118 research outputs found
NOVEL SMART DEVICES FOR THE ADMINISTRATION OF DRUGS INTO HOLLOW MUSCULAR ORGANS
No full textIn questa tesi di dottorato è stato indagato il potenziale di applicazione di smart materials ed in particolare dei cosiddetti polimeri a memoria (SMPs) in campo farmaceutico. Questi ultimi, grazie alla loro capacità di rispondere a stimoli esterni modificando la propria geometria nel tempo, si configurano ad oggi come una delle tematiche di ricerca più all’avanguardia. A partire da questi materiali sono stati sviluppati sistemi di rilascio (drug delivery systems, DDSs) dalle prestazioni innovative e potenzialmente in grado di superare i limiti degli approcci terapeutici attualmente disponibili (e.g. scarsa aderenza alla terapia da parte del paziente, capacità di garantire livelli di attivo efficaci nella zona di interessa per un periodo di tempo prolungato, possibilità di personalizzazione dei sistemi). Date queste premesse, la letteratura scientifica a disposizione è stata oggetto di una valutazione approfondita, con la stesura di una review, nella quale sono stati recensititi tutti i sistemi di rilascio proposti in letteratura e realizzati a partire da SMPs, evidenziando l'obiettivo per cui i cambiamenti di forma sono stati perseguiti.
Da un punto di vista sperimentale, SMPs di grado farmaceutico sono stati impiegati per la prima volta nella realizzazione di DDSs destinati alla ritenzione, per lunghi periodi di tempo, in organi cavi di tipo muscolare, quali vescica e stomaco. A questo proposito, il processo di cambiamento di forma consentirebbe non solo la somministrazione sicura dei sistemi ma anche la relativa permanenza nel sito di interesse. Prototipi di DDSs organo-ritentivi sono stati quindi ottenuti utilizzando tecniche piuttosto innovative per la produzione farmaceutica, ovvero estrusione a caldo e stampa 3D per fused deposition modeling. È da sottolineare come, l’utilizzo di SMPs come materiali di partenza per la stampa 3D, si traduca nel nuovo concetto di stampa 4D.
Successivamente la possibilità di rivestire i campioni precedentemente realizzati e caratterizzati da una geometria particolarmente complessa si è dimostrata una strategia efficace per prolungarne la durata di rilascio senza influenzarne il comportamento di memoria di forma. Infine, i dati sperimentali raccolti sono stati accoppiati ad un modello di simulazione opportunamente validato così da accelerare le fasi di ricerca e sviluppo relative ai DDSs oggetto di studio e migliorarne le prestazioni complessive. Sfruttando questo approccio combinato sarebbe infatti possibile prevedere il comportamento a memoria di forma di prototipi complessi, riducendo al contempo il numero di oggetti fisici da preparare e testare.In this PhD thesis, the potential of smart materials, and particularly of shape memory polymers (SMPs), in pharmaceutics has been widely investigated. SMPs, with their ability to dynamically respond to specific external stimuli by changing their shape over time, currently represent one of the topics at the forefront of research. Within the pharmaceutical field their use was demonstrated able to provide innovative performance and to overcome limitations associated with the already available therapeutic approaches, e.g. poor patient compliance, ability to ensure effective drug levels at the target area for a prolonged period of time, fine tuning and customization of the overall performance. This was the main topic of a comprehensive overview of the scientific literature available, focused on SMP-based drug delivery systems (DDSs) and aimed at highlighting the objective for which the shape changes were pursued. From an experimental point of view, the possibility of using SMPs of pharmaceutical-grade in the development of DDSs intended for long-lasting retention into hollow-muscular organ, such as bladder and stomach, was approached for the first time. In this respect, the shape shifting process would ensure safe administration and enable prolonged retention at the site of interest. Feasibility of prototypes was investigated using quite novel techniques for pharmaceutical manufacturing, i.e. hot melt extrusion and fused deposition modeling 3D printing, the latter providing the tool for 4D printing when dealing with SMPs as starting materials. Film-coating of SMPs-based prototypes having complex geometries was also demonstrated as a viable strategy to prolong the release duration without affecting the shape memory behavior. Moreover, the comprehensive experimental campaign carried out was coupled with computer-aided simulation modelling to accelerate the R&D stages and to improve the overall performance of the DDSs proposed. In fact, thanks to this approach, it would be possible to predict the shape memory behavior of complex prototypes while reducing the number of physical samples to be attained
Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells
No full textThe cooperation of liver X receptors (LXRs) alpha and beta, and retinoic X receptor (RXR) modulate the expression of several genes involved in lipid metabolism in hepatocyte and macrophages. Using cDNA microarray technology, we have shown previously that several of these genes are also expressed in endothelial cells. In the present study, we investigated whether the activation of LXR and RXR affects the expression of genes involved in lipid metabolism in human endothelial cells. Relative expression of ABCA-1, CETP, SR-B1, EL, LPL, PLTP, ApoE and LDLR was investigated in HUVECs, human fibroblasts (hFB) and HepG2 cells by quantitative real-time PCR. For CETP and EL mRNA expression, the results were HUVECs > hFB > HEPG2; for PLTP, LDLR and LPL: hFB > HUVECs > HEPG2; for SR-B1 and ApoE: HEPG2 > HUVECs > hFB; and for ABCA-1 HEPG2: > hFB > HUVECs. Incubation of HUVECs with LXR agonists as 22-(R)-hydroxycholesterol (22-(R)-HC) or T0901317-induced ABCA1 (20.1- and 17.8-fold), LPL (3.46- and 7.03-fold) and CETP (6.34- and 3.98-fold) expression; EL, LDLR and SR-B1 expression was induced only upon incubation with T0901317 (2.40-, 2.83- and 2.19-fold, respectively) while 22-(R)-HC had no effect on EL and SR-B1 expression (0.8- and 0.9-fold) and decreased LDLR expression (0.4-fold). No effect of either 22-(R)-HC or T0901317 on PLTP and ApoE expression was observed. The RXR agonist, 9-cis retinoic acid (9CRA) alone induced the expression of CETP, LPL and SR-B1 (2.8-, 8.2- and 2.4-fold). No effect of 9CRA on ABCA-1, EL, PLTP, ApoE, and LDLR expression was observed. Association of 9CRA with 22-(R)-HC or T0901317 increased the expression of CETP and LPL while no effect on ABCA-1 or LDLR was observed. Activation of LXRs and RXRs in endothelial cells represents a new target of LXR and RXR agonist in the arterial wall. Modulation of gene expression in the endothelium should be taken into account when studying the effects of LXR and RXR agonists on lipid metabolism in the arterial wall
Mediastinistis and pleural empyema after odontogenetic abscess: two cases report and review of the literature
No full textTreatment of large knee osteochondral lesions with a biomimetic scaffold: Results of a multicenter study of 49 patients at 2-year follow-up
No full textBackground: Osteochondral knee lesions represent a challenging condition encountered by orthopaedic surgeons. A variety of methods have been developed to repair articular cartilage defects. However, these techniques are limited by donor site morbidity or by the requirement for a staged procedure. Purpose: To assess the effectiveness of a biomimetic osteochondral scaffold for the treatment of large osteochondral knee lesions. Study Design: Case series; Level of evidence, 4. Methods: From 2009 to 2011, a total of 49 patients affected by isolated large osteochondral knee lesions (mean [± SD] size, 4.35 ± 1.26 cm2) were treated with the biomimetic scaffold. Patients were evaluated using the International Knee Documentation Committee (IKDC), Tegner, and visual analog scale (VAS) pain scores, as well as magnetic resonance imaging (MRI) up to 3-year follow-up. The MOCART (magnetic resonance observation of cartilage repair tissue) score was performed to analyze different variables. Biopsies were carried out in 5 patients. Four of the 5 second-look arthroscopies and biopsies were performed on patients with failed results because of ethical issues. Results: The mean IKDC subjective score increased significantly from 45.45 ± 19.29 preoperatively to 70.86 ± 18.08 at 1-year followup and to 75.42 ± 19.31 at 2-year follow-up (P < .001). The IKDC objective score changed from 50% normal and nearly normal knees before treatment to 89.79% at the 2-year follow-up. There was a statistically significant improvement (P < .005) in VAS score from the preoperative level (6.69 ± 1.88) to the 2-year follow-up (1.96 ± 2.47). Tegner scores increased (P < .001) from the preoperative value (2.20 ± 0.67) to the 2-year follow-up (4.9 ± 1.73) without achieving preinjury level. A correlation was found between the IKDC subjective score and age (P < .001, r = 20.497, r = 20.502). Patients affected by osteochondritis dissecans (OCD) achieved a statistically significantly better outcome (P < .05). A subgroup of 19 competitive athletes showed a statistically significantly improvement (P < .001) in the subjective IKDC (86.5 ± 13.2) compared with the nonathletic subpopulation (69.03 ± 19.41) at the 2-year follow-up. The MRI findings of 30 patients were available at 2-year follow-up: 70% showed complete filling of the lesion, 63.3% had an intact articular surface, and 86% had mild or no effusion. In all cases, in dual T2-weighted fast spin echo sequence, the repair tissue showed a hyperintensive signal with respect to the surrounding subchondral bone; however, no edema was observed. Conclusion: The study findings indicate that the biomimetic scaffold that was investigated is an off-the-shelf, cell-free, and costeffective implant that can regenerate either cartilage or subchondral bone. The scaffold allows a 1-step surgical procedure that can be used for osteochondral lesions, OCD, and in some cases osteonecrosis. © 2014 The Author(s)
