Search

Background/Objectives : Endometrial cancer (EC) is the second most frequent gynecological malignant tumor in postmenopausal women. Pathogenic mechanisms related to the onset and development of the disease are still unknown. To identify dysregulated proteins associated with EC we exploited a combined in vitro/in silico approach analyzing the proteome of exosomes with advanced MS techniques and annotating their results by using Chymeris1 AI tools. Methods : To this aim in this pilot study, we performed a deep proteomics analysis with high resolution MS (HRMS), advanced computational tools and western blotting for proteomics data validation. Results : That allowed us to identify 3628 proteins in serum albumin-depleted exosomes from 10 patients with EC compared to 10 healthy controls. This is the largest number of proteins identified in EC serum EVs. After quantification and statistical analysis, we identified 373 significantly ( p < 0.05) dysregulated proteins involved in neutrophil and platelet degranulation pathways. A more detailed bioinformatics analysis revealed 61 dysregulated enzymes related to metabolic and catabolic pathways linked to tumor invasion. Through this analysis, we identified 49 metabolic and catabolic pathways related to tumor growth. Conclusions : Altogether, data shed light on the metabolic pathways involved in tumors. This is very important for understanding the metabolism of EC and for the development of new therapies.

Despite notable advancements in cardiovascular medicine, morbidity and mortality rates associated with myocardial infarction (MI) remain high. The unfavourable prognosis and absence of robust post-MI protocols necessitate further intervention. In this comprehensive review, we will focus on well-established and novel biomarkers that can provide insight into the processes that occur after an ischemic event. More precisely, during the follow-up, it is of particular importance to monitor biomarkers that indicate an increase in myocardial stretch and stress, damage and death of cardiomyocytes, remodelling of the extracellular matrix, oxidative stress, and inflammation. This enables the identification of abnormalities in a timely manner, as well as the capacity to respond promptly to any changes. Therefore, we would like to highlight the importance of well-known markers, such as natriuretic peptides, high-sensitivity troponins, soluble suppression of tumorigenicity 2, galactin-3, C-reactive protein, and interleukins in post-MI settings, as well as biomarkers such as adrenomedullin, growth differentiation factor-15, insulin-like growth factor binding protein 7, amyloid beta, vitamin D, trimethylamine N-oxide, and advanced glycation end-products that recently emerged in the cardiovascular filed. The implementation of novel post-MI protocols, which encompass the monitoring of the aforementioned biomarkers deemed pertinent, in conjunction with adherence to established cardiac rehabilitation programmes, along with the already well-established therapeutic strategies and control of cardiovascular risk factors, has the potential to markedly enhance patient outcomes and reduce the elevated level of morbidity and mortality.

There is increasing evidence of cardiac involvement in COVID-19 cases, with a broad range of clinical manifestations spanning from acute life-threatening conditions such as ventricular dysrhythmias, myocarditis, acute myocardial ischemia and pulmonary thromboembolism to long-term cardiovascular sequelae. In particular, acute myocarditis represents an uncommon but frightening complication of SARS-CoV-2 infection. Even if many reports of SARS CoV-2 myocarditis are present in the literature, the majority of them lacks histological confirmation of cardiac injury. Here, we report a case of a young lady, who died suddenly a few days after testing positive for SARS-CoV-2, whose microscopic and genetics features suggested a direct cardiac involvement compatible with fulminant myocarditis.

