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Melanoma, the most lethal form of skin cancer, is frequently associated with alterations in several genes, among which the Bcl-2 oncogene plays an important role in progression, chemosensitivity and angiogenesis. Also microRNA (miRNA) are emerging as modulators of melanoma development and progression, and among them, miR-211, located within the melastatin-1/TRPM1 (transient receptor potential cation channel, subfamily M, member 1 protein) gene, is prevalently expressed in the melanocyte lineage and acts as oncosuppressor. Using several human melanoma cell lines and their Bcl-2 stably overexpressing derivatives, we evaluated whether there was a correlation between expression of Bcl-2 and miR-211. Western blot analysis and quantitative real-time polymerase chain reaction demonstrated reduced expression of pri-miR-211, miR-211, TRPM1, and MLANA levels, after Bcl-2 overexpression, associated with increased expression of well-known miR-211 target genes. Overexpression of mature miR-211 in Bcl-2 overexpressing cells rescued Bcl-2 ability to increase cell migration. A decreased nuclear localization of microphthalmia-associated transcription factor (MITF), a co-regulator of both miR-211 and TRPM1, and a reduced MITF recruitment at the TRPM1 and MLANA promoters were also evidenced in Bcl-2 overexpressing cells by immunofluorescence and chromatin immunoprecipitation experiments, respectively. Reduction of Bcl-2 expression by small interference RNA confirmed the ability of Bcl-2 to modulate miR-211 and TRPM1 expression. © 2015 Wiley Periodicals, Inc.

Venous thromboembolism (VTE) is one of the leading causes of morbidity and mortality in acutely ill medical patients. Fondaparinux is recommended for the prevention of VTE in this setting, but little information is available on its safety and effectiveness in unselected, "real world" patients. The aim of this paper was to assess the safety and efficacy of fondaparinux in elderly acutely ill medical patients.Single center, retrospective study. All patients60 years, admitted for acute medical disease, bedridden for at least four days and treated with fondaparinux were evaluated. Occurrence of objectively documented, symptomatic VTE, and of bleeding events during the treatment period and follow-up were reported.Two hundred and ten patients (median age 81 years) were treated with fondaparinux. Seventy patients received fondaparinux 1.5 mg daily, 140 received the 2.5 mg daily dose. However, 29 patients in the first group (with a CrCl≥50 mL/min) and 84 patients in the last group (with a CrCl50 mL/min) did not receive the correct dose of fondaparinux. During treatment, one episode (0.48%, 95% CI 0.1% to 2.6%) of major bleeding and 6 episodes (2.86%, 95% CI 1.3% to 6.1%) of clinically relevant non major bleeding were recorded. Only one thromboembolic event (0.48%, 95% CI 0.1% to 2.6%) was documented. Thirty-nine patients died; no death was related to VTE, unlike one death was due to major bleeding. Cancer was the only significant predictor of bleeding at statistical analysis.In elderly acutely ill hospitalized medical patients, thromboprophylaxis with fondaparinux 2.5 or 1.5mg daily is safe and effective in preventing VTE without increasing bleeding risk.

So far, very few studies in the literature have reported data on the long-term follow-up of patients who have undergone surgery for giant bullous emphysema (GBE), and much still needs to be known on the late fate of these patients.To evaluate patients who have undergone elective surgery due to GBE, early and late mortality following surgery, the early and late reappearance of bullae, and the early and late modifications of clinical and functional data.Forty-one consecutive patients (36 men; mean [+/- SD] age, 48.4 +/- 14.8 years) who underwent elective surgery for GBE were enrolled in a prospective study, and were studied both before and after undergoing bullectomy for a 5-year-follow-up period. Analyses were performed on the whole population and on two subgroups of patients who were divided on the basis of the absence of underlying diffuse emphysema (group A; n = 23) or the presence of underlying diffuse emphysema (group B; n = 18).The early mortality rate was 7.3% (within the first year), and the late mortality rate was 4.9% (overall mortality rate at 5 years, 12.2%; mortality rate in group B, 27.8%). Bullae did not reappear and residual bullae did not become enlarged in any patients at the site of the bullectomy. During the follow-up, the dyspnea score was reduced significantly soon after bullectomy and up to the fourth year of follow-up; intrathoracic gas volume also was reduced significantly (average, 0.7 L). The same was true for the FEV1 percent predicted and the FEV1/vital capacity ratio, which kept increasing until the second year; then, from the third year of follow-up these values were reduced, yet remained above the prebullectomy values until the fifth year of follow-up. When considered separately, the patients in group B appeared to be the most impaired, clinically and functionally (eg, FEV1 showed a similar significant increase up to the second year in both groups after surgery, while a different mean annual decrease was appreciable from the second to the fifth year of follow-up: group A, 25 mL/year; group B, 83 mL/year. Furthermore, patients in group B were the only ones who contributed to the mortality rate, on the whole showing a behavior similar to that of patients who had undergone lung volume reduction surgery.In patients with GBE who were enrolled in the study prospectively and were investigated yearly during a 5-year-follow-up period, elective surgery appears to have been fairly safe, and allowed clinical and functional improvement for at least 5 years. Better results may be expected in patients without underlying diffuse emphysema.