Dendritic cell marker Clec4a4 deficiency limits atherosclerosis progression
No full textBackground and aims: Atherogenesis results from altered lipid metabolism and impaired immune response. Emerging evidence has suggested that dendritic cells (DCs) participate to atherosclerosis-related immune response, but their impact is scarcely characterized. Clec4a4 or DCIR2 (Dendritic cell immunoreceptor 2) is a C-type lectin receptor, mainly expressed by CD8α− DCs, able to modulate T cell immunity. However, whether this DC subset could play a role in the atherogenesis is still poorly understood. Thus, the aim of this study is to investigate whether the absence of Clec4a4 could affect atherosclerosis-related immune response and atherosclerosis itself. Methods: Dcir2−/− Ldlr−/− and Ldlr−/− mice were fed a standard diet or cholesterol-enriched diet for 12 weeks. Subsequently, the profile of circulating and lymph nodes-resident immune cells was investigated together with the analysis of plasma lipid levels and atherosclerotic plaque extension in the aorta. Results: Here, we show that Clec4a4 expression is downregulated under hypercholesterolemia and its deficiency in Ldlr−/− mice results in the reduction of atherosclerotic plaque formation, together with altered lipid metabolism and impaired myeloid immune cell distribution. Conclusions: Our findings suggest a pro-atherosclerotic role of Clec4a4 in experimental atherosclerosis
Dendritic cell immunoreceptor 2 (DCIR2) deficiency decreases hepatic conventional dendritic cell content but not the progression of diet-induced obesity
No full textAims: Inflammatory pathways and immune system dysregulation participate in the onset and progression of cardiometabolic diseases. The dendritic cell immunoreceptor 2 (DCIR2) is a C-type lectin receptor mainly expressed by conventional type 2 dendritic cells, involved in antigen recognition and in the modulation of T cell response. Here, we investigated the effect of DCIR2 deficiency during the development of obesity. Methods: DCIR2 KO mice and the WT counterpart were fed with high-fat diet (HFD) for 20 weeks. Weight gain, glucose and insulin tolerance were assessed, parallel to immune cell subset profiling and histological analysis. Results: After HFD feeding, DCIR2 KO mice presented altered conventional dendritic cell distribution within the liver without affecting markers of hepatic inflammation. These observations were liver restricted, since immune profile of metabolic and lymphoid organs-namely adipose tissue, spleen and mesenteric lymph nodes-did not show differences between the two groups. This reflected in a similar metabolic profile of DCIR2 KO compared to WT mice, characterized by comparable body weight gain as well as adipose tissues, spleen, Peyer's patches and mesenteric lymph nodes weight at sacrifice. Also, insulin response was similar in both groups. Conclusion: Our data show that DCIR2 has a redundant role in the progression of diet-induced obesity and inflammation
The impairment of the High Mobility Group A (HMGA) protein function contributes to the anticancer activity of trabectedin
No full textTrabectedin (Ecteinascidin-743 or ET-743) is a novel antitumour agent of marine
origin with potent antitumour activity both in vitro and in vivo. It interacts with the minor
groove of DNA, interfering with transcriptional activity and DNA repair pathways. Here,
we report a novel mechanism by which trabectedin exerts its cytotoxic effects on carcinoma
cells. It is based on its ability to impair the function of the High-Mobility Group A (HMGA)
proteins. These proteins have a key role in cell transformation, and their overexpression is a
common feature of human malignant neoplasias, representing a poor prognostic index often
correlated to anti-cancer drug resistance. They bind the minor groove of DNA, alter chromatin
structure and, thus, regulate the transcription of several genes by enhancing or suppressing
the activity of transcription factors.
We first report that trabectedin has a higher cytotoxic effect on thyroid and colon carcinoma
cells expressing abundant levels of HMGAs in comparison with cells not expressing them.
