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Among lifestyle factors, nutrition is one of the most important determinants of health, and represents a pivotal element of cancer risk. Nonetheless, epidemiological evidences of the relationship between several cancers and specific foods and nutrients is still inadequate, and solid conclusions are missing. Indeed, caloric restriction without malnutrition is associated to cancer prevention. Food may be also the primary route of exposure to contaminants such as metals, persistent organic pollutants, and pesticides. Exposuredisease associations and the interplay with genetic susceptibility requires further studies on genetic variation, environment, lifestyle, and chronic disease in order to eliminate and reduce associated health risks, thus contributing to improve health outcomes for the population. A primary nutritional approach for Active and Healthy Ageing (AHA) has been developed by the Nutrition group of the European Innovation Partnership (EIP) on AHA. The working group on lifestyles of the Italian Ministry of Health has developed a comprehensive approach to adequate nutrition using a consensus methodology to collect and integrate the available evidences from the literature and from the Italian experiences at the regional level, to raise the interest of other experts and relevant stakeholders to outline and scale-up joint strategies for a primary nutritional approach to cancer prevention.

Among lifestyle factors, nutrition is one of the most important determinants of health, and represents a pivotal element of cancer risk. Nonetheless, epidemiological evidences of the relationship between several cancers and specific foods and nutrients is still inadequate, and solid conclusions are missing. Several epidemiological studies related increased consumption of high fat diet and the risk to develop different types of cancer. Indeed, caloric restriction without malnutrition is associated to cancer prevention, due to the reduction in the activity of pro-aging pathways, of inflammation in precancerous cells, and to the increase of the apoptosis of damaged cells. Food may be also the primary route of exposure to contaminants from multiple chemical classes such as metals, persistent organic pollutants, and pesticides. Exposure-disease associations and the interplay with genetic susceptibility requires further fundamental knowledge and studies on genetic variation, environment, lifestyle, and chronic disease, that are pivotal to provide insights into disease etiology at the population level, in order to eliminate and reduce associated health risks, that contributing to improve health outcomes for the population. A primary nutritional approach for Active and Healthy Ageing (AHA) has been developed by the Nutrition group of the European Innovation Partnership (EIP) on AHA that could prove effective also to sustainable cancer prevention strategies. A comprehensive approach to adequate nutrition is very important to public health, in order to identify and implement the best possible and fair strategies. The working group on lifestyles of the Italian Ministry of Health has been working in this direction. The group used a consensus methodology to collect and integrate the available evidences from the literature and from the Italian experiences at the regional level, to provide a framework aimed at raising the interest of other experts and relevant stakeholders to outline and scale-up joint strategies for a primary nutritional approach to cancer prevention.

Long-living individuals (LLIs) are used to study exceptional longevity. A number of genetic variants have been found associated in LLIs to date, but further identification of variants would improve knowledge on the mechanisms regulating the rate of aging. Therefore, we performed a genome-wide association study on 410 LLIs and 553 young control individuals with a 317K single-nucleotide polymorphism (SNP) chip to identify novel traits associated with aging. Among the top (p

The application of the general clauses and principles to the matter of intellectual property

Il saggio analizza il decisivo contributo di Renato Scognamiglio all'evoluzione del danno alla persona nell'ordinamento giuridico italiano. Dopo aver ripercorso gli studi dedicati da Scognamiglio al tema, il saggio verifica l'impatto di tali studi sulla della riflessione scientifica sul danno non patrimoniale e sugli orientamenti della giurisprudenza. L'autore propone una razionalizzazione e l'integrazione delle conclusioni oggi prevalenti al fine di ridurre, per quanto possibile, le oscillazioni interpretative e l'incertezza applicativa. The essay analyzes the decisive contribution of Renato Scognamiglio to the evolution of damage to the person in the Italian legal system. After having retraced the studies dedicated by Scognamiglio to the topic, the essay verifies the impact of these studies on the scientific reflection on non-pecuniary damage and on the orientations of jurisprudence. The author proposes a rationalization and integration of the conclusions prevalent today in order to reduce, as far as possible, the interpretative fluctuations and the applicative uncertainty.

The aim of this study is to analyze surgical and functional outcomes in order to verify the applicability of surgical treatment guidelines as foreseen by MASCC/ISOO/ASCO 2019. Patients affected by stage 2 MRONJ refractory to conservative management were grouped if underwent surgical resection (Group A) or debridement (Group B). Health-related quality of life was evaluated by using the European Organization for Research and Treatment of Cancer questionnaires, QLQ-C30 and H&amp, N35. Statistical analysis was performed using Wilcoxon/Mann–Whitney test, Kaplan–Meier test, Cox regression model and Cox multivariate regression. Group A showed higher complete healing cases vs. group B. Recurrence rate difference in group A vs. group B was statistically significant. Debridement is an unfavorable prognostic factor when compared to surgical resection (p = 0.0032, HR 4.9). Quality of life mean values showed a marked improvement in Group A and a slight improvement in Group B. Debridement has 4.9 times more risk to develop recurrence when compared to surgical resection. A more satisfactory quality of life was shown in patients subject to resective surgery with an improving trend from baseline. Debridement patients showed more variability of results and an overall negative trend at the end of the 6-month follow-up.

