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Epidemiological evidence shows that diabetic patients have an increased cancer risk and a higher mortality rate. Glucose could play a central role in metabolism and growth of many tumor types, and this possible mechanism is supported by the high rate of glucose demand and uptake in cancer. Thus, growing evidence suggests that hyperglycemia contributes to cancer progression but also to its onset. Many mechanisms underlying this association have been hypothesized, such as insulin resistance, hyperinsulinemia, and increased inflammatory processes. Inflammation is a common pathophysiological feature in both diabetic and oncological patients, and inflammation linked to high glucose levels sensitizes microenvironment to tumorigenesis, promoting the development of malignant lesions by altering and sustaining a pathological condition in tissues. Glycemic control is the first goal of antidiabetic therapy, and glucose level reduction has also been associated with favorable outcomes in cancer. Here, we describe key events in carcinogenesis focusing on hyperglycemia as supporter in tumor progression and in particular, related to the role of a specific hypoglycemic drug class, sodium-glucose linked transporters (SGLTs). We also discuss the possible use of SGLT2 inhibitor drugs also as a novel potential cancer therapy. Our meta-analysis showed that SGLT-2 inhibitors were significantly associated with an overall reduced risk of cancer as compared to placebo (RR = 0.35, CI 0.33- 0.37, P = 0. 00) with a particular effectiveness for dapaglifozin and ertuglifozin (RR = 0. 06, CI 0. 06- 0. 07 and RR = 0. 22, CI 0. 18- 0. 26). Network Medicine approaches may advance the possible repurposing of these drugs in patients with concomitant diabetes and cancer.

Prevention of alveolar bone resorption after tooth extraction may be useful for implant rehabilitation of the edentulous site minimizing the future need for bone augmentation procedures. A number of studies have investigated the efficacy of autologous platelet concentrates for the preservation of the alveolar bone volume after tooth extraction. Although encouraging results have been published, the available data are still controversial. The aim of the present systematic review was to assess the effect of platelet concentrates on alveolar socket preservation after tooth extraction. A literature search was carried out up to September 2017 for prospective controlled trials in which a test group using exclusively a platelet concentrate was compared with a control group in which extraction sockets were left to heal spontaneously. Seven controlled clinical trials published between 2010 and 2016 were included. A total of 320 extractions (170 tests and 150 controls) in 190 patients was considered. A great heterogeneity was found in terms of study design, methodological aspects, and outcome evaluation. For this reason, a quantitative analysis followed by meta-analysis was not possible, and only a descriptive analysis on the role of platelet concentrates in alveolar socket preservation was carried out. There is growing evidence that platelet concentrates may be advantageously used in postextraction sites, mainly to improve soft tissue healing and to reduce postoperative symptoms. Data about their potential in preserving the alveolar bone volume are still scarce and controversial, although recently encouraging results have been presented using more reliable and accurate evaluation technologies, such as the computed tomography. Further, well-designed and methodologically standardized investigations are strongly demanded to reach a higher level of evidence on this topic.

Type 1 diabetes (T1D) is an irreversible degenerative disease with severe complications such as heart disease, nephropathy, neuropathy, and retinopathy. Although exogenous insulin administration is a life-saving therapy, it does not cure the disease. This review addresses the epigenetic mechanisms responsible for the development of T1D and discusses epigenetic-based strategies for prevention and treatment of the disease. We describe novel epigenetic biomarkers for the identification of susceptible individuals and the establishment of innovative therapies with epidrugs and cell therapy to regenerate the lost β-cells. Despite the wealth of promising data regarding the potential benefits of epigenetic tools to reduce the burden of T1D, clinical trials are still very few, and this issue needs to be resolved in the near future.

We read with interest the additional results from the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial ([1][1]), which investigated New York Heart Association functional classes II to IV heart failure (HF) patients with preserved

Almost all known conventional cytotoxic anticancer drugs are less effective in killing tumor cells grown as multicellular spheroids than in killing tumor cells grown as monolayer cell cultures. This“ multicellular resistance” reflects the relative intrinsic drug-resistant phenotype of most solid tumors growing in vivo and is due to factors such as limited drug penetration or reduced fractions of proliferating cells. Proteasome inhibitors such as PS-341, a dipeptide boronic acid analogue, represent an interesting new class of potential anticancer drugs, which are entering early-phase clinical trials. PS-341 has been found to have good broad-spectrum cytotoxic activity in the 60-monolayer cell line National Cancer Institute screen. However, because its relative potency has not been tested in spheroid systems, we analyzed the activity of PS-341 in a spheroid/solid tumor context using four different human ovarian carcinoma cell lines and three prostate carcinoma cell lines, respectively. We found, with one exception, that PS-341 showed equal or greater activity in spheroids than in the respective monolayer cell cultures, even in a prostate cancer spheroid model with a very low growth fraction. PS-341 induced apoptotic cell death in carcinoma cells in both culture systems. We also noted a decrease in XIAP protein, a member of the inhibitor of apoptosis (IAP) family of apoptosis inhibitors, and phosphorylation of Bcl-XL in PS-341-treated ovarian carcinoma cells. Furthermore, DNA fragmentation, a hallmark of apoptosis (in this case, induced by PS-341), was completely inhibited by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD). Taken together, the results indicate that unlike most other known anticancer cytotoxic drugs, PS-341 appears to be as effective in killing tumor cells grown in the form of multicell spheroids as in killing tumor cells grown in monolayer cell culture. Hence, this compound has the potential to circumvent multicellular drug resistance and, as such, may show promising activity against solid tumors with low growth fractions invivo, which are frequently intrinsically resistant to conventional cytotoxic anticancer drugs.

Background: Despite current intensive treatments, hyperglycemic patients have an unfavorable prognosis due to severe CHD and development of complications. The interplay between hyperglycemia and systemic inflammation can modify patterns of gene expression mainly affecting DNA methylation in promoter regions and, thus, endothelial damage. However, DNA methylome of CD04+ and CD08+ T cells, which play a relevant role in endothelial dysfunction has not been studied, especially during increasing hyperglycemia.Purpose: To identify differentially methylated regions (DRMs) in CD04 + and CD08 + T cells by comparing healthy subjects (HS) to Pre-Diab and type 2 (T2D) patients. This approach would investigate possible biomarkers useful to identify vascular damage already at Pre-Diab state.Methods: In this pilot study, we enrolled a subgroup of patients from our ongoing PIRAMIDE clinical trial (NCT03792607) including a total of 14 individuals classified in HS (n=2), Pre-Diab (n=6), and T2D (n=6). The DMRs were identified by using the reduced representation bisulfite sequencing platform (RRBS) which captures the majority of promoters and CpG islands. Big data analysis was performed by using the R package and ChromHMM algorithms.Results: Most of the total DMRs (30-35%) were in the promoter regions in increasing hyperglycemia vs HS. A global analysis of DMR-related genes overlapping between Pre-Diab and T2D patients showed a prevalence of DNA hypermethylation in both T cells. Interestingly, the secreted protein acidic and cysteine rich (SPARC) gene was annotated to the most hypomethylated-DMR in Pre-Diab and its methylation level gradually decreased in T2D patients.Conclusions: Preliminary data indicated that hypomethylation of the SPARC promoter may be a useful biomarker of vascular complications in Pre-Diab patients with a possible role for primary prevention. However, larger multicenter trials are needed to validate our epigenetic data in the clinical arena.

