The era of bioengineering: how will this affect the next generation of cancer immunotherapy?

Immunotherapy consists of activating the patient's immune system to fight cancer and has the great potential of preventing future relapses thanks to immunological memory. A great variety of strategies have emerged to harness the immune system against tumors, from the administration of immunomodulatory agents that activate immune cells, to therapeutic vaccines or infusion of previously activated cancer-specific T cells. However, despite great recent progress many difficulties still remain, which prevent the widespread use of immunotherapy. Some of these limitations include: systemic toxicity, weak immune cellular responses or persistence over time and most ultimately costly and time-consuming procedures. Synthetic and natural biomaterials hold great potential to address these hurdles providing biocompatible systems capable of targeted local delivery, co-delivery, and controlled and/or sustained release. In this review we discuss some of the bioengineered solutions and approaches developed so far and how biomaterials can be further implemented to help and shape the future of cancer immunotherapy. The bioengineering strategies here presented constitute a powerful toolkit to develop safe and successful novel cancer immunotherapies

Dvostruki prijevodi u hrvatsko-dubrovačkom misalu (Neofiti 55) Vatikanske apostolske knjižnice (ovdje Vr)

Uso la denominazione indeterminata di “doppie traduzioni” in modo da includervi tutti i doppioni, di qualunque origine o natura essi siano. Una prima categoria di doppioni è costituita dalla combinazione di lezioni provenienti dall’area glagolitica con lezioni dell’area volgare; esempio Vr 49,5 “a ti Betlem, zemljo i grade judeoski”, dove “zemljo” è prevalente nella tradizione testuale glagolitica e “grade” in quella lezionvolgare. Una seconda categoria presenta la combinazione di lezioni originali di Vr con lezioni prese dalla tradizione: es. Vr 45,18, dove il latino “confitebatur” è tradotto “spovijedaše i hvaljaše”, con il primo termine preso dalla tradizione e il secondo nuovo. Una terza categoria vede la combinazione di termini nuovi di Vr con i della tradizione glagolitica, mentre nella quarta categoria la combinazione e con lezioni della tradizione volgare. La categoria più interessante è la quinta, quella dei doppioni totalmente innovativi (es. Vr 29, 6 con “vectes” tradotto “zavratnice i priječnice”, due termini del tutto assenti nella tradizione letterario-testuale del lezionario), perché ci pone il problema del perché, il come, il quando del raddoppio. Una parziale risposta a tale domanda ce la dà la categoria sesta che ci presenta dei doppioni “in fi eri”, costituiti da termini del testo a cui un’altra mano ha sovrapposto una diversa lezione senza cancellare la prima. Anche in questo Vr è prezioso perché ci permette di toccare con mano il meccanismo di riproduzione/produzione anche della tradizione ad esso precedente.Služim se ovdje neodređenim nazivom “dvostruki prijevodi” kako bih mogao uključiti sve dublete bez obzira na njihovu prirodu ili podrijetlo. Prva kategorija dvostrukih prijevoda sastoji se od spajanja čitanja iz glagoljaške tekstovne tradicije s čitanjima u tekstovima na narodnom jeziku: primjerice, Vr 49,5: “a ti Betlem, zemljo i grade judeoski”, gdje izraz “zemljo” prevladava u glagoljaškoj tekstovnoj predaji, a “grade” u narodnoj. Druga kategorija predstavlja kombinaciju originalnih čitanja iz Vr s čitanjima uzetim iz tradicije: primjerice, Vr 45,18, gdje se latinski “confi tebatur” prevodi kao “spovijedaše i hvaljaše”, od čega je prvi termin uzet iz tradicije dok je drugi nov. U trećoj se kategoriji novi termini iz Vr kombiniraju s čitanjima iz glagoljaške tradicije, dok se u četvrtoj kategoriji kombiniraju s čitanjima iz narodne jezične tradicije. Najzanimljivija je, međutim, peta kategorija koja predstavlja posve nove dublete (npr. Vr 29,6, gdje je latinski “vectes” preveden kao “zavratnice i priječnice”, s dva termina kojih uopće nema u književno-tekstovnoj tradiciji hrvatskog lekcionara), zanimljiva zato jer nam postavlja pitanja kada je, kako i zašto nastala dubleta. Djelomičan odgovor na ta pitanja naći ćemo u šestoj kategoriji, koja nam predstavlja dublete “in fi eri”, dublete koje se sastoje iz termina u tekstu iznad kojih je neka druga ruka ispisala druge termine ne izbrisavši prve. Rukopis Vr je dragocjen jer nam dopušta nazrijeti također stvaralaštvo razdoblja i tradiciju koji su mu prethodili

L’Umanesimo nell’Europa Orientale

La prima domanda che ci si pone accingendoci ad affrontare un capitolo di storia riguardante l’Europa Orientale è quale sia l’Europa Orientale, ovvero quale sia la linea di confine che separa tra loro le due Europe, la Occidentale e la Orientale. Naturalmente si tratta di una linea di confine ideale risultante dalla media dei confini storici esistenti tra le due parti nei vari campi: socio-politico-economico, statale, cultural-religioso. L’Europa Occidentale è nel Medioevo l’Impero Romano d’O..

