Circulating cell-free DNA in liver transplantation: A pre- and post-transplant biomarker of graft dysfunction.

Background: Liver transplantation (LT) is still limited by organ shortage and post-transplant monitoring issues. While machine perfusion techniques allow for improving organ preservation, biomarkers like donor-derived cell-free DNA (dd-cfDNA) and mitochondrial cfDNA (mt-cfDNA) may provide insights into graft injury and viability pre- and post-LT.

Methods: A prospective observational cohort study was conducted on LT recipients (n = 45) to evaluate dd-cfDNA as a biomarker of graft dysfunction during the first 6 months after LT.

Donor-derived Cell-free DNA Evaluation in Pediatric Heart Transplant Recipients: A Single-center 12-mo Experience.

Background: Endomyocardial biopsy (EMB) is considered the gold-standard method to diagnose rejection after heart transplantation. However, the many disadvantages and potential complications of this test restrict its routine application, particularly in pediatric patients. Donor-derived cell-free DNA (dd-cfDNA), released by the transplanted heart as result of cellular injury, is emerging as a biomarker of tissue damage involved in ischemia/reperfusion injury and posttransplant rejection.

Significant Long-Term Prevention of High Sensitization After Kidney Allograft Failure by Maintaining Calcineurin Inhibitor-Based Immunosuppression.

Introduction: Broad national or international programs contribute to mitigating the expected longer waiting list (WL) time for sensitized patients but with minor benefits for highly sensitized subjects. Therefore, strategies to prevent high sensitization are urgently required. In this study, we investigated the risk of developing highly sensitized patients with different immunosuppressive (IS) handling after kidney allograft failure (KAF).

Absence of IL-6 Receptor Blockade Effect on the Outcomes of Transplant Glomerulopathy in the Absence of Anti-HLA Donor-specific Antibodies.

Background: Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs.

Validation of a Simple, Rapid, and Cost-Effective Method for Acute Rejection Monitoring in Lung Transplant Recipients.

Despite advances in immunosuppression therapy, acute rejection remains the leading cause of graft dysfunction in lung transplant recipients. Donor-derived cell-free DNA is increasingly being considered as a valuable biomarker of acute rejection in several solid organ transplants. We present a technically improved molecular method based on digital PCR that targets the mismatch between the recipient and donor at the locus.

HLA-DRB1 mismatch-based identification of donor-derived cell free DNA (dd-cfDNA) as a marker of rejection in heart transplant recipients: A single-institution pilot study.

Background: Donor-derived cell-free DNA (dd-cfDNA) is considered a reliable marker of organ damage with potential applications in the follow-up of transplant recipients.

Methods: In this work we present an assay based on the donor-recipient HLA-mismatch (human leukocyte antigen) at the HLA-DRB1 locus to monitor rejection by quantifying the percentage of dd-cfDNA using a droplet digital PCR (polymerase chain reaction) technique. A panel of probes targeting the HLA-DRB1 locus and covering >85% genetic variability was validated and used to assess dd-cfDNA levels in a prospective cohort of 19 adult heart transplant recipients (mean age 50.

Early effects of first-line treatment with anti-interleukin-6 receptor antibody tocilizumab for chronic active antibody-mediated rejection in kidney transplantation.

Introduction: Chronic active antibody-mediated rejection (cAMR) is a major determinant of late allograft failure. Rituximab/immunoglobulins (IVIg) + plasma exchange (PLEX) showed controversial results in cAMR treatment. Tocilizumab (TCZ), a humanized anti-interleukin 6 receptor antibody, has been recently used as rescue therapy in patients non-responsive to rituximab/IVIg/PLEX with favorable outcomes.

Detection of Angiotensin II type I-receptor antibodies in transplant glomerulopathy.

Background: Transplant glomerulopathy (TG) is an important cause of late graft loss. The role of angiotensin type 1-receptor antibodies (AT R-Ab) in TG is not known.

Methods: All the TG cases (N = 137) between January 2007 and December 2014 (N = 1410) were analyzed.

Treatment with plasmapheresis, immunoglobulins and rituximab for chronic-active antibody-mediated rejection in kidney transplantation: Clinical, immunological and pathological results.