Objective Smoking, unhealthy diet and obesity, sedentary behavior and inability to maintain adequate exercise have significant consequences for several chronic disorders. Blood centers can play a public health role in obesity surveillance and interventions. The purpose study was to evaluate the health status of the blood donors by monitoring the nutritional habits and lifestyle. Methods A descriptive cross-sectional face-to-face questionnaire was developed. It included a 41 item dietary assessment, reporting semi-quantitative food frequency, dietary behavior and questions on self-rated health status. Donors were regular repeat blood donors, eligible to donate. Results Of the 2468 blood donors enrolled between July 2017 and January 2018, 1390 were repeat donors. Only 205 agreed to respond to the questionnaire. Data showed that donors followed mainly a Mediterranean diet and had more awareness to lifestyle, women more than men, in comparison with general population. The prevalence of overweight was found 50.7% in men and 16.9% in women. Conclusions Overweight and obesity are common among regular blood donors and it is more frequent in men than women. The female blood donors seem to be characterized by better knowledge on the relationship between lifestyle and health, and by a better "putting into practice" of the information possessed.

Highlights • SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) and multiple organ failure until death. • Myocarditis, acute myocardial infarction, arrhythmias thromboembolism, and disseminated intravascular coagulation (DIC) are the main complications in patients with cardiovascular comorbidities. • SARSCoV-2 can worsen the clinical status of patients with comorbidities especially pre-existing cardiovascular diseases and this may interfere with therapies., A novel coronavirus SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) with cardiovascular and multiple organ failure till death. The main mechanisms of virus internalization and interaction with the host are down-regulation or upregulation of the ACE2 receptor, the surface glycoprotein competition mechanism for the binding of porphyrin to iron in heme formation as well as interference with the immune system. The interference on renin–angiotensin–aldosterone system (RAAS) activation, heme formation, and the immune response is responsible for infection diffusion, endothelial dysfunction, vasoconstriction, oxidative damage and releasing of inflammatory mediators. The main pathological findings are bilateral interstitial pneumonia with diffuse alveolar damage (DAD). Because ACE receptor is also present in the endothelium of other districts as well as in different cell types, and as porphyrins are transporters in the blood and other biological liquids of iron forming heme, which is important in the assembly of the hemoglobin, myoglobin and the cytochromes, multiorgan damage occurs both primitive and secondary to lung damage. More relevantly, myocarditis, acute myocardial infarction, thromboembolism, and disseminated intravasal coagulation (DIC) are described as complications in patients with poor outcome. Here, we investigated the role of SARSCoV-2 on the cardiovascular system and in patients with cardiovascular comorbidities, and possible drug interference on the heart.

The liver is not the exclusive site of glucose production in humans in the postabsorptive state. Robust data support that the kidney is capable of gluconeogenesis and studies have demonstrated that renal glucose production can increase systemic glucose production. The kidney has a role in maintaining glucose body balance, not only as an organ for gluconeogenesis but by using glucose as a metabolic substrate. The kidneys reabsorb filtered glucose through the sodium‐glucose cotransporters sodium‐glucose cotransporter (SGLT) 1 and SGLT2, which are localized on the brush border membrane of the early proximal tubule with immune detection of their expression in the tubularized Bowman capsule. In patients with diabetes mellitus, the renal maximum glucose reabsorptive capacity, and the threshold for glucose passage into the urine, are higher and contribute to the hyperglycemic state. The administration of SGLT2 inhibitors to patients with diabetes mellitus enhances sodium and glucose excretion, leading to a reduction of the glycosuria threshold and tubular maximal transport of glucose. The net effects of SGLT2 inhibition are to drive a reduction in plasma glucose levels, improving insulin secretion and sensitivity. The benefit of SGLT2 inhibitors goes beyond glycemic control, since inhibition of renal glucose reabsorption affects blood pressure and improves the hemodynamic profile and the tubule glomerular feedback. This action acts to rebalance the dense macula response by restoring adenosine production and restraining renin‐angiotensin‐aldosterone activation. By improving renal and cardiovascular function, we explain the impressive reduction in adverse outcomes associated with heart failure supporting the current clinical perspective.

Network Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein–protein interaction networks, correlation‐based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approaches to Omics Big Data (including genetics, epigenetics, transcriptomics, metabolomics, and proteomics) using computational biology tools and, thereby, has the potential to provide improvements in the diagnosis, prognosis, and treatment of complex diseases. We discuss briefly the types of molecular data that are used in molecular network analyses, survey the analytical methods for inferring molecular networks, and review efforts to validate and visualize molecular networks. Successful applications of molecular network analysis have been reported in pulmonary arterial hypertension, coronary heart disease, diabetes mellitus, chronic lung diseases, and drug development. Important knowledge gaps in Network Medicine include incompleteness of the molecular interactome, challenges in ideNetwork Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein–protein interaction networks, correlation‐based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approaches to Omics Big Data (including genetics, epigenetics, transcriptomics, metabolomics, and proteomics) using computational biology tools and, thereby, has the potential to provide improvements in the diagnosis, prognosis, and treatment of complex diseases. We discuss briefly the types of molecular data that are used in molecular network analyses, survey the analytical methods for inferring molecular networks, and review efforts to validate and visualize molecular networks. Successful applications of molecular network analysis have been reported in pulmonary arterial hypertension, coronary heart disease, diabetes mellitus, chronic lung diseases, and drug development. Important knowledge gaps in Network Medicine include incompleteness of the molecular interactome, challenges in identifying key genes within genetic association regions, and limited applications to human diseasesntifying key genes within genetic association regions, and limited applications to human diseases

Hyperglycaemia can strongly alter the epigenetic signatures in many types of human vascular cells providing persistent perturbations of protein–protein interactions both in micro- and macro-domains. The establishment of these epigenetic changes may precede cardiovascular (CV) complications and help us to predict vascular lesions in diabetic patients. Importantly, these epigenetic marks may be transmitted across several generations (transgenerational effect) and increase the individual risk of disease. Aberrant DNA methylation and imbalance of histone modifications, mainly acetylation and methylation of H3, represent key determinants of vascular lesions and, thus, putative useful biomarkers for prevention and diagnosis of CV risk in diabetics. Moreover, a differential expression of some micro-RNAs (miRNAs), mainly miR-126, may be a useful prognostic biomarker for atherosclerosis development in asymptomatic subjects. Recently, also environmental-induced chemical perturbations in mRNA (epitranscriptome), mainly the N6-methyladenosine, have been associated with obesity and diabetes. Importantly, reversal of epigenetic changes by modulation of lifestyle and use of metformin, statins, fenofibrate, and apabetalone may offer useful therapeutic options to prevent or delay CV events in diabetics increasing the opportunity for personalized therapy. Network medicine is a promising molecular-bioinformatic approach to identify the signalling pathways underlying the pathogenesis of CV lesions in diabetic patients. Moreover, machine learning tools combined with tomography are advancing the individualized assessment of CV risk in these patients. We remark the need for combining epigenetics and advanced bioinformatic platforms to improve the prediction of vascular lesions in diabetics increasing the opportunity for CV precision medicine.