Highlights • Lymphopenia and eosinopenia are associated with the severe form of COVID-19. • Increased levels of D-dimer, procalcitonin, and C reactive protein are prognostic biomarkers predicting coagulopathy. • Corticosteroids resulted the best therapy for the immune dysregulation in severe form of COVID-19. • Anticoagulative therapy is associated with reduced in-hospital mortality for COVID-19., Clinical symptoms of COVID-19 include fever, cough, and fatigue which may progress to acute respiratory distress syndrome (ARDS). The main hematological laboratory findings associated with the severe form of disease are represented by lymphopenia and eosinopenia which mostly occur in the elderly population characterized by cardiovascular comorbidities and immunosenescence. Besides, increased levels of D-dimer, procalcitonin, and C reactive protein (CRP) seem to be powerful prognostic biomarkers helping to predict the onset of coagulopathy. The host immune response to SARS-CoV-2 can lead to an aberrant inflammatory response or “cytokine storm” which contributes to the severity of illness. At immunological level, patients affected by a severe form of COVID-19 show poor clinical trajectories characterized by differential “immunotypes” for which T cell response seems to play a critical role in understanding pathogenic mechanisms of disease. Also, patients with mild to severe COVID-19 displayed macrophage activation syndrome (MAS), very low human leukocyte antigen D related (HLA-DR) expression with a parallel reduction of CD04+ lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Corticosteroids resulted the best therapy for the immune dysregulation whereas repurposing of tocilizumab (IL-6 receptor antagonist) appears to have mixed results in patients with COVID-19. Besides, anticoagulative therapy was associated with reduced in-hospital mortality and need of intubation among COVID-19 patients. Furthermore, the beneficial use of intravenous immunoglobulin (IVIG) and passive immunotherapy with convalescent plasma needs to be validated in large controlled clinical trials. In this review, we summarize the main hematological parameters with a prognostic value in COVID-19 and the basis of immunological reactivity during COVID-19, with a focus on ongoing clinical trials evaluating immune targets as possible therapeutic strategies.

Excessive BK (bradykinin) stimulation is responsible for the exaggerated permeabilization of the endothelium in angioedema. However, the molecular mechanisms underlying these responses have not been investigated. BK receptors are Gq-protein-coupled receptors phosphorylated by GRK2 (G protein-coupled receptor kinase 2) with a hitherto unknown biological and pathophysiological significance. In the present study, we sought to identify the functional role of GRK2 in angioedema through the regulation of BK signaling. We found that the accumulation of cytosolic Ca 2+ in endothelial cells induced by BK was sensitive to GRK2 activity, as it was significantly augmented by inhibiting the kinase. Accordingly, permeabilization and NO production induced by BK were enhanced, as well. In vivo, mice with reduced GRK2 levels in the endothelium (Tie2-CRE/GRK2 fl+/fl − ) exhibited an increased response to BK in terms of vascular permeability and extravasation. Finally, patients with reduced GRK2 levels displayed a severe phenotype of angioedema. Taken together, these findings establish GRK2 as a novel pivotal regulator of BK signaling with an essential role in the pathophysiology of vascular permeability and angioedema.

Il contributo affronta i principali aspetti problematici dell'attuale disciplina del segreto di Stato e del sistema di classificazione, anche alla luce dell'evoluzione della normativa (legislativa e regolamentare) in materia. Particolare rilievo, in quest'ottica, è dato ai principi costituzionali rilevanti e alle connesse dinamiche istituzionali, nell'ottica della ricerca di un equilibrio tra i diversi valori in gioco, ormai al centro di una complessa giurisprudenza della Corte costituzionale.

Analogs of potent CaMKinase II inhibitor, CaM-KNtide, were prepared to explore new structural requirements for the inhibitory activity. The full potency of CaMKII inhibition by CaM-KIINα is contained within a minimal region of 19 amino acids. Here, analysis of the homologous CaM-KIINβ showed that a 17 mer peptide (CN17β) was the shortest sequence that still retained useful inhibitory potency. Ala substitution of almost any residue of CN17β dramatically reduced potency, except for substitution of P3, R14, and V16. Fusion with the tat sequence generated the cell-penetrating inhibitor version tat-5. This tat-5 fusion peptide maintained selectivity for CaMKII over CaMKI and CaMKIV, and appeared to slightly further enhance potency (IC(50) ∼30 nM). Within a breast cancer cell line and in primary human fibroblasts, tat-5 inhibited the Erk signaling pathway and proliferation without any measurable cytotoxicity. Structural analysis of CN17β by CD and NMR indicated an α-helix conformation in the Leu6-Arg11 segment well overlapping with the crystal structure of 21-residue segment of CaM-KNtide bound to the kinase domain of CaMKII.

