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Abstract Aims We report the results of a real‐world study based on heart failure (HF) patients' continuous remote monitoring strategy using the CardioMEMS system to assess the impact of this device on healthcare outcomes, costs, and patients' management and quality of life. Methods and results We enrolled seven patients (69.00 ± 4.88 years; 71.43% men) with HF, implanted with CardioMEMS, and daily remote monitored to optimize both tailored adjustments of home therapy and/or hospital infusions of levosimendan. We recorded clinical, pharmacological, biochemical, and echocardiographic parameters and data on hospitalizations, emergency room access, visits, and costs. Following the implantation of CardioMEMS, we observed a 50% reduction in the total number of hospitalizations and a 68.7% reduction in the number of days in the hospital. Accordingly, improved patient quality of life was recorded with EQ‐5D (pre 58.57 ± 10.29 vs. 1 year post 84.29 ± 19.02, P = 0.008). Echocardiographic data show a statistically significant improvement in both systolic pulmonary artery pressure (47.86 ± 8.67 vs. 35.14 ± 9.34, P = 0.022) and E/e′ (19.33 ± 5.04 vs. 12.58 ± 3.53, P = 0.023). The Quantikine® HS High‐Sensitivity Kit determined elevated interleukin‐6 values at enrolment in all patients, with a statistically significant reduction after 6 months (P = 0.0211). From an economic point of view, the net savings, including the cost of CardioMEMS, were on average €1580 per patient during the entire period of observation, while the analysis performed 12 months after the implant vs. 12 months before showed a net saving of €860 per patient. The ad hoc analysis performed on the levosimendan infusions resulted in 315 days of hospital avoidance and a saving of €205 158 for the seven patients enrolled during the observation period. Conclusions This innovative strategy prevents unplanned access to the hospital and contributes to the efficient use of healthcare facilities, human resources, and costs.

Abstract Ischemia with non-obstructive coronary artery (INOCA) is a common cause of hospital admissions, leading to negative outcomes and reduced quality of life. Central to its pathophysiology is endothelial dysfunction, which contributes to myocardial ischemia despite the absence of significant coronary artery blockage. Addressing endothelial dysfunction is essential in managing INOCA to alleviate symptoms and prevent cardiovascular events. Recent studies have identified diabetes mellitus (DM) as a significant factor exacerbating INOCA complications by promoting endothelial impairment and coronary microvascular dysfunction. MicroRNAs (miRNAs) have emerged as potential biomarkers and therapeutic targets in various biological processes, including endothelial dysfunction and cardiovascular diseases. However, research on miRNA biomarkers in INOCA patients is sparse. In this study, we examined a panel of circulating miRNAs involved in the regulation of endothelial function in INOCA patients with and without DM. We analyzed miRNA expression using RT-qPCR in a cohort of consecutive INOCA patients undergoing percutaneous coronary intervention. We detected a significant dysregulation of miR-363-5p and miR-92a-3p in INOCA patients with DM compared to those without DM, indicating their role as biomarkers for predicting and monitoring endothelial dysfunction in INOCA patients with DM.

Abstract Background Hypertension and chronic kidney disease (CKD) pose significant public health challenges, sharing intertwined pathophysiological mechanisms. Prediabetes is recognized as a precursor to diabetes and is often accompanied by cardiovascular comorbidities such as hypertension, elevating the risk of pre-frailty and frailty. Albuminuria is a hallmark of organ damage in hypertension amplifying the risk of pre-frailty, frailty, and cognitive decline in older adults. We explored the association between albuminuria and cognitive impairment in frail older adults with prediabetes and CKD, assessing cognitive levels based on estimated glomerular filtration rate (eGFR). Methods We conducted a study involving consecutive frail older patients with hypertension recruited from March 2021 to March 2023 at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, followed up after three months. Inclusion criteria comprised age over 65 years, prior diagnosis of hypertension without secondary causes, prediabetes, frailty status, Montreal Cognitive Assessment (MoCA) score 15 ml/min. Results 237 patients completed the study. We examined the association between albuminuria and MoCA Score, revealing a significant inverse correlation (r: 0.8846; p

Background: Cardiovascular diseases (CVDs) are associated with very high rates of re-hospitalization and mortality worldwide, so the complexity of these pathologies requires frequent access to hospital facilities. The guidelines also emphasize the importance of cardiac rehabilitation (CR) programs, which have demonstrated a favorable effect on outcomes, and cardiac telerehabilitation (CTR) could represent an innovative healthcare delivery model. The aim of our review is to study how technologies used in rehabilitation have changed over time and also to understand what types of rehabilitation programs have been used in telerehabilitation. Methods: We searched randomized controlled trials (RCTs) in three electronic databases, PubMed, Web of Science, and Scopus, from January 2015 to January 2024, using relevant keywords. Initially, 502 articles were found, and 79 duplicates were identified and eliminated with EndNote. Results: In total, 16 RCTs fulfilled the pre-defined criteria, which were analyzed in our systematic review. The results showed that after CTR, there was a significant improvement in main outcome measures, as well as in relation to technological advances. Conclusions: Moreover, compared to center-based rehabilitation, CTR can offer further advantages, with better cost-effectiveness, the breakdown of geographical barriers, and the improvement of access to treatment for the female population, which is traditionally more socially committed.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) are highly prevalent conditions, each significantly contributing to the global burden of morbidity and mortality. CVD and CKD share a great number of common risk factors, such as hypertension, diabetes, obesity, and smoking, among others. Their relationship extends beyond these factors, encompassing intricate interplay between the two systems. Within this complex network of pathophysiological processes, vitamin D has emerged as a potential linchpin, exerting influence over diverse physiological pathways implicated in both CKD and CVD. In recent years, scientific exploration has unveiled a close connection between these two prevalent conditions and vitamin D, a crucial hormone traditionally recognized for its role in bone health. This article aims to provide an extensive review of vitamin D’s multifaceted and expanding actions concerning its involvement in CKD and CVD.

