Hemojuvelin-mediated hepcidin induction requires both bone morphogenetic protein type I receptors ALK2 and ALK3.

ABSTRACT: Hemojuvelin (HJV) is a glycosylphosphatidylinositol-anchored protein of the repulsive guidance molecule family acting as a bone morphogenetic protein (BMP) coreceptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin, thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV)-mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp messenger RNA (mRNA) levels, soluble HJV (sHJV), splenic iron content (SIC), as well as phosphorylated small mothers against decapentaplegic protein (pSMAD1/5/8) levels. In contrast, in Alk2fl/fl;Alb-Cre and Alk3fl/fl;Alb-Cre mice, which present with moderate and severe iron overload, respectively, the administration of AAV-HJV induced HJV and sHJV. However, it did not rescue the iron overload phenotypes of those mice. Serum iron levels were induced in Alk2fl/fl;Alb-Cre mice after HJV overexpression. In phosphate-buffered saline-injected Alk3fl/fl;Alb-Cre mice, serum iron levels and the expression of duodenal ferroportin remained high, whereas Hamp mRNA levels were decreased to 1% to 5% of the levels detected in controls. This was reduced even further by AAV-HJV overexpression. SIC remained low in mice with hepatocyte-specific Alk2 or Alk3 deficiency, reflecting disturbed iron homeostasis with high serum iron levels and transferrin saturation and an inability to induce hepcidin by HJV overexpression. The data indicate that ALK2 and ALK3 are both required in vivo for the HJV-mediated induction of hepcidin.

Co-transplantation of pancreatic islets and microvascular fragments effectively restores normoglycemia in diabetic mice.

Insufficient revascularization of pancreatic islets is one of the major obstacles impairing the success of islet transplantation. To overcome this problem, we introduce in the present study a straightforward strategy to accelerate the engraftment of isolated islets. For this purpose, we co-transplanted 250 islets and 20,000 adipose tissue-derived microvascular fragments (MVF) from donor mice under the kidney capsule as well as 500 or 1000 islets with 40,000 MVF into the subcutaneous space of diabetic mice. We found that the co-transplantation of islets and MVF markedly accelerates the restoration of normoglycemia in diabetic recipients compared with the transplantation of islets alone. In fact, the transplantation of 250 islets with 20,000 MVF under the kidney capsule reversed diabetes in 88% of mice and the subcutaneous transplantation of 500 or 1000 islets with 40,000 MVF restored normoglycemia in 100% of mice. Moreover, diabetic mice receiving islets and MVF exhibited plasma insulin levels similar to nondiabetic control animals. Additional immunohistochemical analyses of the grafts revealed a significantly higher number of islet cells and microvessels in the co-transplantation groups. These findings demonstrate that the co-transplantation of islets and MVF is a promising strategy to improve the success rates of islet transplantation, which could be easily implemented into future clinical practice.

Isolated skin recurrence following salvage mastectomy for intramammary recurrence (after initial breast conservation therapy): is it a fatal event?

AIMS: The authors analyzed the outcome of patients with Isolated Skin Recurrence After Salvage Mastectomy (ISRASM) performed after conservative treatment for breast carcinoma, taking into account initial tumor characteristics, intramammary recurrence (first recurrence) characteristics, local skin recurrence (second recurrence) characteristics, and the type of treatment at each stage of the breast cancer continuum. METHODS: Forty-two patients who had ISRASM between 1976 and 2007 were included in this retrospective study. Twenty-six factors were studied in univariate and multivariate analyses. RESULTS: Mean Overall Survival (OS) was 70.3 (±4.1) months. The 5-year OS rate was 66.6%. 31% of patients did not present any recurrence, 52% had locoregional recurrence and 14% metastatic recurrence following ISRASM. Univariate analysis showed that 4 prognostic factors were significantly related to OS and/or Disease-Free Survival (DFS): (1) initial chemotherapy after primary breast cancer (P = 0.09 and 0.01 respectively), (2) presence of emboli at the site of intramammary recurrence (first recurrence) (P = 0.02 and 0.03), (3) interval between first and second surgery of less than 3 years (P = 0.09 and 0.0003), and (4) inflammatory skin involvement at ISRASM (P = 0.005 and 0.17). Multivariate analysis showed that presence of emboli at the site of intramammary recurrence was significantly related to OS and that an interval between first and second recurrence of less than 3 years was significantly related to DFS. CONCLUSION: Our results show that ISRASM affects a group of breast cancer patients with predominantly local rather than metastatic disease. Prognostic factors depend on characteristics at initial breast cancer, first recurrence and second recurrence. Evidence-based guidelines are still required for ISRASM management.