Sacubitril/Valsartan. Potential Impact of ARNi "Beyond the Wall" of ACE2 on Treatment and Prognosis of Heart Failure Patients With Coronavirus Disease-19

From the beginning of the SARS-CoV-2 pandemia, the type 2 angiotensin-converting enzyme (ACE2), probably the most “unloved and neglected” member of the renin-angiotensin-aldosterone (RAAS) family, has attracted increasing attention since it has been shown as the cell receptor through which the virus enters into the cells (1). The physiological action of ACE2, a membrane protein expressed in the heart, lungs, kidneys, liver, and intestine, consists in degrading angiotensin II (Ang II) to angiotensin (1-7), a heptapeptide with a potent vasodilator function through the Mas receptor able to counterbalance the Ang II effects on vasoconstriction, sodium retention, and fibrosis (1). Previous studies have shown that Ang II type 1 receptor (AT1R) blockers (ARBs), ACE inhibitors (ACEI), and mineralocorticoid receptor antagonists (MRA) may up-regulate the expression of ACE2 both in acute and chronic settings of cardiovascular diseases (CVDs), such as hypertension, heart failure (HF) and myocardial infarction (1). These data have generated concern during the early phases of the pandemia, since it has been speculated that the increase in ACE2 level may have contributed to disease virulence and to adverse outcomes particularly in subjects affected by chronic coexisting conditions, namely hypertension, coronary artery disease, HF, and diabetes, who commonly received treatment with RAAS inhibitors and who were characterized by a worse clinical course (2). On the other hand, it has been observed that the binding between coronavirus and ACE2 leads to ACE2 downregulation, resulting in an unopposed production of Ang II by ACE, contributing to lung damage as a consequence of AT1R mediated inflammation, fibrosis, thrombosis, vasoconstriction, and increased vascular permeability. According to these findings, RAAS inhibitors and, in particular, ARBs may even protect against COVID-19 acute lung injury (1). As a matter of fact, epidemiological studies conducted in large populations of COVID-19 patients demonstrated that ARBs or ACE inhibitors had no association with a severe or fatal course of the diseas

Natriuretic Peptides. It Is Time for Guided Therapeutic Strategies Based on Their Molecular Mechanisms

Natriuretic peptides (NPs) are the principal expression products of the endocrine function of the heart. They exert several beneficial effects, mostly mediated through guanylate cyclase-A coupled receptors, including natriuresis, diuresis, vasorelaxation, blood volume and blood pressure reduction, and regulation of electrolyte homeostasis. As a result of their biological functions, NPs counterbalance neurohormonal dysregulation in heart failure and other cardiovascular diseases. NPs have been also validated as diagnostic and prognostic biomarkers in cardiovascular diseases such as atrial fibrillation, coronary artery disease, and valvular heart disease, as well as in the presence of left ventricular hypertrophy and severe cardiac remodeling. Serial measurements of their levels may be used to contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations and to guide tailored pharmacological and non-pharmacological strategies with the aim to improve clinical outcomes. On these premises, multiple therapeutic strategies based on the biological properties of NPs have been attempted to develop new targeted cardiovascular therapies. Apart from the introduction of the class of angiotensin receptor/neprilysin inhibitors to the current management of heart failure, novel promising molecules including M-atrial natriuretic peptide (a novel atrial NP-based compound) have been tested for the treatment of human hypertension with promising results. Moreover, different therapeutic strategies based on the molecular mechanisms involved in NP regulation and function are under development for the management of heart failure, hypertension, and other cardiovascular conditions

Lineamenti vegetazionali della zona costiera dell’alto Adriatico

A synthetic view of coastal vegetation between the Po river delta and Monte Conero (Italy) is given. Quercus ilex woods, hygrophilous wood communities, halophilous and psammophilous vegetation types are analysed by means of cluster analysis methods performed on about 750 phytosocio- logical relevés. Phytosociological attributions of vegetation types recognized are proposed.Na temelju analize oko 750 fitocenoloških snimaka autori donose sintetski pregled današnje kserofilne i higrofilne vegetacije, te halofilnih i psamofilnih fitocenoza obalnog područja sjevernog Jadrana od delte rijeke Po do okolice Ancone (Monte Conero) u Italiji.Nel presente lavoro si propone una sintesi delle conoscenze attualmente disponibili sui principali aspetti della vegetazione costiera (boschi a Quercus ilex, aggruppamenti forestall igrofili, vegetazione alofila e psammofila) del territorio compreso tra le foci del Po e il promontorio del Conero. Le tipologie individuate (per le quali vengono preséntate le relative tabelle sintetiche) sono il risultato di elaborazioni quantitative effettuate mediante cluster analysis su un numero considerevole di rilievi fitosociologici (circa 750) in parte giá pubblicati, in parte inediti

2-O-Acetyl-3,4,5,6-tetra-O-benzyl-D-myo-inosityl diphenylphosphate: a new useful intermediate to inositol phosphate and phospholipids

