Alessandro Addis - Academia.edu (original) (raw)

Papers by Alessandro Addis

Europace, Mar 1, 2018

Methods and results: Seventy-nine patients (33% female, mean age 63612 years, mean LA-diameter 45... more Methods and results: Seventy-nine patients (33% female, mean age 63612 years, mean LA-diameter 456x7mm) with persistent AF underwent CB2-based PVI in three german EP centers. After successful PVI a bonus freeze was applied in 18/79 (23%) patients. In 22/79 (28%) patients a no-bonus freeze protocol was applied. In 39 (49%) patients a time-to-effect protocol was utilized. A total of 313 pulmonary veins (PV) were identified and 313/313 (100%) PVs were successfully isolated. A transient phrenic nerve palsy occurred in 1/79 (1.3%) patients. One patient (1.3%) suffered from a postprocedural pericardial effusion, not requiring pericardial drainage. No further major complications occurred in this cohort. Follow-up was based on outpatient clinic visits at 3, 6 and 12 months including Holter-ECGs and telephonic interviews. Recurrence was defined as a symptomatic and/or documented atrial arrhythmia episode >30 sec excluding a 3-month blanking period. Follow-up was available for 79/79 (100%) patients with a median follow-up duration of 15 months (interquartile range 12-32). A total of 44/79 (55.7%) patients remained in stable sinus rhythm. The time to recurrence was 12 months (interquartile range 6.5-17). Of 22/44 (50%) patients with arrhythmia recurrence, a second procedure using radiofrequency ablation was conducted. After a mean of 1.3þ/-0.5 procedures a total of 59/79 (74.7%) patients remained in stable sinus rhythm. Conclusions: The use of the CB2 for PVI in patients suffering from persistent AF results in a single procedural success rate of 55.7% and a multiple procedural success rate of 74.7% after a median follow-up duration of 15 months.

Clinical Oral Implants Research, Aug 1, 2009

Aim: To evaluate the bone tissue response to zirconia implants with three different surface modif... more Aim: To evaluate the bone tissue response to zirconia implants with three different surface modifications in comparison with the oxidized titanium surface with the goal to optimize osseointegration in terms of strength and speed. Materials and methods: A total of 18 rabbits with 143 implants were used. One hundred and twenty-three were threaded zirconia ceramic implants with three different surface topographies and 20 modified titanium oxide implants were controls. Each rabbit received eight implants and sacrificed after 3 weeks. The removal torque test (RTQ) and histology were performed. Results: Sixteen out of 18 rabbits completed the study with a total of 110 implants. No statistical significance was observed between the chemical modification implants compared with the topographically modified zirconia implant in terms of interfacial shear strength proven by the RTQ applied. No statistical significance was also observed in the bone-toimplant contact between the zirconia implants and the control oxidized implants. Conclusions: The findings suggest that additional specific chemical modifications of the topographically modified zirconia implants do not seem to enhance the bone-to-implant contact and appear not to increase the interfacial shear strength.

Eurointervention, May 1, 2015

Aims: Preclinical studies and translational animal models are fundamental for the development of ... more Aims: Preclinical studies and translational animal models are fundamental for the development of new clinical interventions. Compared to human anatomy, pigs present a more anterior heart position in the chest which may jeopardise the imaging and testing of devices designed to be delivered to the human mitral valve. To imitate human anatomy, we developed a novel model to "humanise" a pig heart. Methods and results: The creation of a neo inferior vena cava with a Dacron tube grafted to the right atrium was tested for transseptal delivery of an experimental mitral annuloplasty device in 35 animals. In 15 animals with native anatomy a conventional right transfemoral access was used. Imaging guidance was achieved with intracardiac or epicardial echocardiography. In all transfemoral approaches (n=15), the delivery of the device was unsuccessful and the handling was dissimilar to a human implant. In all neo-cava approaches (n=35), the handling and manoeuvring were as expected in humans, the targets were reached as intended and all procedures but one were successful. Conclusions: A translational "humanised" animal model with the creation of a neo cava eliminates the differences between pig and human anatomy and is suitable for testing human grade devices.

Journal of Hematology & Oncology, Oct 5, 2014

Background: Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole ex... more Background: Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole exportin mediating transport of many multiple tumor suppressor proteins out of the nucleus. Aim and methods: To verify the hypothesis that XPO1 inhibition affects prostate cancer (PCa) metastatic potential, orally available, potent and selective, SINE compounds, Selinexor (KPT-330) and KPT-251, were tested in preclinical models known to generate bone lesions and systemic tumor spread. Results: In vitro, Selinexor reduced both secretion of proteases and ability to migrate and invade of PCa cells. SINEs impaired secretion of pro-angiogenic and pro-osteolytic cytokines and reduced osteoclastogenesis in RAW264.7 cells. In the intra-prostatic growth model, Selinexor reduced DU145 tumor growth by 41% and 61% at the doses of 4 mg/Kg qd/5 days and 10 mg/Kg q2dx3 weeks, respectively, as well as the incidence of macroscopic visceral metastases. In a systemic metastasis model, following intracardiac injection of PCb2 cells, 80% (8/10) of controls, 10% (1/10) Selinexor-and 20% (2/10) KPT-251-treated animals developed radiographic evidence of lytic bone lesions. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in Selinexor and KPT-251 groups. Analogously, the serum levels of osteoclast markers (mTRAP and type I collagen fragment, CTX), were significantly higher in controls than in Selinexor-and KPT-251-treated animals. Importantly, overall survival and disease-free survival were significantly higher in Selinexor-and KPT-251-treated animals when compared to controls. Conclusions: Selective blockade of XPO1-dependent nuclear export represents a completely novel approach for the treatment of advanced and metastatic PCa.