Chronic kidney disease (CKD) is a global health issue with a rising prevalence, affecting 697.5 million people worldwide. It imposes a substantial burden, contributing to 35.8 million disability-adjusted life years (DALYs) and 1.2 million deaths in 2017. The mortality rate for CKD has increased by 41.5% between 1990 and 2017, positioning it as a significant cause of global mortality. CKD is associated with diverse health complications, impacting cardiovascular, neurological, nutritional, and endocrine aspects. One prominent complication is CKD–mineral and bone disorder (MBD), a complex condition involving dysregulation of bone turnover, mineralization, and strength, accompanied by soft tissue and vascular calcification. Alterations in mineral metabolism, including calcium, phosphate, parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23), and Klotho, play pivotal roles in CKD-MBD. These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy (ROD). Vascular calcification (VC) is a key component of CKD-MBD, accelerated by CKD. The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP). VC is closely linked to cardiovascular events and mortality, emphasizing its prognostic significance. Various serum markers and imaging techniques, including lateral plain X-ray, Kauppila Score, Adragao Score, and pulse wave velocity, aid in VC detection. Additionally, pQCT provides valuable information on arterial calcifications, offering an advantage over traditional scoring systems. CKD poses a substantial global health burden, and its complications, including CKD-MBD and VC, significantly contribute to morbidity and mortality. Understanding the intricate relationships between mineral metabolism, bone disorders, and vascular calcification is crucial for effective diagnosis and therapeutic interventions.

Abstract Aims The angiotensin receptor‐neprilysin inhibitor (ARNI) sacubitril/valsartan (Sac/Val) demonstrated to be superior to enalapril in reducing hospitalizations, cardiovascular and all‐cause mortality in patients with ambulatory heart failure and reduced ejection fraction (HFrEF), in particular when it is maximally up‐titrated. Unfortunately, the target dose is achieved in less than 50% of HFrEF patients, thus undermining the beneficial effects on the outcomes. In this study, we aimed to evaluate the role of Sac/Val and its titration dose on reverse cardiac remodelling and determine which echocardiographic index best predicts the up‐titration success. Methods and results From January 2020 to June 2021, we retrospectively identified 95 patients (65.6 [59.1–72.8] years; 15.8% females) with chronic HFrEF who were prescribed Sac/Val from the HF Clinics of 5 Italian University Hospitals and evaluated the tolerability of Sac/Val high dose (the ability of the patient to achieve and stably tolerate the maximum dose) as the primary endpoint in the cohort. We used a multivariable logistic regression analysis, with a stepwise backward selection method, to determine the independent predictors of Sac/Val maximum dose tolerability, using, as candidate predictors, only variables with a P‐value < 0.1 in the univariate analyses. Candidate predictors identified for the multivariable backward logistic regression analysis were age, sex, body mass index (BMI), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), dyslipidaemia, atrial fibrillation, systolic blood pressure (SBP), baseline tolerability of ACEi/ARBs maximum dose, left ventricle global longitudinal strain (LVgLS), LV ejection fraction (EF), tricuspid annulus plane systolic excursion (TAPSE), right ventricle (RV) fractional area change (FAC), RV global and free wall longitudinal strain (RVgLS and RV‐FW‐LS). After the multivariable analysis, only one categorical (ACEi/ARBs maximum dose at baseline) and three continuous (younger age, higher SBP, and higher TAPSE), resulted significantly associated with the study outcome variable with a strong discriminatory capacity (area under the curve 0.874, 95% confidence interval (CI) (0.794–0.954) to predict maximum Sac/Val dose tolerability. Conclusions Our study is the first to analyse the potential role of echocardiography and, in particular, of RV dysfunction, measured by TAPSE, in predicting Sac/Val maximum dose tolerability. Therefore, patients with RV dysfunction (baseline TAPSE

