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Corrado Pelaia,1 Alessandro Vatrella,2 Andrea Bruni,1 Rosa Terracciano,3 Girolamo Pelaia1 1Department of Medical and Surgical Sciences, Section of Respiratory Diseases, “Magna Græcia” University of Catanzaro, Catanzaro, Italy; 2Department of Medicine, Surgery and Dentistry, Section of Respiratory Diseases, University of Salerno, Salerno, Italy; 3Department of Health Sciences, “Magna Græcia” University of Catanzaro, Catanzaro, Italy Abstract: Asthma is a widespread and heterogeneous inflammatory disease of the airways, which is characterized by several different phenotypes and endotypes. In particular, eosinophilic airway inflammation is a common pathologic trait of both allergic and nonallergic asthma. The key cytokine responsible for maturation, activation, recruitment, and survival of eosinophils is interleukin (IL)-5, which is mainly produced by T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells. Therefore, for uncontrolled patients with severe eosinophilic asthma, who are not fully responsive to corticosteroids, IL-5 represents a very important molecular target for add-on biological therapies. Among these new treatments, anti-IL-5 monoclonal antibodies such as mepolizumab and reslizumab have been developed and clinically evaluated. Furthermore, benralizumab is currently the only available biologic drug that specifically binds to the IL-5 receptor, thus preventing the interaction with its ligand and the consequent pro-inflammatory effects. The effectiveness of benralizumab in improving severe eosinophilic asthma has been well-documented by many randomized controlled trials. Keywords: IL-5, IL-5 receptor, severe eosinophilic asthma, benralizumab

Corrado Pelaia,1 Alessandro Vatrella,2 Maria Teresa Busceti,1 Luca Gallelli,3 Rosa Terracciano,3 Rocco Savino,3 Girolamo Pelaia1 1Department of Medical and Surgical Sciences, Section of Respiratory Diseases, University “Magna Græcia” of Catanzaro, Catanzaro, 2Department of Medicine, Surgery and Dentistry, Section of Respiratory Diseases, University of Salerno, Salerno, 3Department of Health Science, University “Magna Græcia” of Catanzaro, Catanzaro, Italy Abstract: Mepolizumab is an anti-interleukin-5 (IL-5) humanized monoclonal antibody that has been recently approved as an add-on biological treatment for severe eosinophilic asthma, by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Moreover, mepolizumab is also currently included within the step 5 of the Global Initiative for Asthma guidelines, as an add-on therapy for severe uncontrolled asthma. The relevant therapeutic benefits detectable in patients with refractory eosinophilic asthma receiving mepolizumab depend on the pivotal pathogenic role played by IL-5 in these subjects. Indeed, IL-5 is the key cytokine responsible for maturation, activation, proliferation, and survival of eosinophils. Therefore, IL-5 represents a strategic molecular target for anti-eosinophilic treatments. By selectively inhibiting the biological actions of IL-5, mepolizumab provides a valuable therapeutic option for patients with severe eosinophilic asthma, refractory to standard treatments including inhaled and even systemic corticosteroids. In particular, the very important advantages linked to the use of mepolizumab in these difficult-to-treat asthmatic individuals have been well documented by several different trials performed worldwide. Keywords: IL-5, severe eosinophilic asthma, mepolizumab

Girolamo Pelaia,1 Alessandro Vatrella,2 Maria Teresa Busceti,1 Luca Gallelli,3 Mariaimmacolata Preianò,3 Nicola Lombardo,1 Rosa Terracciano,3 Rosario Maselli1 1Department of Medical and Surgical Sciences, Section of Respiratory Diseases, University “Magna Græcia” of Catanzaro, Catanzaro, Italy; 2Department of Medicine and Surgery, Section of Respiratory Diseases, University of Salerno, Salerno, Italy; 3Department of Health Science, University “Magna Græcia” of Catanzaro, Catanzaro, Italy Abstract: Within the context of the heterogeneous phenotypic stratification of asthmatic population, many patients are characterized by moderate-to-severe eosinophilic asthma, not adequately controlled by relatively high dosages of inhaled and even oral corticosteroids. Therefore, these subjects can obtain significant therapeutic benefits by additional biologic treatments targeting interleukin-5 (IL-5), given the key pathogenic role played by this cytokine in maturation, activation, proliferation, and survival of eosinophils. In particular, reslizumab is a humanized anti-IL-5 monoclonal antibody that has been found to be an effective and safe add-on therapy, capable of decreasing asthma exacerbations and significantly improving disease control and lung function in patients experiencing persistent allergic or nonallergic eosinophilic asthma, despite the regular use of moderate-to-high doses of inhaled corticosteroids. These important therapeutic effects of reslizumab, demonstrated by several controlled clinical trials, have led to the recent approval by US Food and Drug Administration of its use, together with other antiasthma medications, for the maintenance treatment of patients suffering from severe uncontrolled asthma. Keywords: IL-5, eosinophilic asthma, reslizumab, chronic obstructive pulmonary disease, MAPK, Janus kinases

