Altered modulation of lamin A/C-HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson-Gilford progeria, a severe LMNA-linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C-HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C-HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms

Social Resources and Emotional Exhaustion: The Role of Communication in Professional Relationships

CC BY-NC-ND 4.0Communication is an element that permeates the lives of individuals, from birth to death. Through it, it is possible to create new shared meanings, relationships, and social networks. The importance of the communication process emerges in different contexts, one of which is undoubtedly the work context: several types of research have affirmed that efficient organizational communication produces positive outcomes at the level of workers and organizations, such as increased work commitment, satisfaction, and the reduction of phenomena such as emotional exhaustion and cynicism. Starting from the theoretical framework of the Job Demands-Job Resources model, which divides the characteristics of each work context according to two general categories – namely job demands (representing workers’ efforts in performing their job tasks) and job resources (facilitating aspects of work that can provide opportunities for personal growth) – the aim of this research is to explore the role of communication between colleagues and superiors in the relationship between a job resource (increased social resources) and a negative outcome, such as emotional exhaustion, by means of a non-parametric structural equation model (PLS-SEM), in a sample of 479 workers. Reliable structural and measurement models yielded excellent fit indices of the hypothesized latent variables. The results show that, for workers, enhancing social resources by asking for feedback from colleagues and bosses does not protect against the risks of emotional exhaustion, but in fact improves communication. The exclusive use of social resources at work does not have a significant impact on the risk of emotional exhaustion if it is not accompanied by perceived communication appropriate to the circumstances and contexts. Communication, therefore, fully mediates the relationship between increased social resources and emotional exhaustion and stands out as a crucial protective factor

Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells Derived from Human Arteries: A Novel Strategy to Accelerate Vascular Ulcer Wound Healing

Vascular ulcers are a serious complication of peripheral vascular disease, especially in diabetics. Several approaches to treat the wounds are proposed but they show poor outcomes and require long healing times. Hepatocyte Growth Factor/Scatter Factor (HGF/SF) is a pleiotropic cytokine exerting many biological activities through the c-Met receptor. This study was aimed at verifying whether HGF/SF influences proliferation, migration, and angiogenesis on mesenchymal stem cells isolated from human arteries (hVW-MSCs). hVW-MSCs were exposed to NIBSC HGF/SF (2.5, 5, 10, and 70 ng/mL) from 6 hrs to 7 days. HGF and c-MET mRNA and protein expression, cell proliferation (Alamar Blue and Ki–67 assay), migration (scratch and transwell assays), and angiogenesis (Matrigel) were investigated. hVW-MSCs displayed stemness features and expressed HGF and c-MET. HGF/SF did not increase hVW-MSC proliferation, whereas it enhanced the cell migration, the formation of capillary-like structures, and the expression of angiogenic markers (vWF, CD31, and KDR). The HGF/SF effects on hVW-MSC migration and angiogenic potential are of great interest to accelerate wound healing process. Local delivery of HGF/SF could therefore improve the healing of unresponsive vascular ulcers

Non-alcoholic fatty liver disease is associated with early left ventricular dysfunction in childhood acute lymphoblastic leukaemia survivors.

Background: Childhood acute lymphoblastic leukaemia (ALL) survivors have an increased risk of metabolic and cardiovascular disease. We aimed to assess the presence of non-alcoholic fatty liver disease (NAFLD) in childhood ALL and if it is associated with early cardiovascular dysfunction. Methods: In total, 53 childhood ALL survivors and 34 controls underwent auxological evaluation, biochemical assay, liver, heart and vascular ultrasound study. Results: NAFLD was more frequent in ALL patients than in controls (39.6% vs 11.7%, P < 0.01). Patients with NAFLD were more obese and insulin resistant than patients without NAFLD. Flow-mediated dilatation and interventricular septum were lower in the ALL group than those in the control group (P < 0.001 for both). The patients with NAFLD showed lower left ventricular ejection fraction than those without NAFLD (P = 0.011). In ALL survivors, BMI-SDS and subcutaneous fat were the strongest predictors of NAFLD, whereas preperitoneal adipose tissue and C-reactive protein were the strongest predictors of left ventricular ejection fraction. Conclusions: Childhood ALL survivors had higher prevalence of NAFLD than healthy controls, which is associated with early left ventricular impairment. In the case of fatty liver, a comprehensive heart evaluation is mandatory. We strongly recommend to prevent visceral adiposity in ALL survivors, to search for metabolic syndrome or its components and to reinforce the need of intervention on diet and lifestyle during the follow-up of these patients