Cancer Research, Jul 15, 2005

CpG-oligodeoxynucleotides (CpG-ODN) exhibit potent immunostimulatory activity by binding with Tol... more CpG-oligodeoxynucleotides (CpG-ODN) exhibit potent immunostimulatory activity by binding with Toll-like receptor 9 (TLR9). Based on the finding that TLR9 is highly expressed and functional in pancreatic tissue, we evaluated the antitumor effects of chemotherapy combined with CpG-ODNs in the orthotopic mouse model of a human pancreatic tumor xenograft. Chemotherapy consisted of the maximum tolerated dose of gemcitabine (i.v., 100 mg/kg, q3dx4). CpG-ODNs were delivered (i.p., 20 Mg/mouse), weekly, after the end of chemotherapy. CpG-ODNs alone had little effect on tumor growth, whereas gemcitabine alone significantly delayed the median time of disease onset (palpable i.p. tumor) and of bulky disease development (extensive peritoneal tumor burden), but did not enhance survival time. When the gemcitabine regimen was followed by administration of the immunostimulator, development of bulky disease was delayed, survival time was significantly improved (median survival time, 106 days; P < 0.02 versus gemcitabine-treated mice). Autoptic examination showed that tumor spread in the peritoneal cavity was reduced to a greater extent than with gemcitabine alone. All treatment regimens were well-tolerated. The use of nude mice excluded a T cell-mediated immune response, whereas the high pancreatic expression of TLR9 might have contributed to the tumor response. The clear improvement of survival observed in an orthotopic murine model of human pancreatic cancer by the combined use of CpG-ODNs with chemotherapy suggests the promise of this therapeutic regimen in the clinical setting.

Background: CRM1 (XPO1) is the exclusive exportin mediating transport of most tumor suppressor pr... more Background: CRM1 (XPO1) is the exclusive exportin mediating transport of most tumor suppressor proteins (TSPs) including p53, pRb, FOXO, APC and p21 out of the nucleus, abrogating their function. Methods: We tested the effects of the potent, selective, clinical stage oral SINE compound KPT-330 in prostate cancer (PrCa) models. Male SCID mice orthotopically (intraprostatic) inoculated with the DU145 PrCa, known to produce highly metastatic tumors with visceral metastases. In parallel, male CD1-nu/nu mice were inoculated with intracardiac and intratibial injections of the aggressive/bone-derived PrCa PC3, known to produce prominent osteolytic bone lesions. The effects of SINEs KPT-330 and KPT-251 on metastatic spreading were determined. Results: We previously demonstrated that SINE CRM1 antagonists KPT330 and KPT251 have potent antitumor effects on PrCa both in vitro and in vivo. Here, we demonstrate that KPT-330 reduces intraprostatic DU145 tumor burden as well as the incidence of macroscopic metastases to lymph nodes, liver and lung, in a dose-dependent manner. The DU145 tumor burden was reduced by 41% with KPT-330 (4 mg/kg qd/5 days) and 61% (10 mg/kg q 3-4 d x 7) when compared to controls. The incidence of PC3-derived bone metastases were significantly reduced with KPT-330 at 10 mg/kg (q 2d x 3 weeks). At 50 days after cell injection, 80% (8/10) of controls and 0% (0/10) of the KPT-330-treated animals developed X-Ray evidence of bone lesions (p&lt;0.05). The burden of bone metastases, measured by lytic bone area, was significantly higher in controls than in KPT-330-treated animals. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in the KPT-330 group (p&lt;0.05). The level of serum markers of osteoclast activity (TRAP and type I collagen fragment, CTX), was significantly higher in controls than in KPT-330-treated animals. The related SINE KPT-251 (100 mg/Kg q 2d x 3 weeks) confirmed the reduction of bone metastasis following CRM1 inhibition. The overall and disease free survival, evaluated at 170 days after tumor injection, were significantly higher in KPT-330- and KPT-251-treated animals versus controls (P&lt; 0.0001). Treatment of PC3 and DU145 cells with KPT-330 lead to significant reductions in the secretion of proteolytic enzymes (MMP-9, MMP-2, uPA) as well as reduced ability of tumor cells to migrate and invade Matrigel. Impaired secretion of pro-angiogenic (VEGF, IL6, IL8) and pro-osteolytic (RANKL, IL6) cytokines was also observed. Conclusions: These data show that selective blockade of CRM1-dependent nuclear export has direct antitumor, anti-metastatic and anti-osteolytic activities in PrCa and thus represents a novel approach for the treatment of advanced/ metastatic PrCa. KPT-330 is now in Phase 1 clinical trials in patients with advanced solid tumors (clinicaltrailas.gov: NCT01607905). Citation Format: Giovanni Luca Gravina, Monica Tortoreto, Andrea Mancini, Paola Muzi, Luca Ventura, Sandra D'ascenzo, Alessandro Addis, Yosef Landesman, Dilara McCauley, Vincenza Dolo, Michael Kauffman, Sharon Shacham, Nadia Zaffaroni, Claudio Festuccia. CRM1-Selective Inhibitors of Nuclear Export (SINE) reduce the incidence of tumor spreading and improve overall survival in preclinical models of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3440. doi:10.1158/1538-7445.AM2013-3440