Girolamo Pelaia,1 Alessandro Vatrella,2 Maria Teresa Busceti,1 Luca Gallelli,3 Cecilia Calabrese,4 Rosa Terracciano,3 Nicola Lombardo,1 Rosario Maselli11Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Catanzaro, 2Department of Medicine and Surgery, University of Salerno, Salerno, 3Department of Health Science, Magna Græcia University of Catanzaro, Catanzaro, 4Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, ItalyAbstract: Bronchodilators are the most important drugs used for the treatment of chronic obstructive pulmonary disease (COPD). In particular, these therapeutic agents are mostly long-acting compounds utilized via inhalation, and include LAMA (long-acting muscarinic receptor antagonists) and LABA (long-acting β2-adrenoceptor agonists). Because LAMA and LABA induce bronchodilation by distinct mechanisms of action, LABA/LAMA combinations provide a reciprocal potentiation of the pharmacological effects caused by each component. Hence, many COPD patients who do not achieve a satisfactory control of their symptoms using a single, either LAMA or LABA bronchodilator, can experience relevant benefits with the use of LAMA/LABA fixed combinations. Many different LAMA/LABA combinations have been recently developed and evaluated in randomized clinical trials. In this context, our review focuses on the pharmacological mechanisms underpinning the bronchodilation elicited by the LAMA tiotropium bromide and the LABA olodaterol. We also discuss the results of the most important clinical studies carried out in COPD patients to assess the efficacy and safety of tiotropium/olodaterol combinations.Keywords: LAMA, LABA, tiotropium, olodaterol, dual bronchodilation, tiotropium/olodaterol combinations

The design of biocompatible and biodegradable nanostructures with controlled morphological features remains a predominant challenge in medical research. Stimuli-responsive vesicles offer significant advantages in drug delivery, biomedical applications, and diagnostic techniques. The combination of poly(2-oxazoline)s with biodegradable polymers could provide exceptional biocompatibility properties and be proposed as a versatile platform for the development of new medicines. Therefore, poly(2-ethyl-2-oxazoline) (PEtOx) and poly(2-isopropyl-2-oxazoline) (P i PrOx) possessing a hydroxy terminal group that acts as an initiator for the ring-opening polymerization of d,l-lactide (DLLA) have been utilized in this study. The resulting amphiphilic block polymers were used to create polymersomes, which undergo solvent-dependent reorganization into bowl-shaped vesicles or stomatocytes. By blending PEtOx- b -PDLLA and P i PrOx- b -PDLLA copolymers, a thermoresponsive stomatocyte was generated, where the opening narrowed and irreversibly closed with a slight increase in the temperature. Detailed transmission electron microscopy analysis reveals the formation of both closed and fused stomatocytes upon heating the sample above the critical solution temperature of P i PrOx.

