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ABSTRACTAcute coronary syndrome (ACS) is the most severe clinical manifestation of coronary heart disease.We performed an epigenome-wide analysis of circulating CD4+and CD8+T cells isolated from ACS patients and healthy subjects (HS), enrolled in the DIANA clinical trial, by reduced-representation bisulphite sequencing (RRBS). In CD4+T cells, we identified 61 differentially methylated regions (DMRs) associated with 57 annotated genes (53% hyper- and 47% hypo-methylated) by comparing ACS patients vsHS. In CD8+T cells, we identified 613 DMRs associated with 569 annotated genes (28% hyper- and 72% hypo-methylated) in ACS patients as compared to HS. In CD4+vsCD8+T cells of ACS patients we identified 175 statistically significant DMRs associated with 157 annotated genes (41% hyper- and 59% hypo-methylated). From pathway analyses, we selected six differentially methylated hub genes (NFATC1, TCF7, PDGFA, PRKCB, PRKCZ, ABCA1) and assessed their expression levels by q-RT-PCR. We found an up-regulation of selected genes in ACS patients vsHS (P< 0.001). ABCA1, TCF7, PDGFA,and PRKCZgene expression was positively associated with CK-MB serum concentrations (r= 0.75, P= 0.03; r= 0.760, P= 0.029; r= 0.72, P= 0.044; r= 0.74, P= 0.035, respectively).This pilot study is the first single-base resolution map of DNA methylome by RRBS in CD4+and CD8+T cells and provides specific methylation signatures to clarify the role of aberrant methylation in ACS pathogenesis, thus supporting future research for novel epigenetic-sensitive biomarkers in the prevention and early diagnosis of this pathology.

Despite improvements in anti-Human Leucocyte Antigens antibody detection, identification, and characterization offer a better in peri-operative management techniques, antibodies remain a serious cause of morbidity and mortality for patients both before and after organ transplantation. Hyperimmune patients are disadvantaged by having to wait longer to receive an organ from a suitably matched donor. They could benefit from desensitization protocols in both pre- and post-transplantation period. Clinical studies are underway to highlight which best desensitization strategies could be assure the best outcome in both heart and kidney transplantation. Although most clinical evidence about desensitization strategies by using anti-CD 20 monoclonal antibodies, proteasome inhibitors, anti-CD38 monoclonal antibodies, interleukin-6 blockade, cysteine protease and complement inhibitors, comes from kidney transplantation studies, many of the debated novel concepts can be easily applied to desensitization also in heart transplantation.

The following paper is an overview on stem cells therapy in patients with peripheral vascular diseases. Recent research shows the ability of stem cells to develop and strengthen the collateral network in ischemic legs. Here, we discuss this clinical and therapeutic approach. To date, research has been mainly focused on patients with ischemic ulcers without possibility of revascularization. Non-invasive stem cell therapy has been proposed as an alternative to the amputation of such patients, but when the ulcers appear it is sometime too late. In our point of view, the selection of patients is a very important issue and we believe that the best candidate for this treatment is the patient with intermittent claudication before the development of ulcers. This choice could allow the optimization of results by the type of treated patients and not only by the type of infused cells. Indeed, several variables still remain to be elucidated for stem cell therapy, including the type of cells to be used, the infusion route, and more importantly, the stage of patients to be treated.

The relevance of anti-human leucocyte antigen (anti-HLA) antibodies in the outcome of organ transplantation has been recognized in the past 40 years. Detection of these antibodies in sensitized recipients plays a pivotal role in this issue. Flow cytometry analysis is one of the choice cell-based techniques together with the pioneer complementdependent cytotoxicity crossmatch. Here, we discuss the advantages and limits of these cell-based assays and their use in the clinical laboratory of immunology of transplantation. Moreover, we compared this approach to other beads-based detection assays introduced more recently in the laboratory practice.