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

U/Th dating of a tufa deposit from the Carsoli intramontane basin (Abruzzo, Italy)

A few km far from the confluence of the Fioi valley into the Carsoli basin, some hundreds m2 wide and ca. 1.5 m thick carbonatic deposit is present, embedded within late Middle Pleistocene alluvial gravel. The deposit formation might be related to sub-aerial deposition of CaCO3 (tufa) from emerging groundwater. A U/Th dating to 46 ± 6 ka BP constrains the deposit within the MIS 3, corresponding to a phase of warming between the MIS 4 and 2

Evoluzione geomorfologica quaternaria della conca intermontana di Carsoli (Aq)

In the present work the results of a geological and geomorphological study are presented. The study has been carried out in the Carsoli intermontane basin (AQ), a wide depression of tectonic origin, located between Abruzzo and Lazio regions, at the boundary of two different palaeogeographic domains, separated by the “Olevano-Antrodoco” tectonic line. The Carsoli basin is filled with a continental sedimentary succession of considerable thickness and extent, which has been classified into several lithostratigraphic units, mainly on the basis of their lithological, morphological and geochronological characteristics. The oldest continental sediments outcropping within the study area are of lacustrine origin (Bosco di Oricola silts, clays and sands). These sediments, whose deposition has probably occurred in the Lower – Middle Pleistocene, are characterized by a maximum thickness of about 200 m. They are widespread in the north-western and central parts of the basin (Bosco di Oricola) and are locally present on the eastern edge of the basin. The lacustrine deposits are cut across by an ancient sub-horizontal erosion surface, and at present, only some remnants remain. The lacustrine sediments are covered, on the north-eastern edge of the basin, by coarse fluvial sediments suspended on the present plain, originally deposited by the paleo-Turano River (Madonna delle Grazie gravels). In the central-western and southern part of the study area, a significant sequence of local volcanic deposits, dated around 530 – 540 kyears BP, outcrops. The volcanic sequence abruptly begins from an articulated erosive surface shaped in lacustrine deposits and Meso-Cenozoic carbonatic bedrock. Three main pyroclastic units are distinguished in the following members: 1) Oricola scalo opening–vent breccias, 2) Oricola Scalo grey tuffs, 3) S. Giovanni red tuffs. Only the last two units widely outcrops in the study area. The Oricola Scalo opening-vent breccias are relative to the early opening phase of the conduit. They consist of a massive structure connected to the depositional mechanisms of airfall and/or debris flow, separated by tuff layers related to base surge phenomena. The Oricola Scalo grey tuffs unit mainly consists of grey ash-lapilli tuffs with surge cross-laminations, and grey lapilli tuffs with a massive structure of pyroclastic flow. The overlying S. Giovanni red tuffs are characterized, instead, by a thickness and distribution greater than that of underlying grey tuffs. The unit is mainly composed of red lapilli tuffs, with dune structures or a parallel lamination of surge and airfall. After the lacustrine sedimentation and the volcanic episodes, the examined area underwent intense fluvial dynamics. This led to the sedimentation, in the central-southern and eastern part of the basin, of a sequence of alluvial deposits belonging to different depositional events. The morpho-litho-stratigraphic analysis of these fluvial deposits, in addition with radiometric ages, allowed for their classification into four units (Prati gravels, sands and silts, Fioio Stream conglomerates, Immagine gravels, sands and silts, Turano River gravels, sands and silts) progressively embedded into each other and ranging in age between the late Middle Pleistocene and the Present. Entrenched in the late Middle Pleistocene alluvial unit, in the southern sector of the basin (Fonte Bosco), a few hundred meters long and 1.5 meters thick calcareous tufa layer, dated by U-series method at 46,000 ± 6,000 years BP outcrops. With regard to the most recent depositional phases, great relevance has to be ascribed to the stratigraphic study carried out on the Fosso Luisa fan (Camerata Nuova) and the radiometric dating of colluvial horizon, there present. This dating, providing a calibrated 14C age of 3,550-3,400 years BP, has allowed for a temporal definition of some sedimentary and erosive events that marked the upper part of the fan during the final part of Holocene

COVID-19 and fat embolism: a hypothesis to explain the severe clinical outcome in people with obesity

none5nononeCinti S.; Graciotti L.; Giordano A.; Valerio A.; Nisoli E.Cinti, S.; Graciotti, L.; Giordano, A.; Antonelli, Valerio; Nisoli, E

Predicting combinations of immunomodulators to enhance dendritic cell-based vaccination based on a hybrid experimental and computational platform

Dendritic cell (DC)-based vaccines have been largely used in the adjuvant setting for the treatment of cancer, however, despite their proven safety, clinical outcomes still remain modest. In order to improve their efficacy, DC-based vaccines are often combined with one or multiple immunomodulatory agents. However, the selection of the most promising combinations is hampered by the plethora of agents available and the unknown interplay between these different agents. To address this point, we developed a hybrid experimental and computational platform to predict the effects and immunogenicity of dual combinations of stimuli once combined with DC vaccination, based on the experimental data of a variety of assays to monitor different aspects of the immune response after a single stimulus. To assess the stimuli behavior when used as single agents, we first developed an in vitro co-culture system of T cell priming using monocyte-derived DCs loaded with whole tumor lysate to prime autologous peripheral blood mononuclear cells in the presence of the chosen stimuli, as single adjuvants, and characterized the elicited response assessing 18 different phenotypic and functional traits important for an efficient anti-cancer response. We then developed and applied a prediction algorithm, generating a ranking for all possible dual combinations of the different single stimuli considered here. The ranking generated by the prediction tool was then validated with experimental data showing a strong correlation with the predicted scores, confirming that the top ranked conditions globally significantly outperformed the worst conditions. Thus, the method developed here constitutes an innovative tool for the selection of the best immunomodulatory agents to implement in future DC-based vaccines.status: publishe

Identification of multinucleated cells in human kidney cortex: A way for tissue repairing?

The presence of multinucleated cells has never been demonstrated in renal tissue, although, polyploid cells were recently observed in the tubules of normal and pathological human kidney. Therefore, the aim of the present study is to identify and quantify, by electron microscopy, multinucleated cells in the cortical tissue of normal human kidney i.e., in the three compartments of renal tubule: the proximal tubule (PT), the distal tubule (DT), and the collecting duct (CD), as well as, in the glomerulus (podocytes). The percentage of the multinucleated cells observed was 5% (95%CI: 3.6%–6.7%) in renal cortical tubules with distribution in each tubular compartment of 6% in PT, 4% in DT and 3% in CD with no statistically significant difference in the distribution of multinucleated cells according to tubular compartments. Four percent of analysed podocytes (in total 149 podocytes) were multinucleated (95%CI: 1.5%−8.6%). In conclusion, multinucleated cells were identified and quantified in functionally normal kidneys, as previously demonstrated in other organs such as the liver