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Horenstein A.L.,University of Turin | Horenstein A.L.,Citta della Salute e della Science Hospital | Chillemi A.,University of Turin | Zaccarello G.,University of Turin | And 6 more authors.
OncoImmunology | Year: 2013

The tumor microenvironment is characterized by of high levels of extracellular nucleotides that are metabolized through the dynamic and sequential action of cell surface enzymes (ectoenzymes). These ectoenzymes operate according to their spatial arrangement, as part of (1) continuous (molecules on the same cell) or (2) discontinuous (molecules on different cells) pathways, the latter being facilitated by restricted cellular microenvironment. The outcome of this catabolic activity is an increase in the local concentration of adenosine, a nucleoside involved in the control of inflammation and immune responses. The aim of the work presented here was to demonstrate that a previously unexplored enzymatic pathway may be an alternate route to produce extracellular adenosine. Our data show that this new axis is driven by the nucleotide-metabolizing ectoenzymes CD38 (an NAD+ nucleosidase), the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, also known as CD203a or PC-1) and the 5' ectonucleotidase (5'-NT) CD73, while bypassing the canonical catabolic pathway mediated by the nucleoside tri- and diphosphohydrolase (NTPDase) CD39. To determine the relative contributions of these cell surface enzymes to the production of adenosine, we exploited a human T-cell model allowing for the modular expression of the individual components of this alternative pathway upon activation and transfection. The biochemical analysis of the products of these ectoenzymes by high-performance liquid chromatography (HPLC) fully substantiated our working hypothesis. This newly characterized pathway may facilitate the emergence of an adaptive immune response in selected cellular contexts. Considering the role for extracellular adenosine in the regulation of inflammation and immunogenicity, this pathway could constitute a novel strategy of tumor evasion, implying that these enzymes may represent ideal targets for antibody-mediated therapy © 2013 Landes Bioscience.


Moretti C.,University of Turin | Moretti C.,Citta della Salute e della Science Hospital | D'Amico M.,University of Catania | D'Ascenzo F.,University of Turin | And 7 more authors.
Journal of Interventional Cardiology | Year: 2014

Aims Impact of periprocedural bleeding after transcatheter aortic valve implantation (TAVI) over mid-term prognosis remains still unclear. Methods Consecutive patients who underwent TAVI from May 2008 to July 2012 were prospectively included and stratified according to life-threatening (LT) and major bleeding (MB). Mid-term all-cause death was the primary end-point, and 30-day death, vascular complications, stroke, and acute kidney injury the secondary ones. All end-points were adjudicated according to VARC. Results Seven hundred fourteen patients with an average age of 81.9 ± 5.8 years were included. 130 (18%) patients suffered a LT, 112 (16%) a MB. A preprocedural GFR <30 ml/min and increasing diameter of sheaths were independent predictors of LT or MB, while transfemoral approach showed a protective effect (OR 0.42; CI: 0.26-0.68; P = 0.035). At 30 days LT (OR 3.3; CI: 1.1-9.7; P = 0.0026) and MB (OR 3.5; CI: 1.4-8.6; P = 0.007) bleeding along with GFR < 30 ml/min (OR 2.3; CI: 1.1-5.5; P = 0.04) were independent predictors of death, while bleeding did not impact survival on mid term (OR 0.9; CI: 0.47-1.7; P = 0.78; all CI 95%). Conclusion Periprocedural bleeding after TAVI was frequent and associated with an increased mortality after 30 days but not after mid-term follow-up. A preprocedural GFR < 30 ml/min was the most important predictor of bleeding, enabling risk stratification and choice of approach for these patients. (J Interven Cardiol 2014;27:293-299) © 2014, Wiley Periodicals, Inc.


Succo G.,University of Turin | Berrone M.,University of Turin | Battiston B.,Citta della Salute e della Science Hospital | Tos P.,Citta della Salute e della Science Hospital | And 4 more authors.
European Archives of Oto-Rhino-Laryngology | Year: 2015

At present, mandibular reconstruction with a fibular free flap is the gold standard for functional and esthetic rehabilitation after oncological surgery. The purpose of this study was to describe the computer-assisted mandibular reconstruction procedure adopting the customized solution Synthes ProPlan CMF. The study reports five consecutive patients with benign or malignant disease requiring mandibular reconstruction using a microvascular fibular free flap, pre-operative virtual planning, construction of cutting guides and customized laser pre-bent titanium plates. The surgical technique is discussed in a step-by-step fashion. The average post-operative hospital stay was 18 ± 3 days. Ischemia time was recorded in all five cases, with an average of 75 ± 8 min. No problems were encountered in any surgical step and there were no major complications. Excellent precision of cutting guides and a good fit of pre-bent plates were found on both the mandible and fibula. There was excellent precision in bone to bone contact and position between mandible and fibula graft. Measurement data from the pre-operative and post-operative CT scans were compared. The average difference (Δ) between programed segment lengths and CT control segment lengths was 0.098 ± 0.077 cm. Microsurgical mandibular reconstruction using a virtual surgical planning yields significantly shorter ischemia times and allows more precise osteotomies. The technology is becoming increasingly recognized for its ability to optimize surgical outcomes and minimize operating time. Considering that the extent of resection can be wider than predicted, this results in safer modeling of the fibula only after frozen sections have demonstrated the radicality of resection. © 2014, Springer-Verlag Berlin Heidelberg.


