Quantitative Plasma Proteomics to Identify Candidate Biomarkers of Relapse in Pediatric/Adolescent Hodgkin Lymphoma

Classical pediatric Hodgkin Lymphoma (HL) is a rare malignancy. Therapeutic regimens for its management may be optimized by establishing treatment response early on. The aim of this study was to identify plasma protein biomarkers enabling the prediction of relapse in pediatric/adolescent HL patients treated under the pediatric EuroNet-PHL-C2 trial. We used untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics at the time of diagnosis—before any therapy—as semiquantitative method to profile plasma proteins specifically associated with relapse in 42 children with nodular sclerosing HL. In both the exploratory and the validation cohorts, six proteins (apolipoprotein E, C4b-binding protein α chain, clusterin, fibrinogen γ chain, prothrombin, and vitronectin) were more abundant in the plasma of patients whose HL relapsed (|fold change| ≥ 1.2, p < 0.05, Student’s t-test). Predicting protein function with the Gene Ontology classification model, the proteins were included in four biological processes (p < 0.01). Using immunoblotting and Luminex assays, we validated two of these candidate biomarkers—C4b-binding protein α chain and clusterin—linked to innate immune response function (GO:0045087). This study identified C4b-binding protein α chain and clusterin as candidate early plasma biomarkers of HL relapse, and important for the purpose of shedding light on the molecular scenario associated with immune response in patients treated under the EuroNet-PHL-C2 trial.     

Open Questions in Cold Atmospheric Plasma Treatment in Head and Neck Cancer: A Systematic Review

Over the past decade, we witnessed a promising application of cold atmospheric plasma (CAP) in cancer therapy. The aim of this systematic review was to provide an exhaustive state of the art of CAP employed for the treatment of head and neck cancer (HNC), a tumor whose late diagnosis, local recurrence, distant metastases, and treatment failure are the main causes of patients’ death. Specifically, the characteristics and settings of the CAP devices and the in vitro and in vivo treatment protocols were summarized to meet the urgent need for standardization. Its molecular mechanisms of action, as well as the successes and pitfalls of current CAP applications in HNC, were discussed. Finally, the interesting emerging preclinical hypotheses that warrant further clinical investigation have risen. A total of 24 studies were included. Most studies used a plasma jet device (54.2%). Argon resulted as the mostly employed working gas (33.32%). Direct and indirect plasma application was reported in 87.5% and 20.8% of studies, respectively. In vitro investigations were 79.17%, most of them concerned with direct treatment (78.94%). Only eight (33.32%) in vivo studies were found; three were conducted in mice, and five on human beings. CAP showed pro-apoptotic effects more efficiently in tumor cells than in normal cells by altering redox balance in a way that oxidative distress leads to cell death. In preclinical studies, it exhibited efficacy and tolerability. Results from this systematic review pointed out the current limitations of translational application of CAP in the urge of standardization of the current protocols while highlighting promising effects as supporting treatment in HNC.     

Assessing T-Cell Immunity in Kidney Transplant Recipients with Absent Antibody Production after a 3rd Dose of the mRNA-1273 Vaccine

The vulnerable population of kidney transplant recipients (KTRs) are low responders to COVID-19 vaccines, so specific immune surveillance is needed. The interferon-gamma (IFN-γ) release assay (IGRA) is effective in assessing T cell-mediated immunity. We assessed SARS-CoV-2-directed T cell responses in KTRs with absent antibody production after a third dose of the mRNA-1273 vaccine, using two different IGRAs. A cohort of 57 KTRs, who were actively followed up, received a third dose of the mRNA-1273 vaccine. After the evaluation of humoral immunity to SARS-CoV-2, 14 seronegative patients were tested with two commercial IGRAs (SD Biosensor and Euroimmun). Out of 14 patients, one and three samples were positive by IGRAs with Euroimmun and SD Biosensor, respectively. The overall agreement between the two assays was 85.7% (κ = 0.444). In addition, multivariate linear regression analysis showed no statistically significant association between the IFN-γ concentration, and the independent variables analyzed (age, gender, years since transplant, total lymphocytes cells/mcl, CD3+ cells/mcl, CD3+ CD4+ cells/mcl, CD3+ CD8+ cells/mcl, CD19+ cells/mcl, CD3-CD16+CD56+ cells/mcl) (p > 0.01). In a vulnerable setting, assessing cellular immune response to complement the humoral response may be advantageous. Since the two commercial IGRAs showed a good agreement on negative samples, the three discordant samples highlight the need for further investigations.     

Elaboration and mechanical characterization of multi-phase alumina-based ultra-fine composites

Al₂O₃-10 vol.% YAG and Al₂O₃-10 vol.% ZrO₂ bi-phase composites as well as Al₂O₃-5 vol.% YAG-5 vol.% ZrO₂ tri-phase composite were developed by controlled surface modification of an alumina powder with inorganic precursors of the second phases. Green bodies were produced by dry pressing and slip casting and then sintered at 1500 °C. In particular, slip casting led to fully dense, defect-free, and highly homogenous samples, made of a fine dispersion of the second phases into the micronic alumina matrix, as observed by SEM. The mechanical characterization proved the predominant role of the final density on the Vickers hardness, while the elastic modulus was affected by the volume fraction of the constituent phases, in fairly good agreement with the rule of mixture prediction. The fracture toughness values of the bi- and tri-phase materials were similar, and their crack paths revealed the importance of the thermal residual stresses at the matrix-reinforcement interfaces, promoting inter-granular propagations.     