Objective: To evaluate humoral and T-cell cellular-mediated immune response after three doses of SARS-CoV-2 mRNA vaccines in patients with systemic lupus erythematosus (SLE) under Belimumab., Patients and Methods: 12 patients on Belimumab and 13 age-matched healthy volunteers were recruited. Patients were in remission or in low disease activity, and they were taking no corticosteroids or only low doses. None of the patients and controls had detectable anti-SARS-CoV-2 antibodies due to previous exposure to the virus. All the patients received three doses of mRNA anti-SARS-CoV-2 vaccines and the humoral and cellular-mediated response were tested 4 weeks after the second dose (T0), 6 months after the second dose (T1) and 4 weeks after the third dose (T2). Comparison with the control group was performed at time T0 (i.e., 4 weeks after the second dose). Total anti-SARS-CoV-2 RBD antibodies were analyzed using a diagnostic assay, while cellular-mediated response was evaluated using the interferon-gamma release assay (IGRA)., Results: A humoral response was documented in all the patients at T0 (median 459; IQR 225.25-758.5), but the antibody titer significantly declined from T0 to T1 (median 44.7; IQR: 30.3-202; p = 0.0066). At T2, the antibody titer significantly increased from T1 (median 2500; IQR: 2500-2500), and it was not different from T0 (respectively p < 0.0001, p = 0.66). Cellular-mediated response significantly declined from T0 to T1 ( p = 0.003) but not from T0 to T2 ( p = 0.3). No differences were found between patients and controls at T0 as regards both humoral and cellular responses ( p = 1.0 and p = 0.09 for humoral and cellular responses, respectively)., Conclusion: The third dose of mRNA COVID-19 vaccine can restore both humoral and cellular immune response in SLE patients on Belimumab.

Small-vessel disease (SVD), also known as microvascular endothelial dysfunction, is a disorder with negative consequences for various organs such as the heart and brain. Impaired dilatation and constriction of small vessels in the heart lead to reduced blood flow and ischemia independently of coronary artery disease (CAD) and are associated with major cardiac events. SVD is usually a silent form of subcortical vascular burden in the brain with various clinical manifestations, such as silent-lacunar-ischemic events and confluent white-matter hyperintensities. Imaging techniques are the main help for clinicians to diagnose cardiac and brain SVD correctly. Markers of inflammation, such as C-reactive protein, tumor-necrosis-factor α, and interleukin 6, provide insight into the disease and markers that negatively influence nitric-oxide bioavailability and promote oxidative stress. Unfortunately, the therapeutic approach against SVD is still not well-defined. In the last decades, various antioxidants, oxidative stress inhibitors, and superoxide scavengers have been the target of extensive investigations due to their potential therapeutic effect, but with unsatisfactory results. In clinical practice, traditional anti-ischemic and risk-reduction therapies for CAD are currently in use for SVD treatment.

(1)Background: Chronic heart failure (CHF) contributes to the overall burden of cardiovascular disease. Early identification of at-risk individuals may facilitate the targeting of precision therapies. Plasma microRNAs are promising circulating biomarkers for their implications with cardiac pathologies. In this pilot study, we investigate the possible exploitability of circulating micro-RNAs (miRNAs) to track chronic heart failure (CHF) occurrence, and progression from NYHA class I to IV. (2)Methods: We screened 367 microRNAs using TaqMan microRNA Arrays in plasma samples from healthy controls (HC) and CHF NYHA-class I-to-IV patients (5/group). Validation was performed by singleplex assays on 10 HC and 61 CHF subjects. Differences in the expression of validated microRNAs were evaluated through analysis of covariance (ANCOVA). Associations between N-terminal pro-BNP (NT-proBNP), left ventricular end-diastolic volume (LVEDV) or peak oxygen uptake (VO2 peak) and plasma microRNA were assessed by multivariable linear regression analysis. (3)Results: Twelve microRNAs showed higher expression in CHF patients vs. HC. Seven microRNAs were associated with NT-proBNP concentration; of these, miR-423-5p was also an independent predictor of LVEDV. Moreover, miR-499-5p was a predictor of the VO2 peak. Finally, a cluster of 5 miRNAs discriminated New York Heart Association (NYHA) class-I from HC subjects. (4)Conclusions: Our data suggest that circulating miRNAs have the potential to serve as pathophysiology-based markers of HF status and progression, and as indicators of pre-symptomatic individuals.

