Expression and functional role of Ccdc80 in normal heart and cardiomyopathies

Background: The gene Coiled Coil Domain Containing 80 (Ccdc80) is widely expressed in normal human tissues, at particularly high levels in heart, skeletal muscle and adipose tissue. Its role is well defined in tumor suppression, axon path finding, glucose homeostasis, bone marrow stromal cells and adipocyte differentiation. Moreover, it plays a role in embryonic development of lens and muscle, but no clear-cut data are available about the role of Ccdc80 in heart development and in heart disease. Aims: To define if Ccdc80 is expressed during embryonic development of zebrafish heart and if its functional block causes alterations of heart structure or contractility; to define the expression pattern of Ccdc80 protein in normal heart vs cardiomyopathies in humans (samples taken from patients with dilated cardiomyopathy – DCM) and rodents (samples taken from right ventricle heart failure induced by monocrotaline – MCT). Results: In zebrafish Ccdc80 is widely expressed in the forming heart, during all the developmental stages; Ccdc80-morphants show defects in the developing heart, with impaired cardiac looping, atrium enlargement, blood stasis and peripheral congestion. These phenotypical alterations, similar to heart failure, are due to a disorder of the late phase of cardiac development, after myocyte differentiation. In normal human and rats, Ccdc80 mRNA, analized by Northern blot technique, showed a higher expression in atria compared to ventricles, while the Ccdc80 protein (108 Kd), analized by Western blot, showed similar expression levels in atria and ventricles. Ccdc80 protein showed different expression patterns, in atria and ventricles with a cytoplasmic localization and co-localization with sarcomeric proteins at immunofluorescence analysis. In pathological samples (DCM and MCT rats) Ccd80 protein showed evident overexpression and different isoforms, related to protein phosphorylation and secreted protein isoform, suggesting a different feature in pathological conditions compared to normal. Conclusions: Our results demonstrated that Ccdc80 has an indispensable role for correct heart development. In complete developed heart, Ccdc80 showed an adaptive function to stress conditions, such as pressure overload, and in cardiomyopathies showed increased expression and different isoform

Detection of Spatial and Temporal Stress Changes During the 2016 Central Italy Seismic Sequence by Monitoring the Evolution of the Energy Index

We consider approximately 23,000 microearthquakes that occurred between 2005 and 2016 in central Italy to investigate the crustal strength before and after the three largest earthquakes of the 2016 seismic sequence (i.e., the Mw 6.2, 24 August 2016 Amatrice, the Mw 6.1, 26 October 2016 Visso, and the Mw 6.5, 30 October 2016 Norcia earthquakes). We monitor the spatiotemporal deviations of observed radiated energy, ES, with respect to theoretical values, ESt, derived from a scaling model between ES and M0 calibrated for background seismicity in central Italy. These deviations, defined here as Energy Index (EI), allow us to identify in the years following the Mw 6.1, 2009 L’Aquila earthquake a progressive evolution of the dynamic properties of microearthquakes and the existence of high EI patches close to the Amatrice earthquake hypocenter. We show the existence of a crustal volume with high EI even before the Mw 6.5 Norcia earthquake. Our results agree with the previously suggested hypothesis that the Norcia earthquake nucleated at the boundary of a large patch, highly stressed by the two previous mainshocks of the sequence. We highlight the mainshocks interaction both in terms of EI and of the mean loading shear stress associated to microearthquakes occurring within the crustal volumes comprising the mainshock hypocenters. Our study shows that the dynamic characteristics of microearthquakes can be exploited as beacons of stress change in the crust and thus be exploited to monitor the seismic hazard of a region and help to intercept the preparation phase of large earthquakes

Effects of antihypertensive treatment on endothelial function in postmenopausal hypertensive women. A significant role for aldosterone inhibition

