The immunometabolic roots of aging.

Aging is one of the greatest risk factors for several chronic diseases and is accompanied by a progressive decline of cellular and organ function. Recent studies have highlighted the changes in metabolism as one of the main drivers of organism dysfunctions during aging and how that strongly deteriorate immune cell performance and function. Indeed, a dysfunctional immune system has been shown to have a pleiotropic impact on the organism, accelerating the overall aging process of an individual.

Stepwise release of Activin-A from its inhibitory prodomain is modulated by cysteines and requires furin coexpression to promote melanoma growth.

The Activin-A precursor dimer can be cleaved by furin, but how this proteolytic maturation is regulated in vivo and how it facilitates access to signaling receptors is unclear. Here, analysis in a syngeneic melanoma grafting model shows that without furin coexpression, Activin-A failed to accelerate tumor growth, correlating with failure of one or both subunits to undergo cleavage in signal-sending cells, even though compensatory processing by host cells nonetheless sustained elevated circulating Activin-A levels. In reporter assays, furin-independent cleavage of one subunit enabled juxtacrine Activin-A signaling, whereas completion of proteolytic maturation by coexpressed furin or by recipient cells stimulated contact-independent activity, crosstalk with BMP receptors, and signal inhibition by follistatin.

Urolithin-A Promotes CD8+ T Cell-mediated Cancer Immunosurveillance via FOXO1 Activation.

Unlabelled: Naïve T cells are key players in cancer immunosurveillance, even though their function declines during tumor progression. Thus, interventions capable of sustaining the quality and function of naïve T cells are needed to improve cancer immunoprevention.In this context, we studied the capacity of Urolithin-A (UroA), a potent mitophagy inducer, to enhance T cell-mediated cancer immunosurveillance.

Enforcing GLUT3 expression in CD8 T cells improves fitness and tumor control by promoting glucose uptake and energy storage.

Despite the tremendous success of adoptive T-cell therapies (ACT) in fighting certain hematologic malignancies, not all patients respond, a proportion experience relapse, and effective ACT of most solid tumors remains elusive. In order to improve responses to ACT suppressive barriers in the solid tumor microenvironment (TME) including insufficient nutrient availability must be overcome. Here we explored how enforced expression of the high-affinity glucose transporter GLUT3 impacted tumor-directed T cells.

TGFβ limits Myc-dependent TCR-induced metabolic reprogramming in CD8 T cells.

T cell activation is dependent upon the integration of antigenic, co-stimulatory and cytokine-derived signals and the availability and acquisition of nutrients from the environment. Furthermore, T cell activation is accompanied by reprogramming of cellular metabolism to provide the energy and building blocks for proliferation, differentiation and effector function. Transforming growth factor β (TGFβ) has pleiotropic effects on T cell populations, having both an essential role in the maintenance of immune tolerance but also context-dependent pro-inflammatory functions.

Ionic Regulation of T-Cell Function and Anti-Tumour Immunity.

The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME).

Innate Immune Cells and Their Contribution to T-Cell-Based Immunotherapy.

In recent years, immunotherapy has become the most promising therapy for a variety of cancer types. The development of immune checkpoint blockade (ICB) therapies, the adoptive transfer of tumor-specific T cells (adoptive cell therapy (ACT)) or the generation of T cells engineered with chimeric antigen receptors (CAR) have been successfully applied to elicit durable immunological responses in cancer patients. However, not all the patients respond to these therapies, leaving a consistent gap of therapeutic improvement that still needs to be filled.

Compartment-Specific Biosensors Reveal a Complementary Subcellular Distribution of Bioactive Furin and PC7.

Furin trafficking, and that of related proprotein convertases (PCs), may regulate which substrates are accessible for endoproteolysis, but tools to directly test this hypothesis have been lacking. Here, we develop targeted biosensors that indicate Furin activity in endosomes is 10-fold less inhibited by decanoyl-RVKR-chloromethylketone and enriched >3-fold in endosomes compared to the trans-Golgi network (TGN). Endogenous PC7, which resists this inhibitor, was active in distinct vesicles.

Ionic mechanisms and vectorial model of early repolarization pattern in the surface electrocardiogram of the athlete.