Transition from stage C to stage D of heart failure (HF) represents an irreversible process toward end-stage disease. Crucial interventions to be adopted in the attempt to interfere with this process are represented by the identification of patients at high risk to develop HF progression and by an effective and prompt management. Markers of worse prognosis and disease progression are well established and include recurrence of HF decompensation, intolerance to the neurohormonal standard pharmacological treatment, and resistance to loop diuretics. In addition, both NT-proBNP and sympathetic nervous system (SNS) overdrive are strong predictors of adverse clinical outcome and allow to identify high-risk HF patients even in the presence of mild symptoms. To counteract the deleterious effects of the SNS activation, new strategies such as a new drug combining angiotensin receptor and neprilysin inhibition and baroreceptor stimulation therapy (BAT) have been investigated. Inability to properly counteract the SNS overdrive leads to acute HF decompensation by different mechanisms. The leading ones are represented by the progressive sodium and water retention with fluid overload and by the blood volume redistribution between splanchnic and non-splanchnic regions. The correct understanding of these mechanisms, together with the availability of new therapeutic options such as peritoneal ultrafiltration, represent the rationale but not infrequently overlooked therapeutic options to improve congestion management in HF patients.

Heart failure (HF) management is challenging due to high clinical heterogeneity of this disease which makes patients responding differently to evidence-based standard therapy established by the current reductionist approach. Better understanding of the genetic and epigenetic interactions may clarify molecular signatures underlying maladaptive responses in HF, including metabolic shift, myocardial injury, fibrosis, and mitochondrial dysfunction. DNA methylation, histone modifications and micro-RNA (miRNAs) may be major epigenetic players in the pathogenesis of HF. DNA hypermethylation of the kruppel-like factor 15 (KLF15) gene plays a key role in switching the failing heart from oxidative to glycolytic metabolism. Moreover, hypomethylation at H3K9 promoter level of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) genes also leads to reactivation of fetal genes in man. The role of miRNAs has been investigated in HF patients undergoing heart transplantation, for whom miR-10a, miR-155, miR-31, and miR-92 may be putative useful prognostic biomarkers. Recently, higher RNA methylation levels have been observed in ischemic human hearts, opening the era of "epitranscriptome" in the pathogenesis of HF. Currently, hydralazine, statins, apabetalone, and omega-3 polyunsatured fatty acids (PUFA) are being tested in clinical trials to provide epigenetic-driven therapeutic interventions. Moreover, network-oriented analysis could advance current medical practice by focusing on protein-protein interactions (PPIs) perturbing the "cardiac" interactome. In this review, we provide an epigenetic map of maladaptive responses in HF patients. Furthermore, we propose the "EPi-transgeneratIonal network mOdeling for STratificatiOn of heaRt Morbidity" (EPIKO-STORM), a clinical research strategy offering novel opportunities to stratify the natural history of HF.

Early identification of coronary atherosclerotic pathogenic mechanisms is useful for predicting the risk of coronary heart disease (CHD) and future cardiac events. Epigenome changes may clarify a significant fraction of this “missing hereditability”, thus offering novel potential biomarkers for prevention and care of CHD. The rap-idly growing disciplines of systems biology and network science are now poised to meet the fields of precision medicine and personalized therapy. Network medicine integrates standard clinical recording and non-invasive, advanced cardiac imaging tools with epigenetics into deep learning for in-depth CHD molecular phenotyping. This approach could potentially explore developing novel drugs from natural compounds (i.e. polyphenols, folic acid) and repurposing current drugs, such as statins and metformin. Several clinical trials have exploited epigenetic tags and epigenetic sensitive drugs both in primary and secondary prevention. Due to their stability in plasma and easiness of detection, many ongoing clinical trials are focused on the evaluation of circulating miRNAs (e.g. miR-8059 and miR-320a) in blood, in association with imaging parameters such as coronary calcifications and stenosis degree detected by coronary computed tomography angiography (CCTA), or functional parameters pro-vided by FFR/CT and PET/CT. Although epigenetic modifications have also been prioritized through network based approaches, the whole set of molecular interactions (interactome) in CHD is still under investigation for primary prevention strategies.

Background Endothelial cells arise from endothelial progenitor cells (EPCs), which reside in bone marrow vascular niches, and are classified according to specific functional differences. Oxidative stress and inflammation lead to endothelial dysfunction that is a critical event in the initiation and progression of atherosclerotic plaques. Patients with chronic renal failure frequently show endothelial dysfunction and are at a greatly increased risk of developing atherosclerosis. Owing to their ability to partially restore vascular damage, both the number and functional changes in EPCs may be considered as useful prognostic biomarkers of cardiovascular events in hemodialysis (HD) patients. Purpose This study investigated EPC features and several biomarkers of systemic vascular inflammation and carotid atherogenesis in hemodialysis (HD) patients. Methods We studied 104 HD patients (males=55 and females 49, mean age: 51±12 years) and 40 healthy controls (males=20/females=20; mean age: 52±11 years). Isolated EPCs were cultured in the fibronectin-covered culture dishes and counted. EPC markers were studied by flow cytometry (FACS) by using anti-CD34, anti-CD133 and anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibodies. Serum levels of intercellular cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), IL-6, TNF-α, and asymmetric dimethyl-arginine (ADMA) were measured by ELISA method. Carotid intima-media thickness (CIMT) and ratio (CIMR) were also evaluated. Results In our experimental conditions, EPC number was decreased in HD patients when compared to controls (p Conclusions Our study shows that EPC number was decreased in HD patients and it was associated with systemic inflammation. TNF-α could activate inhibitory actions on EPC in HD patients. A significant relationship was present between ICAM/VCAM and carotid atherosclerosis, while this was not evident with EPC number. These pathogenic mechanisms can contribute to the high incidence of cardiovascular diseases in HD patients. However, further larger studies should investigate this working hypothesis.

Background Although advances in diagnosis, treatment and prognosis, coronary heart disease (CHD) is still the most prevalent cause of mortality and morbidity worldwide. Thus, there is still the need to identify both novel diagnostic and prognostic biomarkers to improve the clinical decision-making and help to stratify patients for early preventive treatment. Epigenetic-sensitive mechanisms may be related both to pathogenesis and prognosis of CHD. Among the epigenetic hallmarks, microRNAs (miRNAs), acting as flexible modulators of gene expression, could represent attractive candidate biomarkers useful in clinical practice. Purpose We prospectively investigated the expression pattern of circulating miRNAs in patients undergoing Cardiac Computed Tomography (CCT) for suspected CHD (n=95) with the aim to integrate molecular findings with morphological and clinical parameters derived by CCT. Methods CCT was performed with a third-generation dual source multidetector computed tomography scanner. Peripheral venous blood samples were collected into EDTA after a 12 h fasting in the same day of CCT, before imaging execution and the levels of 42 selected plasmatic miRNAs were analyzed by qRT-PCR. Results Let-7c-5p, miR-765, miR-483-5p, miR-31-5p and miR-206 were upregulated in CHD patients (n=66) vs healthy subjects HS (n=29) as well as let-7c-5p, miR-765, miR- 483-5p showed higher expression in obstructive CHD (n=36) compared to no obstructive CHD patients (n=66). In addition, miR-93-5p and miR-433-3p showed an upregulation in patients with critical coronary stenosis. Multivariate regression analysis demonstrated that miR-765, miR-31-5p and miR-206 were independently associated with CHD also in combination with Framingham risk score. Relevantly, miR-765, miR-93-5p and miR-433-3p were obstructive CHD predictors. ROC curve analysis also revealed a good performance for miR-765, miR-93-5p and miR-433-3p on predicting CHD severity. Circulating microRNA expression Conclusions Our study represents a combined epigenetic/imaging approach useful to support the diagnosis and prediction of CHD. Acknowledgement/Funding Italian Ministry of Health grants: “Giovani Ricercatori 2011-12” (project code GR-2011-02349436) and “Ricerca Corrente 2018”