Introduction: Endothelial dysfunction is a well-demonstrated independent predictor of cardiovascular events in hypertensive postmenopausal women. Accordingly, it is plausible that improving endothelial function could represent an adjunctive target for antihypertensive treatment. The aim of our study was to evaluate the effect of pharmacologic treatment on endothelial function in the specific population of hypertensive postmenopausal women.Methods: A total of 320 consecutive hypertensive postmenopausal women underwent a high-resolution ultrasound study of the brachial artery at baseline and after six months, while 'optimal' control of blood pressure (maintenance of blood pressure values below 140/90 mmHg at all follow-up visits) was achieved using antihypertensive therapy. Endothelial function was measured as flow-mediated dilation, using ultrasound method.Results: After six months of treatment, flow-mediated dilatation (FMD) had significantly improved in the majority of patients (n = 257 [80.3% of the entire population]; FMD = 8.1 ± 1.0% at baseline vs. 10.6 ± 1.5% after follow-up; p < 0.001), but it had not changed or worsened in others (n = 63 [19.7%]; FMD = 8.2 ± 1.2% at baseline vs. 7.6 ± 1.0% after six months; p = ns). Improvement of endothelial function, at multivariate analysis, resulted independently associated with the use of aldosterone inhibitors (odds ratio = 2.15; 95% confidence interval: 1.55-2.75; p = 0.001).Conclusions: This study demonstrates that a significant improvement in endothelial function may be obtained after six months of an optimal antihypertensive therapy. Among all hypertensive postmenopausal women that achieved an optimal control of blood pressure during follow-up, the use of drugs that inhibit aldosterone receptors was associated with an improvement of endothelial function, beyond the 'optimal' blood pressure control. © SAGE Publications 2011

Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor

Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients

Can Integrated Care Help in Meeting the Challenges Posed on Our Health Care Systems by COVID-19? Some Preliminary Lessons Learned from the European VIGOUR Project

The COVID-19 pandemic puts health and care systems under pressure globally. This current paper highlights challenges arising in the care for older and vulnerable populations in this context and reflects upon possible perspectives for different systems making use of nested integrated care approaches adapted during the work of the EU-funded project VIGOU

Expression and functional role of Ccdc80 in normal heart and cardiomyopathies

Background: The gene Coiled Coil Domain Containing 80 (Ccdc80) is widely expressed in normal human tissues, at particularly high levels in heart, skeletal muscle and adipose tissue. Its role is well defined in tumor suppression, axon path finding, glucose homeostasis, bone marrow stromal cells and adipocyte differentiation. Moreover, it plays a role in embryonic development of lens and muscle, but no clear-cut data are available about the role of Ccdc80 in heart development and in heart disease. Aims: To define if Ccdc80 is expressed during embryonic development of zebrafish heart and if its functional block causes alterations of heart structure or contractility; to define the expression pattern of Ccdc80 protein in normal heart vs cardiomyopathies in humans (samples taken from patients with dilated cardiomyopathy – DCM) and rodents (samples taken from right ventricle heart failure induced by monocrotaline – MCT). Results: In zebrafish Ccdc80 is widely expressed in the forming heart, during all the developmental stages; Ccdc80-morphants show defects in the developing heart, with impaired cardiac looping, atrium enlargement, blood stasis and peripheral congestion. These phenotypical alterations, similar to heart failure, are due to a disorder of the late phase of cardiac development, after myocyte differentiation. In normal human and rats, Ccdc80 mRNA, analized by Northern blot technique, showed a higher expression in atria compared to ventricles, while the Ccdc80 protein (108 Kd), analized by Western blot, showed similar expression levels in atria and ventricles. Ccdc80 protein showed different expression patterns, in atria and ventricles with a cytoplasmic localization and co-localization with sarcomeric proteins at immunofluorescence analysis. In pathological samples (DCM and MCT rats) Ccd80 protein showed evident overexpression and different isoforms, related to protein phosphorylation and secreted protein isoform, suggesting a different feature in pathological conditions compared to normal. Conclusions: Our results demonstrated that Ccdc80 has an indispensable role for correct heart development. In complete developed heart, Ccdc80 showed an adaptive function to stress conditions, such as pressure overload, and in cardiomyopathies showed increased expression and different isoformsIntroduzione: Il gene Coiled Coil Domain Containing 80 (Ccdc80) è ampiamente espresso in tessuti umani normali, a livelli particolarmente elevati nel cuore, muscolo scheletrico e tessuto adiposo. E’ ben definito il suo ruolo come oncosoppressore, nella innervazione degli assoni, nella omeostasi glicemica, e nel differenziamento delle cellule stromali del midollo osseo e degli adipociti. Inoltre, svolge un ruolo nello sviluppo embrionale muscolare e della lente del cristallino, ma non sono disponibili dati sul ruolo di Ccdc80 nello sviluppo del cuore e nelle malattie cardiache. Obiettivi : Definire se Ccdc80 è espresso durante lo sviluppo embrionale del cuore zebrafish e se il suo blocco funzionale provoca alterazioni della struttura o della contrattilità; definire il pattern di espressione della proteina Ccdc80 nel cuore normale vs cardiomiopatie nell'uomo (campioni prelevati da pazienti con cardiomiopatia dilatativa - DCM ) e roditori (campioni prelevati da ratti con insufficienza ventricolare destra indotta da monocrotalina - MCT). Risultati: In zebrafish Ccdc80 è ampiamente espresso nel cuore in formazione, durante tutte le fasi di sviluppo; i morfanti per Ccdc80 mostrano difetti nello sviluppo cardiaco, con alterato looping, dilatazione atriale, stasi ematica e congestione periferica. Queste alterazioni fenotipiche, simili ad uno scompenso cardiaco, sono dovuti ad un disturbo della fase tardiva dello sviluppo cardiaco, dopo che la differenziazione dei miociti è già stata completata. Nei campioni normali di uomo e ratto, l’RNA messaggero di Ccdc80, analizzato con tecnica di Northern blot, è risultato maggiormente espresso negli atri rispetto ai ventricoli, il mentre l’espressione della proteina Ccdc80 (108 Kd), analizzata con tecnica Western blot, è risultata simile negli atri e nei ventricoli. La proteina Ccdc80 ha mostrato pattern di espressione diversi in atri e ventricoli, con localizzazione citoplasmatica e chiara co-localizzazione con le proteine sarcomeriche all’immunofluorescenza. Nei campioni patologici (DCM ed MCT ratti) la proteina Ccd80 ha mostrato una netta iper-espressione sia negli atri che nei ventricoli, e la presenza di diverse isoforme, suggerendo diverse funzioni in condizioni patologiche rispetto al normale . Conclusioni: I nostri risultati hanno dimostrato che Ccdc80 ha un ruolo indispensabile nello sviluppo cardiaco. Nel cuore adulto, Ccdc80 si manifesta con diverse isoforme e maggiore espressione, rivestendo una funzione adattativa in condizioni di stress, come il sovraccarico di pressione, e nelle cardiomiopati

