Multimedica IRCCS

Sesto San Giovanni, Italy

Multimedica IRCCS

Sesto San Giovanni, Italy
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Mangialardi G.,University of Bristol | Monopoli A.,NicOx | Ongini E.,NicOx | Spinetti G.,Multimedica IRCCS | And 3 more authors.
British Journal of Pharmacology | Year: 2011

BACKGROUND AND PURPOSE Statins, a major component of the prevention of cardiovascular disease, aid progenitor cell functions in vivo and in vitro. Statins bearing a NO-releasing moiety were developed for their enhanced anti-inflammatory/anti-thrombotic properties. Here, we investigated if the NO-donating atorvastatin (NCX 547) improved the functions of circulating angiogenic cells (CACs). EXPERIMENTAL APPROACH Circulating angiogenic cells (CACs) were prepared from peripheral blood monocytes of healthy volunteers and type-2 diabetic patients and were cultured in low (LG) or high glucose (HG) conditions, in presence of atorvastatin or NCX 547 (both at 0.1 μM) or vehicle. Functional assays (outgrowth, proliferation, viability, senescence and apoptosis) were performed in presence of the endothelial NOS inhibitor L-NIO, the NO scavenger c-PTIO or vehicle. KEY RESULTS Culturing in HG conditions lowered NO in CACs, inhibited outgrowth, proliferation, viability and migration, and induced cell senescence and apoptosis. NCX 547 fully restored NO levels and functions of HG-cultured CACs, while atorvastatin prevented only apoptosis in CACs. The activity of Akt, a pro-survival kinase, was increased by atorvastatin in LG-cultured but not in HG-cultured CACs, whereas NCX 547 increased Akt activity in both conditions. L-NIO partially blunted and c-PTIO prevented NCX 547-induced improvements in CAC functions. Finally, NCX 547 improved outgrowth and migration of CACs prepared from patients with type 2 diabetes. CONCLUSIONS AND IMPLICATIONS NCX 547 was more effective than atorvastatin in preserving functions of CACs. This property adds to the spectrum of favourable actions that would make NO-releasing statins more effective agents for treating cardiovascular disease. © 2011 The British Pharmacological Society.


D'Elia E.,Azienda Ospedaliera Papa Giovanni XXIII | Pascale A.,University of Pavia | Marchesi N.,University of Pavia | Ferrero P.,Azienda Ospedaliera Papa Giovanni XXIII | And 5 more authors.
Heart Failure Reviews | Year: 2014

The review aims to discuss the role of nerve growth factor (NGF) as a potential novel biomarker in post-myocardial infarction (MI) and in heart failure (HF), with a specific focus on neural remodeling and sprouting processes occurring after tissue damage. Many experimental data show that MI induces nerve sprouting, leading to increased sympathetic outflow and higher risk of ventricular arrhythmias and sudden cardiac death. In this framework, cardiac and circulating NGF might be an indicator of the innervation process and neural remodeling: it dramatically increases after MI, while it declines along with advanced HF and ventricular dysfunction. The bimodal behavior of NGF in acute and chronic settings leads to the speculation that NGF modulation may be a pharmacological target for intervention in different stages of the ischemic heart disease. Specifically, a fascinating possibility is to support or to inhibit NGF receptors, in order to prevent negative cardiac remodeling after MI and consequent ventricular dysfunction. © Springer Science+Business Media 2013.


Vono R.,Multimedica IRCCS | Spinetti G.,Multimedica IRCCS | Gubernator M.,Royal Infirmary | Madeddu P.,Royal Infirmary
Journal of Cardiovascular Translational Research | Year: 2012

Coronary artery disease (CAD) is exceedingly prevalent and requires care optimization. Regenerative medicine holds promise to improve the clinical outcome of CAD patients. Current approach consists in subsidizing the infarcted heart with boluses of autologous stem cells from the bone marrow. Moreover, mesenchymal stem cells (MSCs) are in the focus of intense research owing to an apparent superiority in plasticity and regenerative capacity compared with hematopoietic stem cells. In this review, we report recent findings indicating the presence, within the heterogeneous MSC population, of perivascular stem cells expressing typical pericyte markers. Moreover, we focus on recent research showing the presence of similar cells in the adventitia of large vessels. These discoveries were fundamental to shape a roadmap toward clinical application in patients with myocardial ischemia. Adventitial stem cells are ideal candidates for promotion of cardiac repair owing to their ease of accessibility and expandability and potent vasculogenic activity. © 2012 Springer Science+Business Media, LLC.