High glucose–induced endothelial dysfunction is an important pathological feature of diabetic vasculopathy. While genome-wide studies have identified an association between type 2 diabetes mellitus (T2DM) and increased expression of a C2 calcium-dependent domain containing 4B (C2CD4B), no study has yet explored the possible direct effect of C2CD4B on vascular function. Vascular reactivity studies were conducted using a pressure myograph, and nitric oxide and oxidative stress were assessed through difluorofluorescein diacetate and dihydroethidium, respectively. We demonstrate that high glucose upregulated both mRNA and protein expression of C2CD4B in mice mesenteric arteries in a time-dependent manner. Notably, the inhibition of C2CD4B expression by genetic knockdown efficiently prevented hyperglycemia–induced oxidative stress, endothelial dysfunction, and loss of nitric oxide (NO) bioavailability. Recombinant C2CD4B evoked endothelial dysfunction of mice mesenteric arteries, an effect associated with increased reactive oxygen species (ROS) and decreased NO production. In isolated human umbilical vein endothelial cells (HUVECs), C2CD4B increased phosphorylation of endothelial nitric oxide synthase (eNOS) at the inhibitory site Thr495 and reduced eNOS dimerization. Pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and PKCα effectively attenuated oxidative stress, NO reduction, impairment of endothelial function, and eNOS uncoupling induced by C2CD4B. These data demonstrate, for the first time, that C2CD4B exerts a direct effect on vascular endothelium via a phosphoinositide 3-kinase (PI3K)/Akt/PKCα–signaling pathway, providing a new perspective on C2CD4B as a promising therapeutic target for the prevention of oxidative stress in diabetes–induced endothelial dysfunction.

Obesity is a growing public health epidemic worldwide and is implicated in slowing improved life expectancy and increasing cardiovascular (CV) risk; indeed, several obesity-related mechanisms drive structural, functional, humoral, and hemodynamic heart alterations. On the other hand, obesity may indirectly cause CV disease, mediated through different obesity-associated comorbidities. Diet and physical activity are key points in preventing CV disease and reducing CV risk; however, these strategies alone are not always sufficient, so other approaches, such as pharmacological treatments and bariatric surgery, must support them. Moreover, these strategies are associated with improved CV risk factors and effectively reduce the incidence of death and CV events such as myocardial infarction and stroke; consequently, an individualized care plan with a multidisciplinary approach is recommended. More precisely, this review explores several interventions (diet, physical activity, pharmacological and surgical treatments) to address CV risk in obese patients and emphasizes the importance of adherence to treatments.

Sacubitril/valsartan (Sac/Val) reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) compared to enalapril. However, its effects on functional capacity remain uncertain; consequently, we sought to compare Sac/Val vs. standard medical therapy, in terms of effects on prognostically significant CPET parameters, in HFrEF patients during a long follow-up period. We conducted a single-center, observational study in an HF clinic; specifically, we retrospectively identified that 12 patients switched to Sac/Val and 13 patients that managed with standard, optimal medical therapy (control group). At each visit, baseline, and follow-up (median time: 16 months; IQ range: 11.5–22), we collected demographic information, medical history, vital signs, cardiopulmonary exercise testing, standard laboratory data, pharmacological treatment information, and echocardiographic parameters. The study’s primary end-point was the change from baseline in peak VO2 (adjusted to body weight). We did not observe significant differences between the two study groups at baseline. Similarly, we did not observe any significant differences during the follow-up in mean values of peak VO2 corrected for body weight: Sac/Val baseline: 12.2 ± 4.6 and FU: 12.7 ± 3.3 vs. control group: 13.1 ± 4.2 and 13.0 ± 4.2 mL/kg/min; p = 0.49. No significant treatment differences were observed for changes in VE/VCO2 slope: Sac/Val baseline: 35.4 ± 7.4 and FU: 37.2 ± 13.1 vs. control group: 34.6 ± 9.1 and 34.0 ± 7.3; p = 0.49. In conclusion, after a median follow-up period of 16 months, there was no significant benefit of Sac/Val on peak VO2 and other measures of CPET compared with standard optimal therapy in patients with HFrEF.

During the last years, the management of heart failure (HF) made substantial progress, focusing on device-based therapies to meet the demands of this complex syndrome. In this case report, we present a multistep approach to deal with HF. Specifically, we report the first patient subjected to the implantation of both Optimizer Smart® (Impulse Dynamics Inc., Marlton, NJ, USA) and CardioMEMS devices. A 72-year-old male patient with HF and reduced ejection fraction (HFrEF) was admitted to our cardiology department in January 2021, following a progressive shortening of the time between hospitalizations for levosimendan infusions. Specifically, the patient was monitored daily by CardioMEMS, and a strategy of levosimendan infusions guided by the device had been adopted. He was also a carrier of MitraClips and cardiac resynchronization therapy defibrillator (CRT-D) and had optimized HF medical therapy. In January 2021, the patient implanted Optimizer Smart® device for cardiac contractility modulation (CCM) therapy because of poor response to therapy and elevated pulmonary artery pressure (PAP). CCM significantly reduced PAP values following discharge (systolic PAP 33.67 ± 2.92 vs. 40.6 ± 3.37 mmHg, diastolic PAP 14.5 ± 2.01 vs. 22.5 ± 2.53 mmHg, mean PAP 22.87 ± 2.20 vs. 30.9 ± 2.99 mmHg, HR 60.93 ± 1.53 vs. 80.83 ± 3.66 bpm; p < 0.0001), with persisting effect at 9 months. The usefulness of CCM is objectively demonstrated for the first time by continuous invasive monitoring of PAP by CardioMEMS, which can suggest the correct timing for CCM implantation.