International Angiology, Jun 1, 2023

Neurocritical Care, Feb 29, 2016

Background Therapeutic hypothermia (i.e., temperature management) is an effective option for impr... more Background Therapeutic hypothermia (i.e., temperature management) is an effective option for improving survival and neurological outcome after cardiac arrest and is potentially useful for the care of the critically ill neurological patient. We analyzed the feasibility of a device to control the temperature of the brain by controlling the temperature of the blood flowing through the neck. Methods A lumped parameter dynamic model, with onedimensional heat transfer, was used to predict cooling effects and to test experimental hypotheses. The cooling system consisted of a flexible collar and was tested on 4 adult sheep, in which brain and body temperatures were invasively monitored for the duration of the experiment. Results Model-based simulations predicted a lowering of the temperature of the brain and the body following the onset of cooling, with a rate of 0.4°C/h for the brain and 0.2°C/h for the body. The experimental findings showed comparable cooling rates in the two body compartments, with temperature reductions of 0.6 (0.2)°C/h for the brain and 0.6 (0.2)°C/h for the body. For a 70 kg adult human subject, we predict a temperature reduction of 0.64°C/h for the brain and 0.43°C/h for the body. Conclusions This work demonstrates the feasibility of using a non-invasive method to induce brain hypothermia using a portable collar. This device demonstrated an optimal safety profile and represents a potentially useful method for the administration of mild hypothermia and temperature control (i.e., treatment of hyperpyrexia) in cardiac arrest and critically ill neurologic patients.

Clinical Oral Implants Research, Dec 29, 2010

:Objectives: The aim of the present study was to evaluate a Ca–P coated implant surface in a rabb... more :Objectives: The aim of the present study was to evaluate a Ca–P coated implant surface in a rabbit model. The Ca–P surface (test) was compared to the titanium porous oxide surface (control) in terms of bone‐to‐implant contact (BIC) and removal torque value.Materials and methods: Two hundred and sixteen dental implants were inserted in the tibia and in the femur of 36 rabbits. One hundred and eight were represented by Ca–P oxidized surface implant and other 108 were titanium porous oxide surface modified implants. Each rabbit received six implants. Animals were sacrificed after 2, 4 and 9 weeks of healing. Each group included 12 rabbits. The femoral implant and the proximal implant of the tibia of each animal were subjected to the histologic analysis and the distal implants of the tibia underwent removal torque test (RTQ).Results: Histological analysis in terms of BIC and RTQ did not revealed any significant difference between the Ca–P oxidized surface and the oxidized surface at 2 and 4 weeks. At 9 weeks, the oxidized surface demonstrated better results in terms of RTQ in the tibia.Conclusion: In conclusion, findings from the present study suggested that the Ca–P coating had no beneficial effect in improving bonding strength at the bone–implant interface either at 2, 4 and 9 weeks. To cite this article: Fontana F, Rocchietta I, Addis A, Schupbach P, Zanotti G, Simion M. Effects of a calcium phosphate coating on the osseointegration of endosseous implants in a rabbit model Clin. Oral Impl. Res. 22, 2011; 760–766 doi: 10.1111/j.1600‐0501.2010.02056.x

European Urology Supplements, Nov 1, 2013

The Annals of Thoracic Surgery, Jun 1, 2011

We describe a modification of the Cox-Maze III using bipolar radiofrequency combined with off-pum... more We describe a modification of the Cox-Maze III using bipolar radiofrequency combined with off-pump coronary artery surgery for the treatment of patients with coronary artery disease and long-standing permanent atrial fibrillation. This study reports the midterm outcome of 12 patients with coronary artery disease and long-standing permanent atrial fibrillation who underwent off-pump coronary artery surgery and concomitant modified Maze with bipolar radiofrequency. At a mean follow-up of 23 months, all patients were alive, and 75% (9 of 12) had sinus rhythm. Our modified Maze can be safely and effectively combined with coronary artery surgery in an off-pump setting.

Gaceta dental: Industria y profesiones, 2016

El objetivo de este estudio histologico era evaluar la osteointegracion de los implantes de titan... more El objetivo de este estudio histologico era evaluar la osteointegracion de los implantes de titanio cuyas superficies fueron tratadas con diferentes metodos en cerdos enanos.Se evaluaron seis superficies diferentes: SLA-Ti5 (aleacion de titanio, arenado utilizando oxido de aluminio y grabado utilizando acido nitrico y fluoridico); SLA-Ti4 (titanio comercialmente puro (CP)-Ti, arenado utilizando particulas grandes de arenilla de oxido de aluminio ademas de grabado acido con acido clorhidrico/sulfurico); HA (CP-Ti, arenado utilizando hidroxiapatita ademas de grabado con acido nitrico); DAE (aleacion de titanio, doble acido grabador utilizando acido fluorhidrico ademas de acido clorhidrico y sulfurico); ASD-Ti5 (aleacion de titanio, sedimentacion anodica provocada); ASD-Ti4 (CP-Ti, sedimentacion anodica provocada). Se utilizo un escaner microscopico electronico para evaluar la superficie microtopografica. Se detecto la composicion de los elementos de la superficie mediante EDS (espectroscopio de dispersion de energia). Se insertaron seis implantes (uno por grupo) en cada tibia proximal de dos cerdos enanos y se dejaron inmersos durante tres meses. Despues se tomo una biopsia de hueso y se llevo a cabo el analisis histologico de la misma. Se eva luo el contacto entre el hueso y el implante (BIC) en la zona cortical. Se evaluo tambien el cociente de estabilidad del implante (ISQ) en el momento de la colocacion y en la retirada.El mayor contacto entre hueso e implante (BIC) se obtuvo sobre los implantes que utilizaron arenado con grabado acido (HA, SLA-Ti5, SLA-Ti4). El contacto entre hueso - implante resulto positivamente correlacionado con la rugosidad de la superficie. El mayor aumento de cociente de estabilidad (ISQ) se observo en el grupo ASD-T4. En la zona medular, la superficie SLA mostro la mejor respuesta osteogenica. Se detecto infiltracion celular inflamatoria alrededor de los implantes ASD-T5 y DAE.Las superficies con arenado grabado acido demostraron ligeramente mejor oseointegracion que las superficies con acabado anodizado o con grabado acido dual. La rugosidad de la superficie resulto positivamente correlacionada con la oseointegracion