Background: The electrocardiogram (ECG) of the athlete displays particular characteristics as a consequence of both electrophysiological and autonomic remodeling of the heart that follows continued physical training. However, doubts persist on how these changes directly interact during ventricular activation and repolarization ultimately affecting surface ECG waveforms in athletes.

Objective: This article considers an in deep rationale for the electrocardiographic pattern known as early repolarization based on both electrophysiological mechanisms at cellular level and the vectorial theory of the cardiac activation.

Spectral turbulence analysis of the signal-averaged electrocardiogram of the atrial activation as predictor of recurrence of idiopathic and persistent atrial fibrillation.

The frequency domain analysis of the P-wave signal-averaged ECG (P-SAECG) is able to identify patients at risk for lone atrial fibrillation (AF) after cardioversion to sinus rhythm. The terminal portion of the P-wave of right precordial leads on 12-lead ECG is associated with electrical abnormalities in the atria. The aim of this study was to assess the spectral turbulence analysis (STA) of the P-SAECG as a predictor of recurrence of idiopathic AF.

Noninvasive cardiac assessment in children of women with systemic lupus erythematosus.

Objective: Noninvasive cardiac assessment of newborns and infants of women with systemic lupus erythematosus. The children had no congenital total atrioventricular block and were compared with the children of healthy women.

Methods: We prospectively assessed 13 newborns and infants aged 1 to 60 days, children of women with systemic lupus erythematosus and without congenital total atrioventricular block.

Detection of incipient left ventricular hypertrophy in mild to moderate arterial hypertension with normal electrocardiogram and echocardiogram: a new use for signal-averaged electrocardiography.

Objective: To assess signal-averaged electrocardiogram (SAECG) for diagnosing incipient left ventricular hypertrophy (LVH).

Methods: A study with 115 individuals was carried out. The individuals were divided as follows: GI - 38 healthy individuals; GII - 47 individuals with mild to moderate hypertension and normal findings on echocardiogram and ECG; and GIII - 30 individuals with hypertension and documented LVH.

Clinical assessment of the effect of digital filtering on the detection of ventricular late potentials.

Ventricular late potentials are low-amplitude signals originating from damaged myocardium and detected on the body surface by ECG filtering and averaging. Digital filters present in commercial equipment may interfere with the ability of arrhythmia stratification. We compared 40-Hz BiSpec (BI) and classical 40- to 250-Hz band-pass Butterworth bidirectional (BD) filters in terms of impact on time domain variables and diagnostic properties.

Analysis of the prevalence of ventricular late potentials in the late phase of myocardial infarction based on the site of infarction.

Objective: The initial site of myocardial infarction (MI) may influence the prevalence of ventricular late potentials (VLP), high-frequency signals, due to the time course of ventricular activation. The prevalence of VLP in a period of more than 2 years after acute MI was assessed focusing on the initially injured wall.

Methods: The prevalence of VLP in a late phase after MI (median of 924 days) in anterior/antero-septal and inferior/infero-dorsal wall lesion was analyzed using signal-averaged electrocardiogram in time domain.

Atrial activation during sinus rhythm in patients with rheumatic and non-rheumatic paroxysmal atrial fibrillation. Frequency-domain analysis using signal-averaged electrocardiography.

Objective: Using P-wave signal-averaged electrocardiography, we assessed the patterns of atrial electrical activation in patients with idiopathic atrial fibrillation as compared with patterns in patients with atrial fibrillation associated with structural heart disease.

Methods: Eighty patients with recurrent paroxysmal atrial fibrillation were divided into 3 groups as follows: group I - 40 patients with atrial fibrillation associated with non-rheumatic heart disease; group II - 25 patients with rheumatic atrial fibrillation; and group III - 15 patients with idiopathic atrial fibrillation. All patients underwent P-wave signal-averaged electrocardiography for frequency-domain analysis using spectrotemporal mapping and statistical techniques for detecting and quantifying intraatrial conduction disturbances.

The frequency analysis of signal-averaged ECG of P wave as predictor of efficacy of class III antiarrhythmic drugs to maintain sinus rhythm in recurrent idiopathic atrial fibrillation.