Arterial hypertension (AH) is a progressive issue that grows in importance with the increased average age of the world population. The potential role of artificial intelligence (AI) in its prevention and treatment is firmly recognized. Indeed, AI application allows personalized medicine and tailored treatment for each patient. Specifically, this article reviews the benefits of AI in AH management, pointing out diagnostic and therapeutic improvements without ignoring the limitations of this innovative scientific approach. Consequently, we conducted a detailed search on AI applications in AH: the articles (quantitative and qualitative) reviewed in this paper were obtained by searching journal databases such as PubMed and subject-specific professional websites, including Google Scholar. The search terms included artificial intelligence, artificial neural network, deep learning, machine learning, big data, arterial hypertension, blood pressure, blood pressure measurement, cardiovascular disease, and personalized medicine. Specifically, AI-based systems could help continuously monitor BP using wearable technologies; in particular, BP can be estimated from a photoplethysmograph (PPG) signal obtained from a smartphone or a smartwatch using DL. Furthermore, thanks to ML algorithms, it is possible to identify new hypertension genes for the early diagnosis of AH and the prevention of complications. Moreover, integrating AI with omics-based technologies will lead to the definition of the trajectory of the hypertensive patient and the use of the most appropriate drug. However, AI is not free from technical issues and biases, such as over/underfitting, the “black-box” nature of many ML algorithms, and patient data privacy. In conclusion, AI-based systems will change clinical practice for AH by identifying patient trajectories for new, personalized care plans and predicting patients’ risks and necessary therapy adjustments due to changes in disease progression and/or therapy response.

Cardiovascular diseases (CVDs) are the leading cause of death and illness in Europe and worldwide, responsible for a staggering 47% of deaths in Europe. Over the past few years, there has been increasing evidence pointing to bioactive sphingolipids as drivers of CVDs. Among them, most studies place emphasis on the cardiovascular effect of ceramides and sphingosine-1-phosphate (S1P), reporting correlation between their aberrant expression and CVD risk factors. In experimental in vivo models, pharmacological inhibition of de novo ceramide synthesis averts the development of diabetes, atherosclerosis, hypertension and heart failure. In humans, levels of circulating sphingolipids have been suggested as prognostic indicators for a broad spectrum of diseases. This article provides a comprehensive review of sphingolipids’ contribution to cardiovascular, cerebrovascular and metabolic diseases, focusing on the latest experimental and clinical findings. Cumulatively, these studies indicate that monitoring sphingolipid level alterations could allow for better assessment of cardiovascular disease progression and/or severity, and also suggest them as a potential target for future therapeutic intervention. Some approaches may include the down-regulation of specific sphingolipid species levels in the circulation, by inhibiting critical enzymes that catalyze ceramide metabolism, such as ceramidases, sphingomyelinases and sphingosine kinases. Therefore, manipulation of the sphingolipid pathway may be a promising strategy for the treatment of cardio- and cerebrovascular diseases.

Dilated cardiomyopathy (DCM) is a complex disease affecting young adults. It is a pathological condition impairing myocardium activity that leads to heart failure and, in the most severe cases, transplantation, which is currently the only possible therapy for the disease. DCM can be attributed to many genetic determinants interacting with environmental factors, resulting in a highly variable phenotype. Due to this complexity, the early identification of causative gene mutations is an important goal to provide a genetic diagnosis, implement pre-symptomatic interventions, and predict prognosis. The advent of next-generation sequencing (NGS) has opened a new path for mutation screening, and exome sequencing provides a promising approach for identifying causal variants in known genes and novel disease-associated candidates. We analyzed the whole-exome sequencing (WES) of 15 patients affected by DCM without overloading (hypertension, valvular, or congenital heart disease) or chronic ischemic conditions. We identified 70 pathogenic or likely pathogenic variants and 1240 variants of uncertain clinical significance. Gene ontology enrichment analysis was performed to assess the potential connections between affected genes and biological or molecular function, identifying genes directly related to extracellular matrix organization, transcellular movement through the solute carrier and ATP-binding cassette transporter, and vitamin B12 metabolism. We found variants in genes implicated to a different extent in cardiac function that may represent new players in the complex genetic scenario of DCM.

Omega-3 fatty acids have been shown to exert several beneficial effects in the prevention of cardiovascular and cerebrovascular diseases. The objective of the present study was to analyze the effects of a novel high-load omega-3 lysine complex, AvailOm®, its related constituents and a novel mixture of AvailOm® with specific vasoactive anthocyanins on vascular function in mice resistance artery. Pressure myograph was used to perform vascular reactivity studies. Nitric oxide and oxidative stress were assessed by difluorofluorescein diacetate and dihydroethidium, respectively. Increasing doses of AvailOm® exerted a dose-response vasorelaxation via AMPK-eNOS-mediated signaling. Omega-3 Ethyl Ester was identified as the main bioactive derivative of AvailOm®, being capable of inducing vasorelaxant action to the same extent of entire product. The combination of AvailOm® with a mix of potent vasoactive anthocyanins (C3-glu + DP3-glu + Mal3-glu + Mal3-gal + PEO3-gal), strongly protected mesenteric arteries from vascular dysfunction and oxidative stress evoked by oxidized-LDL. These data demonstrate for the first time the direct effects of AvailOm® on resistance arteries. The evidence that the combination of specific vasoactive anthocyanins and AvailOm® further enhanced the vasculoprotective properties of these compounds, may offer new promising perspectives for preventing the onset of cardiovascular and cerebrovascular events.

