1,727 research outputs found
Correction to: Lenvatinib as a salvage therapy for advanced metastatic medullary thyroid cancer (Journal of Endocrinological Investigation, (2021), 44, 10, (2139-2151), 10.1007/s40618-020-01491-3)
No full textThe article “Lenvatinib as a salvage therapy for advanced metastatic medullary thyroid cancer” written by A. Matrone, A. Prete, A. Nervo, A. Ragni, L. Agate, E. Molinaro, C. Giani, L. Valerio, E. Minaldi, A. Piovesan and R. Elise was originally published online on the publisher’s internet portal on 17th February 2021 with Open Access under a Creative Commons Attribution (CC BY) license 4.0 With the authors’ decision to cancel Open Access the copyright of the article changed on 28th April 2021 to © Italian Society of Endocrinology (SIE) 2021 with all rights reserved. The original article has been corrected
[Old Issues and New Trends in Enforcing Orders of Specific Performance in Italy]
No full textAfter a brief analysis of the issues affecting enforcement proceedings in Italy, the author discusses the impact of a recent reform that introduced a generally applicable coercive measure in Italian legal system
Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Ka and PI3Kb Activities and Is Promoted by RAS
No full textPhosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should be dosed below their hyperglycemic threshold to achieve isoform selectivity. Insulin signaling is believed to be mediated by PI3Kα activity, which depends on RAS. Molinaro et al. show that maximal insulin-induced AKT phosphorylation, but not downstream signaling, depends on RAS. They show that insulin signaling in hepatocytes and insulin action on glycemia are mediated by redundant PI3Kα and PI3Kβ activities.</p
Microfluidic Assembly of Liposomes with Tunable Size and Coloading Capabilities
No full textLiposomes used for the delivery of pharmaceuticals have difficulties scaling up and reaching clinical translation as they suffer from batch-to-batch variability. Here, we describe a microfluidic approach for creating reproducible, homogenous nanoparticles with tunable characteristics. These nanoparticles of sizes ranging from 30 to 500 nm are rapidly self-assembled by controlling the flow rates of ethanol and aqueous streams. This method of microfluidic assembly allows for the efficient encapsulation of both hydrophobic and hydrophilic drugs in the lipid bilayer and particle core, respectively, either separately or in combination
Papillary thyroid microcarcinoma: Toward an active surveillance strategy
No full textIn the last decades, the incidence of thyroid cancer (TC) has m ore than doubled, but the disease-specific mortality rate was stable. To date, 30-40% of all TC is represented by papilla ry microcarcinomas (mPTC), an indolent tumor, that probably remained undiagnosed before routine ultrasound use. In 1993, Miyauchi was the first who hypothesized a conservative approach for low-risk mPTC and introduced the co ncept of active surveillance (AS) in its clinical management. The progression rate of mPTC during AS was low and delaying surgery did not impact the efficacy of treatment or outcome. Since then, several authors from all over the world have reported their experience of AS in mPTCs. As suggested by current guidelines, AS can be considered as an alternative to immediate surgery to avoid overtreatment in low-risk mPTC and may be the strategy to avoid complications from unnecessary surgery. In the last years, AS inclusion criteria have been extended to both bigger tumors and to younger/healthier patients. The adoption of AS should take into consideration not only tumor characteris tics but also patient psychological profiles and medical team expertise. Its safety and efficacy have been demonstrated in long-term outcome studies and in other types of tumors; however, skepticism in patients, families and physician s should be overcome by strong recommendations coming from scientific guidelines. This review analyses the seve ral and different experiences of AS and the potential obstacles in implementing it as a routine approach in mPTC pati ents
An interactive DSS to improve decision-making in the (r,Q) policy
No full textThis paper proposes a Decision Support System (DSS) to consistently improve decision-making in a (r,Q) policy-based inventory system. Although literature offers a wide selection of contributions on (r,Q) policy, a solution that provides a systemic way to set the related inventory parameters seems to be lacking. The purpose of this paper is to develop a DSS based on what-if analyses that aims to identify the most suitable balance between service level and inventory cost. The application of the DSS in a real case study shows the benefits of the proposed solution