Pennesi G.,MultiMedica IRCCS | Scaglione S.,Centro Biotecnologie Avanzate CBA | Scaglione S.,University of Genoa | Giannoni P.,Centro Biotecnologie Avanzate CBA | Quarto R.,University of Genoa
Current Pharmaceutical Biotechnology | Year: 2011

A stem cell is defined as a cell able to self-renew and at the same time to generate one or more specialized progenies. In the adult organism, stem cells need a specific microenvironment where to reside. This tissue-specific instructive microenvironment, hosting stem cells and governing their fate, is composed of extracellular matrix and soluble molecules. Cell-matrix and cell-cell interactions also contribute to the specifications of this milieu, regarded as a whole unitary system and referred to as "niche". For many stem cell systems a niche has been identified, but only partially defined. In regenerative medicine and tissue engineering, biomaterials are used to deliver stem cells in specific anatomical sites where a regenerative process is needed. In this context, biomaterials have to provide informative microenvironments mimicking a physiological niche. Stem cells may read and decode any biomaterial and modify their behavior and fate accordingly. Any material is therefore informative in the sense that its intrinsic nature and structure will anyway transmit a signal that will have to be decoded by colonizing cells. We still know very little of how to create local microenvironments, or artificial niches, that will govern stem cells behavior and their terminal fate. Here we will review some characteristics identifying specific niches and some of the requirements allowing stem cells differentiation processes. We will discuss on those biomaterials that are being projected/engineered/manufactured to gain the informative status necessary to drive proper molecular cross-talk and cell differentiation; specific examples will be proposed for bone and cartilage substitutes. © 2011 Bentham Science Publishers Ltd.


Fagoonee S.,University of Turin | Bearzi C.,Multimedica IRCCS | Bearzi C.,National Research Council Italy | Di Cunto F.,University of Turin | And 9 more authors.
PLoS ONE | Year: 2013

In pluripotent stem cells, there is increasing evidence for crosstalk between post-transcriptional and transcriptional networks, offering multifold steps at which pluripotency can be controlled. In addition to well-studied transcription factors, chromatin modifiers and miRNAs, RNA-binding proteins are emerging as fundamental players in pluripotency regulation. Here, we report a new role for the RNA-binding protein ESRP1 in the control of pluripotency. Knockdown of Esrp1 in mouse embryonic stem cells induces, other than the well-documented epithelial to mesenchymal-like state, also an increase in expression of the core transcription factors Oct4, Nanog and Sox2, thereby enhancing self-renewal of these cells. Esrp1-depleted embryonic stem cells displayed impaired early differentiation in vitro and formed larger teratomas in vivo when compared to control embryonic stem cells. We also show that ESRP1 binds to Oct4 and Sox2 mRNAs and decreases their polysomal loading. ESRP1 thus acts as a physiological regulator of the finely-tuned balance between self-renewal and commitment to a restricted developmental fate. Importantly, both mouse and human epithelial stem cells highly express ESRP1, pinpointing the importance of this RNA-binding protein in stem cell biology. © 2013 Fagoonee et al.


Ferratini M.,Don Carlo Gnocchi Foundation | Marianeschi S.,Niguarda Ca Granda Hospital | Santoro F.,Niguarda Ca Granda Hospital | Vitali E.,Instituto Clinico Humanitas IRCCS | And 8 more authors.
International Journal of Cardiology | Year: 2013

Despite the high burden of rheumatic fever in sub-Saharan African, there is currently no sustained and comprehensive strategy to control the disease. Consequently in this area the number of patients affected by rheumatic valve disease (RVD), most with a surgical indication, is 10-20 fold higher than in industrialised countries and estimates indicate that more than 50% of African RVD patients will die before age 25. In this paper, we review clinical and management issues of RVD in children in sub-Saharan Africa. Severe heart failure and undergrowth are the prevalent presentation of the illness. Severe mitral regurgitation is the commonest rheumatic valvulopathy observed in the first and second decades. Valve repair, the approach of choice, may be associated with unfavourable outcomes in patients with extreme cardiomegaly. In young people, whenever correct anticoagulation may reasonably be achieved, mechanical mitral prostheses should be preferred, even in females. The early deterioration of biologic mitral prostheses strongly suggests limiting their use to those cases in which correct anticoagulation is not feasible. In most sub-Saharan countries, socioeconomic factors strongly limit access to health services and to cardiac surgery in particular. Efforts to overcome these barriers have resulted in humanitarian projects along two patterns: creation of high tech on site health care structures or transfer of children with complex diseases to receive highly specialised cardiac surgical care abroad. We summarise the experience of our programme that followed the latter approach. © 2012 Elsevier Ireland Ltd.