Blood vessels are essential for maintaining tumor growth, progression, and metastasis, yet the tumor vasculature is under a constant state of remodeling. Since the tumor vasculature is an attractive therapeutic target, there is a need to predict the dynamic changes in intratumoral fluid pressure and velocity that occur across the tumor microenvironment (TME). The goal of this study was to obtain insight into perfusion anisotropy within lung tumors. To achieve this goal, we used the perfusion marker Hoechst 33342 and vascular endothelial marker CD31 to stain tumor sections from C57BL/6 mice harboring Lewis lung carcinoma tumors on their flank. Vasculature, capillary diameter, and permeability distribution were extracted at different time points along the tumor growth curve. A computational model was generated by applying a unique modeling approach based on the smeared physical fields (Kojic Transport Model, KTM). KTM predicts spatial and temporal changes in intratumoral pressure and fluid velocity within the growing tumor. Anisotropic perfusion occurs within two domains: capillary and extracellular space. Anisotropy in tumor structure causes the nonuniform distribution of pressure and fluid velocity. These results provide insights regarding local vascular distribution for optimal drug dosing and delivery to better predict distribution and duration of retention within the TME.

3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is a hereditary disorder of leucine catabolism caused by pathogenetic variants in the MCCC1 or MCCC2 genes. Typically diagnosed through newborn screening (NBS), 3MCCD is characterized by elevation of 3-hydroxyisovalerylcarnitine (C5OH) in blood as well as increased excretion of 3-methylcrotonylglycine (3-MCG) in urine. While most diagnosed children remain asymptomatic, data on adults are scarce. To date, only 39 molecularly confirmed adult individuals have been reported, all being mothers diagnosed subsequent to their child NBS results. Herein, we present a 36-year-old asymptomatic man who was incidentally diagnosed with 3MCCD following his son NBS recall. Molecular analysis revealed compound heterozygosity for two pathogenic variants in the MCCC1 gene. This is the first molecularly confirmed adult man with 3MCCD reported. This case highlights the need for additional longitudinal follow-up data on individuals with 3MCCD to clarify the clinical significance of this condition and guide clinical practice, including NBS strategy., Competing Interests: The authors declare that there is no potential conflict of interest related to this work., (© 2024 The Authors. Published by Elsevier Inc.)

Background: Due to their complexity and to the presence of common clinical features, differentiation between asthma and chronic obstructive pulmonary disease (COPD) can be a challenging task, complicated in such cases also by asthma-COPD overlap syndrome. The distinct immune/inflammatory and structural substrates of COPD and asthma are responsible for significant differences in the responses to standard pharmacologic treatments. Therefore, an accurate diagnosis is of central relevance to assure the appropriate therapeutic intervention in order to achieve safe and effective patient care. Induced sputum (IS) accurately mirrors inflammation in the airways, providing a more direct picture of lung cell metabolism in comparison to those specimen that reflect analytes in the systemic circulation., Methods: An integrated untargeted metabolomics and lipidomics analysis was performed in IS of asthmatic (n = 15) and COPD (n = 22) patients based on Ultra-High-Pressure Liquid Chromatography-Mass Spectrometry (UHPLC-MS) and UHPLC-tandem MS (UHPLC-MS/MS). Partial Least Squares-Discriminant Analysis (PLS-DA) was applied to resulting dataset. The analysis of main enriched metabolic pathways and the association of the preliminary metabolites/lipids pattern identified to clinical parameters of asthma/COPD differentiation were explored. Multivariate ROC analysis was performed in order to determine the discriminatory power and the reliability of the putative biomarkers for diagnosis between COPD and asthma., Results: PLS-DA indicated a clear separation between COPD and asthmatic patients. Among the 15 selected candidate biomarkers based on Variable Importance in Projection scores, putrescine showed the highest score. A differential IS bio-signature of 22 metabolites and lipids was found, which showed statistically significant variations between asthma and COPD. Of these 22 compounds, 18 were decreased and 4 increased in COPD compared to asthmatic patients. The IS levels of Phosphatidylethanolamine (PE) (34:1), Phosphatidylglycerol (PG) (18:1;18:2) and spermine were significantly higher in asthmatic subjects compared to COPD., Conclusions: This is the first pilot study to analyse the IS metabolomics/lipidomics signatures relevant in discriminating asthma vs COPD. The role of polyamines, of 6-Hydroxykynurenic acid and of D-rhamnose as well as of other important players related to the alteration of glycerophospholipid, aminoacid/biotin and energy metabolism provided the construction of a diagnostic model that, if validated on a larger prospective cohort, might be used to rapidly and accurately discriminate asthma from COPD., (© 2024. The Author(s).)