mRNA vaccines: a new opportunity for malaria, tuberculosis and HIV

The success of the first licensed mRNA-based vaccines against COVID-19 has created a widespread interest on mRNA technology for vaccinology. As expected, the number of mRNA vaccines in preclinical and clinical development increased exponentially since 2020, including numerous improvements in mRNA formulation design, delivery methods and manufacturing processes. However, the technology faces challenges such as the cost of raw materials, the lack of standardization, and delivery optimization. MRNA technology may provide a solution to some of the emerging infectious diseases as well as the deadliest hard-to-treat infectious diseases malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), for which an effective vaccine, easily deployable to endemic areas is urgently needed. In this review, we discuss the functional structure, design, manufacturing processes and delivery methods of mRNA vaccines. We provide an up-to-date overview of the preclinical and clinical development of mRNA vaccines against infectious diseases, and discuss the immunogenicity, efficacy and correlates of protection of mRNA vaccines, with particular focus on research and development of mRNA vaccines against malaria, tuberculosis and HIV.info:eu-repo/semantics/publishedVersio

mRNA vaccines: a new opportunity for malaria, tuberculosis and HIV

The success of the first licensed mRNA-based vaccines against COVID-19 has created a widespread interest on mRNA technology for vaccinology. As expected, the number of mRNA vaccines in preclinical and clinical development increased exponentially since 2020, including numerous improvements in mRNA formulation design, delivery methods and manufacturing processes. However, the technology faces challenges such as the cost of raw materials, the lack of standardization, and delivery optimization. MRNA technology may provide a solution to some of the emerging infectious diseases as well as the deadliest hard-to-treat infectious diseases malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), for which an effective vaccine, easily deployable to endemic areas is urgently needed. In this review, we discuss the functional structure, design, manufacturing processes and delivery methods of mRNA vaccines. We provide an up-to-date overview of the preclinical and clinical development of mRNA vaccines against infectious diseases, and discuss the immunogenicity, efficacy and correlates of protection of mRNA vaccines, with particular focus on research and development of mRNA vaccines against malaria, tuberculosis and HIV

Development of a new mRNA vaccine platform for tuberculosis

Background Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is the frst cause of death by an infectious disease worldwide, killed 1.6 million people in 2021. Bacillus Calmette-Guerin (BCG) is the only approved vaccine for TB to date. However, while BCG is efective in preventing severe forms in children, its efcacy in adults is inconsistent and it does not prevent transmission, highlighting the need for new vaccine development [1]. The recent success of COVID-19 vaccines raised the interest for mRNA-based vaccines, as they are efective, safe and easy to produce. This project aims to develop a new mRNA vaccine platform for TB, based on mRNA coding for antigenic peptides from BCG and M.tb identifed by immunopeptidomics [2], and formulated with a patented technology of lipid nanoemulsions (NE) (WO2019138139A1), adapted for efcient intracellular delivery of mRNA [3]. Materials and methods We tested diferent prototypes of NE-mRNA formulations, coding for EGFP, in vitro. Human alveolar basal epithelial cells (A549), human monocytic cells (THP-1), and primary human monocyte-derived macrophages, were transfected with NE-mRNA formulations. Transfection efciency was assessed by measuring the percentage of transfected cells, and the intensity of GFP fuorescence. The cytotoxicity of the formulations was evaluated using AlamarBlue, and by 7-AAD viability staining. Results In vitro preliminary data using EGFP-mRNA-NE formulations indicate that NE formulations can efciently deliver mRNA and induce expression of the encoded protein in diferent cell types, with low cytotoxicity. Conclusions The NE technology presented here is safe, stable, and can efciently deliver mRNA to various cell types. Selected NE formulations will be used as a carrier for a new vaccine candidate against TB, based on mRNA encoding relevant antigenic peptides. These will be tested in mice for safety, immunogenicity, efcacy and dose optimization in order to generate an efective and sustained humoral and cellular immune response against TB. The mRNA vaccines are rapid and relatively simple to produce. The vaccine platform described here could be adapted to develop vaccines against other infectious diseases, particularly to quickly respond to emerging pathogens.info:eu-repo/semantics/publishedVersio

A long pentraxin-3-derived pentapeptide for the therapy of FGF8b-driven steroid hormone-regulated cancers

