Pancreatic ductal adenocarcinoma (PDAC) represents a great challenge to the successful delivery of the anticancer drugs. The intrinsic characteristics of the PDAC microenvironment and drugs ...resistance make it suitable for therapeutic approaches with stimulus-responsive drug delivery systems (DDSs), such as pH, within the tumor microenvironment (TME). Moreover, the high expression of uPAR in PDAC can be exploited for a drug receptor-mediated active targeting strategy. Here, a pH-responsive and uPAR-targeted Gemcitabine (Gem) DDS, consisting of polymeric micelles (Gem@TpHResMic), was formulated by microfluidic technique to obtain a preparation characterized by a narrow size distribution, good colloidal stability, and high drug-encapsulation efficiency (EE%). The Gem@TpHResMic was able to perform a controlled Gem release in an acidic environment and to selectively target uPAR-expressing tumor cells. The Gem@TpHResMic displayed relevant cellular internalization and greater antitumor properties than free Gem in 2D and 3D models of pancreatic cancer, by generating massive damage to DNA, in terms of H2AX phosphorylation and apoptosis induction. Further investigation into the physiological model of PDAC, obtained by a co-culture of tumor spheroids and cancer-associated fibroblast (CAF), highlighted that the micellar system enhanced the antitumor potential of Gem, and was demonstrated to overcome the TME-dependent drug resistance. In vivo investigation is warranted to consider this new DDS as a new approach to overcome drug resistance in PDAC.
Background. Yearly influenza epidemics have considerable effects on public health worldwide. The 2017-2018 influenza season in Italy was of greater severity than previous seasons. The aim of this ...study was to describe the 2017-2018 influenza season in Southern Italy and the molecular characteristics of the circulating viral strains. Methods. The incidence of influenza-like illness (ILI) was analysed. Nasopharyngeal swabs collected from patients with ILI from week 46/2017 to week 17/2018 were tested to identify influenza A viruses (IAV) and influenza B viruses (IBV). Sequencing and phylogenetic analysis of haemagglutinin genes were also performed on 73 positive samples (35 IBV, 36 IAV H1, and 2 IAV H3 strains). Results. During the 2017-2018 season, the peak incidence was 14.32 cases per 1,000 inhabitants. IBV strains were identified in 71.0% of cases. The 35 characterised IBV strains belonged to Yamagata lineage clade 3, the 36 A/H1N1pdm09 strains clustered with the genetic subgroup 6B.1, and the 2 A/H3N2 strains clustered with the genetic subgroup 3C.2a. Intensive-care unit (ICU) admission was required in 50 cases of acute respiratory distress syndrome (ARDS). Among the >64-year age group, 18 out of 26 ICU-ARDS cases (69.2%) were caused by IBV, and 14 of these (77.8%) were B/Yamagata lineage. Conclusions. The 2017-2018 influenza season was one of the most severe in a decade in Southern Italy. IBV mismatch between the trivalent vaccine and the circulating strains occurred. The high number of ICU-ARDS cases caused by B/Yamagata strains in the >64-year age group suggests that further data on the effectiveness of the available influenza vaccines are needed to determine the best way to protect the elderly against both IBV lineages.
To describe an operating protocol for bloody diarrhea (BD) in a pediatric population as a rapid response to a public health threat represented by an excess of pediatric HUS cases in the Apulia region ...(Southern Italy) starting from 2013. The protocol was set up with the goal of correct clinical management of Shiga toxin-producing
Escherichia coli
(STEC) infections, reductions in subsequent cases of hemolytic uremic syndrome (HUS), and improved short- and long-term disease outcomes. The protocol consisted of rapid hospitalization of children with bloody diarrhea (BD), hematochemical laboratory tests every 12–24 hours, and prompt laboratory diagnosis of STEC. No antibiotics were recommended until diagnosis. Children positive for STEC infections underwent early vigorous volume expansion. In June–December 2018, 438 children with BD were hospitalized, of which 53 (12.1%) had a STEC infection. The most common serogroups were O26 (36.1%), O111 (23.0%), and O157 (14.8%). Thirty-one samples carried the
stx2
gene. Four cases evolved into HUS (7.5%), all with favorable outcome despite neurological involvement in two cases. Prompt and accurate laboratory diagnosis of STEC infections is of the utmost importance in patients with BD for correct clinical management. The strict adherence to the protocol could reduce the progression rate of STEC infections to HUS and prevents complications. Enhanced BD surveillance may help reduce cases of pediatric HUS in Southern Italy.
