-up, but still less vascular numbers than native islets. The oxygen tension in 2-month-old intramuscular islet grafts was sixfold higher than in corresponding renal subcapsular grafts, and 70% of that in native islets. However, the oxygenation of surrounding muscle was only 50% of that in renal cortex, and connective tissue constituted a larger proportion of the intramuscular than the renal subcapsular grafts, suggesting exaggerated early islet cell death at the former site. We conclude that the intramuscular site provides excellent conditions for vascular engraftment, but that interventions to improve early islet survival likely are needed before clinical application. Such could include bioengineered matrices that not only spatially disperse the islet, but also could provide local supply of oxygen carriers, growth and survival factors, strategies that are much more easily applied at the intramuscular than the intrahepatic site.
Aims/hypothesis The blood perfusion of individual pancreatic islets is highly variable, with a subgroup of islets having high perfusion and blood vessels responsive to further blood flow increase induced by glucose. This study tested the hypothesis that there is heterogeneity between islets with regard to beta cell proliferation, function and gene expression based on differences in their blood perfusion. Methods Fluorescent microspheres were injected into the ascending aorta, and then microsphere-containing and nonmicrosphere-containing pancreatic islets were isolated for investigation. By this procedure, the 5% of islets with the greatest blood perfusion were identified for study. Islet endothelial cells were isolated separately to investigate the role of improved vascular support in the observed differences. Results The vascular network was found to be more dense and tortuous in microsphere-containing than other islets. The most highly blood-perfused islets also had a higher rate of beta cell proliferation, superior beta cell function and a markedly different gene expression from other islets. Cultured islets exposed to islet endothelial cell products had a similarly increased beta cell proliferation rate, yet significantly fewer changes in gene expression than observed in the most highly blood-perfused islets.Conclusions/interpretation A novel heterogeneity between islets was observed, with superior beta cell proliferation, function and gene expression in a subpopulation of islets identified by high blood perfusion. In contrast with a previously described population of low-oxygenated, sleeping islets, which are recruited into functionality when needed, the presently described heterogeneity is shown to remain in vitro after islet isolation.
Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30–50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. Methods: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). Results: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. Conclusions: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer.
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