Low-grade gliomas (LGG) are infiltrative primary brain tumors that in 70% of the cases undergo anaplastic transformation, deeply affecting prognosis. However, the timing of progression is heterogeneous. Recently, the tumor microenvironment (TME) has gained much attention either as prognostic factor or therapeutic target. Through the release of extracellular vesicles, the TME contributes to tumor progression by transferring bioactive molecules such as microRNA. The aim of the study was to take advantage of glioma-associated stem cells (GASC), an in vitro model of the glioma microenvironment endowed with a prognostic significance, and their released exosomes, to investigate the possible role of exosome miRNAs in favoring the anaplastic transformation of LGG. Therefore, by deep sequencing, we analyzed and compared the miRNA profile of GASC and exosomes obtained from LGG patients characterized by different prognosis. Results showed that exosomes presented a different signature, when compared to their cellular counterpart and that, although sharing several miRNAs, exosomes of patients with a bad prognosis, selectively expressed some miRNAs possibly responsible for the more aggressive phenotype. These findings get insights into the value of TME and exosomes as potential biomarkers for precision medicine approaches aimed at improving LGG prognostic stratification and therapeutic strategies.

Survivors after a myocardial infarction (MI), especially those with diabetes mellitus (DM),remain at high risk of further events. Identifying and treating factors that may influence survivalmay open new therapeutic strategies. We assessed the impact on prognosis of DM andhypovitaminosis D (hypovitD), alone or combined. In this prospective, observational study, 1081patients were enrolled surviving an MI and divided into four groups according to their diabetic andVitD status. The primary end-point was composite of all-cause mortality, angina/MI and heartfailure (HF). Secondary outcomes were mortality, HF and angina/MI. During a follow-up of 26.1months (IQR 6.6-64.5), 391 subjects experienced the primary end-point. Patients with DM orhypovitD had similar rate of the composite end-point. Patients with only hypovitD or DM did notdiffer regarding components of composite end-point (angina p = 0.97, HF p = 0.29, mortality p = 0.62).DM and VitD deficiency had similarly adjusted risks for primary end-point (HR 1.3, 95%CI 1.05-1.61; HR 1.3, 95% CI 1.04-1.64). The adjusted HR for primary composite end-point for patients withhypovitD and DM was 1.69 (95%CI 1.25-2.29, p = 0.001) in comparison to patients with neitherhypoD nor DM. In conclusion, DM and hypovitD, individually and synergistically, are associatedwith a worse outcome after MI.

Background: The clinical outcome of patients affected by dilated cardiomyopathy (DCM) is heterogeneous, since its pathophysiology is only partially understood. Interleukin 1β levels could predict the mortality and necessity of cardiac transplantation of DCM patients., Objective: To investigate mechanisms triggering sterile inflammation in dilated cardiomyopathy (DCM)., Methods: Hearts explanted from 62 DCM patients were compared with 30 controls, employing immunohistochemistry, cellular and molecular biology, as well as metabolomics studies., Results: Although misfolded protein accumulation and aggresome formation characterize DCM hearts, aggresomes failed to trigger the autophagy lysosomal pathway (ALP), with consequent accumulation of both p62 SQSTM1 and dysfunctional mitochondria. In line, DCM hearts are characterized by accumulation of lipoperoxidation products and activation of both redox responsive pathways and inflammasome. Consistently with the fact that mTOR signaling may impair ALP, we observed, an increase in DCM activation, together with a reduction in the nuclear localization of Transcription Factor EB -TFEB- (a master regulator of lysosomal biogenesis). These alterations were coupled with metabolomic alterations, including accumulation of branched chain amino acids (BCAAs), known mTOR activators. Consistently, reduced levels of PP2Cm, a phosphatase that regulates the key catabolic step of BCAAs, coupled with increased levels of miR-22, a regulator of PP2Cm levels that triggers senescence, characterize DCM hearts. The same molecular defects were present in clinically relevant cells isolated from DCM hearts, but they could be reverted by downregulating miR-22., Conclusion: We identified, in human DCM, a complex series of events whose key players are miR-22, PP2Cm, BCAA, mTOR, and ALP, linking loss of proteostasis with inflammasome activation. These potential therapeutic targets deserve to be further investigated.