Background How metabolic impairment leads to cardiac dysfunction in diabetics is unknown. A recent theory, derived mainly from rodent models, involves lipid over-storage to cardiomyocytes. Previous human study demonstrated cardiac steatosis on explanted hearts of diabetics with heart failure. However, this study did not provide any evidence about the effects of diabetes milieu on implanted non-diabetic heart. Purpose We evaluated intramyocyte lipid infiltration in explanted heart of type 2 diabetics with end-stage heart failure. Moreover, we studied the effects of diabetic milieu on myocyte lipid infiltration and cardiac function of non-diabetic implanted hearts in type 2 diabetics one year after heart transplantation (HTx). Methods We conducted a prospective study with a follow-up of 12 months on 88 patients over 18 years of age underwent first HTX. Patients with pre-HTx diabetes duration for at least 6 months were included in the study. Patients with endomyocardial biopsy (EMB) considered positive for rejection, according to International Society for Heart Lung Transplantation (ISHLT), and with post-HTx diabetes were excluded from the study. All patients underwent immunosuppression induction according ISHLT indications. All patients were followed applying internationally accepted patient evaluations (echocardiography and metabolic control) and EMB schedules. EBM from patients without rejection evidences were evaluated for intramyocyte lipid infiltration with oil red-O staining (Or-O). Results The patients were divided in diabetics (44%, age 51.6±7.2 y, diabetes duration 11±3 y) and no-diabetics (56%, 52.1±10.9 y). The patients were matched on the basis of eligibility for a HTx. Seven patients (3 diabetics and 4 no-diabetics) died in hospital. 5 (11%) patients developed post- HTx diabetes. No differences were seen in rejection (12% vs. 10%), infection (9% vs. 10%), renal dysfunction (9% vs. 8%) or mortality (7% vs. 8%). Therefore, the study population included 23 no-diabetics and 22 diabetics. After 1 year, we evidenced an impairment of both sx and dx ventricular function as showed by a significantly reduction of ejection fraction and TAPSE in diabetic patients (Figure-A). Although diastolic function not show significant differences among groups, the E/e' ratio showed lower reduction in diabetics. Or-O evidenced that 91% of diabetic and only 2 of no-diabetic explanted hearts (9%) showed intramyocyte lipid infiltration (Figure-B). Moreover, Or-O of EMB, for monitoring heart transplant during 1 year, evidenced a progressive intramyocyte lipid infiltration in 18 diabetics (81%), whereas none of no-diabetics showed intramyocyte lipid infiltration. Conclusions Our data show that almost all of the explanted diabetic hearts had intramyocyte lipid infiltration. More interesting, we observed that healthy heart transplanted in recipients with pretransplant diabetes were affected early by metabolic disorders leading to intramyocyte lipid infiltration.

Background Treatment with valsartan/sacubitril was found to be associated both with reduction in mortality risk for HF. Purpose To investigate the effect of sacubitril/valsartan on physical frailty (PF) in advanced HF patients in waiting list for heart transplantion (HT) in a two years follow-up study. Methods We enrolled 45 consecutive patients (status 2B UNOs). Patients tolerant to ACE-inhibitor and/or ARBs were treated with valsartan/sacubitril. Patients were required to have left ventricular ejection fraction (LVEF) of ≤35% and to be taking a stable dose of a β-blocker and an ACE inhibitor or an ARB for at least 4 weeks before enrollment. The dosage of sacubitril/valsartan was increased if tolerance was good. Frailty was assessed using an adapted version of Fried's Frailty Phenotype used in advanced HF patients in waiting list for transplantation. Patients were followed up until HT, device (TAH/LVAD) implant, or last follow-up visit. Results Mean NYHA class was 3.1±0.4, with 5.7% NYHA 2, 62.9% NYHA 3 and 31.4% NYHA 3B. LVEF was 25.1±6.4, VO2 max (ml/kg/min) was 10.3±2.3, cardiac index (L/min/m2) was 2.3±0.6, and NT-proBNP (pg/ml) was 4054.8±3977. At 3 months, 31.5% of patients received the target dose of 97/103 mg/BID, 31.6% the half dose (49/51mg BID) and 26.3% the low dose (24/26 mg BID) and 10.5% the half low dose (24/26 mg daily). The baseline mean value of physical frailty was 3.86±0.8, specifically 94.3% showed exhaustion, 91.4% physical inactivity, 88.6% weakness, 85.7% slowness and 28.6% loss of appetite. All patients had a frailty score ≥3. During follow-up there were no deaths. After treatment, NYHA class improved significantly (2.4±0.6 vs 3.1±0.4; p=0.002), with 5.7% NYHA 1, 48.6% NYHA 2, 42.9% NYHA 3 and 2.9% NYHA 3B (p Conclusions Our study shows an improvement in PH in patients with advanced HF in waiting list for HT after therapy with sacubitril/valsartan. These changes seem to appear very early after introduction of the treatment and to be maintained over time. The improvement in all physical domain was paralleled by VO2 max and 6-minute walking test increase. The pro-BNP-NT reduction was significant in the first month of treatment and remain quite stable in the follow-up.

Progresses in liquid-based assays may provide novel useful non-invasive indicators of cardiovascular (CV) diseases. By analysing circulating cells or their products in blood, saliva and urine samples, we can investigate molecular changes present at specific time points in each patient allowing sequential monitoring of disease evolution. For example, an increased number of circulating endothelial cells may be a diagnostic biomarker for diabetic nephropathy and heart failure with preserved ejection fraction. The assessment of circulating cell-free DNA (cfDNA) levels may be useful to predict severity of acute myocardial infarction, as well as diagnose heart graft rejection. Remarkably, circulating epigenetic biomarkers, including DNA methylation, histone modifications and non-coding RNAs are key pathogenic determinants of CV diseases representing putative useful biomarkers and drug targets. For example, the unmethylatedFAM101Agene may specifically trace cfDNA derived from cardiomyocyte death providing a powerful diagnostic biomarker of apoptosis during ischaemia. Moreover, changes in plasma levels of circulating miR-92 may predict acute coronary syndrome onset in patients with diabetes. Now, network medicine provides a framework to analyse a huge amount of big data by describing a CV disease as a result of a chain of molecular perturbations rather than a single defect (reductionism). We outline advantages and challenges of liquid biopsy with respect to traditional tissue biopsy and summarise the main completed and ongoing clinical trials in CV diseases. Furthermore, we discuss the importance of combining fluid-based assays, big data and network medicine to improve precision medicine and personalised therapy in this field.