Aplicación del “Planeamiento Estratégico" en una empresa prestadora de servicios médicos situada en la provincia de Mendoza

La presente investigación se enfoca en las oportunidades y ventajas que brinda a una pequeña empresa la posibilidad de aplicar de forma integral un Planeamiento Estratégico, junto con la importancia del análisis interno y externo en sus distintas aristas para armar la estrategia y trabajar el plan estratégico; con el fin de comenzar a transcurrir por el camino de la generación de valor en el tiempo. Su razón de ser tiene origen en el adverso contexto económico que atraviesa actualmente la República Argentina, y en particular la provincia de Mendoza, y en la necesidad que tiene todo emprendimiento de generar utilidades, dado que las Pymes cumplen un rol fundamental en la economía del país. Para llevar a cabo dicho trabajo, se tomaron algunas entrevistas y cuestionarios a gerentes, accionistas y trabajadores de una empresa prestadora de servicios médicos y se concluyó que el análisis del Planeamiento Estratégico es de vital importancia para el desarrollo económico de la entidad.The purpose of this research focuses on the opportunities and advantages offered to a small company by the possibility of comprehensively applying a Strategic Planning in an integral way, together with the importance of internal and external analysis in its different edges to put together the strategy and work on the strategic plan; in order to begin to go through the path of generating value over time. This research focuses on the opportunities and advantages offered to a small company by the possibility of applying a Strategic Planning Its reason originates from the adverse economic context that the Argentine Republic is currently going through, and in particular the province of Mendoza, and from the need for any undertaking to generate profits, given that SMEs play a fundamental role in the economy of the country. To carry out this work, some interviews and questionnaires were taken with managers, shareholders and workers of a company providing medical services and it was concluded that the analysis of the Strategic Planning is of vital importance for the economic development of the entity.Fil: Armendariz, Tomas Eugenio. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Graciotti Tarquini, Marco. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas

A cancer vaccine with dendritic cells differentiated with GM-CSF and IFNα and pulsed with a squaric acid treated cell lysate improves T cell priming and tumor growth control in a mouse model.

<i> <b>Introduction:</b> </i> Ovarian cancer is one of the most lethal gynecologic cancers. Relapses after remission are common, hence novel strategies are urgently needed. Our group has previously developed a vaccination approach based on dendritic cells pulsed with HOCl-oxidized tumor lysates. Here we investigate the improvement of this vaccine strategy using squaric acid treatment of cancer cells during tumor lysate preparation and by differentiating dendritic cells in the presence of GM-CSF and IFNα. <i> <b>Methods:</b> </i> Induction of cell death by squaric acid treatment was assessed with propidium iodide (PI) and Annexin V in ID8 tumor cells. High mobility group box 1 (HMGB1) immunogenic status was analyzed using a western blot-based method, as previously described. For immunological tests, ID8 cells expressing ovalbumin (ova-ID8) were treated with squaric acid before cell lysis. DCs prepared with the canonical GM-CSF and IL-4 differentiation cocktail or IFNα and GM-CSF were pulsed with tumor cell lysates and further matured in the presence of IFNγ and LPS (4-DCs and α-DCs respectively). DCs were then used in co-culture assays with ova-specific T cells and IFNγ and IL-4 secretion measured by ELISA. DC phenotypes were characterized by FACS. Finally, DCs were tested in an ovarian cancer mouse model measuring body weight and animal survival. <i> <b>Results:</b> </i> Squaric acid treatment of mouse ovarian cancer cells induced tumor cell death as well as preserve HMGB1, a crucial Damage-associated molecular pattern (DAMP) signal, in its active reduced form. Squaric acid treatment of ID8-ova cells increased IFNγ and decreased IL-4 production from ova-specific T cells in co-culture experiments, promoting a more immunogenic cytokine secretion pattern. DCs differentiated in the presence of IFNα induced a considerable decrease in IL-4 production compared to canonical 4-DCs, without affecting IFNγ release. DC phenotyping demonstrated a more mature and immunogenic phenotype for IFNα-differentiated DCs. Vaccination in tumor-bearing mice showed that IFNα-differentiated DCs pulsed with squaric acid-treated lysates were the most potent at delaying tumor growth, improving animal survival. <i> <b>Conclusion:</b> </i> We identified squaric acid as a novel immunogenic treatment of tumor cells for cancer vaccines particularly efficient in prolonging animal survival when used in combination with IFNα-differentiated DCs. These promising results support future efforts for the clinical translation of this approach

IL-15 and a Two-Step Maturation Process Improve Bone Marrow-Derived Dendritic Cell Cancer Vaccine

In the last 20 years, dendritic cells (DCs) have been largely used as a platform for therapeutic vaccination in cancer patients. However, despite its proven safety and ability to induce cancer specific immune responses, the clinical benefits of DC-based immunotherapy are currently very limited. Thus, novel approaches are still needed to boost its efficacy. Our group recently showed that squaric acid treatment of antigens is an important adjuvant that can increase vaccine-induced downstream immune responses and therapeutic outcomes. Here we further improved this dendritic cell vaccine formulation by developing a new method for differentiating and maturing DCs from their bone marrow precursors. Our data demonstrate that bone marrow-derived DCs differentiated with GM-CSF and IL-15 and matured with a maturation cocktail in two steps present a more mature and immunogenic phenotype, compared to standard DC preparations. Further suppression of the prostaglandin E2 pathway achieved even more immunogenic DC phenotypes. This vaccine was more potent at delaying tumor growth, improved animal survival and induced a more immunogenic and Th1-skewed T cell response in an ovarian cancer mouse model. These promising results support future efforts for the clinical translation of this approach

Toll like receptor signaling in "inflammaging": microRNA as new players.

none7nopubblicazione scientificaopenOlivieri F; Rippo MR; Prattichizzo F; Babini L; Graciotti L; Recchioni R; Procopio ADOlivieri, Fabiola; Rippo, Maria Rita; Prattichizzo, Francesco; Babini, Lucia; Graciotti, Laura; Recchioni, R; Procopio, Antonio Domenic