Polymer foams are among the most studied scaffold for tissue engineering. Among them, cross-linke... more Polymer foams are among the most studied scaffold for tissue engineering. Among them, cross-linked polyurethane foams (PUFs) with slow degradation rate can be used as scaffolds for soft tissue engineering or as matrices of porous composites containing inorganic salts for hard tissue engineering. The foaming process has been set up using polymeric MDI, 2% water as expanding agent and Fe-acetyl acetonate as catalyst. On the whole, two families of foams (EC and EF) were developed using two different polyether-polyol formulations, the EF-type being more hydrophilic and more flexible than the EC-one. In vitro cytocompatibility tests with different cell lines demonstrated the ability of these matrices to stimulate cell adhesion and proliferation. In this work we investigated the in vivo behaviour of both EC and EF PU foams in the rat animal model to evaluate the extent of inflammatory reaction and the biodegradation rate. Discs of the EC- and EF-type foams were implanted in the dorsal subcutaneous tissue of male rats up to 42 weeks, explanted and histologically inspected together with the surrounding tissues by haematoxylin and eosin staining. The obtained results indicated a good biocompatibility of both foam types, the evoked inflammatory response being physiological. In particular, for the EF-based foams, at the material/tissue interface neovascularization and formation of new peripheral nerves were noticed. Moreover, the EF PUFs seem to promote the formation of mesenchimal tissue that, under particular stimuli, could promote the regeneration of the intended tissue

Résumé/Abstract This study is a first step to evaluate the properties of the new bioactive glass ... more Résumé/Abstract This study is a first step to evaluate the properties of the new bioactive glass Crystal Bio Tech both as a bulk and a macroporous material. Both types of glass have been used to repair a 10 mm defect in six rabbit limbs and the implants have been ...

Journal of the Pancreas, 2007

Silk fibroin (SF) is the inner component of the silk fiber spun by Bombyx mori silkworm. It is co... more Silk fibroin (SF) is the inner component of the silk fiber spun by Bombyx mori silkworm. It is considered a valuable material for biotechnology and biomedical applications due to its unique properties including biocompatibility, oxygen and water vapor permeability, biodegradability, and minimal inflammatory reaction. Sericin, which constitutes the outer layer of the fiber, was recently studied by several authors who underlined its antioxidant, antibacterial and anti-inflammatory properties, its protective action for serum deprived cells, being moreover considered a triggering molecule for apatite deposition. Fibroin and sericin can be processed to obtain powders, films, gels, filaments, etc., so making different materials that can tailored to the requirements of the specific application. These processes induce structural transitions and morphological changes that have a great influence on the physical and biological properties of the resulting materials. In this work two different SF-based hydrogels (100% SF and 90/10SF-Ser) and a pure fibroin sponge were compared in an in vivo critical size defect study in order to evaluate their bone regeneration capability

Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery, 2010

Anson Cheung, Jian Ye, David Wood, Christopher Thompson, Samuel Lichtenstein, John Webb. St. Paul... more Anson Cheung, Jian Ye, David Wood, Christopher Thompson, Samuel Lichtenstein, John Webb. St. Paul’s Hospital, Vancouver, BC Canada. Objective: Clinical use of bioprosthetic valve in the treatment of mitral valve disease has been growing. More complex and high-risk elderly patients with prosthetic valve dysfunction will require redo procedures. Re-operative mitral valve surgery in these patients is associated with high morbidity and mortality. We report a series of patient underwent transcatheter transapical mitral valve-in-valve implantations. Methods: Apical access was obtained thru a small left anterior thoracotomy via the 5 or 6 intercostal space. Mitral valve prosthesis was crossed using a wire under fluoroscopic and echocardiographic guidance. A 26 mm balloon expandable Sapien transcatheter valve (Edwards LifeSceinces, CA USA) was used in all cases. The transcatheter valve was deployed within the pre-existing mitral xenograft under rapid ventricular pacing. Postoperative clinical and echocardiographic follow up was obtained. Results: Seven high-risk patients with mitral prosthetic valve dysfunction underwent transcatheter transapical valve-in-valve implantations. The mean age was 80 6 and six were female. No valve malpositioning or embolization occurred in any cases. No thirty-day mortality was observed. One patient died on post-operative day 45 from respiratory failure and all remaining patients are alive and well with a median follow-up of 72 days (inter-quartile range 30 120 days, longest follow-up 345 days). Serial echocardiographic examinations demonstrated a reduction of mean gradient from 12.9 5.4 to 8.0 1.3 mmHg, valve area improvement from 0.7 0.4 to 1.7 0.4 cm and a reduction in regurgitation grade in all patients. Conclusions: Transcatheter transapical mitral valve-in-valve implantation is technically feasible. Transapical approach to the mitral xenograft is direct and coaxial. Excellent short-term clinical outcomes were observed. Transcatheter transapical valve-in-valve implantation may play an important role in the treatment of bioprosthetic mitral valve dysfunction.