Inositol phosphates and inositol phospholipids are ubiquitous in biochemistry and play a central role in cell signaling and regulation events. For this reason, their synthesis has attracted widespread interest. This paper describes the preparation of a new optically active inositol phosphate derivative, 2-O-acetyl-3,4,5,6-tetra-O-benzyl-D-myo-inosityl diphenylphosphate (6), and its characterization by spectroscopic methods. Compound (6) represents a useful intermediate for the preparation of inositol phosphate and phospholipids, in particular of glycerophosphoinositol (GPI), a natural anti-inflammatory agent

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study

Pembrolizumab; Non-small-cell lung cancerPembrolizumab; Cáncer de pulmón de células no pequeñasPembrolizumab; Càncer de pulmó de cèl·lules no petitesClinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations

Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC

Biomarker; Pembrolizumab; Tissue tumor mutational burdenBiomarcador; Pembrolizumab; Càrrega mutacional del tumor tissularBiomarcador; Pembrolizumab; Carga mutacional del tumor tisularIntroduction We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials. Methods This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome. Results Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status. Conclusions These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.All authors’ institutions received research funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, for the conduct of this study

Chronic heart failure is characterized by altered mitochondrial function and structure in circulating leucocytes

Oxidative stress is currently viewed as a key factor in the genesis and progression of Heart Failure (HF). The aim of this study was to characterize the mitochondrial changes linked to oxidative stress generation in circulating peripheral blood mononuclear cells isolated from chronic HF patients (HF_PBMCs) in order to highlight the involvement of mitochondrial dysfunction in the pathophysiology of HF. To assess the production of reactive oxygen species (ROS), mitochondrial function and ultrastructure and the mitophagic flux in circulating PBMCs we enrolled 15 patients with HF and a control group of ten healthy subjects. The HF_PBMCs showed a mitochondrial population consisting of damaged and less functional organelles responsible of higher superoxide anion production both at baseline and under in vitro stress conditions, with evidence of cellular apoptosis. Although the mitophagic flux at baseline was enhanced in HF_PBMCs at level similar to those that could be achieved in control PBMCs only under inflammatory stress conditions, the activation of mitophagy was unable to preserve a proper mitochondrial dynamics upon stress stimuli in HF. In summary, circulating HF_PBMCs show structural and functional derangements of mitochondria with overproduction of reactive oxidant species. This mitochondrial failure sustains a leucocyte dysfunctional status in the blood that may contribute to development and persistence of stress conditions within the cardiovascular system in HF

Emulsifying properties of sugar-based surfactants prepared by chemoenzymatic synthesis

Sugar Fatty Acid Esters (SFAEs) are a class of non-ionic surfactants that can be synthesized from inexpensive natural resources. Depending on carbon chain length and nature of the sugar head group, SFAEs cover a wide range of hydrophilic–lipophilic balance (HLB) values, which result in tunable tenside properties and in turn relevant for a wide variety of industrial applications. Three sugar-based surfactants (6-O-lauroyl-, 6-O-palmitoyl- and 6-O-stearoyl-1-O-butyl glucopyranosides) have been prepared by a lipase-catalyzed esterification of isomeric mixture of n-butyl glucosides. Specifically, their interfacial features together with W/O emulsifying properties and stability over time have been finely evaluated (interfacial tension (IFT) values, W/O emulsion turbidity water droplet size distribution, first order kinetic constants of de-emulsification)

Selective and sensitive poly-<i>ortho</i>-phenylenediamine-shielded microsensore and biosensors for in vivo neurochemical monitoring

Different methodologies are being developed, such as imaging, spectroscopy and electrochemistry, to study neurochemical dynamics in cell cultures or in intact brain [1-2]. One of these techniques involves the in-situ detection of biologically active molecules, including nitric oxide (NO) [3], glucose [4], glutamate (GLUT) [5-6] and lactate [1,7], in brain extracellular fluid (ECF), using implanted microsensors and biosensors. NO is a water-soluble free radical that readily diffuses through membranes and its actions in the CNS are largely studied

Functional Role of Natriuretic Peptides in Risk Assessment and Prognosis of Patients with Mitral Regurgitation

The management of mitral valve regurgitation (MR), a common valve disease, represents a challenge in clinical practice, since the indication for either surgical or percutaneous valve replacement or repair are guided by symptoms and by echocardiographic parameters which are not always feasible. In this complex scenario, the use of natriuretic peptide (NP) levels would serve as an additive diagnostic and prognostic tool. These biomarkers contribute to monitoring the progression of the valve disease, even before the development of hemodynamic consequences in a preclinical stage of myocardial damage. They may contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations, thus requiring surgical management rather than a conservative approach. This article provides a comprehensive overview of the available evidence on the role of NPs in the management, risk evaluation, and prognostic assessment of patients with MR both before and after surgical or percutaneous valve repair. Despite largely positive evidence, a series of controversial findings exist on this relevant topic. Recent clinical trials failed to assess the role of NPs following the interventional procedure. Future larger studies are required to enable the introduction of NP levels into the guidelines for the management of MR