Then, we have shown that trabectedin treatment displaces HMGA proteins from the
HMGA-responsive promoters, including ATM promoter, impairing their transcriptional
activity
Arthroscopic treatment of knee stiffness
No full textA loss of range of motion, commonly defined as stiffness, is a relatively common complication after knee surgery or traumatic injury [1]. The high incidence of postoperative knee stiffness observable in the past reduced significantly with improvement of surgical techniques and rehabilitation protocols [2]. Any symptomatic loss of knee flexion or extension compared with the opposite normal knee should be considered and treated as knee stiffness. In order to address conservative or surgical therapy, the cause, the type and the degree of stiffness must be identified and staged
PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement
No full textBackground and aims: Proprotein convertase subtilisin kexin type 9 (PCSK9) induces degradation of the low-density lipoprotein-receptor (LDLR). Smooth muscle cells (SMCs) in human atherosclerotic plaques and cultured SMCs express PCSK9. The present study aimed at defining the role of PCSK9 on vascular response to injury.
Methods: Carotid neointimal lesions were induced by positioning a non-occlusive collar in PCSK9 knockout (PCSK9(-/-)) and wild type littermate (PCSK9(+/+)) mice.
Results: In PCSK9(-/-) mice, we observed a significantly less intimal thickening (p < 0.05), a lower intimal media ratio (p < 0.02), and a tendency to higher lumen area, compared to PCSK9(+/+) mice. When compared with PCSK9(-/-), lesions of PCSK9(+/+) mice had a higher content of SMCs (p < 0.05) and collagen (p < 0.05), while no difference was observed in the accumulation of macrophages. PCSK9 was detectable in both left and right carotids artery in regions occupied by medial and neointimal SMCs. SMCs freshly isolated from PCSK9(-/-), when compared to PCSK9(+/+) cells, showed higher levels of alpha-smooth muscle actin (alpha-SMA; 2.24 +/- 0.36 fold; p < 0.01) and myosin heavy chain II (MHC-II; 8.65 +/- 1.55 fold; p < 0.01), and lower levels of caldesmon mRNA (-54 +/- 14%; p < 0.01). PCSK9(-/-) cells also showed a slower proliferation rate, and an impaired migratory capacity and G1/S progression of the cell cycle. The reconstitution of PCSK9 expression, by retroviral infection of PCSK9(-/-) SMCs, led to a downregulation of a-SMA (-56 +/- 2%; p < 0.01), MHC-II(-45% +/- 25.5 fold: p = 0.06) and calponin (-25% +/- 0.8 fold: p < 0.05) and induction of caldesmon mRNA (1.46 +/- 0.3 fold; p < 0.05). Proliferation rate of SMCs PCSK9(-/-) was significantly lower compared to PCSK9 reconstituted cells.
Conclusions: Taken together, the present results suggest that PCSK9, by sustaining SMC synthetic phenotype, proliferation, and migration, may play a pro-atherogenic role in the arterial wall
Can a biomimetic osteochondral scaffold be a reliable alternative to prosthetic surgery in treating late-stage SPONK?
No full textBackground: This study aimed to assess the reliability of the Maioregen (R) biomimetic osteochondral scaffold (Finceramica Faenza SpA, Faenza, Italy) as a salvage and joint-preserving procedure in the treatment of late-stage osteonecrosis of the knee.Methods: Eleven active patients aged under 65 years and presenting with clinical and radiological signs of SPONK were treated with Maioregen. All were clinically evaluated pre-operatively and yearly thereafter for a minimum of two years. Subjective IKDC and Lysholm Knee Scale scores were used to assess clinical outcome. A VAS scale served to quantify pre-operative pain and post-operative pain. Activity levels were evaluated pre-operatively and at follow-up using the Tegner Activity Scale.Results: Subjective IKDC (40 +/- 15.0 to 65.7 +/- 14.8 (mean +/- SD)) and Lysholm Knee Scale (49.7 +/- 17.9 to 86.6 +/- 12.7 (mean +/- SD)) scores improved significantly from pre-operative evaluation (p < .01). VAS scores decreased from a pre-operative mean (+/- SD) of 6.3 +/- 2.5 to 1.6 +/- 2.7 at two years. The Tegner Activity Scale showed no significant differences between pre-injury and two-year follow-up.Two out of the 11 patients were symptomatic at 18 months post implant and progressed to condylar collapse. These patients required total knee arthroplasty.Conclusions: Use of a biomimetic scaffold can be a valid option in the surgical treatment of SPONK in relatively young active patients. Indeed, this surgical technique, originally developed for osteochondritis dissecans, has been found to give good clinical results at medium-term follow-up of late-stage osteonecrosis treatment and could postpone or even avoid the need for joint replacement procedures
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