Noninvasive positive pressure mechanical ventilation (NIPPV) in exacerbated chronic obstructive pulmonary disease (COPD) has been investigated early and after 1 yr of follow-up. To this end, 30 patients were enrolled in a prospective, controlled trial: 15 had early administration of NIPPV (Group A), 15 had medical therapy only (Group B); assignment was made on the basis of equipment availability only. In-hospital mortality, need for endotracheal intubation and mean length of hospitalization were lower in Group A, though the difference was not statistically significant. Arterial oxygen tension in arterial blood (Pa,O2), carbon dioxide tension in arterial blood (Pa,CO2) and HCO3 - improved significantly in both groups from admission to discharge: 45.8

Il saggio intende sottolineare il rapporto storico tra aura e riproducibilità, identificando nell'opera d'arte il veicolo mediante cui si abbandona la dimensione rituale per accedere alla dimensione tecnica

Mitotic proteins are attractive targets to develop molecular cancer therapeutics due to the intimate interdependence between cell proliferation and mitosis. In this work, we have explored the therapeutic potential of the kinetochore (KT) protein Hec1 (Highly Expressed in Cancer protein 1) as a molecular target to produce massive chromosome missegregation and cell death in cancer cells. Hec1 is a constituent of the Ndc80 complex, which mediates KT-microtubule (MT) attachments at mitosis and is upregulated in various cancer types. We expressed Hec1 fused with enhanced green fluorescent protein (EGFP) at its N-terminus MT-interaction domain in HeLa cells and showed that expression of this modified Hec1, which localized at KTs, blocked cell proliferation and promoted apoptosis in tumour cells. EGFP-Hec1 was extremely potent in tumour cell killing and more efficient than siRNA-induced Hec1 depletion. In striking contrast, normal cells showed no apparent cell proliferation defects or cell death following EGFP-Hec1 expression. Live-cell imaging demonstrated that cancer cell death was associated with massive chromosome missegregation within multipolar spindles after a prolonged mitotic arrest. Moreover, EGFP-Hec1 expression was found to increase KT-MT attachment stability, providing a molecular explanation for the abnormal spindle architecture and the cytotoxic activity of this modified protein. Consistent with cell culture data, EGFP-Hec1 expression was found to strongly inhibit tumour growth in a mouse xenograft model by disrupting mitosis and inducing multipolar spindles. Taken together, these findings demonstrate that stimulation of massive chromosome segregation defects can be used as an anti-cancer strategy through the activation of mitotic catastrophe after a multipolar mitosis. Importantly, this study represents a clear proof of concept that targeting KT proteins required for proper KT-MT attachment dynamics constitutes a powerful approach in cancer therapy.Oncogene advance online publication, 18 August 2014; doi:10.1038/onc.2014.265.

La finitezza è tradizionalmente associata alle categorie morfo-sintattiche di tempo e persona. La nozione di ‘finitezza’ dovrebbe comunque essere considerata in una prospettiva più ampia dal momento che essa ha implicazioni semantiche e pragmatiche, un dato che ha indotto diversi autori (ad esempio, Lasser 1997; Maas 2004) a proporre una distinzione tra la finitezza morfologica e la finitezza semantica. Il lavoro tenta di giustificare la rilevanza di tale distinzione per la descrizione e lo studio dei processi acquisizionali. Nel corso dell’ultimo decennio, l’acquisizione della finitezza è stata analizzata attraverso una prospettiva essenzialmente formale, comparando, nel corso del tempo, le produzioni orali spontanee o semi-guidate fornite dagli apprendenti. Attraverso l’impiego della stessa metodologia, il lavoro esamina e pone a confronto i processi acquisizionali di informatori che apprendono il francese, l’olandese e il tedesco come L1 (bambini) o come L2 (appredenti adulti), ovvero lingue in cui la finitezza è marcata per il tramite della morfologia verbale. Vengono dunque descritte le tappe di acquisizione che si susseguono, interrogandosi sulle notevoli differenze che emergono tra l’acquisizione infantile (L1) e quella adulta (L2) e sul modo in cui tali divergenze possono aiutare a comprendere il funzionamento del meccanismo della finitezza.