The preparatory process of the 2023 Mw 7.8 Türkiye earthquake

Abstract To verify the existence of a preparatory process for the 6 February 2023, Mw 7.8 Kahramanmaraş earthquake, southern Türkiye, we analyze the temporal evolution of seismic catalog information for ~ 7500 earthquakes with magnitudes ML ≥ 1.5, which occurred along the main segments of the East Anatolian Fault (EAF) since 2014. We find the EAF fault segments showing different temporal patterns in the proportion of nonclustered seismicity, which we interpret as temporal variation of coupling. We also study the evolution of the b-value, fractal dimension and energy rate. These seismic features show for the Amanos and Pazarcık fault segments a long-term trend during the period 2020–2022 that might correspond to a quiescence phase. The latter is followed by a change in earthquakes clustering and characteristics that starts about eight months before the Mw 7.8 Kahramanmaraş event. Our observations confirm the existence of a long-lasting preparatory phase for the 2023, Mw 7.8 Kahramanmaraş earthquake and can stimulate new investigations on the East Anatolian Fault mechanic. Intercepting when a fault starts deviating from its steady behavior, might be the key for identifying the preparatory phase of large earthquakes and mitigate seismic risk

Left main coronary artery thrombosis with distal coronary embolization in a patient with methyltetrahydrofolate reductase C677T mutation presenting with STEMI

No abstract availabl

On catching the preparatory phase of damaging earthquakes: an example from central Italy

Abstract How, when and where large earthquakes are generated remain fundamental unsolved scientific questions. Intercepting when a fault system starts deviating from its steady behavior by monitoring the spatio-temporal evolution and dynamic source properties of micro-to-small earthquakes can have high potential as tool for identifying the preparatory phase of large earthquakes. We analyze the seismic activity that preceded the Mw 6.3 earthquake that hit L’Aquila on 6 April 2009 in central Italy, and we show that the seismic catalog information can be transformed into features allowing us to track in a statistical framework the spatio-temporal evolution of seismicity. Features associated to foreshocks show different patterns from the background seismicity that occurred in the previous years. We show that features ensemble allows to clearly capture the activation phase of the main event. Nonetheless, foreshocks share similar clustering properties of previous seismic sequences not culminating in large earthquakes, and thus generating questions on their use as potential precursor for earthquake sequences prone to evolve into catastrophic sequences