In the past decades, myocardial infarction periacute mortality markedly declined since coronary reperfusion therapy has been adopted. Despite immediate benefits of coronary blood flow restoration, the percentage of new onset heart failure has increased over time suggesting that ischemia can run detrimental consequences beyond the immediate anoxic hit. By accepting to aggregate all types of heart failure regardless of underlying cause, the current practice did not help to shed light on the complex postischemic cardiac biology indicating that heart failure is somewhat unavoidable. In the ischemic sequel, the activated mechanisms aim to repair the infarcted zone and to compensate for the lost myocyte functions, thus allowing the heart to maintain the efficient cardiac output for vital organs. The variety of underlying preexisting conditions, as well as the multifaceted components of cardiac molecular structure, cellular state, and electrophysiological postischemic events pave the way for long-term adverse cardiac remodeling. We focused our attention on multiple factors, which include myocyte loss, hypertrophy, hyperplasia, extracellular matrix changes linked to myocardial fibrosis and scar, metabolic imbalance, as well as immunologic response occurring in the acute myocardial aftermath. Moreover, we reported both current pharmacological strategies and future perspectives that might be useful in clinical practice. Furthermore, we discussed the cardiac magnetic resonance as the most promising noninvasive imaging tool, which could be helpful in identifying the amount of myocardial damage. Despite the redundancy of molecular pathogenic mechanisms making it impossible to estimate the proportionate contributions in generating the heart failure phenotype, a deeper understanding will contribute to more customized patient management.

Aim Hyperglycemia status induces endothelial dysfunction, although the underlying pathogenic mechanisms are not fully understood. There are several studies connecting sugar/sweetened beverages to the cardiovascular disease. Currently, many sweeteners have been extensively introduced into lifestyle to normalize blood glucose levels without altering the sweet taste. However, there is growing concern for their impact on metabolic health. Methods Human endothelial cells were treated with Glucose, Fructose, Aspartame, Rebaudioside A, Stevioside, or Steviol. Morphological characteristics, in vitro angiogenesis and array gene expression were analyzed. Results High-glucose and fructose concentrations significantly decreased cell features such as angiogenic capability. Interestingly, non-caloric sweeteners did not significantly modified all cell characteristics and they did not compromised cell angiogenic ability. Array gene expression analysis revealed that the chemokine fractalkine (CX3CL1) and the enzyme transferase (HPRT1) were always significantly upregulated and downregulated respectively, after glucose and fructose treatments (P > .05), whereas they were non-differentially expressed with all the other sweeteners. Interestingly, both genes are considered as cardiovascular disease risk biomarkers. Specifically, upregulation of CX3CL1/CX3CR1 occurs in the human placenta and serum levels of the ligand are associated with markers of insulin resistance in GDM. Conclusions Differently from glucose and fructose, steviol glycosides do not damage endothelial cells. Prospective preclinical studies and clinical trials are warranted to confirm the long-term safety of such compounds.

Longevity is mainly conditioned by genetic, epigenetic and environmental factors. Different genetic modifications seem to be positively associated to longevity, including SNPs in SIRT1, APOE, FOXO3A, ACE, ATM, NOS1 and NOS2 gene. Epigenetic changes as DNA hyper- and hypo-methylation influence significantly human longevity by activating/deactivating different genes involved in physiological mechanisms. Several studies have confirmed that centenarians have a lower DNA methylation content compared to young subjects, which showed more homogeneously methylated DNA region. Also the up-regulation of miR-21 seems to be more associated with longevity in different populations of long-lived subjects, suggesting its role as potential epigenetic biomarkers. A non-pharmacological treatment that seems to contrast age-related diseases and promote longevity is represented by dietary intervention. It has been evaluated the effects of dietary restriction of both single nutrients or total calories to extend lifespan. However, in daily practice it is very difficult to guarantee adherence/compliance of the subjects to dietary restriction and at the same time avoid dangerous nutritional deficiencies. As consequence, the attention has focused on a variety of substances both drugs and natural compounds able to mime the beneficial effects of caloric restriction, including resveratrol, quercetin, rapamycin, metformin and 2-deoxy-D-glucose.

Cardiovascular diseases (CVDs) are the first cause of death in the World. Mediator (MED) is an evolutionarily conserved protein complex, which mediates distinct protein-protein interactions. Pathogenic events in MED subunit have been associated with human diseases. Novel increasing evidence showed that missense mutations in MED13L gene are associated with transposition of great arteries while MED12, MED13, MED15, and MED30, have been correlated with heart development. Moreover, MED23 and MED25 have been associated with heart malformations in humans. Relevantly, MED1, MED13, MED14, MED15, MED23, MED25, and CDK8, were found modify glucose and/or lipid metabolism. Indeed, MED1, MED15, MED25, and CDK8 interact in the PPAR- and SREBP-mediated signaling pathways. MED1, MED14 and MED23 are involved in adipocyte differentiation, whereas MED23 mediates smooth muscle cell differentiation. MED12, MED19, MED23, and MED30 regulate endothelial differentiation by alternative splicing mechanism. Thus, MEDs have a central role in early pathogenic events involved in CVDs representing novel targets for clinical prevention and therapeutic approaches.

The regenerative potential of tissues and organs could promote survival, extended lifespan and healthy life in multicellular organisms. Niches of adult stemness are widely distributed and lead to the anatomical and functional regeneration of the damaged organ. Conversely, muscular regeneration in mammals, and humans in particular, is very limited and not a single piece of muscle can fully regrow after a severe injury. Therefore, muscle repair after myocardial infarction is still a chimera. Recently, it has been recognized that epigenetics could play a role in tissue regrowth since it guarantees the maintenance of cellular identity in differentiated cells and, therefore, the stability of organs and tissues. The removal of these locks can shift a specific cell identity back to the stem-like one. Given the gradual loss of tissue renewal potential in the course of evolution, in the last few years many different attempts to retrieve such potential by means of cell therapy approaches have been performed in experimental models. Here we review pathways and mechanisms involved in the in vivo repair of cardiovascular muscle tissues in humans. Moreover, we address the ongoing research on mammalian cardiac muscle repair based on adult stem cell transplantation and pro-regenerative factor delivery. This latter issue, involving genetic manipulations of adult cells, paves the way for developing possible therapeutic strategies in the field of cardiovascular muscle repair.

A great interest in the scientific community is focused on the improvement of the cure rate in patients with bone malignancies that have a poor response to the first line of therapies. Novel treatments currently include epigenetic compounds or molecules targeting epigenetic-sensitive pathways. Here, we offer an exhaustive review of such agents in these clinical settings. Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102 (Olutasidenib), inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 (Tazemetostat) To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of Phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers.