Serum uric acid (sUA) has been associated with cardiovascular risk. Although the recent mechanistic hypothesis poses the basis for the association between sUA and left ventricular mass index (LVMi), the issue remains poorly investigated in a clinical setup. Through a retrospective analysis of the database of the departmental Hypertension Clinic of University Hospital of Salerno Medical School, we identified 177 essential hypertensives (age 60.3 ± 13.3 years; 85 men), free from uric acid-modulating medications and severe chronic kidney disease, and whose sUA values, anthropometric, clinical, and echocardiographic data were available. In the studied cohort, the average duration of hypertension was 8.4 ± 7.1 years. LVMi associated with classical determinants, such as age, blood pressure, and kidney function, although after multivariate correction, only age remained significant. Also, sUA correlated positively with LVMi, as well as body size, metabolism, and kidney function. In a multivariate analysis, sUA confirmed the independent association with LVMi. Also, levels of sUA >5.6 mg/dl are associated with larger cardiac size. We confirmed our data in a replicate analysis performed in a larger population (1,379 hypertensives) from an independent clinic. Our results demonstrate that sUA increases with LVMi, and a cutoff of 5.6 mg/dl predict larger LV sizes. Our data suggest that hyperuricemia might help to stratify the risk of larger cardiac size in hypertensives.

Insulin resistance (IRES) is a pathophysiological condition characterized by the reduced response to insulin of several tissues, including myocardial and skeletal muscle. IRES is associated with obesity, glucose intolerance, dyslipidemia, and hypertension, evolves toward type 2 diabetes, and increases the risk of developing cardiovascular diseases. Several studies designed to explore the mechanisms involved in IRES allowed the identification of a multitude of potential molecular targets. Among the most promising, G Protein Coupled Receptor Kinase type 2 (GRK2) appears to be a suitable one given its functional implications in many cellular processes. In this review, we will discuss the metabolic role of GRK2 in those conditions that are characterized by insulin resistance (diabetes, hypertension, heart failure), and the potentiality of its inhibition as a therapeutic strategy to revert both insulin resistance and its associated phenotypes.

Aging can be seen as process characterized by accumulation of oxidative stress induced damage. Oxidative stress derives from different endogenous and exogenous processes, all of which ultimately lead to progressive loss in tissue and organ structure and functions. The oxidative stress theory of aging expresses itself in age-related diseases. Aging is in fact a primary risk factor for many diseases and in particular for cardiovascular diseases and its derived morbidity and mortality. Here we highlight the role of oxidative stress in age-related cardiovascular aging and diseases. We take into consideration the molecular mechanisms, the structural and functional alterations, and the diseases accompanied to the cardiovascular aging process.

Abstract DNA methyltransferase 3 A mutations (DNMT3A MT) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3A MT can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3A MT identified out of 5,603 consecutive MNs, of whom 8.4% had multiple DNMT3A MT hits. They were most frequent in acute myeloid leukemia (AML) with R882 variant accounting for 13.3% of the multi-hits. Multiple DNMT3A MT more likely coincided with IDH2 (P = 0.005) and ETV6 (P = 0.044) mutations compared to patients with single DNMT3A MT. When the sum of variant allele frequencies (VAFs) for multiple DNMT3A MT exceeded 60%, we found a significant positive clonal burden correlation of the two DNMT3A variants (P

Abstract PHF6 mutations (PHF6 MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6 MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 are co-mutated with PHF6. In contrast, female cases reveal co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6 MT. Next, proteomics analysis reveals a direct interaction between PHF6 and RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrate a negative prognostic role of PHF6 MT, especially in association with RUNX1. The negative effects on survival are additive as PHF6 MT cases with RUNX1 mutations have worse outcomes when compared to cases carrying single mutation or wild-type.

Background: Alzheimer’s disease is a slowly progressing neurodegenerative illness and the most common form of dementia. This pathology leads to an increase in cognitive decline and is responsible, in patients, for several difficulties in performing various activities of daily living, such as oral hygiene. Several experimental studies have shown that oral health in patients with Alzheimer’s disease worsens in direct proportion to the progression of the disease due to the appearance of gingivitis and periodontitis. Methods: This clinical literature review aims to evaluate a possible correlation between periodontal disease and Alzheimer’s disease, trying to understand if the periopathogens can contribute to the onset or the progression of Alzheimer’s disease (AD). The study was conducted on the database PubMed (MEDLINE) of full-text systematic reviews in English on humans and animals that were published in the last five years, from 2018 to 2023. This returned 50 publications, which, once the eligibility criteria were applied, resulted in the 10 publications examined in this review. The selected articles were organized through the construction of tables, analyzed, and compared through Judith Garrard’s Matrix method to arrive at the review results. Results: Infection by periopathogens can increase the risk of developing Alzheimer’s disease, but also the onset of the latter can make it more difficult to maintain proper oral hygiene, favoring the onset of periodontal disease: it is possible to affirm the existence of a correlation between periodontitis and AD. It was found that patients exposed to chronic periodontitis have a greater risk of developing a cognitive decline or AD and that oral pathogens can be responsible for neuropathologies and increasing systemic inflammation. Conclusions: Periodontitis and periodontal pathogens represent a real risk factor for the onset or worsening of AD; however, the pathogenetic mechanism is still not completely clear.