Background: Ghrelin may exert positive effects on cardiac structure and function in heart failure (HF) patients., Methods: We assessed ghrelin levels in 266 dilated cardiomyopathy (DCM) patients and in 200 age, gender and body mass index (BMI) matched controls. Further, we evaluated the expression of ghrelin and growth hormone secretagogue-receptor (GHSR) in the myocardium of 41 DCM patients and in 11 controls., Results: DCM patients had significantly lower levels of total, acylated and unacylated ghrelin when compared to controls ( p < 0.05 for all). In controls, we observed a negative correlation of ghrelin with age, male gender and BMI. These correlations were lost in the DCM group, except for male gender. Total ghrelin was higher in patients with more recent diagnosis when compared to patients with longer duration of the DCM ( p = 0.033). Further, total ghrelin was higher in patients with lower left ventricular systolic function (<40% LVEF, vs. 40% ≤ LVEF < 49% vs. LVEF ≥ 50%: 480.8, vs. 429.7, vs. 329.5 pg/mL, respectively, p = 0.05). Ghrelin prepropeptide was expressed more in DCM patients than in controls (p = 0.0293) while GHSR was expressed less in DCM patients (p < 0.001). Furthermore, ghrelin showed an inverse correlation with its receptor (= -0.406, p = 0.009), and this receptor showed a significant inverse correlation with Interleukin-1 (= -0.422, p = 0.0103)., Conclusion: DCM duration and severity are accompanied by alterations in the ghrelin-GHSR system., Competing Interests: The authors declare no conflict of interest.

Background: Acute myocardial infarction (AMI) survivors are at risk of major adverse cardiac events and their risk stratification is a prerequisite to tailored therapeutic approaches. Biomarkers could be of great utility in this setting., Methods: We sought to evaluate the utility of the combined assessment of Galectin 3 (Gal-3) and Galectin 3 binding protein (Gal-3bp) for post-AMI risk stratification in a large, consecutive population of AMI patients. The primary outcomes were: Recurrent angina/AMI and all-cause mortality at 12 months after the index event., Results: In total, 469 patients were included. The median Gal-3bp was 9.1 μg/mL (IQR 5.8-13.5 μg/mL), while median Gal-3 was 9.8 ng/mL (IQR 7.8-12.8 ng/mL). During the 12 month follow-up, 34 patients died and 41 had angina pectoris/reinfarction. Gal-3 was associated with all-cause mortality, while Gal-3bp correlated with the risk of angina/myocardial infarction even when corrected for other significant covariates. The final multivariable model for mortality prediction included patients' age, left ventricular ejection fraction (LVEF), Gal-3, and renal function. The ROC curve estimated for this model has an area under the curve (AUC) of 0.84 (95%CI 0.78-0.9), which was similar to the area under the ROC curve obtained using the GRACE score 1-year mortality., Conclusions: The integrated assessment of Gal-3 and Gal-3bp could be helpful in risk stratification after AMI.

Soluble ST2 (sST2) has recently emerged as a promising biomarker in the field of acute cardiovascular diseases. Several clinical studies have demonstrated a significant link between sST2 values and patients' outcome. Further, it has been found that higher levels of sST2 are associated with an increased risk of adverse left ventricular remodeling. Therefore, sST2 could represent a useful tool that could help the risk stratification and diagnostic and therapeutic work-up of patients admitted to an emergency department. With this review, based on recent literature, we have built sST2-assisted flowcharts applicable to three very common clinical scenarios of the emergency department: Acute heart failure, type 1, and type 2 acute myocardial infarction. In particular, we combined sST2 levels together with clinical and instrumental evaluation in order to offer a practical tool for emergency medicine physicians.