Epigenetic mechanisms represent potential molecular routes which could bridge the gap between genetic background and environmental risk factors contributing to the pathogenesis of pulmonary diseases. In patients with chronic obstructive pulmonary disease (COPD), asthma, and pulmonary arterial hypertension (PAH), there is emerging evidence of aberrant epigenetic marks, mainly including DNA methylation and histone modifications which directly mediate reversible modifications to the DNA without affecting the genomic sequence. Post-translational events and microRNAs can be also epigenetically regulated and potentially participate to disease pathogenesis. Thus, novel pathogenic mechanisms and putative biomarkers may be detectable in peripheral blood, sputum, nasal and buccal swabs, or lung tissue. Besides, DNA methylation plays an important role during the early phases of fetal development and may be impacted by environmental exposures, ultimately influencing an individual's susceptibility to COPD, asthma, and PAH later in life. With the advances in omics platforms and the application of computational biology tools, modelling the epigenetic variability in a network framework, rather than as single molecular defects, is providing insights into the possible molecular pathways underlying the pathogenesis of COPD, asthma, and PAH. Epigenetic modifications may have clinical applications as non-invasive biomarkers of pulmonary diseases. Moreover, combining molecular assays with network analysis of epigenomic data may aid in clarifying the multi-stage transition from a "pre-disease" to "disease" state, with the goal of improving primary prevention of lung diseases and its subsequent clinical management.We describe epigenetic mechanisms known to be associated with pulmonary diseases and discuss how network analysis could improve our understanding of lung diseases.

In recent years, the seroprevalence of anti-hepatitis E virus immunoglobulins (HEV) has increased in European countries with significant variability among the different geographical areas. HEV infection is spread in a wide range of animal species of which domestic pigs and wild boar represent the main reservoirs of genotype 3 and 4 (the genotypes present also in Europe). European citizens are incidental hosts, mainly infected by direct contact or consumption of foods derived from undercooked or insufficient hygiene handling infected pork products or wild boar meat. Epidemiologically, the HEV incidence is low in humans but serological data show a high proportion of subclinical infection caused by genotypes 3 or 4. In the general population, asymptomatic infection represents a high potential risk in particular subjects such as blood component recipients or occupationally exposed workers. This review offers a landscape of the current epidemiological status of HEV infection (genotypes 1, 2, 3, 4, 7) both in European asymptomatic subjects, patients with chronic diseases, and domestic pig impact on humans. We also underline advantages/disadvantages of high sensitivity and specificity tests using for detecting viral RNA or anti-HEV antibodies.

Objectives Nitric oxide (NO) represents the most powerful endogenous molecule with vasodilator action mainly produced by endothelial nitric oxide synthase (eNOS) enzyme. Polymorphisms and epigenetic-sensitive mechanisms can modulate the expression of eNOS gene, leading to the endothelial dysfunction. This review updates on the mechanistic role of NO in the regulation of platelet activation, as well as the impact of eNOS genetic and epigenetic modifications on arterial thrombosis onset. Design A systematic search was addressed to examination of PubMed databases with the following terms: nitric oxide; arterial thrombosis; endothelial dysfunction; DNA variations; epigenetic modifications; personalized therapy; network medicine. Results G894T, -786T/C, and 4b/4a variable number tandem repeat (VNTR), are the main classes of polymorphisms harbored in eNOS gene associated to increased arterial thrombosis risk. DNA methylation, histone/non-histone modifications, and microRNA (miRNAs) can modulate eNOS gene expression. Investigators largely focused on the role of miRNAs in modulating NO production in arterial thrombosis development. In detail, miR-195, and miR-582 are inversely correlated both to eNOS and NO levels, thus suggesting novel biomarkers. Conclusion We are far from incorporating omics pathogenic data from bench to arterial thrombosis bedside. Network medicine is an emerging paradigm that ideally overcomes the current shortcomings of the reductionist approach. Despite several clinical limitations, the network-based analysis of the interactome might reveal the key nodes underlying the perturbations of the arterial thrombosis, thus advancing personalized therapy.

In pulmonary arterial hypertension (PAH), the Warburg effect (glycolytic shift) and mitochondrial fission are determinants of phenotype alterations characteristic of the disease, such as proliferation, apoptosis resistance, migration, endothelial-mesenchymal transition, and extracellular matrix stiffness. Current therapies, focusing largely on vasodilation and antithrombotic protection, do not restore these aberrant phenotypes suggesting that additional pathways need be targeted. The multifactorial nature of PAH suggests epigenetic changes as potential determinants of vascular remodeling. Transgenerational epigenetic changes induced by hypoxia can result in permanent changes early in fetal development increasing PAH risk in adulthood. Unlike genetic mutations, epigenetic changes are pharmacologically reversible, making them an attractive target as therapeutic strategies for PAH. This review offers a landscape of the most current clinical, epigenetic-sensitive changes contributing to PAH vascular remodeling both in early and later life, with a focus on a network medicine strategy. Furthermore, we discuss the importance of the application (from morphogenesis to disease onset) of molecular network-based algorithms to dissect PAH molecular pathobiology. Additionally, we suggest an integrated network-based program for clinical disease gene discovery that may reveal novel biomarkers and novel disease targets, thus offering a truly innovative path toward redefining and treating PAH, as well as facilitating the trajectory of a comprehensive precision medicine approach to PAH.

Epigenetic-sensitive mechanisms may be correlated both to pathogenesis and prognosis of coronary heart disease (CHD). We prospectively investigated some plasma circulating microRNA levels in patients undergoing cardiac computed tomography for suspected CHD (n = 95). We show that let-7c-5p, miR-765, miR-483-5p, miR-31-5p, and miR-206 were upregulated in CHD patients (n = 66) versus healthy subjects HS (n = 29); moreover, let-7c-5p, miR-765, miR- 483-5p showed higher expression in obstructive CHD (n = 36) compared to no obstructive CHD patients (n = 66). Remarkably, miR-765, miR-93-5p, and miR-433-3p showed an upregulation in patients with critical coronary stenosis. Multivariate regression analysis demonstrated that miR-765, miR-31-5p, and miR-206 were independently associated with CHD while circulating levels of miR-765 (p = 0.035), miR-433-3p (p = 0.043), and miR-93-5p (p = 0.041) were significantly higher in critical stenosis patients. Receiver operating characteristic curve analysis revealed a good performance for miR-765, miR-93-5p, and miR-433-3p on predicting CHD severity. In conclusion, our study represents a combined epigenetic/imaging approach useful to support the diagnosis and prediction of CHD.

This study sought to determine the possible detrimental effects of several low- or non-caloric sweeteners on endothelial progenitor cells (EPCs), inflammation and behavioural changes in mice. C57BL/6 male mice received low and high dose of natural and artificial sweeteners for 4 weeks. EPCs, physical and biochemical variables, inflammation and behavioural changes were evaluated. A significant reduction of about 25% of EPCs was found when mice received a moderate amount of all sweeteners (p p p p

Introduction: Stem cells (ESC, iPSC, MSC) are known to have intrinsic regenerative properties. In the last decades numerous findings have favored the development of innovative therapeutic protocols based on the use of stem cells (Regenerative Medicine/Cell Therapy) for the treatment of numerous diseases including PAD, with promising results in preclinical studies. So far, several clinical studies have shown a general improvement of the patient's clinical outcome, however they possess many critical issues caused by the non-randomized design of the limited number of patients examined, the type cells to be used, their dosage, the short duration of treatment and also their delivery strategy. Areas covered: In this context, the use of the most advanced molecular imaging techniques will allow the visualization of very important physio-pathological processes otherwise invisible with conventional techniques, such as angiogenesis, also providing important structural and functional data. Expert opinion: The new frontier of cell therapy applied to PAD, potentially able to stop or even the process that causes the disease, with particular emphasis on the clinical aspects that different types of cells involve and on the use of more innovative molecular imaging techniques now available.