Background: Periodontal disease is an inflammatory, chronic, and multifactorial disease. The objective of this study is to analyze the association between periodontal disease and some disorders such as papillomas (benign lesions), lichen planus (a chronic immune-mediated disorder), leukoplakia (potentially malignant lesions), and oral cancer (malignant lesions). Methods: For this study, 42 patients were recruited whose supragingival and subgingival plaque was qualitatively analyzed using a phase-contrast microscope, which allowed for the detection of compatible bacterial flora (immobile and composed mainly of cocci) indicative of periodontal health and incompatible bacterial flora (mobile and composed mainly of spirochetes) indicative of periodontal pathology. Patients with incompatible bacterial flora were then subjected to a laser-assisted periodontal treatment with irrigation with hydrogen peroxide within the periodontal pockets (a non-surgical laser-assisted periodontal protocol which is referred to as dye-free photodynamic therapy). Results: Based on the 42 patients recruited, there was no association between oral cavity lesions and periodontal pathogenic bacteria. Four of them were found to have incompatible bacterial flora. Indeed, it was found that almost all the patients had been previously instructed in the proper techniques of home oral hygiene, and more than half of them reported that they carried out periodic check-ups by a dental hygienist. Of the four patients with signs and symptoms of periodontitis, two stated a willingness to undergo the non-surgical laser-assisted periodontal protocol and showed improvements in periodontal indices such as CAL, PPD, and BoP. Conclusions: hygienists and dentists are determining factors in the prevention of periodontal disease and for the maintenance of good oral health.

A new mathematical model that can be applied to both single-cell and bulk DNA sequencing data sheds light on the processes governing population dynamics in stem cells.

KMT2A (alias: mixed-lineage leukemia [MLL]) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the KMT2A gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30–40% and overall survival below 25%. Less intensive regimens are used in pediatric patients, while new combination therapies and targeted immunotherapeutic agents are being explored in adults. Beneficial therapeutic effects, and even cure, can be reached with hematopoietic stem cell transplantation, mainly in young children with dismal molecular lesions; however, delayed related toxicities represent a concern. Herein, we summarize the translocation partner genes and partial tandem duplications of the KMT2A gene, their molecular impact, clinical aspects, and novel targeted therapies.

Abstract Background TP53 mutations (TP53 MT ) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis. Methods We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model by identifying an optimal VAF cutoff using a statistically robust strategy of sampling-based regression on survival data to accurately classify the TP53 allelic configuration and assess prognosis more precisely. Results Overall, TP53 MT were found in 1010 patients. Following the traditional criteria, 36% of the cases were classified as single hits, while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53 MT . Interestingly, our method was able to upstage 192 out of 352 (54.5%) traditionally single hit lesions into a probable biallelic category. Such classification was further substantiated by a survival-based model built after re-categorization. Among cases traditionally considered monoallelic, the overall survival of those with probable monoallelic mutations was similar to the one of wild-type patients and was better than that of patients with a biallelic configuration. As a result, patients with certain biallelic hits, regardless of the disease subtype (AML or MDS), had a similar prognosis. Similar results were observed when the model was applied to an external cohort. In addition, single-cell DNA studies unveiled the biallelic nature of previously considered monoallelic cases. Conclusion Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.

Abstract Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological and clinical features have dominated the classical criteria for diagnosis and classification, incorporation of molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning can identify functional objective molecular clusters, irrespective of anamnestic clinico-morphological features, despite the complexity of the molecular alterations in myeloid neoplasia. Our approach reflects disease evolution, informed classification, prognostication, and molecular interactions. We apply machine learning methods on 3588 patients with myelodysplastic syndromes and secondary acute myeloid leukemia to identify 14 molecularly distinct clusters. Remarkably, our model shows clinical implications in terms of overall survival and response to treatment even after adjusting to the molecular international prognostic scoring system (IPSS-M). In addition, the model is validated on an external cohort of 412 patients. Our subclassification model is available via a web-based open-access resource ( https://drmz.shinyapps.io/mds_latent ).

Abstract Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

Abstract Isolated chronic idiopathic neutropenia (CIN) is a rare disease with multiple contributing etiologies that must be ruled out before establishing a diagnosis. We studied clinical and molecular data of 238 consecutive adult patients with CIN. Autoimmune neutropenia was present in 28% of our cohort. In contrast, T cell-mediated neutropenia was the main underlying pathological mechanism among patients with T cell expansions, such as T-cell large granular lymphocytic leukemia (T-LGL) and T cell clonopathy of undetermined significance, found in 37% and 8% of cases, respectively. Patients with neutropenia also had hypogammaglobulinemia (6%) and/or monoclonal gammopathy of undetermined significance (5%). NGS application has further broadened the spectrum of causes of CIN by including manifestations of clonal hematopoiesis, present in 12% of cases. TET2 (3%), TP53 (2%), and IDH1/IDH2 (2%) mutations were the most commonly found and were enriched in cases with T-LGL. We show that these clinico-molecular associations can be simultaneously present, complicating a proper diagnostic distinction within the broader entity of seemingly idiopathic neutropenia of autoimmune origin. Identification of etiologic culprits may also guide rational selection of therapies.