Se denominan medicamentos de alto riesgo a aquellos medicamentos que tienen una probabilidad muy elevada de causar daños graves o incluso mortales en el neonato cuando se produce un error en el curso ...de su administración. Trabajar en pos de la mejora en el manejo de medicamentos de alto riesgo en la Unidad de Cuidados Intensivos Neonatales (UCIN) es un indicador de calidad. Permite introducir recomendaciones, estrategias o propuestas de mejora continua de la seguridad del paciente. La estandarización de medicamentos trata de reducir la complejidad y la variabilidad de los procesos y hacerlos menos dependientes. Es una práctica recomendada como una herramienta para la seguridad del paciente. La finalidad de esta propuesta fue definir en primer lugar el listado de medicamentos LASA (look alike, sound alike; medicamentos que se asemejan en su aspecto o tienen nombres parecidos) y medicamentos de alto riesgo. Una vez definidos se utilizó como estrategias estandarizar el etiquetado por colorimetría según la Disposición ANMAT N.º 8278/2011 para los medicamentos de alto riesgo de administración en infusión continua y estandarización por colorimetría de los medicamentos de alto riesgo que se administran en infusión intermitente. Cuando los procesos comienzan a desarrollarse teóricamente son ideales, pero cuando se comienzan a implementar en la práctica diaria, es importante poder realizar estudios de intervención para medir el impacto de su funcionalidad y obtener información para mejorar el proceso. Estas prácticas deben estar basadas en los tres principios básicos de las estrategias de seguridad: 1) reducir la posibilidad de que se produzcan errores, 2) hacer los errores visibles cuando ocurren, para evitar que lleguen al paciente, y, 3) minimizar el daño, cuando fallan las estrategias anteriores y los errores llegan al paciente.
Stimulation of macrophages with interferon-γ (IFN-γ) and interleukin 4 (IL-4) triggers distinct and opposing activation programs. During mixed infections or cancer, macrophages are often exposed to ...both cytokines, but how these two programs influence each other remains unclear. We found that IFN-γ and IL-4 mutually inhibited the epigenomic and transcriptional changes induced by each cytokine alone. Computational and functional analyses revealed the genomic bases for gene-specific cross-repression. For instance, while binding motifs for the transcription factors STAT1 and IRF1 were associated with robust and IL-4-resistant responses to IFN-γ, their coexistence with binding sites for auxiliary transcription factors such as AP-1 generated vulnerability to IL-4-mediated inhibition. These data provide a core mechanistic framework for the integration of signals that control macrophage activation in complex environmental conditions.
Recent advances in the field of meta-omics sciences and related bioinformatics tools have allowed a comprehensive investigation of human-associated microbiota and its contribution to achieving and ...maintaining the homeostatic balance. Bioactive compounds from the microbial community harboring the human gut are involved in a finely tuned network of interconnections with the host, orchestrating a wide variety of physiological processes. These includes the bi-directional crosstalk between the central nervous system, the enteric nervous system, and the gastrointestinal tract (i.e., gut-brain axis). The increasing accumulation of evidence suggest a pivotal role of the composition and activity of the gut microbiota in neurodegeneration. In the present review we aim to provide an overview of the state-of-the-art of meta-omics sciences including metagenomics for the study of microbial genomes and taxa strains, metatranscriptomics for gene expression, metaproteomics and metabolomics to identify and/or quantify microbial proteins and metabolites, respectively. The potential and limitations of each discipline were highlighted, as well as the advantages of an integrated approach (multi-omics) to predict microbial functions and molecular mechanisms related to human diseases. Particular emphasis is given to the latest results obtained with these approaches in an attempt to elucidate the link between the gut microbiota and the most common neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).
