649 research outputs found
La gestione JIT della rete di distribuzione dei ricambi automobilistici: il caso Toyota Motor Italy
No full textImpact of anti-CD20 tumor-targeting therapeutic monoclonal antibodies on human Natural Killer cell responsiveness and plasticity: relevance of FcgammaRIIIA/CD16 affinity ligation conditions
No full textMy study is focused on understanding the mechanisms underlying the modulation of NK cell responsiveness and plasticity induced by tumor targeting therapeutic anti-CD20 monoclonal antibodies (mAbs) nowadays routinely used in the treatment of B-cell malignancies and autoimmune disorders. Anti-CD20 mAbs are grouped into type I and II subtypes. Type I mAbs induce CD20 redistribution into lipid rafts and display a remarkable ability to activate complement-dependent cytotoxicity (CDC). On the other hand, type II mAbs, which are not able to localize CD20 complexes into lipid rafts and induce weak or no CDC, evoke more homotypic adhesion and direct killing of target cells. Both type I and II mAbs demonstrate efficient phagocytosis and antibody-dependent cytotoxicity (ADCC). Natural Killer (NK) cell-mediated ADCC, based on the recognition of IgG-opsonized targets by the low affinity Fc receptor for IgG FcgammaRIIIA/CD16, represents one of the main mechanisms by which anti-CD20 mAbs mediate their anti-tumor effects. Besides ADCC, CD16 ligation also results in the production of cytokines such as IFN-gamma that plays a key role in the shaping of adaptive immune responses. Rituximab is a chimeric type I anti-CD20 mAb of 1st generation and is considered the reference molecule for the comparison with new generation anti-CD20 mAbs, designed to optimize clinical efficacy. Among them, obinutuzumab is a humanized Fc-glycoengineered type II anti-CD20 mAb of 3rd generation designed to increase the affinity for CD16 receptor and consequently the killing of mAb-opsonized targets. However, the impact of CD16 ligation in optimized affinity conditions on NK functional program is not completely understood. Herein, I demonstrated that CD16 affinity ligation conditions may dictate both the amplitude of NK responsiveness (cytotoxicity and IFN-gamma production) as well as the ability to shift the NK functional program. Indeed, I observed that the interaction of NK cells with obinutuzumab-opsonized targets results in enhanced cytotoxicity and IFN-gamma production as compared with the parental non-glycoengineered mAb or the reference molecule rituximab, independently from the CD16-158V/F allotype. The affinity ligation conditions also strictly correlate with the ability to induce CD16 surface down-modulation and lysosomal targeting of receptor-coupled signaling elements. Indeed, a preferential degradation of FcepsilonRIgamma chain and Syk tyrosine kinase was observed upon obinutuzumab stimulation independently from the CD16-158V/F allotype. Notably, although the down-regulation of FcepsilonRIgamma/Syk module hesitates in the impairment of cytotoxic function induced by CD16, NKp46 and NKp30 activating receptors, obinutuzumab-experienced NK cells exhibit an increased ability to produce IFN-gamma in response to cytokines and target stimulation as well as to obinutuzumab-mediated CD16 re-stimulation.
Relying on the observation that obinutuzumab-experienced NK cells, under molecular and functional profile, resemble the distinctive features of the long-lived and highly functional “memory” NK cells, a population recently identified in HCMV seropositive individuals, I assessed the capability of anti-CD20 mAbs to affect the expansion as well as the phenotypic and functional properties of the “memory” NK subset. My data show that the majority of the analysed healthy donors is HCMV seropositive and exhibits a detectable population of “memory” NK cells (CD3- CD56+ FcepsilonRIgamma- CD16+) accounting for 3 to 50% of peripheral blood NK cells. I observed that “memory” NK cells selectively undergo 2- to 12-fold expansion upon co-culturing with anti-CD20-opsonized targets; on the opposite, the proliferation of “conventional” NK cells (CD3- CD56+ FcepsilonRIgamma+ CD16+) is not affected by CD16 stimulation. I also noted that anti-CD20 mAb in vitro expanded “memory” NK cells show the molecular and functional hallmarks of their freshly isolated counterpart, including the increased expression of NKG2C receptor, the reduced expression of NKp46 receptor associated to an enhanced functional activity in response to CD16 re-stimulation, particularly in terms of IFN-gamma production
L'entomologia forense
No full textL’entomologia forense ha per anni studiato il ruolo degli insetti nei
processi di decadimento cadaverico contribuendo così in misura rilevante
alle stime sull’epoca di morte. La grande variabilità dei classici segni
post-mortali quali ipostasi, rigidità, raffreddamento cadaverico e putrefazione
ha portato a privilegiare l’uso del metodo entomologico in ambito
medico-legale in ragione della maggiore oggettività e ripetibilità dei tempi
di sviluppo degli insetti che per primi colonizzano la materia organica
in decomposizione. Le conoscenze acquisite nel tempo, tuttavia, hanno
permesso di verificare che lo studio degli insetti associati ad un cadavere
fornisce utili indicazioni non solo in ambito tanatocronologico ma anche
sui mezzi e sulla causa del decesso (v. entomotossicologia), risultando
talora dirimenti per il patologo forense in eventi di interesse tipicamente
medico-legale quali omicidi, intossicazioni, politraumatismi, depezzamenti,
abusi e maltrattamenti, etc. Una analisi approfondita e altamente specialistica degli insetti che partecipano ai processi di trasformazione
della materia organica consente altresì di verificare fatti circostanziali
o elementi investigativi correlati alle modalità delittuose dell’evento,
ai luoghi ove questo è stato perpetrato e all’eventuale sospetto autore del
reato contribuendo così, talvolta in maniera anche decisiva, alle indagini
di Polizia Giudiziaria.
Il presente capitolo illustra le basi scientifiche della disciplina entomologica
forense e i risvolti applicativi in ambito medico-legale, esaminando
vantaggi e svantaggi alla luce delle recenti acquisizioni sperimentali
- …
