3 research outputs found
Endothelial Dysfunction Syndromes after Allogeneic Stem Cell Transplantation
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only therapy with a curative potential for a variety of malignant and non-malignant diseases. The major limitation of the procedure is the significant morbidity and mortality mainly associated with the development of graft versus host disease (GVHD) as well as with a series of complications related to endothelial injury, such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), transplant-associated thrombotic microangiopathy (TA-TMA), etc. Endothelial cells (ECs) are key players in the maintenance of vascular homeostasis and during allo-HSCT are confronted by multiple challenges, such as the toxicity from conditioning, the administration of calcineurin inhibitors, the immunosuppression associated infections, and the donor alloreactivity against host tissues. The early diagnosis of endothelial dysfunction syndromes is of paramount importance for the development of effective prophylactic and therapeutic strategies. There is an urgent need for the better understanding of the pathogenetic mechanisms as well as for the identification of novel biomarkers for the early diagnosis of endothelial damage. This review summarizes the current knowledge on the biology of the endothelial dysfunction syndromes after allo-HSCT, along with the respective therapeutic approaches, and discusses the strengths and weaknesses of possible biomarkers of endothelial damage and dysfunction
Endothelial Injury Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: Angiopetin-2 as a Novel Predictor of the Outcome and the Role of Functional Autoantibodies against Angiotensin II Type 1 and Endothelin A Receptor
Transplant-associated thrombotic microangiopathy (TMA) occurs in a significant percentage of patients after allogeneic stem cell transplantation (allo-SCT) and is associated with significant morbidity and mortality. The aim of the present study was to examine the association of serum angiopoetin-2 (Ang2) levels and the presence of antibodies against angiotensin II type 1 (AT1R) and ndothelin A Recreptor (ETAR) with the outcome of patients with TMA and/or graft-versus-host disease (GVHD) after allo-SCT. Analysis of our data showed that elevated serum Ang2 levels at the time of TMA diagnosis are significantly associated with increased non-relapse mortality and decreased overall survival. To our knowledge, this is the first study demonstrating an association between raised Ang2 levels and poor outcomes in patients with TMA. Antibodies against AT1R (AT1R-Abs) and ETAR (ETAR-Abs) were detected in 27% and 23% of the patients, respectively, but there was no association between the presence of autoantibodies and the outcome of patients with TMA. However, a significant finding was the strong positive correlation between the presence of AT1R-Abs with the occurrence of chronic fibrotic GVHD, such as scleroderma and cryptogenic organizing pneumonia, raising the possibility of the contribution of autoantibodies in the pathogenesis of fibrotic GVHD manifestations
Unusual α-Carbon Hydroxylation of Proline Promotes Active-Site Maturation
The full extent of proline (Pro)
hydroxylation has yet to be established,
as it is largely unexplored in bacteria. We describe here a so far
unknown Pro hydroxylation activity which occurs in active sites of
polysaccharide deacetylases (PDAs) from bacterial pathogens, modifying
the protein backbone at the C<sub>α</sub> atom of a Pro residue
to produce 2-hydroxyproline (2-Hyp). This process modifies with high
specificity a conserved Pro, shares with the deacetylation reaction
the same active site and one catalytic residue, and utilizes molecular
oxygen as source for the hydroxyl group oxygen of 2-Hyp. By providing
additional hydrogen-bonding capacity, the Pro→2-Hyp conversion
alters the active site and enhances significantly deacetylase activity,
probably by creating a more favorable environment for transition-state
stabilization. Our results classify this process as an active-site
“maturation”, which is highly atypical in being a protein
backbone-modifying activity, rather than a side-chain-modifying one