Therapy-related myeloid neoplasms (t-MN) arise after a documented history of chemo/radiotherapy as treatment for an unrelated condition and account for 10–20% of myelodysplastic syndromes and acute myeloid leukemia. T-MN are characterized by a specific genetic signature, aggressive features and dismal prognosis. The nomenclature and the subsets of these conditions have changed frequently over time, and despite the fact that, in the last classification, they lost their autonomous entity status and became disease qualifiers, the recognition of this feature remains of major importance. Furthermore, in recent years, extensive studies focusing on clonal hematopoiesis and germline variants shed light on the mechanisms of positive pressure underpinning the rise of driver gene mutations in t-MN. In this manuscript, we aim to review the evolution of defining criteria and characteristics of t-MN from a clinical and biological perspective, the advances in mechanistic aspects of malignant progression and the challenges in prevention and management.

Summary: RNA splicing dysfunctions are more widespread than what is believed by only estimating the effects resulting by splicing factor mutations (SFMT) in myeloid neoplasia (MN). The genetic complexity of MN is amenable to machine learning (ML) strategies. We applied an integrative ML approach to identify co-varying features by combining genomic lesions (mutations, deletions, and copy number), exon-inclusion ratio as measure of RNA splicing (percent spliced in, PSI), and gene expression (GE) of 1,258 MN and 63 normal controls. We identified 15 clusters based on mutations, GE, and PSI. Different PSI levels were present at various extents regardless of SFMT suggesting that changes in RNA splicing were not strictly related to SFMT. Combination of PSI and GE further distinguished the features and identified PSI similarities and differences, common pathways, and expression signatures across clusters. Thus, multimodal features can resolve the complex architecture of MN and help identifying convergent molecular and transcriptomic pathways amenable to therapies.

In the last twenty years, we have witnessed a paradigm shift in the treatment and prognosis of acute myeloid leukemia (AML), thanks to the introduction of new efficient drugs or approaches to refine old therapies, such as Gemtuzumab Ozogamicin, CPX 3-5-1, hypomethylating agents, and Venetoclax, the optimization of conditioning regimens in allogeneic hematopoietic stem cell transplantation and the improvement of supportive care. However, the long-term survival of non-M3 and non-core binding factor-AML is still dismal. For this reason, the expectations for the recently developed immunotherapies, such as antibody-based therapy, checkpoint inhibitors, and chimeric antigen receptor strategies, successfully tested in other hematologic malignancies, were very high. The inherent characteristics of AML blasts hampered the development of these treatments, and the path of immunotherapy in AML has been bumpy. Herein, we provide a detailed review of potential antigenic targets, available data from pre-clinical and clinical trials, and future directions of immunotherapies in AML.

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis. This review summarizes the biology and current treatment strategies for PNH with the aim of reaching a general audience with an interest in hematologic disorders.

Abstract Background The ongoing SARS-CoV-2 pandemic requires the availability of accurate and rapid diagnostic tests, especially in such clinical settings as emergency and intensive care units. The objective of this study was to evaluate the diagnostic performance of the Vivalytic SARS-CoV-2 rapid PCR kit in lower respiratory tract (LRT) specimens. Methods Consecutive LRT specimens (bronchoalveolar lavage and bronchoaspirates) were collected from Intensive Care Units of San Martino Hospital (Genoa, Italy) between November 2020 and January 2021. All samples underwent RT-PCR testing by means of the Allplex™ SARS-CoV-2 assay (Seegene Inc., South Korea). On the basis of RT-PCR results, specimens were categorized as negative, positive with high viral load [cycle threshold (Ct) ≤ 30] and positive with low viral load (Ct of 31–35). A 1:1:1 ratio was used to achieve a sample size of 75. All specimens were subsequently tested by means of the Vivalytic SARS-CoV-2 rapid PCR assay (Bosch Healthcare Solutions GmbH, Germany). The diagnostic performance of this assay was assessed against RT-PCR through the calculation of accuracy, Cohen’s κ, sensitivity, specificity and expected positive (PPV) and negative (NPV) predictive values. Results The overall diagnostic accuracy of the Vivalytic SARS-CoV-2 was 97.3% (95% CI: 90.9–99.3%), with an excellent Cohen’s κ of 0.94 (95% CI: 0.72–1). Sensitivity and specificity were 96% (95% CI: 86.5–98.9%) and 100% (95% CI: 86.7–100%), respectively. In samples with high viral loads, sensitivity was 100% (Table 1). The distributions of E gene Ct values were similar (Wilcoxon’s test: p = 0.070), with medians of 35 (IQR: 25–36) and 35 (IQR: 25–35) on Vivalytic and RT-PCR, respectively (Fig. 1). NPV and PPV was 92.6% and 100%, respectively. Table 1 Demographic characteristics and data sample type of the study cases (N = 75) Male, N (%) 56 (74.6%) Age (yr), Median (IQR) 65 (31–81) BAS, N (%) 43 (57.3%) Negative 30.2% Positive—High viral load [Ct ≤ 30] 27.9% Positive—Low viral load [Ct 31–35] 41.9% BAL, N (%) 32 (42.7%) Negative 37.5% Positive—High viral load [Ct ≤ 30] 40.6% Positive—Low viral load [Ct 31–35] 21.9% Data were expressed as proportions for categorical variables. Specimens were categorized into negative, positive with high viral load [cycle threshold (Ct) ≤ 30] and positive with low viral load (Ct of 31–35). BAS bronchoaspirates, BAL bronchoalveolar lavage, Ct cycle threshold Fig. 1 Distribution of E gene cycle threshold values of the rapid PCR and RT-PCR Conclusions Vivalytic SARS-CoV-2 can be used effectively on LRT specimens following sample liquefaction. It is a feasible and highly accurate molecular procedure, especially in samples with high viral loads. This assay yields results in about 40 min, and may therefore accelerate clinical decision-making in urgent/emergency situations.