The calcium/calmodulin-dependent kinase II (CaMKII) participates with Ras to Raf-1 activation, and it is necessary for activation of the extracellular signal-regulated kinase (ERK) by different factors in epithelial and mesenchimal cells. Raf-1 activation is a complex multistep process, and its maximal activation is achieved by phosphorylation at Y341 by Src and at S338 by other kinase/s. Although early data proposed the involvement of p21-activated kinase 3 (Pak3), the kinase phosphorylating S338 remains to be definitively identified. In this study, we verified the hypothesis that CaMKII phosphorylates Raf-1 at Ser338. To do so, we determined the role of CaMKII in Raf-1 and ERK activation by oncogenic Ras and other factors. Serum, fibronectin, Src (Y527) and Ras (V12) activated CaMKII and ERK, at different extents. The inhibition of CaMKII attenuated Raf-1 and ERK activation by all these factors. CaMKII was also necessary for the phosphorylation of Raf-1 at S338 by serum, fibronectin and Ras. Conversely, inhibition of Pak3 activation by blocking phosphatidylinositol 3-kinase was ineffective. The direct phosphorylation of S338 Raf-1 by CaMKII was demonstrated in vitro by interaction of purified kinases. These results demonstrate that Ras activates CaMKII, which, in turn, phosphorylates Raf-1 at S338 and participates in ERK activation upon different stimuli.

La voce "Commercio elettronico", dell'Enc. dir., analizza in chiave sistematica la disciplina giuridica del Commercio elettronico, sia in riferimento al diritto interno, sia in riferimento al diritto europeo, ponendo altresì in evidenza ed affrontando gli aspetti problematici che la materia presenta.

Dal modello "fordista" convergente alla diversificazione sui mercati globali: la concertazione locale come fattore di competizione globale. Dopo la vicenda Fiat e gli accordi separati, quale sindacato e quale modello contrattuale per l'Italia?

RET/papillary thyroid carcinoma (PTC), TRK-T, or activating mutations of Ras and BRaf are frequent genetic alterations in PTC, all leading to the activation of the extracellular-regulated kinase (Erk) cascade. The aim of this study was to investigate the role of calmodulin-dependent kinase II (CaMKII) in the signal transduction leading to Erk activation in PTC cells. In normal thyroid cells, CaMKII and Erk were in the inactive form in the absence of stimulation. In primary PTC cultures and in PTC cell lines harboring the oncogenes RET/PTC-1 or BRafV600E, CaMKII was active also in the absence of any stimulation. Inhibition of calmodulin or phospholipase C (PLC) attenuated the level of CaMKII activation. Expression of recombinant RET/PTC-3, BRafV600E, or RasV12 induced CaMKII activation. Inhibition of CaMKII attenuated Erk activation and DNA synthesis in thyroid papillary carcinoma (TPC-1), a cell line harboring RET/PTC-1, suggesting that CaMKII is a component of the Erk signal cascade in this cell line. In conclusion, PTCs contain an active PLC/Ca2+/calmodulin-dependent signal inducing constitutive activation of CaMKII. This kinase is activated by BRafV600E, oncogenic Ras, and by RET/PTC. CaMKII participates to the activation of the Erk pathway by oncogenic Ras and RET/PTC and contributes to their signal output, thus modulating tumor cell proliferation.

Insulin effects are mediated by multiple integrated signals generated by the insulin receptor. Fibroblasts, as most of mammalian cells, are a target of insulin action and are important actors in the vascular pathogenesis of hyperinsulinemia. A role for calcium-calmodulin-dependent kinases ( CaMK) in insulin signaling has been proposed but has been under investigated. We investigated the role of the CaMK isoform II in insulin signaling in human fibroblasts. A rapid and transient increase of intracellular calcium concentration was induced by insulin stimulation, followed by increase of CaMKII activity, via L type calcium channels. Concomitantly, insulin stimulation induced Raf-1 and ERK activation, followed by thymidine uptake. Inhibition of CaMKII abrogated the insulin-induced Raf-1 and ERK activation, resulting also in the inhibition of thymidine incorporation. These results demonstrate that in fibroblasts, insulin-activated CaMKII is necessary, together with Raf-1, for ERK activation and cell proliferation. This represents a novel mechanism in the control of insulin signals leading to fibroblast proliferation, as well as a putative site for pharmacological intervention.

Il contributo analizza il fenomeno del lavoro sommerso in Italia sia nella sua dimensione quantitativa che in quella qualitativa. In particolare, l'interesse è rivolto alle diverse tipologie di lavoro irregolare e alle politiche per contrastarle.

Sono analizzate le modificazioni introdotte dal d. lgs. n. 181/2000, così come dal d. lgs. n. 297/2002, cui si deve il superamento del sistema del collocamento pubblico.