Europace, Mar 1, 2018

Methods and results: Seventy-nine patients (33% female, mean age 63612 years, mean LA-diameter 45... more Methods and results: Seventy-nine patients (33% female, mean age 63612 years, mean LA-diameter 456x7mm) with persistent AF underwent CB2-based PVI in three german EP centers. After successful PVI a bonus freeze was applied in 18/79 (23%) patients. In 22/79 (28%) patients a no-bonus freeze protocol was applied. In 39 (49%) patients a time-to-effect protocol was utilized. A total of 313 pulmonary veins (PV) were identified and 313/313 (100%) PVs were successfully isolated. A transient phrenic nerve palsy occurred in 1/79 (1.3%) patients. One patient (1.3%) suffered from a postprocedural pericardial effusion, not requiring pericardial drainage. No further major complications occurred in this cohort. Follow-up was based on outpatient clinic visits at 3, 6 and 12 months including Holter-ECGs and telephonic interviews. Recurrence was defined as a symptomatic and/or documented atrial arrhythmia episode >30 sec excluding a 3-month blanking period. Follow-up was available for 79/79 (100%) patients with a median follow-up duration of 15 months (interquartile range 12-32). A total of 44/79 (55.7%) patients remained in stable sinus rhythm. The time to recurrence was 12 months (interquartile range 6.5-17). Of 22/44 (50%) patients with arrhythmia recurrence, a second procedure using radiofrequency ablation was conducted. After a mean of 1.3þ/-0.5 procedures a total of 59/79 (74.7%) patients remained in stable sinus rhythm. Conclusions: The use of the CB2 for PVI in patients suffering from persistent AF results in a single procedural success rate of 55.7% and a multiple procedural success rate of 74.7% after a median follow-up duration of 15 months.

Clinical Oral Implants Research, Aug 1, 2009

Aim: To evaluate the bone tissue response to zirconia implants with three different surface modif... more Aim: To evaluate the bone tissue response to zirconia implants with three different surface modifications in comparison with the oxidized titanium surface with the goal to optimize osseointegration in terms of strength and speed. Materials and methods: A total of 18 rabbits with 143 implants were used. One hundred and twenty-three were threaded zirconia ceramic implants with three different surface topographies and 20 modified titanium oxide implants were controls. Each rabbit received eight implants and sacrificed after 3 weeks. The removal torque test (RTQ) and histology were performed. Results: Sixteen out of 18 rabbits completed the study with a total of 110 implants. No statistical significance was observed between the chemical modification implants compared with the topographically modified zirconia implant in terms of interfacial shear strength proven by the RTQ applied. No statistical significance was also observed in the bone-toimplant contact between the zirconia implants and the control oxidized implants. Conclusions: The findings suggest that additional specific chemical modifications of the topographically modified zirconia implants do not seem to enhance the bone-to-implant contact and appear not to increase the interfacial shear strength.

Eurointervention, May 1, 2015

Aims: Preclinical studies and translational animal models are fundamental for the development of ... more Aims: Preclinical studies and translational animal models are fundamental for the development of new clinical interventions. Compared to human anatomy, pigs present a more anterior heart position in the chest which may jeopardise the imaging and testing of devices designed to be delivered to the human mitral valve. To imitate human anatomy, we developed a novel model to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;humanise&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; a pig heart. Methods and results: The creation of a neo inferior vena cava with a Dacron tube grafted to the right atrium was tested for transseptal delivery of an experimental mitral annuloplasty device in 35 animals. In 15 animals with native anatomy a conventional right transfemoral access was used. Imaging guidance was achieved with intracardiac or epicardial echocardiography. In all transfemoral approaches (n=15), the delivery of the device was unsuccessful and the handling was dissimilar to a human implant. In all neo-cava approaches (n=35), the handling and manoeuvring were as expected in humans, the targets were reached as intended and all procedures but one were successful. Conclusions: A translational &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;humanised&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; animal model with the creation of a neo cava eliminates the differences between pig and human anatomy and is suitable for testing human grade devices.

Journal of Hematology & Oncology, Oct 5, 2014

Background: Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole ex... more Background: Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole exportin mediating transport of many multiple tumor suppressor proteins out of the nucleus. Aim and methods: To verify the hypothesis that XPO1 inhibition affects prostate cancer (PCa) metastatic potential, orally available, potent and selective, SINE compounds, Selinexor (KPT-330) and KPT-251, were tested in preclinical models known to generate bone lesions and systemic tumor spread. Results: In vitro, Selinexor reduced both secretion of proteases and ability to migrate and invade of PCa cells. SINEs impaired secretion of pro-angiogenic and pro-osteolytic cytokines and reduced osteoclastogenesis in RAW264.7 cells. In the intra-prostatic growth model, Selinexor reduced DU145 tumor growth by 41% and 61% at the doses of 4 mg/Kg qd/5 days and 10 mg/Kg q2dx3 weeks, respectively, as well as the incidence of macroscopic visceral metastases. In a systemic metastasis model, following intracardiac injection of PCb2 cells, 80% (8/10) of controls, 10% (1/10) Selinexor-and 20% (2/10) KPT-251-treated animals developed radiographic evidence of lytic bone lesions. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in Selinexor and KPT-251 groups. Analogously, the serum levels of osteoclast markers (mTRAP and type I collagen fragment, CTX), were significantly higher in controls than in Selinexor-and KPT-251-treated animals. Importantly, overall survival and disease-free survival were significantly higher in Selinexor-and KPT-251-treated animals when compared to controls. Conclusions: Selective blockade of XPO1-dependent nuclear export represents a completely novel approach for the treatment of advanced and metastatic PCa.