Circulating biomarkers available in clinical practice do not allow to stratify patients with coronary heart disease (CHD) prior the onset of a clinically relevant event. We evaluated the methylation status of specific genomic segments and gene expression in peripheral blood of patients undergoing Cardiac Computed Tomography (CCT) for CHD (n = 95). We choose to investigate cholesterol metabolism. Methylation and gene expression of low density lipoprotein receptor (LDLR), sterol regulatory element-binding factor 2 (SREBF2) and ATP-binding cassette transporter 1 (ABCA1) were evaluated by qRT-PCR. Calcium score (CACS), stenosis degree, total plaque volume (TPV), calcified plaque volume (CPV), non-calcified plaque volume (NCPV) and plaque burden (PB) were assessed in all CHD patients (n = 65). The percentage of methylation at the specific analyzed segment of LDLR promoter was higher in CHD patients vs healthy subjects (HS) (n = 30) (p = 0.001). LDLR, SREBF2 and ABCA1 mRNAs were up-regulated in CHD patients vs HS (p = 0.02; p = 0.019; p = 0.008). SREBF2 was overexpressed in patients with coronary stenosis 50% vs subjects with stenosis

INTRODUCTION: Blood transfusion is a lifesaving procedure for patients affected by hematological diseases or hemorrhage risk. AIM: This retrospective study was aimed to evaluate clinical safety of pediatric transfusions by comparing the frequency of adverse events caused by apheretic blood components vs whole blood. METHODS: From 2011 to 2015, 214 patients (blood malignancy patients, n = 144 and thalassemic patients, n = 70) received 12 531 units of blood components. The adverse acute reactions occurred during patient hospitalization were reported to the Hemovigilance system and assessed by fitting a logistic mixed-effect model. RESULTS: A total of 33 (0.3%) adverse acute events occurred. Odds ratio (OR) of adverse events from apheresis vs whole blood transfusion adjusted by patient classification was not statistically significant (OR [95% CI], 0.75 [0.23-2.47]). CONCLUSION: Our findings showed no significant differences in the prevalence of adverse acute events between blood component collected by apheresis vs whole blood in our study center.

Epigenetic mechanisms including deoxyribonucleic acid (DNA) methylation, histone modifications (eg, histone acetylation), and microribonucleic acids (miRNAs) have gained much scientific interest in the last decade as regulators of genes expression and cellular function. Epigenetic control is involved in the modulation of inflammation and immunity, and its dysregulation can contribute to cell damage and organ dysfunction. There is growing evidence that epigenetic changes can contribute to the development of multiorgan dysfunction syndrome (MODS), a leading cause of mortality in the intensive care unit (ICU). DNA hypermethylation, histone deacetylation, and miRNA dysregulation can influence cytokine and immune cell expression and promote endothelial dysfunction, apoptosis, and end-organ injury, contributing to the development of MODS after a critical injury. Epigenetics processes, particularly miRNAs, are emerging as potential biomarkers of severity of disease, organ damage, and prognostic factors in critical illness. Targeting epigenetics modifications can represent a novel therapeutic approach in critical care. Inhibitors of histone deacetylases (HDCAIs) with anti-inflammatory and antiapoptotic activities represent the first class of drugs that reverse epigenetics modifications with human application. Further studies are required to acquire a complete knowledge of epigenetics processes, full understanding of their individual variability, to expand their use as accurate and reliable biomarkers and as safe target to prevent or attenuate MODS in critical disease.

Although venous thromboembolism (VTE) shows a polygenic nature, the crossroad between genome and environment is not fully understood. Genetics explains only a part of VTE hereditability and not defined molecular causes are found in approximately 50% of thrombotic patients. Thus, a major understanding of molecular mechanisms may clarify the missing hereditability. Concerning epigenetics, a particular histone modification (citrullination) plays a key role in increasing the rate of venous occlusive events by inducing neutrophil apoptosis and expulsion of neutrophil extra-cellular traps (NETs), which may be useful biomarkers of active disease. Moreover, an over-expression of miR-320a/b, miR-582, miR-195, miR-424-5p, and miR-532, or a down-regulation of miR495, miR-136-5p and miR-26a may improve the accuracy of VTE diagnosis. No clinical studies have focused on DNA methylation in VTE. Nowadays, no validated epigenetics biomarkers are routinely used for diagnosis and prevention of VTE. In the era of personalized therapy, several clinical trials are investigating the putative role of statins, a class of lipid-lowering epigenetic-based drugs, as additional therapeutic agents in VTE. Furthermore, single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1, and MIR133 genes can help physicians to predict individual warfarin dose requirement. Consequently, a comprehensive understanding of the mechanisms involved in the control of blood clot development is crucial to design novel therapeutic strategies. This review summarizes the current clinical concepts both in genetic and epigenetic VTE framework. Furthermore, we discuss the contribution of the innovative network medicine paradigm into advancing our knowledge about molecular underpinnings needed to support novel VTE diagnostic and therapeutic options.

Human leukocyte antigen (HLA) matching exerts a protective effect in organ transplantation, ensuring better graft function, fewer episodes of rejection, longer graft survival, and the possibility of lower immunosuppression.1, 2, 3 However, the precise influence of HLA incompatibility in heart transplants remains to be determined, and prospective HLA matching is seldom achieved. We previously demonstrated that the odds of in-hospital mortality after heart transplantation is greater in the case of HLA-DR mismatch.4 The goal of the present study was to evaluate the effect of DR mismatch on long-term mortality.

Objectives The objective of this study was to evaluate the effect on mortality of self-reported physical activity evaluated by the physical activity scale for the elderly (PASE) in elderly patients with advanced heart failure enrolled in a cardiac rehabilitation unit after heart failure decompensation (NYHA class IIIB). Methods The study prospectively enrolled 314 elderly patients (≥65 years) with heart failure in NYHA class IIIB (symptomatic with a recent history of dyspnoea at rest) consecutively admitted to cardiac rehabilitation between January 2010 and July 2011. Comprehensive geriatric assessment was performed. Physical activity was evaluated by PASE and stratified in tertiles (0–15, 16–75 and >75). Mortality was collected from September to October 2015 in 300 patients. Results The mean age was 74.5 ± 6.1 (range 65–89); 74.7% were men, 132 patients (44.0%) died during the follow-up (44.1 ± 20.7 months). Univariate analysis shows that physical activity level conducted before heart failure decompensation was inversely related to mortality (from 76.0% to 8.2%, P = 0.000). Multivariate analysis confirms that the PASE score predicts mortality independently of several demographic and clinical variables (hazard rate 0.987, 95% confidence interval (CI) 0.980–0.994, P = 0.000). Notably, when considering PASE 0–15 versus 16–75 score and PASE 0–15 versus > 75 score, the hazard rate is 4.06 (95% CI 1.67–9.84, P Conclusions Physical activity level evaluated by the PASE score is inversely related to mortality in elderly patients with advanced heart failure confirming the reduction of mortality exerted by moderate physical activity in such patients.