Restored perfusion and reduced inflammation in the infarcted heart after grafting stem cells with a hyaluronan-based scaffold

The aim of this study is to investigate the blood perfusion and the inflammatory response of the myocardial infarct area after transplanting a hyaluronan-based scaffold (HYAFF\uae11) with bone marrow mesenchymal stem cells (MSCs). Nine-week-old female pigs were subjected to a permanent left anterior descending coronary artery ligation for 4 weeks. According to the kind of the graft, the swine subjected to myocardial infarction were divided into the HYAFF\uae11, MSCs, HYAFF\uae11/MSCs and untreated groups. The animals were killed 8 weeks after coronary ligation. Scar perfusion, evaluated by Contrast Enhanced Ultrasound echography, was doubled in the HYAFF\uae11/MSCs group and was comparable with the perfusion of the healthy, non-infarcted hearts. The inflammation score of the MSCs and HYAFF\uae11/MSCs groups was near null, revealing the role of the grafted MSCs in attenuating the cell infiltration, but not the foreign reaction strictly localized around the fibres of the scaffold. Apart from the inflammatory response, the native tissue positively interacted with the HYAFF\uae11/MSCs construct modifying the extracellular matrix with a reduced presence of collagene and increased amount of proteoglycans. The border-zone cardiomyocytes also reacted favourably to the graft as a lower degree of cellular damage was found. This study demonstrates that the transplantation in the myocardial infarct area of autologous MSCs supported by a hyaluronan-based scaffold restores blood perfusion and almost completely abolishes the inflammatory process following an infarction. These beneficial effects are superior to those obtained after grafting only the scaffold or MSCs, suggesting that a synergic action was achieved using the cell-integrated polymer construct

Preoperative evaluation of pulmonary artery morphology and pulmonary circulation in neonates with pulmonary atresia - usefulness of MR angiography in clinical routine

BACKGROUND: To explore the role of contrast-enhanced magnetic resonance angiography (CE-MRA) in clinical routine for evaluating neonates with pulmonary atresia (PA) and to describe their pulmonary artery morphology and blood supply.CE-MRA studies of 15 neonates with PA (12 female; median weight: 2900 g) were retrospectively evaluated by two radiologists in consensus. Each study was judged to be either diagnostic or non-diagnostic depending on the potential to evaluate pulmonary artery morphology and pulmonary blood supply. In those cases where surgery or conventional angiocardiography was performed results were compared. RESULTS: CE-MRA was considered diagnostic in 87%. Pulmonary artery morphology was classified as "confluent with (n = 1) and without (n = 1) main pulmonary artery", "non-confluent" (n = 6) or "absent" (n = 7). Source of pulmonary blood supply was "a persistent arterial duct" (n = 12), "a direct" (n = 22) or "indirect (n = 9) aortopulmonary collateral artery (APCA)" or "an APCA from the ascending aorta" (n = 2). In no patient were there any additional findings at surgery or conventional angiocardiography which would have changed the therapeutic or surgical approach. CONCLUSIONS: CE-MRA is a useful diagnostic tool for the preoperative evaluation of the morphology of pulmonary arteries and blood supply in neonates with PA. In most cases diagnostic cardiac catheterization can be avoided

Epidemiology of gastroenteropancreatic neuroendocrine neoplasms: a review and protocol presentation for bridging tumor registry data with the Italian association for neuroendocrine tumors (Itanet) national database

: Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083)