Fibroblast growth factor-8b (FGF8b) affects the epithelial/stromal compartments of steroid hormone-regulated tumors by exerting an autocrine activity on cancer cells and a paracrine pro-angiogenic function, thus contributing to tumor progression. The FGF8b/FGF receptor (FGFR) system may therefore represent a target for the treatment of steroid hormone-regulated tumors. The soluble pattern recognition receptor long pentraxin-3 (PTX3) binds various FGFs, including FGF2 and FGF8b, thus inhibiting the angiogenic and tumorigenic activity of androgen-regulated tumor cells. Nevertheless, the complex/proteinaceous structure of PTX3 hampers its pharmacological exploitation. In this context, the acetylated pentapeptide Ac-ARPCA-NH2 (ARPCA), corresponding to the N-terminal amino acid sequence PTX3(100-104), was identified as a minimal FGF2-binding peptide able to antagonize the biological activity of FGF2. Here, we demonstrate that ARPCA binds FGF8b and inhibits its capacity to form FGFR1-mediated ternary complexes with heparan sulphate proteoglycans. As a FGF8b antagonist, ARPCA inhibits FGFR1 activation and signalling in endothelial cells, hampering the angiogenic activity exerted in vitro and in vivo by FGF8b. Also, ARPCA suppresses the angiogenic and tumorigenic potential of prototypic androgen/FGF8b-dependent Shionogi 115 mammary carcinoma cells and of androgen/FGF8b/FGF2-dependent TRAMP-C2 prostate cancer cells. In conclusion, ARPCA represents a novel FGF8b antagonist with translational implications for the therapy of steroid hormone-regulated tumor

High PM10 concentrations in the city of Buenos Aires and their relationship with meteorological conditions

In this work, the first long-term (eight years) record of hourly concentrations of carbon monoxide (CO), nitrogen dioxide (NO2) and particulate matter with diameter less than 10 μm (PM10) from three sites in the city of Buenos Aires is analysed. Considering the short-term guidelines suggested by the WHO, the daily mean PM10 concentrations present a relatively large number of exceedances at the three sites. Different statistical techniques are combined to study the relationship between these relatively high PM10 concentrations and relevant surface meteorological variables. For all pollutants and sites, wind speed shows the largest differences between the lowest and highest concentration quartiles. To further explore its role on daily mean PM10 concentration, a k-means algorithm is applied, grouping days with similar surface 1h-wind sequences. Five wind sequence clusters are found, presenting distinctive air quality data features. Two clusters (1 and 2) show that PM10 exceedances occurring with winds entering the city from the river represent between 10 and 21% of total events at the three sites. The frequency of exceedance under these conditions decreases with the distance to the coast. For cluster 1, the hourly PM10 concentration profile and its associated daily wind sequence suggest an important contribution to exceedance events from the city's southernmost power plant. Two clusters (3 and 4), exhibiting continental winds, account for 49–59% of the exceedances and co-occur with relatively drier air conditions. The correlation between CO and PM10 for days belonging to cluster 3 supports the hypothesis of a potential remote or distributed source contribution with SW winds. For cluster 4, differences among sites in the number of events under NNW winds suggest an important contribution from the city's widest avenue to the PM10 levels at the most coastal site. A large contribution coming from urban sources is also indicated for these winds. Finally, cluster 5, exhibiting low wind speed sequences, accounts for 23–33% of the exceedances at the three sites. The average PM10 concentration increases with persistence of this cluster, which could be a driver for exceedances. These results contribute to show the importance of simple methods such as clustering analysis to obtain insights into air quality features such as exceedances and their potential drivers. They also suggest that further efforts in monitoring, modelling and emission estimates may help to better understand local, urban and regional source contributions to these events in the city of Buenos Aires.Fil: Pineda Rojas, Andrea Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; ArgentinaFil: Borge, Rafael. Universidad Politécnica de Madrid; EspañaFil: Mazzeo, Nicolás A.. Universidad Tecnológica Nacional. Facultad Regional Avellaneda; ArgentinaFil: Saurral, Ramiro Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; ArgentinaFil: Matarazzo, Bruno Nicolas. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias de la Atmósfera y los Océanos; ArgentinaFil: Cordero, Jose M.. Universidad Politécnica de Madrid; EspañaFil: Kropff, Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

El monstruo en la escuela: la filosofía como espacio político de las infancias

El trabajo busca pensar posibles vínculos entre las nociones de infancia y monstruosidad en el marco de prácticas de indagación filosófica en instituciones educativas. Se retoma la noción de monstruo para pensar ciertas formas de novedad e indagar en las implicancias políticas de construir un espacio donde éste tome la palabra. Nos parece oportuno reflexionar en torno a otras formas de concebir a las infancias y así identificar distintas aristas y potencias de este concepto. Incorporar la idea de lo monstruoso a estas reflexiones nos permite mirar lo no mirado, estar atentos/as a lo no esperado y, sobre todo, a continuar pensando la construcción de espacios de diálogo e intercambio filosófico como una acción política. Así, nos preguntamos si es posible asociar la monstruosidad con escuela, filosofía e infancias: ¿en qué sentidos podemos habitar una novedad monstruosa?, ¿cómo podemos pensar que los intercambios de diálogo filosófico den lugar a una infancia monstruosa

Therapeutic Synergy Between Antibiotics and Pulmonary Toll-Like Receptor 5 Stimulation in Antibiotic-Sensitive or -Resistant Pneumonia