Background: The use of class III antiarrhythmic drugs (ADIII) has been considered a good predictor of sinus rhythm in patients post-cardioversion from atrial fibrillation (AF). Several studies using frequency domain analysis of signal-averaged ECG (FDSAECG) of the P wave were able to identify patients at risk for AF. The aim of this study was to assess the FDSAECG in predicting recurrence of idiopathic persistent AF (IPAF) in patients under ADIII therapy.

[Evaluation of fragmented potentials in right bundle branch block without structural myocardium abnormalities. Study made by signal-averaged electrocardiogram on time and frequency domain].

Purpose: To evaluate if the presence of right bundle branch block (RBBB), without structural myocardial abnormalities (SMA) can generate fragmented potentials (FP) and spectral turbulence on signal-averaged electrocardiogram (SAECG).

Methods: Twelve children with atrial septal defect (ASD) and incomplete right bundle branch block (IRBBB without SMA (group I) were compared to 17 children with post-operative tetralogy of Fallot (TF) with CRBBB, all with SMA, 5 with ventricular premature beats and 2 with sustained ventricular tachycardia (group II). All had SAECG on time (TD) and frequency domain (FD) with 5 variables analysed.

[High resolution electrocardiogram in frequency domain. Use of statistical techniques of spectral correlation for identification of patients with sustained monomorphic ventricular tachycardia].

Purpose: To evaluate the diagnostic accuracy of monomorphic ventricular tachycardia (MVT), in patients with structural heart diseases and episodes of sustained MVT, using the signal-averaged ECG (SAECG) in the time (TD) and the frequency domain (FD) with statistical techniques of spectral correlation.

Methods: Twenty seven patients with at least one episode of sustained MVT, 30 patients with structural heart diseases and no evidence of ventricular arrhythmias and 80 subjects with no evidence of heart disease have been studied. SAECG was performed in all patients with the following parameters: duration of the filtered QRS, RMS 40 and LAS40 in TD and the mean and the standard deviation of both signal energy intersegmentar spectral correlation and energy frequency edge track in FD.

[Obstructive ischemic involvement of the anterior descending coronary artery in asymmetrical septal form of hypertrophic cardiomyopathy].

Purpose: The significance of necrosis and fibrosis of the interventricular septum in hypertrophic cardiomyopathy (HCM) is controversial. The purpose of this study was then to evaluate the clinical impact of left anterior descending artery (LAD) disease in HCM.

Methods: Among 158 patients presenting with HCM, 6 (3.

[Is the apical hypertrophic cardiomyopathy seen in one population in Rio de Janeiro city similar to that found in the East?].

Purpose: To investigate the differences between clinical aspects and evolution of apical hypertrophic cardiomyopathy (AHCM) seen in Rio de Janeiro and the Oriental form, which was the first described.

Methods: In 156 patients with AHCM diagnosed in our institution, there were 13 (8.34%) with the apical form of the disease, whose clinical settings, diagnostic procedures and evolution were studied.

[Depressed electrical atrial activity in hypertrophic and dilated cardiomyopathies. An electrocardiographic, vectorcardiographic and echocardiographic study].

Purpose: To evaluate the "normal" or low-voltage P wave of the 12-leads conventional electrocardiogram (ECG), in patients with serious electric ventricular disturbances in hypertrophic (HC) and dilated (DC) cardiomyopathies.

Methods: Twenty cases of cardiomyopathies, 11 HC and 9 DC, ages ranging from 23 to 73 (x = 41) years have been studied. The analysis of the P wave was performed with ECG, amplified ECG at 1 mv = 20 mm and speed-paper at 50 mm/sec (ECG2), and the Frank-system vector-cardiogram (VCG).

[Apical hypertrophic cardiomyopathy with right ventricular involvement].

We report right ventricular involvement in apical hypertrophic cardiomyopathy (HCMP) in two women and one man, aged from 19 to 44 years-old, who presented different signs from those with left ventricular disease (who have good clinical evolution), with signs and symptoms of severe diastolic restriction, showing great atrial enlargement and two with atrial fibrillation and death due to thromboembolism. The right ventricular involvement in apical HCMP leads to a worst prognosis than isolated left ventricular disease, does not have the typical electrocardiographic changes and presents with ventricular restriction and tricuspid regurgitation.