The interplay between "low" and "high" energy CP-violation in leptogenesis
No full textWe analyse, within the "flavoured" leptogenesis scenario of baryon asymmetry generation, the interplay of "low energy" CP-violation, originating from the PMNS neutrino mixing matrix U, and "high energy" CP-violation, which can be present in the matrix of neutrino Yukawa couplings, lambda, and can manifest itself only in "high" energy scale processes. The type I see-saw model with three heavy right-handed Majorana neutrinos having a hierarchical spectrum is considered. The "orthogonal" parameterisation of the matrix of neutrino Yukawa couplings, which involves a complex orthogonal matrix R, is employed. In this approach the matrix R is the source of "high energy" CP-violation. Results for normal hierarchical (NH) and inverted hierarchical (IH) light neutrino mass spectrum are derived in the case of decoupling of the heaviest right-handed Majorana neutrino. It is shown that taking into account the contribution to Y (B) due to the CP-violating phases in the neutrino mixing matrix U can change drastically the predictions for Y (B) , obtained assuming that only "high energy" CP-violation from the R-matrix is operative in leptogenesis. In the case of the IH spectrum, in particular, there exist significant regions in the corresponding parameter space where the purely "high energy" contribution in Y (B) plays a subdominant role in the production of baryon asymmetry compatible with the observations
Focusing New Ataxia Telangiectasia Therapeutic Approaches
No full textAtaxia Telangiectasia (AT) is a rare worldwide disease inherited as autosomal recessive with a poor prognosis in its classical form. It is characterized by neurological impairment (progressive cerebellar ataxia, axonal peripheral neuropathy, oculomotor apraxia, and movement disorders such as dystonia, choreoathetosis, myoclonus, tremor, Parkinsonism), telangiectasias, recurrent sino pulmonary infections, proneness to cancer, increased alpha-fetoprotein and decreased IgA levels and radio hypersensitivity. AT is caused by biallelic mutations in ATM gene, which plays a pivotal role in the control of cell cycle and in the response to DNA double strand break damage and chromatin changes. The management of patients, as well as prognosis, depends on the severity of the phenotype; only symptomatic therapies are by now available. Here we discuss the classical and the new therapeutic approaches in the light of the most recent reports in the literature
Role of mechanical stress on modulating the differentiation of myogenic cells
No full textI segnali meccanici sono importanti regolatori della proliferazione cellulare e del differenziamento. Le cellule sono in grado di percepire le modificazioni del microambiente e di produrre una risposta: proliferazione, differenziamento, migrazione o apoptosi. Le cellule del muscolo scheletrico non sono in grado di rigenerarsi dopo aver subito un grave danno. Pertanto, in seguito a danno tissutale dovuto, ad esempio, a una malattia degenerativa lo sviluppo di tessuti muscolari, in vitro, per sostituire quelli danneggiati è una delle più grandi sfide. In questo contesto è importante comprendere la relazione che intercorre tra il microambiente e la cellula. Lo scopo di questo lavoro è valutare l’effetto dello stress meccanico sul processo di differenziamento cellulare e di comprendere meglio il ruolo che la proteina YAP svolge in esso. Il modello sperimentale utilizzato è costituito da cellule miogeniche in quanto il muscolo è continuamente esposto a stress meccanico. Sono stati applicati due diversi tipi di stress: (1) cellule mioblastiche sono state seminate in una matrice 3D composta da polietilen glicole e fibrinogeno (PEG-F) per mimare una condizione fisiologica. E’ stato valutato il ruolo della compressione applicata dalla stessa matrice a diverse concentrazioni (7 e 14 mg/ml) e, in seguito, è stato valutato il ruolo della compressione applicata da un dispositivo appositamente costruito; (2) mesoangioblasti sono stati seminati su uno strato di nanowires (NWs) di ZnO ed è stato valutato il loro effetto sul differenziamento cellulare. E’ stato valutato il livello di fosforilazione della proteina YAP in cellule cresciute in due differenti microambienti: un substrato di polistirene (2D) e una matrice di PEG-F (3D). È stato osservato che in cellule seminate nella matrice 3D la fosforilazione