Anselmino M.,University of Turin | Scaglione M.,Cardinal Guglielmo Massaia Hospital | Di Biase L.,The Texas Institute | Gili S.,University of Turin | And 8 more authors.
Heart Rhythm | Year: 2014

Background Left atrial appendage (LAA) is the major source of cardiac thrombi in atrial fibrillation (AF) and plays a major role in cardioembolic events. Objective To investigate the correlation between LAA morphology and the burden of silent cerebral ischemia (SCI) as a new thromboembolic risk marker in patients with AF. Methods A total of 348 patients with AF undergoing transcatheter ablation were enrolled. A cerebral magnetic resonance (MR) was performed to assess SCI burden, while LAA morphology was studied by MR or computed tomography and categorized as follows: cactus in 52 (14.9%) patients, chicken wing in 177 (50.9%), wind sock in 101 (29.0%), and cauliflower in 18 (5.2%). Results SCIs were detected in 295 (84.8%) patients, with a median number of lesions of 23. SCI burden was related to LAA complexity: 30.8% and 17.3% patients with cactus, 30.5% and 22.0% with chicken wing, 13.9% and 27.7% with wind sock, and 16.7% and 38.9% with cauliflower LAA morphologies were in the first and fourth quartiles of number of SCI per patient, respectively (P =.035). After adjustment for potential confounders, only age (β 0.12; 95% CI 0.08-0.16; P <.001), chicken wing (β-0.28; 95% CI-0.51 to-0.04; P =.021), wind sock (β 0.38; 95% CI 0.12-0.65; P =.005), and cauliflower (β 0.61; 95% CI 0.07-1.14; P =.026) LAA morphologies were significantly related to SCI burden. Conclusion LAA morphology relates to the burden of SCI in AF patients. Future research should corroborate if accessible methods (eg, echocardiography) are able to describe LAA morphology, permitting its use within universal thromboembolic risk predictors in AF patients. © 2014 Heart Rhythm Society. All rights reserved.


Chillemi A.,University of Turin | Zaccarello G.,University of Turin | Quarona V.,University of Turin | Lazzaretti M.,University of Parma | And 7 more authors.
Frontiers in Bioscience - Landmark | Year: 2014

This review summarizes the events ruled by CD38 in shaping the bone marrow environment, recapitulating old and new aspects derived from the body of knowledge on the molecule. The disease models considered were myeloma and chronic lymphocytic leukemia (CLL). CD38 has been analyzed considering its twin function as receptor and enzyme, roles usually not considered in clinics, where it is used as a routine marker. Another aspect pertaining basic science concerns the role of the molecule as a member of an ectoenzyme network, potentially metabolizing soluble factors not yet analyzed (e.g., NAD+, ATP, NAM) or influencing hormone secretion (e.g., oxytocin). The last point is focused on the use of CD38 as a target of an antibody-mediated therapeutic approach in myeloma and CLL. A recent observation is that CD38 may run an escape circuit leading to the production of adenosine. The generation of local anergy may be blocked by using anti-CD38 antibodies. Consequently, not only might CD38 be a prime target for mAb-mediated therapy, but its functional block may contribute to general improvement in cancer immunotherapy and outcomes.


Chillemi A.,University of Turin | Zaccarello G.,University of Turin | Quarona V.,University of Turin | Ferracin M.,University of Ferrara | And 5 more authors.
Molecular Medicine | Year: 2013

In vivo use of monoclonal antibodies (mAbs) has become a mainstay of routine clinical practice in the treatment of various human diseases. A number of molecules can serve as targets, according to the condition being treated. Now entering human clinical trials, CD38 molecule is a particularly attractive target because of its peculiar pattern of expression and its twin role as receptor and ectoenzyme. This review provides a range of analytical perspectives on the current progress in and challenges to anti- CD38 mAb therapy. We present a synopsis of the evidence available on CD38, particularly in myeloma and chronic lymphocytic leukemia (CLL). Our aim is to make the data from basic science helpful and accessible to a diverse clinical audience and, at the same time, to improve its potential for in vivo use. The topics covered include tissue distribution and signal implementation by mAb ligation and the possibility of increasing cell density on target cells by exploiting information about the molecule's regulation in combination with drugs approved for in vivo use. Also analyzed is the behavior of CD38 as an enzyme: CD38 is a component of a pathway leading to the production of adenosine in the tumor microenvironment, thus inducing local anergy. Consequently, not only might CD38 be a prime target for mAb-mediated therapy, but its functional block may contribute to general improvement in cancer immunotherapy and outcomes.