Cancer Research, Jul 15, 2005

CpG-oligodeoxynucleotides (CpG-ODN) exhibit potent immunostimulatory activity by binding with Tol... more CpG-oligodeoxynucleotides (CpG-ODN) exhibit potent immunostimulatory activity by binding with Toll-like receptor 9 (TLR9). Based on the finding that TLR9 is highly expressed and functional in pancreatic tissue, we evaluated the antitumor effects of chemotherapy combined with CpG-ODNs in the orthotopic mouse model of a human pancreatic tumor xenograft. Chemotherapy consisted of the maximum tolerated dose of gemcitabine (i.v., 100 mg/kg, q3dx4). CpG-ODNs were delivered (i.p., 20 Mg/mouse), weekly, after the end of chemotherapy. CpG-ODNs alone had little effect on tumor growth, whereas gemcitabine alone significantly delayed the median time of disease onset (palpable i.p. tumor) and of bulky disease development (extensive peritoneal tumor burden), but did not enhance survival time. When the gemcitabine regimen was followed by administration of the immunostimulator, development of bulky disease was delayed, survival time was significantly improved (median survival time, 106 days; P < 0.02 versus gemcitabine-treated mice). Autoptic examination showed that tumor spread in the peritoneal cavity was reduced to a greater extent than with gemcitabine alone. All treatment regimens were well-tolerated. The use of nude mice excluded a T cell-mediated immune response, whereas the high pancreatic expression of TLR9 might have contributed to the tumor response. The clear improvement of survival observed in an orthotopic murine model of human pancreatic cancer by the combined use of CpG-ODNs with chemotherapy suggests the promise of this therapeutic regimen in the clinical setting.

Background: CRM1 (XPO1) is the exclusive exportin mediating transport of most tumor suppressor pr... more Background: CRM1 (XPO1) is the exclusive exportin mediating transport of most tumor suppressor proteins (TSPs) including p53, pRb, FOXO, APC and p21 out of the nucleus, abrogating their function. Methods: We tested the effects of the potent, selective, clinical stage oral SINE compound KPT-330 in prostate cancer (PrCa) models. Male SCID mice orthotopically (intraprostatic) inoculated with the DU145 PrCa, known to produce highly metastatic tumors with visceral metastases. In parallel, male CD1-nu/nu mice were inoculated with intracardiac and intratibial injections of the aggressive/bone-derived PrCa PC3, known to produce prominent osteolytic bone lesions. The effects of SINEs KPT-330 and KPT-251 on metastatic spreading were determined. Results: We previously demonstrated that SINE CRM1 antagonists KPT330 and KPT251 have potent antitumor effects on PrCa both in vitro and in vivo. Here, we demonstrate that KPT-330 reduces intraprostatic DU145 tumor burden as well as the incidence of macroscopic metastases to lymph nodes, liver and lung, in a dose-dependent manner. The DU145 tumor burden was reduced by 41% with KPT-330 (4 mg/kg qd/5 days) and 61% (10 mg/kg q 3-4 d x 7) when compared to controls. The incidence of PC3-derived bone metastases were significantly reduced with KPT-330 at 10 mg/kg (q 2d x 3 weeks). At 50 days after cell injection, 80% (8/10) of controls and 0% (0/10) of the KPT-330-treated animals developed X-Ray evidence of bone lesions (p&lt;0.05). The burden of bone metastases, measured by lytic bone area, was significantly higher in controls than in KPT-330-treated animals. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in the KPT-330 group (p&lt;0.05). The level of serum markers of osteoclast activity (TRAP and type I collagen fragment, CTX), was significantly higher in controls than in KPT-330-treated animals. The related SINE KPT-251 (100 mg/Kg q 2d x 3 weeks) confirmed the reduction of bone metastasis following CRM1 inhibition. The overall and disease free survival, evaluated at 170 days after tumor injection, were significantly higher in KPT-330- and KPT-251-treated animals versus controls (P&lt; 0.0001). Treatment of PC3 and DU145 cells with KPT-330 lead to significant reductions in the secretion of proteolytic enzymes (MMP-9, MMP-2, uPA) as well as reduced ability of tumor cells to migrate and invade Matrigel. Impaired secretion of pro-angiogenic (VEGF, IL6, IL8) and pro-osteolytic (RANKL, IL6) cytokines was also observed. Conclusions: These data show that selective blockade of CRM1-dependent nuclear export has direct antitumor, anti-metastatic and anti-osteolytic activities in PrCa and thus represents a novel approach for the treatment of advanced/ metastatic PrCa. KPT-330 is now in Phase 1 clinical trials in patients with advanced solid tumors (clinicaltrailas.gov: NCT01607905). Citation Format: Giovanni Luca Gravina, Monica Tortoreto, Andrea Mancini, Paola Muzi, Luca Ventura, Sandra D'ascenzo, Alessandro Addis, Yosef Landesman, Dilara McCauley, Vincenza Dolo, Michael Kauffman, Sharon Shacham, Nadia Zaffaroni, Claudio Festuccia. CRM1-Selective Inhibitors of Nuclear Export (SINE) reduce the incidence of tumor spreading and improve overall survival in preclinical models of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3440. doi:10.1158/1538-7445.AM2013-3440

