The Impact of the ‘Mis-Peptidome’ on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet’s disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8⁺ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the “mis-immunopeptidome” that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8⁺ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.     

Autonomic Nervous System in Obesity and Insulin-Resistance—The Complex Interplay between Leptin and Central Nervous System

The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.     

AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations

Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials.     

Isothermal crystallization of PLA: Nucleation density and growth rates of α and α' phases

From a technological point of view, poly(lactic acid) (PLA) is one of the most important polymers produced from renewable sources, due to its versatility, relatively acceptable processability, and low cost. However, a significant limitation exists in its slow crystallization kinetics, which results in amorphous products having low mechanical properties and thermal resistance. For this reason, quantitative knowledge of the phenomenon of crystallization kinetics is fundamental. In this work, the crystallization kinetics in quiescent conditions of a commercial grade of PLA was analyzed in terms of nucleation and growth rates by direct morphological observations at different crystallization temperatures (T_c) and by calorimetric analysis in isothermal and non-isothermal conditions. The optical analysis showed a spherulitic morphology with radial growth of the lamellae. The analysis of the growth rate evidenced the α/α'-crystals polymorphism with a transition temperature of ~120°C. Based on experimental observation, the crystallization kinetics of the two crystalline phases were assessed.     

Antioxidant packaging development and optimization using agroindustrial wastes

The increasing use of non-biodegradable materials and the difficulty in recycling most of the available packaging have been pushing the development of biodegradable packaging. In this study, the potential uses of agroindustrial wastes to produce biodegradable films with antioxidant capacity were investigated. Starch films were produced by casting method using bran from jaboticaba peel, mango peel, and broccoli stalk. The influence of the concentration or type of bran in the properties of the films was evaluated through a central composite design. The results were analyzed by response surface and desirability function. Except for elongation and water solubility, the fitted equations were predictive in all studied properties. The films prepared from a higher concentration of mango peel exhibited better antioxidant capacity, while the broccoli stalk had no significant effect on antioxidant properties. The optimal formulation of the film (2.8% of jaboticaba peel and 20.0% of mango peel) and their predicted response variables (0.8 MPa for tensile strength, 40.0 MPa for Young's modulus, 4.5 mg/ml for IC₅₀, and 41.6% for inhibition percentage) were defined according to the results. The optimization was satisfactory and the film presented high antioxidant capacity and moderate mechanical properties, proving to be an alternative to replace plastic packaging.     

Characterisation of oleoresins extracted from tomato waste by liquid and supercritical carbon dioxide

Tomato waste is characterised by high amounts of bioactive compounds, such as carotenoids, polyphenols and essential fatty acids. In this work, oleoresins were produced from tomato waste (skins + seeds) and skins using carbon dioxide under liquid and supercritical conditions. The use of ethanol as a co-solvent was also evaluated. Compositions of the oleoresins were analysed and compared to oleoresin obtained by means of an organic solvent, which was used as the control. Oleoresin extraction from the waste by liquid and supercritical CO₂ provided the highest yields (12.5%–12.9%). The extracts obtained from the skins with supercritical CO₂ without ethanol had the highest content of α- and γ-tocopherols (80 and 575 mg/100 g oleoresin, respectively), while lycopene and β-carotene were found at 205 and 75 mg/100 g oleoresin, respectively. The highest quantity of polyphenols (9305 mg GAE/100 g oleoresin) was found in the oleoresin extracted from skin by supercritical CO₂ with ethanol. All oleoresins were characterised by a high antioxidant activity, which improved with the synergy of carotenoids, tocopherols and polyphenols.     

Microarray Patches: Poking a Hole in the Challenges Faced When Delivering Poorly Soluble Drugs

Poorly soluble drugs constitute more than 60% of currently marketed pharmaceuticals with over two-thirds of promising new chemical entities failing to enter a clinical setting due to solubility issues. Although oral formulations have made some impact, alternative enhancement strategies for administration of such molecules are actively sought. Over the last decade, innovation on a global scale has enabled the expansion of the frontiers of microarray patches (MAPs) further than ever before. Initially designed to load low doses of hydrophilic and potent therapeutic agents, MAPs are now becoming a viable strategy for the immediate and long-acting delivery of poorly soluble drugs through the skin. This together with the advantages of transdermal administration over the oral and parenteral routes, make of MAPs an appealing platform for the development of products with increased patient compliance. Undoubtedly, MAPs will soon become a readily available therapeutic alternative, and experts from academia, industry and regulatory bodies are working together aiming to facilitate the progression of MAPs toward safe and effective clinical use. This review aims to highlight the ability of MAPs to deliver poorly soluble actives, discuss the mechanisms behind in-skin drug absorption, and evaluate the future direction of the field.     

The effect of different cementing strategies and adhesive interface aging on microtensile bond strength (μTBS) of lithium disilicate ceramics to dentin

This study evaluated the effect of different cementing strategies and adhesive interface aging on microtensile bond strength (μTBS) of lithium disilicate ceramic (IPS e.max CAD) to dentin. Forty coronal dentin fragments were randomly assigned to four groups according to the cementing strategy used to bond lithium disilicate ceramic to coronal dentin surface (n = 10): U200 (self-adhesive resin cement (RC) RelyX U200®/3 M ESPE), SBU (single-step self-etching adhesive system (AS) Single Bond Universal®/3 M ESPE + RelyX ARC®/3 M ESPE RC), AdperSB (two-step etch-and-rinse AS Single Bond 2®/3 M + RelyX ARC®/3 M ESPE RC) and Scotchbond (three-step etch-and-rinse AS Scotchbond Multi-Purpose®/3 M + RelyX ARC®/3 M RC). After 48 h, the ceramic-tooth blocks were sectioned perpendicular to the adhesive interface in the form of sticks and randomly subdivided into two groups according to when they were to be submitted to μTBS testing: immediately or 6 months after storage in water. Some sticks were kept for analysis of the adhesive interface by scanning electron microscopy (SEM). The μTBS test was performed in a universal testing machine (0.5 mm/min). The data (MPa) were analyzed using split-plot ANOVA and Tukey’s test (α = 0.05). Water storage decreased μTBS in all cementing strategies. The μTBS was greatest in the Scotchbond group and lowest in the U200 group, at both storage times. No signs of interface degradation were detected under SEM after water storage. In conclusion, water storage decreased bond strength, regardless of the adhesive cementation strategy, and that the three-step adhesive system/dual-cure resin cement ultimately performed better in terms of bond strength.     

Ambient levels of nitrogen dioxide (NO2) may reduce pollen viability in Austrian pine (Pinus nigra Arnold) trees--correlative evidence from a field study

A fully randomized sampling design was adopted to test whether pollen viability of Austrian pine (Pinus nigra Arnold) was impacted by NO(2) pollution. Spatial strata (500500 m each) with high (41.9-44.6 microg m(-3)) and low (15.4-21.0 microg m(-3)) NO(2) were selected from a defined population in a small area (236.5 km(2), <200 m range in elevation) in Northern Italy. Pollen viability was measured by means of the Tetrazolium (TTC) test. Analysis of variance by means of a generalised linear model showed that NO(2) was a significant factor (P=0.0425) affecting pollen viability. Within the treatment, no significant differences were detected among replicates. Within each replicate, sampling unit data were significantly different (P=0.000) and this suggested some improvement in the applied sampling design was needed. Pollen viability was significantly related to pollen germination (P<0.01) and tube length (P<0.01). This suggested a possible impact of NO(2) on the regeneration of Austrian pine in polluted environments.