Conrotto F.,Citta della Salute e della Science Hospital | D'ascenzo F.,Citta della Salute e della Science Hospital | Francesca G.,Citta della Salute e della Science Hospital | Colaci C.,Citta della Salute e della Science Hospital | And 6 more authors.
Journal of Interventional Cardiology | Year: 2014

Introduction Transcatheter aortic valve implantation (TAVI) may be performed using the transfemoral (TF) or transapical (TA) approach in most patients with aortic stenosis. The impact of access choice on peri-procedural and midterm results remains to be defined.Methods Medline and Cochrane Library were searched for articles describing differences in baseline, peri-procedural, and midterm outcomes among patients undergoing TF or TA TAVI. The primary end-point was all-cause mortality after at least 1-year follow-up, while secondary end-points were 30 days mortality and in-hospital complications (bleeding and cerebrovascular events). The independent impact of access choice was evaluated with pooled analysis using a random-effect model.Results Thirteen studies with 10,468 patients were included. TF was the most exploited strategy (69.5% vs. 30.5%). After adjusting for confounding variables, 30-day and midterm follow-up mortality (median 365 days, range 222-400) were lower in TF patients with a pooled adjusted odds ratio of 0.81 (0.68-0.97 I2 99%) and 0.85 (0.80-0.90 I2 96%), respectively. Regarding periprocedural outcomes, TF reduced risk of bleedings and strokes (OR of 0.74 [0.66-0.82 I2 95%] and 0.91 [0.83-0.99] I2 86%, respectively).Conclusions The TF approach reduces mortality in TAVI patients, due to lower rates of periprocedural bleedings and strokes. (J Interven Cardiol 2014;27:500-508) © 2014, Wiley Periodicals, Inc.


Dimuccio V.,University of Turin | Ranghino A.,University of Turin | Barbato L.P.,Citta Della Salute e Della Science Hospital | Fop F.,Citta Della Salute e Della Science Hospital | And 3 more authors.
PLoS ONE | Year: 2014

Extracellular vesicles (EVs) present in the urine are mainly released from cells of the nephron and can therefore provide information on kidney function. We here evaluated the presence of vesicles expressing the progenitor marker CD133 in the urine of normal subjects and of patients undergoing renal transplant. We found that EV expressing CD133 were present in the urine of normal subjects, but not of patients with end stage renal disease. The first day after transplant, urinary CD133+ EVs were present at low levels, to increase thereafter (at day 7). Urinary CD133+ EVs significantly increased in patients with slow graft function in respect to those with early graft function. In patients with a severe pre-transplant vascular damage of the graft, CD133+ EVs did not increase at day 7. At variance, the levels of EVs expressing the renal exosomal marker CD24 did not vary in the urine of patients with end stage renal disease or in transplanted patients in respect to controls. Sorted CD133+ EVs were found to express glomerular and proximal tubular markers. These data indicate that urinary CD133+ EVs are continuously released during the homeostatic turnover of the nephron and may provide information on its function or regenerative potential. © 2014 Dimuccio et al.


Tesio V.,University of Turin | Torta D.M.E.,University of Turin | Colonna F.,Citta della Salute e della Science Hospital | Leombruni P.,University of Turin | And 5 more authors.
Arthritis Care and Research | Year: 2015

Objective: Patients with fibromyalgia (FM) syndrome often report a cluster of cognitive disorders that strongly interferes with their work and daily life, but the relationship between impaired cognitive function and self-reported dysfunction remains unclear. We aimed to investigate the presence of cognitive impairments in patients with FM and to analyze the relationship between the impairments and their evaluation by the patients through a comparison with a group of healthy controls.Methods: In total, 30 FM patients and 30 healthy controls performed a neuropsychological and clinical evaluation of short-term, long-term, and working memory; executive function; and self-evaluation of cognitive impairment and depressive and anxiety symptoms. To thoroughly investigate executive function, we adopted the Miyake model that identifies 4 domains: shifting, inhibition, updating, and access.Results: Our results confirmed the presence of impairments of attention, long-term memory, working memory, and shifting and updating executive functions in FM patients compared with healthy controls. These impairments are reflected in patient reports independently of depressive symptoms.Conclusion: The use of a self-reported questionnaire in clinical practice would provide a first and easy screen for the presence of cognitive impairment in FM patients and, in most cases, obviate the need for a time-consuming full neuropsychological test battery. © 2015, American College of Rheumatology.


Vargas M.,University of Naples Federico II | Sutherasan Y.,Mahidol University | Gregoretti C.,Citta della Salute e della Science Hospital | Pelosi P.,University of Genoa
The Scientific World Journal | Year: 2014

Positive end expiratory pressure (PEEP) may prevent cyclic opening and collapsing alveoli in acute respiratory distress syndrome (ARDS) patients, but it may play a role also in general anesthesia. This review is organized in two sections. The first one reports the pathophysiological effect of PEEP on thoracic pressure and hemodynamic and cerebral perfusion pressure. The second section summarizes the knowledge and evidence of the use of PEEP in general anesthesia and intensive care. More specifically, for intensive care this review refers to ARDS and traumatic brain injured patients. © 2014 M. Vargas et al.

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