Blue fish burgers: nutritional characterisation and sensory optimisation

In order to reduce waste of marine resources, valorise fishing discards and move towards fish consumption, a new ready-to-cook seafood product was developed. In particular, a chemical investigation on chub mackerel and hake was conducted to the aim of mixing the two fish species to produce nutritionally balanced fish burgers. In addition, to evaluate consumer opinion about these new fresh products and best acceptability of different proportions of mackerel and hake, focus group interviews and consumer test were also performed. The results of the chemical analyses achieved on both selected fish species gave rise to minimally processed fish products with a high amount of chub mackerel, therefore providing the desired nutritional properties and low level of hake in order to obtain firmer and wetter burgers. By means of focus group interviews, the novelty and high level of convenience of the developed fresh commodity was highlighted. Consumer test declared that the most successful sample was that with 70% chub mackerel and 30% hake.     

Phase Evolution in Synthesis of Manganese Ferrite Nanoparticles

Physico-chemical equilibria that influence oxide powders' precipitation from an aqueous solution can be substantially altered when the process is carried out in a microemulsion system. To obtain nanosized MnFe₂O₄ and gain information about the physico-chemical characteristics of products, Mn²⁺ and Fe³⁺ metal ions were induced to precipitate in a toluene/water/sodium dodecylbenzenesulfonate microemulsion system. Portions of the precipitated powder were differently treated, both in solution and in the solid state, and the role of restricted aqueous domains in the obtained materials was investigated. X-ray diffraction profile-fitting methods and chemical analysis were applied to characterize the powder particles. Samples obtained from the selected microemulsion were identified as nanosized mixed hydroxide compounds. A low metal content and a limited matter exchange among aqueous nanodroplets appear to inhibit hydroxide to oxide transformation inside the selected micellar system. A calcination process of precipitated powder was required to obtain a manganese ferrite compound.     

Effect of Heating Rate on Phase and Microstructural Evolution During Pressureless Sintering of a Nanostructured Transition Alumina

Deagglomeration of a nanocrystalline transition alumina performed using different techniques was first demonstrated to be active in the achievement of a better powder compaction ability under uniaxial pressing and consequently in the development of a highly dense and homogeneous microstructure during pressureless sintering. A major effect, however, was associated to the heating rate chosen during the densification cycle. In fact, the influence of different heating rates (10°C/min or 1°C/min) on phase and microstructural evolution during sintering was investigated in depth on the above best green bodies. A low-rate thermal cycle leads to a significant reduction of the α-Al₂O₃ crystallization temperature and promotes a more effective particle rearrangement during phase transformation. As a consequence, in the low-rate treated material, it was possible to avoid the development of a vermicular structure as usually expected during the densification of a transition alumina and to yield a more homogenously fired microstructure.     

Mild Effects of Sunscreen Agents on a Marine Flatfish: Oxidative Stress,Energetic Profiles,Neurotoxicity and Behaviour in Response to Titanium Dioxide Nanoparticles and Oxybenzone

UV filters are potentially harmful to marine organisms. Given their worldwide dissemination and the scarcity of studies on marine fish, we evaluated the toxicity of an organic (oxybenzone) and an inorganic (titanium dioxide nanoparticles) UV filter, individually and in a binary mixture, in the turbot (Scophthalmus maximus). Fish were intraperitoneally injected and a multi-level assessment was carried out 3 and 7 days later. Oxybenzone and titanium dioxide nanoparticles induced mild effects on turbot, both isolated and in mixture. Neither oxidative stress (intestine, liver and kidney) nor neurotoxicity (brain) was found. However, liver metabolic function was altered after 7 days, suggesting the impairment of the aerobic metabolism. An increased motility rate in oxybenzone treatment was the only behavioural alteration (day 7). The intestine and liver were preferentially targeted, while kidney and brain were unaffected. Both infra- and supra-additive interactions were perceived, with a toxicodynamic nature, resulting either in favourable or unfavourable toxicological outcomes, which were markedly dependent on the organ, parameter and post-injection time. The combined exposure to the UV filters did not show a consistent increment in toxicity in comparison with the isolated exposures, which is an ecologically relevant finding providing key information towards the formulation of environmentally safe sunscreen products.     

Synthesis,SAR, and Biological Evaluation of α‐Sulfonylphosphonic Acids as Selective Matrix Metalloproteinase Inhibitors

Selective MMP inhibitors : Eleven α‐sulfonylphosphonates were synthesized and tested as MMP inhibitors. The IC₅₀ values for most of them are in the nanomolar range against MMP‐2, ‐8, ‐13, and ‐14, with an interesting selectivity profile versus MMP‐9.

     

Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N''-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of “aggressive” breast carcinoma.