MicroRNA profiling of paediatric AML with FLT-ITD or MLL-rearrangements: Expression signatures and in vitro modulation of miR-221-3p and miR-222-3p with BRD4/HATs inhibitors.

Novel therapeutic strategies are needed for paediatric patients affected by Acute Myeloid Leukaemia (AML), particularly for those at high-risk for relapse. MicroRNAs (miRs) have been extensively studied as biomarkers in cancer and haematological disorders, and their expression has been correlated to the presence of recurrent molecular abnormalities, expression of oncogenes, as well as to prognosis/clinical outcome. In the present study, expression signatures of different miRs related both to presence of myeloid/lymphoid or mixed-lineage leukaemia 1 and Fms like tyrosine kinase 3 internal tandem duplications rearrangements and to the clinical outcome of paediatric patients with AML were identified. Notably, miR-221-3p and miR-222-3p resulted as a possible relapse-risk related miR. Thus, miR-221-3p and miR-222-3p expression modulation was investigated by using a Bromodomain‑containing protein 4 (BRD4) inhibitor (JQ1) and a natural compound that acts as histone acetyl transferase inhibitor (curcumin), alone or in association, in order to decrease acetylation of histone tails and potentiate the effect of BRD4 inhibition. JQ1 modulates miR-221-3p and miR-222-3p expression in AML with a synergic effect when associated with curcumin. Moreover, changes were observed in the expression of CDKN1B, a known target of miR-221-3p and miR-222-3p, increase in apoptosis and downregulation of miR-221-3p and miR-222-3p expression in CD34+ AML primary cells. Altogether, these findings suggested that several miRs expression signatures at diagnosis may be used for risk stratification and as relapse prediction biomarkers in paediatric AML outlining that epigenetic drugs, could represent a novel therapeutic strategy for high-risk paediatric patients with AML. For these epigenetic drugs, additional research for enhancing activity, bioavailability and safety is needed

Switching cytolytic nanopores into antimicrobial fractal ruptures by a single side chain mutation

Disruption of cell membranes is a fundamental host defense response found in virtually all forms of life. The molecular mechanisms vary but generally lead to energetically favored circular nanopores. Here, we report an elaborate fractal rupture pattern induced by a single side-chain mutation in ultrashort (8–11-mers) helical peptides, which otherwise form transmembrane pores. In contrast to known mechanisms, this mode of membrane disruption is restricted to the upper leaflet of the bilayer where it exhibits propagating fronts of peptide-lipid interfaces that are strikingly similar to viscous instabilities in fluid flow. The two distinct disruption modes, pores and fractal patterns, are both strongly antimicrobial, but only the fractal rupture is nonhemolytic. The results offer wide implications for elucidating differential membrane targeting phenomena defined at the nanoscale

EXERCISE-INDUCED MUSCLE DAMAGE (EIMD) AND NATURAL POLYPHENOLS

Although it is well known that physical activity contributes to a healthy life style, unaccustomed exercise or high eccentric muscle contraction lead to exercise-induced muscle damage (EIMD) inducing pains and affecting exercise training in athletes. Several approaches, including nutrition based on a polyphenols-rich diet or supplementation, have been showed to prevent and/or reduce muscle damage in athletes after physical exercise. In this manuscript we addressed the effect of natural polyphenols as antioxidant and anti- inflammatory agent that are used on recovery of EIMD in athletes

EXERCISE-INDUCED MUSCLE DAMAGE (EIMD) AND NATURAL POLYPHENOLS

Although it is well known that physical activity contributes to a healthy life style, unaccustomed exercise or high eccentric muscle contraction lead to exercise-induced muscle damage (EIMD) inducing pains and affecting exercise training in athletes. Several approaches, including nutrition based on a polyphenols-rich diet or supplementation, have been showed to prevent and/or reduce muscle damage in athletes after physical exercise. In this manuscript we addressed the effect of natural polyphenols as antioxidant and antiinflammatory agent that are used on recovery of EIMD in athletes

Chronic kidney disease is associated with increased risk of venous thromboembolism recurrence

Introduction It is currently unclear whether chronic kidney disease (CKD) and the decrease in renal function can influence the risk of venous thromboembolism (VTE) recurrence. Materials and methods We performed an ambispective observational study on 409 patients with a previous episode of VTE. All the patients were included in the retrospective analysis whereas a subgroup of 260 individuals, without history of recurrence and that stopped oral anticoagulation, were then followed-up for a mean of 52.3 \ub1 20.7 months. Results At the enrollment, subjects with history of recurrent VTE were prevalently male with higher blood pressure and lower eGFR. Prevalence of CKD (defined as eGFR < 60 ml/min/1.73 m2) was higher in patients with previous VTE recurrence with an adjusted OR of 5.69 (IC95% 2.17\u201314.90, p < 0.001) compared to patients with normal eGFR. Similar findings were obtained from the prospective study where an adjusted 5.32 HR for VTE recurrence was seen in patients with CKD compared to subjects with normal renal function (IC95% 1.49\u201318.95, p = 0.010). An increase in the risk of recurrent VTE was also observed in patients with mild decrease in renal function (eGFR 60\u201390 vs 65 90 ml/min/1.73 m2 adjusted HR 2.84, IC95% 1.13\u20137.11, p = 0.025). Moreover, a multivariate Cox regression analysis including eGFR as continuous variable showed that renal function decrease was independently associated with the risk of VTE recurrence (p = 0.001). Conclusions CKD and mild decrease in renal function are associated with a significant increase in the risk of recurrent VTE. \ua9 2017 Elsevier Lt