Bacterial infections of the respiratory tract constitute a major cause of death worldwide. Given the constant rise in bacterial resistance to antibiotics, treatment failure is increasingly frequent. In this context, innovative therapeutic strategies are urgently needed. Stimulation of innate immune cells in the respiratory tract [via activation of Toll-like receptors (TLRs)] is an attractive approach for rapidly activating the body's immune defenses against a broad spectrum of microorganisms. Previous studies of the TLR5 agonist flagellin in animal models showed that standalone TLR stimulation does not result in the effective treatment of pneumococcal respiratory infection but does significantly improve the therapeutic outcome of concomitant antibiotic treatment. Here, we investigated the antibacterial interaction between antibiotic and intranasal flagellin in a mouse model of pneumococcal respiratory infection. Using various doses of orally administered amoxicillin or systemically administered cotrimoxazole, we found that the intranasal instillation of flagellin (a dose that promotes maximal lung pro-inflammatory responses) induces synergistic rather than additive antibacterial effects against antibiotic–susceptible pneumococcus. We next set up a model of infection with pneumococcus that is resistant to multiple antibiotics in the context of influenza superinfection. Remarkably, the combination of amoxicillin and flagellin effectively treated superinfection with the amoxicillin-resistant pneumococcus since the bacterial clearance was increased by more than 100-fold compared to standalone treatments. Our results also showed that, in response to flagellin, the lung tissue generated an innate immune response even though it had been damaged by the influenza virus and pneumococcal infections. In conclusion, we demonstrated that the selective boosting of lung innate immunity is a conceptually advantageous approach for improving the effectiveness of antibiotic treatment and fighting antibiotic-resistant bacteria

Minimally Invasive Laser Treatment of Ureterocele

Introduction: Ureterocelemay cause severe pyelo-ureteral obstruction with afebrile urinary tract infections in infants and children. Early decompressive treatment is advocated to reduce the risk of related renal and urinary tract damage. Endoscopic techniques of incision have been offered utilizing diathermic electrode. We adopted laser energy to release the obstruction of the ureterocele and reduce the need of further surgery. Our technique is described and results are presented, compared with a group of matched patients treated by diathermic energy.Materials and methods: Decompression was performed by endoscopic multiple punctures at the basis of the ureterocele. Holmium YAG Laser was utilized with 0.5–0.8 joule energy, through 8–9.8F cystoscope under general anesthesia. The control group received ureterocele incision by diathermic energy through pediatric resettoscope. Foley indwelling catheter was removed after 18–24 h. Renal ultrasound was performed at 1, 3, 6, and 12 months follow-up. Voiding cysto-urethrogram and radionuclide renal scan were done at 6–18 months in selected cases. Statistical analysis was utilized for data evaluation.Results: From January 2012 to December 2017, 64 endoscopic procedures were performed: 49 were ectopic and 15 orthotopicureteroceles. Fifty-three were in duplex systems, mostly ectopic. Mean age at endoscopy was 6.3 months (1–168). Immediate decompression of the ureterocele was obtained, but in five cases (8%) a second endoscopic puncture was necessary at 6–18 months follow-up for recurrent dilatation. Urinary tract infections and de novo refluxes occurred in 23.4 and 29.7% in the study group, compared to 38.5 and 61.5% in the 26 controls (p < 0.05). Further surgery was required in 12 patients (18%) at 1–5 years follow-up (10 in ectopic ureteroceles with duplex systems): seven ureteral reimplantation for reflux, five laparoscopic hemy-nephro-ureterectomy. Orthotopic ureteroceceles had better outcome. Secondary surgery was necessary in 13 patients (50.0%) of control group (p < 0.05).Conclusions: Early endoscopic decompression should be considered first line treatment of obstructing ureterocele in infants and children. Multiple punctures at the basis of the ureterocele, performed by low laser energy, is resulted a really minimally invasive treatment, providing immediate decompression of the upper urinary tract, and reducing the risk of further aggressive surgery

Long pentraxin-3 follows and modulates bladder cancer progression

Bladder tumors are a diffuse type of cancer. Long pentraxin-3 (PTX3) is a component of the innate immunity with pleiotropic functions in the regulation of immune response, tissue remodeling, and cancer progression. PTX3 may act as an oncosuppressor in different contexts, functioning as an antagonist of the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system, rewiring the immune microenvironment, or acting through mechanisms not yet fully clarified. In this study we used biopsies and data mining to assess that PTX3 is differentially expressed during the different stages of bladder cancer (BC) progression. BC cell lines, representative of different tumor grades, and transgenic/carcinogen-induced models were used to demonstrate in vitro and in vivo that PTX3 production by tumor cells decreases along the progression from low-grade to high-grade advanced muscle invasive forms (MIBC). In vitro and in vivo data revealed for the first time that PTX3 modulation and the consequent impairment of FGF/FGR systems in BC cells have a significant impact on different biological features of BC growth, including cell proliferation, motility, metabolism, stemness, and drug resistance. PTX3 exerts an oncosuppressive effect on BC progression and may represent a potential functional biomarker in BC evolution. Moreover, FGF/FGFR blockade has an impact on drug resistance and stemness features in BC