Micello D.,Multimedica IRCCS | Marando A.,University of Insubria | Sahnane N.,University of Insubria | Riva C.,University of Insubria | And 3 more authors.
Virchows Archiv | Year: 2010

The estrogen receptor (ER)/progesterone receptor (PR)-negative breast carcinomas (BCs) encompass three molecular subtypes: one with human epidermal growth factor receptor 2 (HER) overexpression, one normal like, and the triple negative. The androgen receptor (AR) is expressed in 70-90% of invasive BCs. The aim of our study is to detect the expression of AR in a series of ER/PR-negative BCs to ascertain if there is clinical significance in relation to BC molecular subtypes. A immunohistochemical study for all receptors and cytokeratin expression was performed in 232 cases of ER/PR-negative BCs. According to cytokeratin expression, BCs were classified into two groups: luminal-type BCs (44.2%) and basal-like-type BCs (55.8%). According to the expression of HER2, 59.3% were triple-negative BCs (when ER, PR, and HER2 were negative) and 40.7% were HER2-positive BCs. AR expression was observed in 128 tumors (56.6%). One hundred and ten cases (48.8%) had >10% and 18 (7.8%) had <10% of positively stained cells. AR immunoreactivity was found in 31.2% basal-like BCs, while in the luminal group 71.1% of cases were positive, showing highly significant correlation (p∈<∈10-8). Regarding HER2 status, 76.7% of HER2-positive BC cases were AR positive compared with only 30.4% of triple-negative BC types, showing a strong statistically significant correlation. In conclusion, we show that AR is frequently expressed in ER/PR-negative BCs and that expression of HER2 and AR is highly correlated (p∈<∈0.005). Our results point out the role of AR and HER2 in the pathogenesis of BCs and suggest the potential role of AR in clinical management of ER/PR-negative BCs. © 2010 Springer-Verlag.


Airoldi F.,Multimedica IRCCS | Faglia E.,Multimedica IRCCS | Losa S.,Multimedica IRCCS | Tavano D.,Multimedica IRCCS | And 4 more authors.
CardioVascular and Interventional Radiology | Year: 2011

Subintimal angioplasty (SAP) is frequently performed for the treatment of critical limb ischemia (CLI) and has been recognized as an effective technique for these patients. Nevertheless, this approach is limited by the lack of controlled re-entry into the true lumen of the target vessel. We describe a novel device for true lumen re-entry after subintimal recanalization of superficial femoral arteries (SFA). We report our experience with six patients treated between April 2009 and January 2010 with a novel system designed to facilitate true lumen re-entry. The device was advanced by ipsilateral antegrade approach through a 6-French sheath. Successful reaccess into the true lumen was obtained in five of six patients without complications. The patient in whom the reaccess to the true lumen was not possible underwent successful bypass surgery. At 30 days follow-up, the SFA was patent in all patients according to echo-Doppler examination. Our preliminary experience indicates that this novel re-entry device increases the success rate of percutaneous revascularization of chronically occluded SFA. © Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2010.


PubMed | Hebrew University of Jerusalem and Multimedica IRCCS
Type: Journal Article | Journal: Organic letters | Year: 2015

The synthesis and the structural characterization of dipeptides composed of unnatural fluorine-substituted (2,3)-diarylamino acid and L-alanine are reported. Depending on the stereochemistry of the amino acid, these dipeptides are able to self-assemble into proteolytic stable nanotubes. These architectures were able to enter the cell and locate in the cytoplasmic/perinuclear region and represent interesting candidates for biomedical applications.


Dominek P.,University of Bristol | Campagnolo P.,University of Bristol | H-Zadeh M.,University of Bristol | Krankel N.,University of Bristol | And 8 more authors.
British Journal of Cancer | Year: 2010

Background: Human tissue kallikrein (hK1) generates vasodilator kinins from kininogen and promotes angiogenesis by kinin-dependent and kinin-independent mechanisms. Here, we investigate the expression and functional relevance of hK1 in human gastrointestinal stromal tumour (GIST). Methods: Vascularisation and hK1 expression of GIST samples were assessed by immunohistochemistry. In two GIST cell lines, hK1 expression was assessed by PCR, and hK1 protein levels and activity were measured by ELISA and an amidolytic assay, respectively. The effect of hK1 silencing, inhibition or overexpression on GIST cell proliferation, migration and paracrine induction of angiogenesis was studied. Finally, local and systemic levels of hK1 were assessed in mice injected with GIST cells. Results: Human tissue kallikrein was detected in 19 out of 22 human GIST samples. Moreover, GIST cells express and secrete active hK1. Titration of hK1 demonstrated its involvement in GIST invasive behaviour, but not proliferation. Furthermore, hK1 released by GIST cells promoted endothelial cell migration and network formation through kinin-dependent mechanisms. Gastrointestinal stromal tumour implantation in nude mice resulted in local and systemic hK1 expression proportional to tumour dimension.Conclusions:Human tissue kallikrein is produced and released by GIST and participates in tumour invasion. Further studies are needed to validate hK1 as a diagnostic biomarker and therapeutic target in GIST. © 2010 Cancer Research UK.

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