Single-unit umbilical cord blood transplantation from unrelated donors in patients with hematological malignancy using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning regimen

Attempts to optimize outcomes in cord blood transplantation (CBT) by using new conditioning regimens and standardization of cord blood unit selection are warranted. In all, 88 patients (18 children and 70 adults) with hematological malignancy from nine Spanish institutions underwent a single-unit CBT after an i.v. BU-based myeloablative conditioning regimen. All evaluable patients except one engrafted. The overall cumulative incidence (CI) of myeloid engraftment was 94% at a median time of 19 days. In multivariate analysis, nonadvanced disease stage was the only factor with a favorable impact on myeloid engraftment. The CI of acute GVHD grades II-IV and chronic extensive GVHD were 24% each. The CI of nonrelapse mortality at 100 days, 180 days and 5 years was 14, 23 and 44%, respectively. The 5-year CI of relapse was 18%, whereas disease-free survival (DFS) was 46%, 39% and 11% for patients transplanted in early, intermediate and advanced stages of the disease, respectively. Our study shows high rates of engraftment with fast neutrophil recovery in patients undergoing single-unit CBT using a BU-based conditioning regimen. Long-term DFS can be achieved in a substantial number of patients with high-risk hematological malignancies, particularly when transplanted in an early stage of the disease.     

A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT

An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT.     

Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.     

Actualización en cardiología geriátrica

This article contains a review of the main developments in the field of geriatric cardiology reported during 2011. The principle focus is on research into the characteristics of elderly patients with heart failure, arrhythmias (e.g. into atrial fibrillation and implantable cardioverter-defibrillators), ischemic heart disease and percutaneous interventions.     

Renal insufficiency and vascular complications after primary angioplasty via femoral route. Impact of vascular closure devices use

Introduction and objectives

We sought to determine the incidence of vascular complications in patients with chronic kidney disease undergoing primary angioplasty via the femoral route; we also evaluated the safety and efficacy of the use of vascular closure devices in this setting.

Methods

Registry of 527 patients undergoing primary angioplasty via the femoral route from January 2003 to December 2008. Chronic kidney disease was defined as creatinine clearance less than 60 mL/min. The primary endpoint was the presence of major vascular complications.

Results

Baseline chronic kidney disease was observed in 166 (31.5%) patients. Patients with chronic kidney disease experienced higher rates of major vascular complications compared to those without worsening of renal function (8.4% vs 4.2%; P=.045), especially those requiring transfusion (6.6% vs 1.9%; P=.006). Among patients with chronic kidney disease, 129 (77.7%) received a vascular closure device and manual compression was used in 37 patients (22.3%). The risk of major vascular complications was significantly lower with vascular closure device use compared to manual compression (4.7% vs 21.6%; P=.003). Multivariable logistic regression analysis showed that the use of a vascular closure device was independently associated with a decreased risk of major vascular complications in patients with chronic kidney disease undergoing primary angioplasty (odds ratio=0.11; 95% confidence interval, 0.03-0.41; P=.001).

Conclusions

Patients with chronic kidney disease undergoing primary angioplasty via the femoral route experience higher rates of major vascular complications. The use of vascular closure devices in this group of patients is safe and is associated with lower rates of major vascular complications compared to manual compression.Full English text available from:www.revespcardiol.org     

Increased nitric oxide production and gender-dependent changes in PPARα expression and signaling in the fetal lung from diabetic rats

The fetal lung is affected by maternal diabetes. Nuclear receptor PPARα regulates nitric oxide (NO) overproduction in different tissues. We aimed to determine whether fetal lung PPARα expression is altered by maternal diabetes, and if there are gender-dependent changes in PPARα regulation of NO production in the fetal lung. Fetal lungs from control and diabetic rats were explanted on day 21 of gestation and evaluated for PPARα expression and NO production. Fetuses were injected with the PPARα ligand LTB(4) on days 19, 20 and 21, and the fetal lung explanted on day 21 to evaluate PPARα and the inducible isoform of NO synthase (iNOS). Besides, pregnant rats were fed with olive oil- and safflower oil-supplemented diets, enriched in PPAR ligands, for evaluation of fetal lung NO production and PPARα expression. We found reduced PPARα concentrations only in the lung from male fetuses from the diabetic group when compared to controls, although maternal diabetes led to NO overproduction in both male and female fetal lungs. Fetal activation of PPARα led to changes in lung PPARα expression only in female fetuses, although this treatment increased iNOS expression in both male and female fetuses in the diabetic group. Diets supplemented with olive oil and not with safflower oil led to a reduction in NO production in male and female fetal lungs. In conclusion, there are gender-dependent changes in PPARα expression and signaling in the fetal lung from diabetic rats, although PPARα activation prevents maternal diabetes-induced lung NO overproduction in both male and female fetuses.