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The custom microenvironment “vascular niche” is a potential therapeutic target for several pathophysiological conditions. Osteoblasts act as regulators of the hematopoietic stem cell niche, and activation of the parathyroid hormone (PTH) receptor may increase the number of cells mobilized into the bloodstream. The authors demonstrate that PTH may enhance the efficiency of hematopoietic stem cell-based therapy in a recognized model of peripheral ischemia. Background The custom microenvironment 'vascular niche' is a potential therapeutic target for several pathophysiological conditions. Osteoblasts regulate the hematopoietic stem cell niche, and activation of the parathyroid hormone (PTH) receptor can increase the number of cells mobilized into the bloodstream. Methods C57Bl/6 mice were randomly assigned treatment with granulocyte-colony stimulating factor (G-CSF), PTH, G-CSF plus PTH or saline. All mice underwent hindlimb ischemia. Blood flow was measured by laser Doppler imaging. Indices of capillary activity were determined by electron microscopy in muscle tissue. CD34 + and Ki67 + cells were detected and evaluated by immunofluorescence, apoptosis by TUNEL, surface antigen and endothelial progenitor cells by fluorescence-activated cell sorting analysis, and vascular endothelial growth factor-164 and angiopoietin-1 expression by reverse-transcriptase polymerase chain reaction. Frozen bone marrow sections were stained for antigen-specific B cells and fibronectin and analyzed by confocal laser scanning microscopy. Results Following mobilization induced by G-CSF treatment, mice also treated with PTH showed increases in blood flow, capillary density, nitrite/nitrate release, angiogenic factors and circulating progenitor cells, as well as reduced apoptosis, fibrosis, oxidative stress and inflammation in ischemic muscles. Furthermore, hematopoietic antigen-specific B cells in the bone marrow were also increased by G-CSF alone and in combination with PTH. Conclusions PTH might increase the efficiency of hematopoietic stem-cell-based therapy in a recognized model of peripheral ischemia. Our translational experimental therapeutic targeting of the vascular niche points to novel clinical targets for the hematopoietic stem-cell treatment of ischemic vascular diseases. Key Points The vascular niche is a potential therapeutic target for peripheral arterial disease We present a translational research study investigating whether targeting the niche with parathyroid hormone (PTH) might improve stem cell-based therapy in an experimental model of hindlimb ischemia that would be relevant to the clinical use of hematopoietic stem-cell-driven angiogenesis After mobilization induced by granulocyte-colony stimulating factor (G-CSF), mice also receiving PTH showed increased blood flow, capillary density, nitrite/nitrate release, angiogenic factors and circulating progenitor cells together with reduced apoptosis, fibrosis, oxidative stress and inflammation in ischemic muscles Our translational study could stimulate clinical trials aimed at increasing the effectiveness of hematopoietic stem cell therapy in peripheral arterial disease by targeting the hematopoietic stem cell niche with PTH In a recent phase I clinical trial, 38 PTH (up to 100µg for 14 days) was tolerated well and there was no dose-limiting toxicity; thus, the clinical efficacy of PTH will need to be tested in a larger phase II study

Double heterozygosity (DH) in BRCA1 and BRCA2 genes and double mutation (DM) in BRCA1 or BRCA2 are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the BRCA1/2 genes with a frequency of 0.3% and three probands with DM in the BRCA2 gene with a frequency of 0.5%. The DH BRCA1 c.547+2T>A (IVS8+2T>A)/BRCA2 c.2830A>T (p.Lys944Ter) and BRCA1 c.3752_3755GTCT (p.Ser1253fs)/BRCA2 c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in BRCA2, c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of BRCA1 pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that BRCA2 pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.

Purpose The pathogenic role of angiotensin-converting enzyme (ACE) inhibition in hypertensive patients regarding endothelial progenitor-cell (EPC) function is still poorly understood. The aim of the study was to evaluate EPC number, function, and relationship to carotid intima media thickness (IMT) progression. Methods We studied 36 newly diagnosed mildly hypertensive patients free of cardiovascular disease and related risk factors without prior or concurrent therapy with ACE inhibitors. Patients were randomized to receive enalapril 20 mg/day ( n  = 18) or zofenopril 30 mg/day ( n  = 18). EPC number and migrating capacity, plasma nitrite and nitrate (NOx), and isoprostane concentrations were evaluated. Carotid IMT was determined by ultrasonography at baseline and after 1 and 5 years of follow-up. Results EPC number increased during the follow-up, with no statistical differences between treatment groups. There was an inverse correlation between circulating EPCs and IMT increase over time. Plasma NOx decreased during the study without evident differences between treatment groups. Isoprostanes decreased more markedly in zofenopril-treated patients. Multiple linear regression model demonstrated that carotid IMT was significantly inversely correlated with EPC but not with migratory cells after adjusting for confounders. Conclusions The study demonstrated that EPC levels increased during the follow-up in both groups of newly diagnosed hypertensive patients treated with ACE inhibitors. These drugs prevented progression of vascular damage, with an inverse correlation between circulating EPC levels and IMT values.