International Angiology, Jun 1, 2023

Neurocritical Care, Feb 29, 2016

Background Therapeutic hypothermia (i.e., temperature management) is an effective option for impr... more Background Therapeutic hypothermia (i.e., temperature management) is an effective option for improving survival and neurological outcome after cardiac arrest and is potentially useful for the care of the critically ill neurological patient. We analyzed the feasibility of a device to control the temperature of the brain by controlling the temperature of the blood flowing through the neck. Methods A lumped parameter dynamic model, with onedimensional heat transfer, was used to predict cooling effects and to test experimental hypotheses. The cooling system consisted of a flexible collar and was tested on 4 adult sheep, in which brain and body temperatures were invasively monitored for the duration of the experiment. Results Model-based simulations predicted a lowering of the temperature of the brain and the body following the onset of cooling, with a rate of 0.4°C/h for the brain and 0.2°C/h for the body. The experimental findings showed comparable cooling rates in the two body compartments, with temperature reductions of 0.6 (0.2)°C/h for the brain and 0.6 (0.2)°C/h for the body. For a 70 kg adult human subject, we predict a temperature reduction of 0.64°C/h for the brain and 0.43°C/h for the body. Conclusions This work demonstrates the feasibility of using a non-invasive method to induce brain hypothermia using a portable collar. This device demonstrated an optimal safety profile and represents a potentially useful method for the administration of mild hypothermia and temperature control (i.e., treatment of hyperpyrexia) in cardiac arrest and critically ill neurologic patients.

Clinical Oral Implants Research, Dec 29, 2010

:Objectives: The aim of the present study was to evaluate a Ca–P coated implant surface in a rabb... more :Objectives: The aim of the present study was to evaluate a Ca–P coated implant surface in a rabbit model. The Ca–P surface (test) was compared to the titanium porous oxide surface (control) in terms of bone‐to‐implant contact (BIC) and removal torque value.Materials and methods: Two hundred and sixteen dental implants were inserted in the tibia and in the femur of 36 rabbits. One hundred and eight were represented by Ca–P oxidized surface implant and other 108 were titanium porous oxide surface modified implants. Each rabbit received six implants. Animals were sacrificed after 2, 4 and 9 weeks of healing. Each group included 12 rabbits. The femoral implant and the proximal implant of the tibia of each animal were subjected to the histologic analysis and the distal implants of the tibia underwent removal torque test (RTQ).Results: Histological analysis in terms of BIC and RTQ did not revealed any significant difference between the Ca–P oxidized surface and the oxidized surface at 2 and 4 weeks. At 9 weeks, the oxidized surface demonstrated better results in terms of RTQ in the tibia.Conclusion: In conclusion, findings from the present study suggested that the Ca–P coating had no beneficial effect in improving bonding strength at the bone–implant interface either at 2, 4 and 9 weeks. To cite this article: Fontana F, Rocchietta I, Addis A, Schupbach P, Zanotti G, Simion M. Effects of a calcium phosphate coating on the osseointegration of endosseous implants in a rabbit model Clin. Oral Impl. Res. 22, 2011; 760–766 doi: 10.1111/j.1600‐0501.2010.02056.x

European Urology Supplements, Nov 1, 2013

The Annals of Thoracic Surgery, Jun 1, 2011

We describe a modification of the Cox-Maze III using bipolar radiofrequency combined with off-pum... more We describe a modification of the Cox-Maze III using bipolar radiofrequency combined with off-pump coronary artery surgery for the treatment of patients with coronary artery disease and long-standing permanent atrial fibrillation. This study reports the midterm outcome of 12 patients with coronary artery disease and long-standing permanent atrial fibrillation who underwent off-pump coronary artery surgery and concomitant modified Maze with bipolar radiofrequency. At a mean follow-up of 23 months, all patients were alive, and 75% (9 of 12) had sinus rhythm. Our modified Maze can be safely and effectively combined with coronary artery surgery in an off-pump setting.

Gaceta dental: Industria y profesiones, 2016

El objetivo de este estudio histologico era evaluar la osteointegracion de los implantes de titan... more El objetivo de este estudio histologico era evaluar la osteointegracion de los implantes de titanio cuyas superficies fueron tratadas con diferentes metodos en cerdos enanos.Se evaluaron seis superficies diferentes: SLA-Ti5 (aleacion de titanio, arenado utilizando oxido de aluminio y grabado utilizando acido nitrico y fluoridico); SLA-Ti4 (titanio comercialmente puro (CP)-Ti, arenado utilizando particulas grandes de arenilla de oxido de aluminio ademas de grabado acido con acido clorhidrico/sulfurico); HA (CP-Ti, arenado utilizando hidroxiapatita ademas de grabado con acido nitrico); DAE (aleacion de titanio, doble acido grabador utilizando acido fluorhidrico ademas de acido clorhidrico y sulfurico); ASD-Ti5 (aleacion de titanio, sedimentacion anodica provocada); ASD-Ti4 (CP-Ti, sedimentacion anodica provocada). Se utilizo un escaner microscopico electronico para evaluar la superficie microtopografica. Se detecto la composicion de los elementos de la superficie mediante EDS (espectroscopio de dispersion de energia). Se insertaron seis implantes (uno por grupo) en cada tibia proximal de dos cerdos enanos y se dejaron inmersos durante tres meses. Despues se tomo una biopsia de hueso y se llevo a cabo el analisis histologico de la misma. Se eva luo el contacto entre el hueso y el implante (BIC) en la zona cortical. Se evaluo tambien el cociente de estabilidad del implante (ISQ) en el momento de la colocacion y en la retirada.El mayor contacto entre hueso e implante (BIC) se obtuvo sobre los implantes que utilizaron arenado con grabado acido (HA, SLA-Ti5, SLA-Ti4). El contacto entre hueso - implante resulto positivamente correlacionado con la rugosidad de la superficie. El mayor aumento de cociente de estabilidad (ISQ) se observo en el grupo ASD-T4. En la zona medular, la superficie SLA mostro la mejor respuesta osteogenica. Se detecto infiltracion celular inflamatoria alrededor de los implantes ASD-T5 y DAE.Las superficies con arenado grabado acido demostraron ligeramente mejor oseointegracion que las superficies con acabado anodizado o con grabado acido dual. La rugosidad de la superficie resulto positivamente correlacionada con la oseointegracion

