👤 Massimo Volpe

Although recommended for cardiovascular (CV) risk stratification in adults, the role of lipoprotein(a) [Lp(a)] in hypertension is not fully established. To evaluate Lp(a) levels in adult outpatients with essential arterial hypertension. A retrospective, observational study was conducted in outpatients of both sexes, aged ≥ 18 years, with treated or untreated essential hypertension, who were consecutively evaluated at the Hypertension Unit, Excellence Hypertension Center, Sant'Andrea Hospital, Rome, Italy. Participants underwent office and out-of-office blood pressure (BP) measurements, as well as assessment of hypertension-mediated organ damage (HMOD). BP measurements were performed, and hypertension phenotypes were classified according to 2023 European hypertension guidelines. Lp(a) levels were measured, and the study population was stratified according to a Lp(a) cut-off value of ≥50 mg/dl. Due to the non-uniform distribution, absolute Lp(a) values were logarithmically transformed. A total of 230 patients with available Lp(a) values were included (42.6% women, mean age 66.3 ± 11.5 years, BMI 27.1 ± 4.5 kg/m2, office BP 137.1 ± 18.1/83.7 ± 11.0 mmHg, 24-hour BP 129.8 ± 14.5/79.6 ± 9.8 mmHg, Lp(a) 51.4 ± 65.3 mg/dL), among whom 32.2% had Lp(a) ≥50 mg/dl. There were significantly higher proportions of men (74.3% vs. 49.4%; P < 0.001), dyslipidaemia (97.3% vs. 75.0%; P < 0.001) and comorbidities (55.4% vs. 30.8%; P < 0.001) in patients with high Lp(a) than in those with normal Lp(a), who also received more frequently lipid lowering therapies (P < 0.001) and aspirin (P = 0.003). However, lower office systolic BP values (133.5±18.8 vs. 138.8±17.6 mmHg: P = 0.036) were observed in patients with Lp(a) ≥50 mg/dL than in those with < 50 mg/dl. Also, no significant differences for Lp(a) levels were observed among various hypertension phenotypes, as defined by office (P = 0.156) or out-of-office BP values (P = 0.065). No significant correlations were found between Lp(a) and office or out-of-office BP levels, both in treated and untreated hypertensive outpatients. In our population, Lp(a) levels were not associated with either office or out-of-office BP values, irrespective of antihypertensive treatment status. The role of Lp(a) in hypertension warrants further investigation. Show less

Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease. Show less

Nucleic acid-based therapies are being rapidly developed for prevention and management of cardiovascular diseases (CVD). Remarkable advancements have been achieved in the delivery, safety, and effectiveness of these therapeutics in the past decade. These therapies can also modulate therapeutic targets that cannot be sufficiently addressed using traditional drugs or antibodies. Among the nucleic acid-targeted therapeutics under development for CVD prevention are RNA-targeted approaches, including antisense oligonucleotides (ASO), small interfering RNAs (siRNA), and novel genome editing techniques. Genetic studies have identified potential therapeutic targets that are suggested to play a causative role in development and progression of CVD. RNA- and DNA-targeted therapeutics can be particularly well delivered to the liver, where atherogenic lipoproteins and angiotensinogen (AGT) are produced. Current targets in lipid metabolism include proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein A (ApoA), apolipoprotein C3 (ApoC3), angiopoietin-like 3 (ANGPTL3). Several large-scale clinical development programs for nucleic acid-targeted therapies in cardiovascular prevention are under way, which may also be attractive from a therapy adherence point of view, given the long action of these therapeutics. In addition to genome editing, the concept of gene transfer is presently under assessment in preclinical and clinical investigations as a potential approach for addressing low-density lipoprotein receptor deficiency. Furthermore, ongoing research is exploring the use of RNA-targeted therapies to treat arterial hypertension by reducing hepatic angiotensinogen (AGT) production. This review summarizes the rapid translation of siRNA and ASO therapeutics as well as gene editing into clinical studies to treat dyslipidemia and arterial hypertension for CVD prevention. It also outlines potential innovative therapeutic options that are likely relevant to the future of cardiovascular medicine. Show less

The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3 Show less

The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype-phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes Show less

Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease-causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next-Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (≤25 years) and 35 with late (≥65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20× (mean coverage 620×). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective. Show less

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. Show less

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in sarcomere protein genes. MYBPC3 mutations are reported as a frequent cause of HCM. We aimed to identify the gene mutation underlying HCM in an Italian patient and his family composed of 13 relatives. Mutation screening of 658 known mutations was performed using a rapid and efficient mutation detection system based on semiautomated MALDI-TOF mass spectrometry using the Sequenom MassArray System and iPLEX Gold genotyping chemistry. Subsequently, direct sequencing of the coding exons and flanking intronic regions was performed for the most suitable HCM genes (MYBPC3, MYH7, TNNT2, TNNI3, and TPM1) in the index patient. We found a novel MYBPC3 gene mutation: G13999T (Gln689His). No other sarcomere gene mutation was found in this family. This genetic variant, which changes the last amino acid of MYBPC3 exon 21, affects a highly conserved residue. Furthermore, the Gln689His does not appear in public databases and has never been described as a polymorphism. The potential pathogenic role of this novel mutation was underlined by its absence in a sample of healthy subjects (n = 122) from the general Italian population. In summary, a novel MYBPC3 gene mutation has been identified in a patient affected by HCM, whereas it was absent in 244 reference alleles. Show less

Eukaryotic cells commit in G1 to a new mitotic cycle or to diverse differentiation processes. Here we show that Whi3 is a negative regulator of Cln3, a G1 cyclin that promotes transcription of many genes to trigger the G1/S transition in budding yeast. Whi3 contains an RNA-recognition motif that specifically binds the CLN3 mRNA, with no obvious effects on Cln3 levels, and localizes the CLN3 mRNA into discrete cytoplasmic foci. This is the first indication that G1 events may be regulated by locally restricting the synthesis of a cyclin. Moreover, Whi3 is also required for restraining Cln3 function in meiosis, filamentation, and mating, thus playing a key role in cell fate determination in budding yeast. Show less

WHI3 is a gene affecting size control and cell cycle in the yeast Saccharomyces cerevisiae. The whi3 mutant has small cells, while extra doses of WHI3 produce large cells, and a large excess of WHI3 produces a lethal arrest in G1 phase. WHI3 seems to be a dose-dependent inhibitor of Start. Whi3 and its partially redundant homolog Whi4 have an RNA-binding domain, and mutagenesis experiments indicate that this RNA-binding domain is essential for Whi3 function. CLN3-1 whi3 cells are extremely small, nearly sterile, and largely nonresponsive to mating factor. Fertility is restored by deletion of CLN2, suggesting that whi3 cells may have abnormally high levels of CLN2 function. Show less

In the yeast Saccharomyces cerevisiae, commitment to cell division (Start) requires growth to a critical cell size. The G1 cyclins Cln1, Cln2 and Cln3 activate the Cdc28 protein kinase and are rate-limiting activators of Start. When glucose is added to cells growing in a poor carbon source, the critical cell size required for Start is reset from a small to a large size. In yeast, glucose acts through Ras proteins to stimulate adenylyl cyclase, activating the three cyclic AMP-dependent protein kinases Tpk1, Tpk2 and Tpk3 (refs 8, 9). We find that stimulation of the Ras/cAMP pathway represses expression of CLN1, CLN2 and co-regulated genes, inhibiting Start. This helps explain the increase in critical size when cells are shifted from poor to rich medium. This connection between the molecules controlling growth (Ras/cAMP) and those controlling division (cyclins) helps explain how division is co-ordinated with growth. Show less