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

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

Dystrophin Is Required for the Normal Function of the Cardio-Protective KATP Channel in Cardiomyocytes

Duchenne and Becker muscular dystrophy patients often develop a cardiomyopathy for which the pathogenesis is still unknown. We have employed the murine animal model of Duchenne muscular dystrophy (mdx), which develops a cardiomyopathy that includes some characteristics of the human disease, to study the molecular basis of this pathology. Here we show that the mdx mouse heart has defects consistent with alteration in compounds that regulate energy homeostasis including a marked decrease in creatine-phosphate (PC). In addition, the mdx heart is more susceptible to anoxia than controls. Since the cardio-protective ATP sensitive potassium channel (KATP) complex and PC have been shown to interact we investigated whether deficits in PC levels correlate with other molecular events including KATP ion channel complex presence, its functionality and interaction with dystrophin. We found that this channel complex is present in the dystrophic cardiac cell membrane but its ability to sense a drop in the intracellular ATP concentration and consequently open is compromised by the absence of dystrophin. We further demonstrate that the creatine kinase muscle isoform (CKm) is displaced from the plasma membrane of the mdx cardiac cells. Considering that CKm is a determinant of KATP channel complex function we hypothesize that dystrophin acts as a scaffolding protein organizing the KATP channel complex and the enzymes necessary for its correct functioning. Therefore, the lack of proper functioning of the cardio-protective KATP system in the mdx cardiomyocytes may be part of the mechanism contributing to development of cardiac disease in dystrophic patients

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

Correction: 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.

[This corrects the article DOI: 10.15171/bi.2018.24.]

Caratteristiche geomorfologiche dell’Isola di Pianosa.

Pianosa Island belongs to the Tuscany Archipelago; it has an extension of 10 km2, 18 km of coastal development and a max altitude of 29 m a.s.l. The island is made up of neogenic and quaternary sediments; pelitic Miocene sediments outcrops at the base of the cliff in the south-western coast, while the bio-calcarenitic Pliocene sediments cover most part of the island. Quaternary deposits are established by biodetrital shore sediments of Tyrrhenian age and by Late Pleistocene colluvial deposits. The island is characterized by cliffs in the western and southern sector, by plain surfaces and by a small beach in the east side. Cliffs have been distinguished in 3 different types. In the first type is always present a developing wave notch. When the coast is not characterized by cliff we can found erosion plains (at maximum level of approximately 4 m) formed during the Tyrrhenian high stand (Isotopic stage 5e). These erosion planes can be suspended and sub-horizontal (when the layers of the pliocenic substrate dip towards inland), or gently tilted towards sea (when the layers of the pliocenic substrate dip towards sea). On these various erosion planes are always present rock pools characterized by different shape and dimension, besides rare fossiliferous shore deposits (Panchina). In these sediments have been recognized, between others: Strombus bubonius, Patella ferruginea and Conus testudinarius, dating Tyrrhenian age. On the island we can found three different order of erosion planes at 2-4 m, 8 m and 25 m a.s.l. Karst process produced erosion epigean micro-landforms, such us dissolutional flutes, dissolutional groves and dissolutional pans (kamenitza), macro-landforms represented by E-W karst oval basin depressions, enlarged hundred meters and few meters deep. The same process left isolated rock promontory residual of the tyrrhenian cliffs coast lines. Much diffused are hypogean karst shape such as caves and conduits that, sometimes, are opened on the cliff and are visible only by the sea. In some of these caves, characterized by speleothemes, we discovered, at a quote of 7 m a.s.l., marine deposits and litodomes holes probably of Tyrrhenian age. Frequently is the founding of breccias breeded by collapse of caves and conduits. Surface karst landforms are widening covered by high agricoltural activity developed in the last two centuries due to the presence of the agricoltural penal colony