Polymer foams are among the most studied scaffold for tissue engineering. Among them, cross-linke... more Polymer foams are among the most studied scaffold for tissue engineering. Among them, cross-linked polyurethane foams (PUFs) with slow degradation rate can be used as scaffolds for soft tissue engineering or as matrices of porous composites containing inorganic salts for hard tissue engineering. The foaming process has been set up using polymeric MDI, 2% water as expanding agent and Fe-acetyl acetonate as catalyst. On the whole, two families of foams (EC and EF) were developed using two different polyether-polyol formulations, the EF-type being more hydrophilic and more flexible than the EC-one. In vitro cytocompatibility tests with different cell lines demonstrated the ability of these matrices to stimulate cell adhesion and proliferation. In this work we investigated the in vivo behaviour of both EC and EF PU foams in the rat animal model to evaluate the extent of inflammatory reaction and the biodegradation rate. Discs of the EC- and EF-type foams were implanted in the dorsal subcutaneous tissue of male rats up to 42 weeks, explanted and histologically inspected together with the surrounding tissues by haematoxylin and eosin staining. The obtained results indicated a good biocompatibility of both foam types, the evoked inflammatory response being physiological. In particular, for the EF-based foams, at the material/tissue interface neovascularization and formation of new peripheral nerves were noticed. Moreover, the EF PUFs seem to promote the formation of mesenchimal tissue that, under particular stimuli, could promote the regeneration of the intended tissue

Résumé/Abstract This study is a first step to evaluate the properties of the new bioactive glass ... more Résumé/Abstract This study is a first step to evaluate the properties of the new bioactive glass Crystal Bio Tech both as a bulk and a macroporous material. Both types of glass have been used to repair a 10 mm defect in six rabbit limbs and the implants have been ...

Journal of the Pancreas, 2007

Silk fibroin (SF) is the inner component of the silk fiber spun by Bombyx mori silkworm. It is co... more Silk fibroin (SF) is the inner component of the silk fiber spun by Bombyx mori silkworm. It is considered a valuable material for biotechnology and biomedical applications due to its unique properties including biocompatibility, oxygen and water vapor permeability, biodegradability, and minimal inflammatory reaction. Sericin, which constitutes the outer layer of the fiber, was recently studied by several authors who underlined its antioxidant, antibacterial and anti-inflammatory properties, its protective action for serum deprived cells, being moreover considered a triggering molecule for apatite deposition. Fibroin and sericin can be processed to obtain powders, films, gels, filaments, etc., so making different materials that can tailored to the requirements of the specific application. These processes induce structural transitions and morphological changes that have a great influence on the physical and biological properties of the resulting materials. In this work two different SF-based hydrogels (100% SF and 90/10SF-Ser) and a pure fibroin sponge were compared in an in vivo critical size defect study in order to evaluate their bone regeneration capability

Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery, 2010

Anson Cheung, Jian Ye, David Wood, Christopher Thompson, Samuel Lichtenstein, John Webb. St. Paul... more Anson Cheung, Jian Ye, David Wood, Christopher Thompson, Samuel Lichtenstein, John Webb. St. Paul’s Hospital, Vancouver, BC Canada. Objective: Clinical use of bioprosthetic valve in the treatment of mitral valve disease has been growing. More complex and high-risk elderly patients with prosthetic valve dysfunction will require redo procedures. Re-operative mitral valve surgery in these patients is associated with high morbidity and mortality. We report a series of patient underwent transcatheter transapical mitral valve-in-valve implantations. Methods: Apical access was obtained thru a small left anterior thoracotomy via the 5 or 6 intercostal space. Mitral valve prosthesis was crossed using a wire under fluoroscopic and echocardiographic guidance. A 26 mm balloon expandable Sapien transcatheter valve (Edwards LifeSceinces, CA USA) was used in all cases. The transcatheter valve was deployed within the pre-existing mitral xenograft under rapid ventricular pacing. Postoperative clinical and echocardiographic follow up was obtained. Results: Seven high-risk patients with mitral prosthetic valve dysfunction underwent transcatheter transapical valve-in-valve implantations. The mean age was 80 6 and six were female. No valve malpositioning or embolization occurred in any cases. No thirty-day mortality was observed. One patient died on post-operative day 45 from respiratory failure and all remaining patients are alive and well with a median follow-up of 72 days (inter-quartile range 30 120 days, longest follow-up 345 days). Serial echocardiographic examinations demonstrated a reduction of mean gradient from 12.9 5.4 to 8.0 1.3 mmHg, valve area improvement from 0.7 0.4 to 1.7 0.4 cm and a reduction in regurgitation grade in all patients. Conclusions: Transcatheter transapical mitral valve-in-valve implantation is technically feasible. Transapical approach to the mitral xenograft is direct and coaxial. Excellent short-term clinical outcomes were observed. Transcatheter transapical valve-in-valve implantation may play an important role in the treatment of bioprosthetic mitral valve dysfunction.