The identification of human leukocyte antigen (HLA) antibodies in the sera of candidates awaiting organ transplantation has evolved over time. This has been possible because of the introduction of more sensitive techniques and to the increasing focus on the structural aspects of the HLA epitopes. The use of the HLAMatchmaker algorithm in the analysis of positive sera and the verification of HLA ABC epitopes in the HLA Epitope Registry website provide new stimuli on the interpretation of antibody reactivity. The epitopes defined by eplet pairs often involve a nonself-eplet and a self-eplet (nonself-self paradigm), suggesting that the antibody response to an HLA mismatch must have an auto-reactive component. Here, we report an application of the nonself-self paradigm that provides a basis for better knowledge and interpretation of HLA-antibody reactivity in Luminex assays with single alleles.

Cardiovascular disease is still the major cause of death worldwide despite the remarkable progress in its prevention and treatment. Endothelial progenitor cells (EPCs) have recently emerged as key players of vascular repair and regenerative medicine applied to cardiovascular disease. A large amount of effort has been put into discovering the factors that could aid or impair the number and function of EPCs, and also into characterizing these cells at the molecular level in order to facilitate their therapeutic applications in vascular disease. Interestingly, the major cardiovascular risk factors have been associated with reduced number and function of EPCs. The bacterial contribution to cardiovascular disease represents a long-standing controversy. The discovery that Bartonella henselae can infect and damage EPCs revitalizes the enduring debate about the microbiological contribution to atherosclerosis, thus allowing the hypothesis that this infection could impair the cardiovascular regenerative potential and increase the risk for cardiovascular disease. In this review, we summarize the rationale suggesting that Bartonella henselae could favour atherogenesis by infecting and damaging EPCs, thus reducing their vascular repair potential. These mechanisms suggest a novel link between communicable and non-communicable human diseases, and put forward the possibility that Bartonella henselae could enhance the susceptibility and worsen the prognosis in cardiovascular disease.

Hemoglobinopathies are inherited disorders characterized by anomalies of structure, function or production of globin chains. From conception to adulthood, the different expressions over time of the various globin chains depend on the activation/deactivation of different globin genes through methylation and chromatin remodeling processes. The most significant clinical disorders are β-thalassemia and sickle cell disease. The clinical management of these disorders engages regular blood transfusions. Another therapy is represented by allogeneic hematopoietic cells transplantation. There are several studies based on the innovative therapeutic strategies that involve some epigenetic mechanisms focused on the reactivation of γ-globin gene expression. The induction of fetal hemoglobin expression in adulthood is an effective therapy for these disorders. Particularly interesting are the recent data on miRNAs showing the interaction of these molecules with different transcription factors such as MYB, KLF, BCL11A and SOX6. The aim of this review was to report an update on the dynamic epigenetic modifications as targets for therapy in hemoglobinopathies.

Serological assays are still considered the most useful tests in the diagnosis of syphilis. Since no single serological assay is able to provide a satisfactory result, in our laboratory we have evaluated the usefulness of a commercially-available immunoblot to diagnose syphilis infection among blood donors. From October 2012 to June 2013, 4572 blood donors were screened for syphilis with an automated chemiluminescent microparticle immunoassay (CMIA). To confirm the presence of treponemal antibodies, CMIA-reactive sera were tested by standard Treponema pallidum haemagglutination assay (TPHA). In addition, an alternative confirmatory test – the immunoblot INNO-LIA assay was introduced in our laboratory. Since two additional positives among CMIA-reactive-TPHA-negative samples were found, we concluded that the INNO-LIA immunoblot allowed a better detection of syphilis compared to TPHA. A confirmatory strategy based on the use of two treponemal assays could meet the screening requirements for blood donors as well as in our centre.

The search of HLA antibodies is currently more accessible by solid-phase techniques (Luminex) in the immunized patients leading to an expansion of the antibody patterns. The aim of this study was to investigate low median fluorescence intensity value in unexpected reactivity patterns. Here, we performed HLAMatchmaker analyses to evaluate the potential functional epitopes that can elicit HLA-specific alloantibody responses in a pregnancy-sensitized woman with an epitope defined by the 82LR. Surprisingly, in according to the registry of HLA epitopes, we found that 82LR epitope covered all allelic specificities of our unexpected antibody patterns, shared between Bw4-positive HLA-B antigen and HLA-A23, -A24, -A25 and -A32. This finding is consistent with the verification of HLA ABC epitope recorded in the website-based HLA Epitope Registry and addresses the importance of determining HLA antibody epitope-specificities on Luminex technique-dependent antibody reactivity. 2015 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.

Genome-wide association studies have revealed several genes predisposing to autoimmunity, however, concordance rates in monozygotic twins are significantly below 50% for several autoimmune diseases. The limited presence of a strong genetic association only in some patients supports that other non-genetic mechanisms are active in these pathologies. Epigenetic modifications such as DNA methylation, histone modification, and microRNA signaling regulate gene expression and are sensitive to external stimuli and they might be as bridging between genetic and environmental factors. Some evidence has highlighted the involvement of epigenetic alterations in the pathogenesis of various autoimmune diseases giving rise to great expectations among clinicians and researchers. The direct role of these alterations in the initiation/progression of autoimmune diseases is still unclear. The knowledge in depth of these pathogenic and epigenetic mechanisms will increase the possibility of the control and/or prevention of autoimmune diseases through the use of drugs that target epigenetic pathways. Moreover, we could use epigenetic-related biomarkers to follow this complicated framework (for example H3K4me3 and miRNA-155 are among those proposed biomarkers). This article reviews current understanding of the epigenetic involvement in the field of autoimmune diseases especially in systemic lupus erythematosus, rheumatoid arthritis, sclerosis multiple and type 1 diabetes.

Background Patients with end-stage liver disease (ESLD) have a compromised nutritional status because of the liver crucial role in regulating metabolic homeostasis and energy balance. Data sources A systematic review of literature based on extensive relevant articles published from 2001 to 2017 in English in PubMed database was performed by searching keywords such as liver disease, non-alcoholic liver disease, alcoholic liver disease, malnutrition, epigenetics, gut microbiota, and probiotics. Results Liver transplantation would be one eligible therapy for ESLD patients, even if, the clinical outcome is negatively influenced by malnutrition and/or infections. The malnutrition is a condition of nutrient imbalance with a high incidence in ESLD patients. An accurate evaluation of nutritional status could be fundamental for reducing complications and prolonging the survival of ESLD patients including those undergoing liver transplantation. In addition, the interaction among nutrients, diet and genes via epigenetics has emerged as a potential target to reduce the morbidity and mortality in ESLD patients. The malnutrition induces changes in gut microbiota causing dysbiosis with a probable translocation of bacteria and/or pathogen-derived factors from the intestine to the liver. Gut microbiota contribute to the progression of chronic liver diseases as well as hepatocellular carcinoma. The administration of probiotics modulating gut microbiota could improve all chronic liver diseases. Conclusions This review provides an update on malnutrition status linked to epigenetics and the potential benefit of some probiotics on the management of ESLD patients. In support of this view and to reveal the constant and growing interest in this field, some clinical trials are reported.