Aim: To evaluate the role of a therapeutic regimen with plasma exchange, intravenous immunoglobulins and rituximab in chronic-active antibody-mediated rejection (cAMR) settings.

Methods: We compared 21 kidney transplant recipients (KTRs) with a diagnosis of cAMR in a retrospective case-control analysis: nine KTRs treated with plasmapheresis, intravenous immunoglobulins and rituximab (PE-IVIG-RTX group) 12 patients (control group) not treated with antibody-targeted therapies. We examined kidney survival and functional outcomes 24 mo after diagnosis.

Transfemoral implantation of CoreValve Evolut-R aortic prosthesis in patient with prior ball-cage mechanical mitral valve prosthesis.

Transcatheter aortic valve replacement remains challenge in patients with ball-cage-type mechanical valve in mitral position. Potential under-expansion of the percutaneous valve and interaction between the mitral ball-cage mechanical valve tilted towards the left ventricular outflow tract and the percutaneous valve adds risk during and after implantation. We report a successful implantation of the novel CoreValve Evolut-R self-expanding in a patient with severe aortic stenosis and a mitral Starr-Edwards mechanical valve implanted 28years ago.

NADPH oxidase 2 (NOX2) enzyme activation in patients with chronic inflammatory demyelinating polyneuropathy.

Background And Purpose: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immunomediated condition affecting the peripheral nervous system where probably macrophages are the primary effector cells for demyelination. Reactive oxygen species (ROS), catalyzed by the NOX family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzymes, can induce peroxidation and are potentially injurious to myelin. Our aim was to assess the activity of NOX2, an isoform of NOX, in a series of CIDP patients and to analyze the effect of intravenous immunoglobulin (IVIg) on NOX2.

Protein disulfide isomerase A3-specific Th1 effector cells infiltrate colon cancer tissue of patients with circulating anti-protein disulfide isomerase A3 autoantibodies.

To investigate novel colorectal cancer (CRC)-associated antigens that could be targets of humoral or cellular responses, we analyzed the reactivity of serum from a long-surviving CRC patient (for more than 100 months of follow-up) in clinical remission, by serologic proteome analysis. Two-dimensional Western blotting (2D-WB) and mass spectrometry analysis revealed a strong reactivity of this serum against protein disulfide isomerase A3 (PDIA3). Anti-PDIA3 antibodies are not a diagnostic marker of CRC, 2D-WB and Luminex analysis revealed that they were equally present in about 10% of sera from healthy subjects and CRC patients.

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients.

Aims/hypothesis: Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes.

Methods: Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation.

Phosphorylated alpha-enolase induces autoantibodies in HLA-DR8 pancreatic cancer patients and triggers HLA-DR8 restricted T-cell activation.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-induced death in the Western World. In PDAC patients, alpha-enolase (ENOA), a glycolytic enzyme that also acts as plasminogen receptor, is up-regulated and elicits the production of autoantibodies. Our previous studies revealed that most PDAC patients specifically produce antibodies to Serine(419)phosphorylated ENOA (Ser(419)P-ENOA) isoforms (ENOA1,2), and that this humoral response correlates with a better clinical outcome.

Statin pretreatment and risk of in-hospital atrial fibrillation among patients undergoing cardiac surgery: a collaborative meta-analysis of 11 randomized controlled trials.

Aims: Statin pretreatment in patients undergoing cardiac surgery is understood to prevent postoperative atrial fibrillation (AF). However, this is based on observational and limited randomized trial evidence, resulting in uncertainty about any genuine anti-arrhythmic benefits of these agents in this setting. We therefore aimed to quantify precisely the association between statin pretreatment and postoperative AF among patients undergoing cardiac surgery.

NADPH oxidase (NOX2) activity is a modifier of survival in ALS.

NADPH-oxidases (NOX) catalyze the formation of reactive oxygen species (ROS), which play a role in the development of neurological diseases, particularly those generated by the phagocytic isoform NOX2. Increased ROS has been observed in the amyotrophic lateral sclerosis (ALS) SOD1 transgenic mouse, and in this preclinical model the inactivation of NOX2 decreases ROS production and extends survival. Our aim was to evaluate NOX2 activity measuring neutrophil oxidative burst in a cohort of 83 ALS patients, and age- and gender-matched healthy controls.

Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes.

Aims/hypothesis: Mesenchymal stem cells (MSCs) have been shown to abrogate in vitro the proinflammatory response in type 1 diabetes. The mechanism involves paracrine factors, which may include microvesicles (MVs). We evaluated whether MVs derived from heterologous bone-marrow MSCs exert an immunomodulatory effect on T cell responses against GAD (glutamic acid decarboxylase) antigen in type 1 diabetes.

Chimeric rat/human HER2 efficiently circumvents HER2 tolerance in cancer patients.

Purpose: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained. We studied the feasibility of using DNA coding for chimeric rat/human HER2 as a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP).

Experimental Design: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast (n = 28) and pancreatic (n = 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 fusion proteins and used to activate autologous T cells.

The Ibero-American transcatheter aortic valve implantation registry with the CoreValve prosthesis. Early and long-term results.

Background: Transcatheter aortic valve implantation (TAVI) is the recommended therapy for patients with severe aortic stenosis who are not suitable candidates for surgery. The aim of this study was to describe early experience and long-term follow-up with the CoreValve self-expanding aortic prosthesis at 42 Ibero-American hospitals.

Methods: Multiple centre observational study including 1220 consecutive patients with symptomatic severe aortic stenosis who are not suitable candidates for surgery and underwent transcatheter aortic valve implantation with the self-expanding Medtronic CoreValve System between December 2007 and May 2012.

[Transcatheter aortic valve implantation: experience in 17 patients].

Background: Transcatheter aortic valve implantation (TAVI) is taking a leading role in the management of patients with severe aortic stenosis. Valve replacement surgery prolongs survival and is the technique of choice considering its historical background and long experience worldwide. Recently however, TAVI has positioned itself as the only standard therapy for symptomatic patients who are not candidates for surgery.

Amyloid-β protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau.

Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer's disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration.

Human mesenchymal stem cells modulate cellular immune response to islet antigen glutamic acid decarboxylase in type 1 diabetes.

Context: Mesenchymal stem cells (MSCs) exert an immunosuppressive effect on the immune system. However, studies on the immunomodulatory potential of MSCs in type 1 diabetes are lacking.

Objective: We aimed to evaluate whether human MSCs may inhibit in vitro pancreatic islet antigen-specific T cell activation in type 1 diabetes.

CCL16 enhances the CD8+ and CD4+ T cell reactivity to human HER-2 elicited by dendritic cells loaded with rat ortholog HER-2.

T cells from HLA-A2+ healthy donors were co-cultured with autologous dendritic cells (DC) loaded with apoptotic tumor cells expressing rat neu, and were induced to mature by tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta (mDC(neu)) or by the CCL16 chemokine (CCL16/mDC(neu)). Priming by CCL16/mDC(neu) induces a larger population of T cells that express cytoplasmatic interferon (IFN)gamma, TNFalpha, perforin and granzyme B compared to those primed by mDC(neu). T cells primed by CCL16/mDC(neu) release IFNgamma in response to human HER-2+ cells and kill human HER-2+ target cells more efficiently than those primed by mDC(neu).

Lack of plasma protein hemopexin dampens mercury-induced autoimmune response in mice.

Several factors affect the autoimmune response, including iron-dependent modulation of T cells. Hemopexin is the plasma protein with the highest binding affinity to heme. It mediates heme-iron recovery in the liver, thus controlling heme-iron availability in peripheral cells.

Pravastatin immunomodulates IL-6 and C-reactive protein, but not IL-1 and TNF-alpha, in cardio-pulmonary bypass.

Background: While statins are increasingly used in cardiopulmonary bypass (CPB), the anti-inflammatory effects of individual statins, within the context of various treatment regimes, need further examination. The present study evaluates the anti-inflammatory effectiveness of the short-term, preoperative and intensive postoperative use of pravastatin in CPB.

Method: Forty three patients undergoing CPB were enrolled in a randomized, prospective clinical study.