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BACKGROUND: The link between serum uric acid (SUA) and the risk of cardiovascular disease is well established. However, the impact of SUA levels on the risk of venous thromboembolism (VTE) recurrence is unknown.OBJECTIVES: To investigate the association between SUA and the risk of VTE recurrence.PATIENTS AND METHODS: We performed a monocenter, prospective study on 280 patients with a previous episode of VTE that completed the oral anticoagulant period. SUA levels at enrollment were correlated with the risk of VTE recurrence (mean follow-up 71.1\ub129.2months).RESULTS: Patients were stratified according to SUA tertiles distribution at baseline (tertiles cut-off: I 644.37mg/dL, II 4.38--5.54mg/dL, III 655.55mg/dL). Fifty episodes of VTE recurrence occurred during the follow-up and Kaplan-Meier survival analysis showed that subjects in the lower tertile of SUA distribution had significantly lower risk of future VTE recurrence (P=.003). No differences were seen among patients belonging to the second and the third tertile of SUA distribution. A multivariate Cox regression analysis showed that higher tertiles of SUA distribution had about three-fold increase in the risk of VTE recurrence as compared to subjects with SUA 644.37, independently from potential confounders (hazard ratio [HR] 3.04, 95% confidence interval [CI] 1.15--8.05 P=.025). Moreover, we observed that the adjusted hazard of VTE recurrence increased by 30% for each additional unit of SUA (mg/dL; HR 1.30, 95% CI 1.01--1.22, P=.040).CONCLUSION: Elevated SUA levels are associated with increased risk of future VTE recurrence independently from traditional risk factors

PERCEIVED STRESS AND HEPATIC PARAMETERS

Introduction: The aim of the study is to evaluate work-related subjective stress in a group of employees, of both sexes, operating in the healthcare and welfare, through the administration of a questionnaire (HSE "Indicator Tool"), specifically developed and officially validated, and to analyze any possible correlations between stress levels taken from the questionnaire scores and the concentrations of three main hepatic parameters (GOT, GPT, GGT). Materials and Methods: We studied a final sample of 232 subjects (143 males and 89 females) operating in the health and welfare sector. For research purposes during the medical examination each subject underwent the HSE indicator tool, a collection of information about relevant clinical and medical history and a venous blood sample for the assay of GOT, GPT and GGT. All questionnaires were analyzed using special software provided by the HSE. The results obtained from the questionnaires were statistically compared with the blood concentrations of hepatic parameters. Results: The dimensions found to be critical, associated with a stressful condition (yellow area) or a highly stressful condition (red area), are: managers support, colleagues support, quality of relationships and changes. The Pearson’s correlation showed a statistically significant negative correlation (p &lt;0.05) between the mean values of all the critical dimensions and the concentrations of the hepatic parameters, both on the total sample and after subdivision by gender. These results were confirmed in the multiple linear regression analysis, which indicated that the critical dimensions are the main significant variables contributing to the liver parameters alterations. Discussion: Preliminary results indicate that a critical perception of stress at work can be statistically associated with increases in mean concentrations of GOT, GPT and GGT in a working asymptomatic population. These results provide a starting point for future studies on this topic, to a greater definition of the link between stress and liver injury, to confirm the effects on the parameters of liver injury (GOT, GPT, GGT) and to investigate possible correlations with the cholestasis parameters (bilirubin, alkaline phosphatase) and serum albumin

Testicular torsion during the COVID-19 pandemic: Results of a multicenter study in northern Italy

The literature reported an increased avoidance of the Emergency Department (ED) during COrona VIrus Disease 19 (COVID-19) pandemic, causing a subsequent increase of morbidity and mortality for acute conditions. Testicular torsion is a surgical emergency, which can lead to the loss of the affected testicle if a delayed treatment occurs. As testicular loss is time-related, outcome was hypothesized to be negatively affected by the pandemic

Low CD34+cells, high neutrophils and the metabolic syndrome are associated with an increased risk of venous thromboembolism

The relationship between MetS (metabolic syndrome), levels of circulating progenitor/immune cells and the risk of VTE (venous thromboembolism) has not yet been investigated. We studied 240 patients with previous VTE and 240 controls. The presence of MetS was identified according to NCEP ATP III guidelines and flow cytometry was used to quantify circulating CD34+ cells. VTE patients showed higher BMI (body mass index), waist circumference, triacylglycerol (triglyceride) levels, blood glucose, hs-CRP (high-sensitivity C-reactive protein) and lower HDL-C (high-density lipoprotein cholesterol) levels. The prevalence of MetS was significantly higher in VTE (38.3%) than in control individuals (21.3%) with an adjusted OR (odds ratio) for VTE of 1.96 (P=0.002). VTE patients had higher circulating neutrophils (P<0.0001), while the CD34+ cell count was significantly lower among patients with unprovoked VTE compared with both provoked VTE (P=0.004) and controls (P=0.003). Subjects were also grouped according to the presence/absence of MetS (MetS+ or MetS-) and the level (high/low) of both CD34+ cells and neutrophils. Very high adjusted ORs for VTE were observed among neutrophils_high/MetS+ (OR, 3.58; P<0.0001) and CD34+_low/MetS+ (OR, 3.98; P<0.0001) subjects as compared with the neutrophils_low/MetS- and CD34+_high/MetS- groups respectively. In conclusion, low CD34+ blood cell count and high circulating neutrophils interplay with MetS in raising the risk for venous thromboembolic events