della proteina YAP si verifica prima rispetto alle cellule seminate sulla matrice 2D. Le cellule sono state seminate nella matrice PEG-F a due differenti concentrazioni (7 e 14 mg/ml) ed è stata valutata la risposta cellulare e la correlazione con il processo di differenziamento. È risultato che nelle cellule seminate nella matrice alla concentrazione di 7mg/ml la proteina YAP è maggiormente attiva a livello trascrizionale e i marcatori del differenziamento sono più espressi. Successivamente è stato valutato l’effetto della compressione sulle cellule C2C12 cresciute nella matrice ed è stato dimostrato che la compressione induce il differenziamento cellulare. Nella seconda parte del lavoro cellule mesangioblastiche sono state seminate su un substrato funzionalizzato con NWs verticali di ZnO. È stato dimostrato che questa tipologia di substrato è compatibile con la vitalità cellulare, ma le cellule assumono una forma rotondeggiante. Ulteriori esperimenti suggeriscono che le cellule non sono in grado di assumere la loro classica forma perché i NWs impediscono loro di aderire al substrato. In queste condizioni le cellule sono in grado di preservare la capacità di differenziare, infatti quando le cellule vengono staccate da questo substrato e riseminate su un supporto privo di NWs sono in grado di prendere contatto con esso e di differenziare, suggerendo che questo sistema può utilizzato per controllare il differenziamento cellulare.Mechanical signals are important regulators of cellular proliferation and differentiation. Cells are able to sense microenvironment perturbations and to produce a response such as proliferation, differentiation, migration, apoptosis. Skeletal muscle cells are not able to regenerate after a severe loss of tissue. The engineering of muscle in vitro is a major challenge in view of possible replacements of tissue damage after degenerative diseases or accidents. In this context, the comprehension of the relationship that exists between the substrate (microenvironment) and the cellular response is pivotal for the creation of artificial tissues. The aim of this study is to test the role of mechanical stress on differentiation processes and to highlight the role of yes-associated protein (YAP) in this processes. We decided to use as experimental model skeletal muscle cells because muscle is continuously exposed to mechanical stress. We decided to induce two different type of stress: (1) in the first one we embedded myoblast cells (C2C12) in a 3D matrix made of polyethylene glycol and fibrinogen (PEG-F) because in this way we can mimic a physiological environment. We evaluate the role of compression applied by the hydrogel at two different concentration and then we compressed cells embedded into the hydrogel by a devices built specifically to this purpose; (2) in the second approach we seeded mesoangioblast cells (Mabs) on a layer of high density vertical ZnO nanowires (NWs) to evaluate the ability of Mabs cells to differentiate on it. For the first study, we characterized the YAP phosphorylation level in cells growing in two different microenvironment: polystyrene substrate (2D) and PEG-F matrix (3D). We observed that in cells embedded into a 3D matrix YAP phosphorylation occurs earlier compared to 2D. Then we evaluated cellular response to a different PEG-F matrix concentrations and correlate it to myoblast differentiation markers. We found that YAP is more active at a transcriptional level in cells embedded in a soft matrix and that the differentiation markers show an higher level. Then we evaluated the effect of compression on C2C12 cells encapsulated in the PEG-F matrix, demonstrating that compression induce differentiation in a marked way in a very short range of time. In the second approach we seeded Mabs cells on glasses functionalized with high density vertical ZnO NWs. We show that this support is compatible with cells viability but cells assume a round shape. Further experiments suggested that cells are not able to assume a classic conformation because NWs structure impede them to take contact with the substrate. Cells seeded on ZnO NWs preserve the ability to differentiate, in fact, when cells are detached from the ZnO NWs layer and seeded again on a glass not functionalized they are able to take contact with the substrate and then to differentiate, indicating that ZnO NWs can be a system to finely control cellular differentiation
Structural determination of the complex exopolysaccharide from the virulent strain of Cryphonectria parasitica
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