Structural and functional variability of human leukocyte antigen (HLA) is the foundation for competent adaptive immune responses against pathogen and tumor antigens as it assures the breadth of the presented immune-peptidome, theoretically sustaining an efficient and diverse T cell response. This variability is presumably the result of the continuous selection by pathogens, which over the course of evolution shaped the adaptive immune system favoring the assortment of a hyper-polymorphic HLA system able to elaborate efficient immune responses. Any genetic alteration affecting this diversity may lead to pathological processes, perturbing antigen presentation capabilities, T-cell reactivity and, to some extent, natural killer cell functionality. A highly variable germline HLA genotype can convey immunogenetic protection against infections, be associated with tumor surveillance or influence response to anti-neoplastic treatments. In contrast, somatic aberrations of HLA loci, rearranging the original germline configuration, theoretically decreasing its variability, can facilitate mechanisms of immune escape that promote tumor growth and immune resistance.The purpose of the present review is to provide a unified and up-to-date overview of the pathophysiological consequences related to the perturbations of the genomic heterogeneity of HLA complexes and their impact on human diseases, with a special focus on cancer.

Summary: Background: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection. Methods: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose. Findings: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p

Summary: Background: Haploinsufficiency (HI) resulting from deletion of the long arm of chromosome 5 [del(5q)] and the accompanied loss of heterozygosity are likely key pathogenic factors in del(5q) myeloid neoplasia (MN) although the consequences of del(5q) have not been yet clarified. Methods: Here, we explored mutations, gene expression and clinical phenotypes of 388 del(5q) vs. 841 diploid cases with MN [82% myelodysplastic syndromes (MDS)]. Findings: Del(5q) resulted as founder (better prognosis) or secondary hit (preceded by TP53 mutations). Using Bayesian prediction analyses on 57 HI marker genes we established the minimal del(5q) gene signature that distinguishes del(5q) from diploid cases. Clusters of diploid cases mimicking the del(5q) signature support the overall importance of del(5q) genes in the pathogenesis of MDS in general. Sub-clusters within del(5q) patients pointed towards the inherent intrapatient heterogeneity of HI genes. Interpretation: The underlying clonal expansion drive results from a balance between the “HI-driver” genes (e.g., CSNK1A1, CTNNA1, TCERG1) and the proapoptotic “HI-anti-drivers” (e.g., RPS14, PURA, SIL1). The residual essential clonal expansion drive allows for selection of accelerator mutations such as TP53 (denominating poor) and CSNK1A1 mutations (with a better prognosis) which overcome pro-apoptotic genes (e.g., p21, BAD, BAX), resulting in a clonal expansion. In summary, we describe the complete picture of del(5q) MN identifying the crucial genes, gene clusters and clonal hierarchy dictating the clinical course of del(5q) patients. Funding: Torsten Haferlach Leukemia Diagnostics Foundation. US National Institute of Health (NIH) grants R35 HL135795, R01HL123904, R01 HL118281, R01 HL128425, R01 HL132071, and a grant from Edward P. Evans Foundation.

The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients. We characterized VISTA mRNA expression levels in leukemia cell lines and in large publicly available cohorts of specimens from bone marrow of healthy individuals and AML patients at diagnosis by deploying bulk and single-cell RNA sequencing. We also defined the correlations with leukemia-associated burden using results of whole-exome sequencing of AML samples at disease onset. We showed that VISTA expression linearly increased across the myeloid differentiation tree in normal hematopoiesis. Accordingly, its transcript was highly enriched in AML cell lines as well as in AML patients at diagnosis presenting with myelomonocytic and monocytic differentiation. A strong correlation was seen with NPM1 mutations regardless of the presence of FLT3 lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and NPM1 mutations, a subgroup traditionally considered as favorable according to current diagnostic schemes. Indeed, when compared to patients with long-term remission (>5 years after standard chemotherapy regimens), cases relapsing within 2 years from diagnosis had increased VISTA expression in both leukemia and T cells. Our results suggest a rationale for developing VISTA-targeted therapeutic strategies to treat molecularly defined subgroups of AML patients to prevent disease recurrence and treatment resistance.