Fibromyalgia (FM) is a central disorder characterized by chronic pain, fatigue, insomnia, depression, and other minor symptoms. Knowledge about pathogenesis is lacking, diagnosis difficult, clinical ...approach puzzling, and patient management disappointing. We conducted a theoretical study based on literature data and computational analysis, aimed at developing a comprehensive model of FM pathogenesis and addressing suitable therapeutic targets. We started from the evidence that FM must involve a dysregulation of central pain processing, is female prevalent, suggesting a role for the hypothalamus-pituitary-gonadal (HPG) axis, and is stress-related, suggesting a role for the HP-adrenocortical (HPA) axis. Central pathogenesis was supposed to involve a pain processing loop system including the thalamic ventroposterolateral nucleus (VPL), the primary somatosensory cortex (SSC), and the thalamic reticular nucleus (TRN). For decreasing GABAergic and/or increasing glutamatergic transmission, the loop system crosses a bifurcation point, switching from monostable to bistable, and converging on a high-firing-rate steady state supposed to be the pathogenic condition. Thereafter, we showed that GABAergic transmission is positively correlated with gonadal-hormone-derived neurosteroids, notably allopregnanolone, whereas glutamatergic transmission is positively correlated with stress-induced glucocorticoids, notably cortisol. Finally, we built a dynamic model describing a multistable, double-inhibitory loop between HPG and HPA axes. This system has a high-HPA/low-HPG steady state, allegedly reached in females under combined premenstrual/postpartum brain allopregnanolone withdrawal and stress condition, driving the thalamocortical loop to the high-firing-rate steady state, and explaining the connection between endocrine and neural mechanisms in FM pathogenesis. Our model accounts for FM female prevalence and stress correlation, suggesting the use of neurosteroid drugs as a possible solution to currently unsolved problems in the clinical treatment of the disease.
Prangos ferulacea (L.) Lindl, which belongs to the Apiaceae family, is a species that mainly grows in the eastern Mediterranean region and in western Asia. It has been largely used in traditional ...medicine in several countries and it has been shown to possess several interesting biological properties. With the aim to provide new insights into the phytochemistry and pharmacology of this species, the essential oils of flowers and leaves from a local accession that grows in Sicily (Italy) and has not yet been previously studied were investigated. The chemical composition of both oils, obtained by hydrodistillation from the leaves and flowers, was evaluated by GC-MS. This analysis allowed us to identify a new chemotype, characterized by a large amount of (Z)-β-ocimene. Furthermore, these essential oils have been tested for their possible antimicrobial and antioxidant activity. P. ferulacea essential oils exhibit moderate antimicrobial activity; in particular, the flower essential oil is harmful at low and wide spectrum concentrations. They also exhibit good antioxidant activity in vitro and in particular, it has been shown that the essential oils of the flowers and leaves of P. ferulacea caused a decrease in ROS and an increase in the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) in OZ-stimulated PMNs. Therefore, these essential oils could be considered as promising candidates for pharmaceutical and nutraceutical preparations.
Background and Aims: The gut patients affected by Crohn's disease (CD), are abnormally colonized by pathogenic Adherent-Invasive Escherichia coli (AIEC) able to invade the intestinal epithelial cells ...and macrophages, and also to replicate in lysosomal vacuoles via binding CEACAM6 and LAMP1 receptors, respectively. In this study we tested the pathogenic role of two AIEC strains, LF82 and O83:H1, analyzing CEACAM6, LAMP1 and TNF-alpha expression in organ cultures of CD patients. Methods: Colonic biopsies were obtained from 12 patients with quiescent CD and cultured in vitro for 3 h with only medium (N) or 108 CFU/mL of non-pathogenic E. coli (NP) or LF82 or O83:H1 strains. Immunohistochemistry analysis assessed the expression of CEACAM6, LAMP1, HLA-DR and Intercellular Adhesion Molecule 1 (ICAM1). mRNA level of TNF-alpha, isolated from frozen section of colonic biopsies, was determined by RT-PCR. Results: Epithelial expression of CEACAM6 and LAMP1 expression on either epithelium and lamina propria mononuclear cells were higher in biopsies cultured in the presence of both O83:H1 and LF82 than in biopsies cultured with NP. Moreover, both AIEC strains induced increased expression of ICAM-1 on blood vessels and HLA-DR on lamina propria mononuclear cells. Finally, we observed higher level of TNF-alpha transcripts in biopsies cultured with both AIEC strains than in those cultured with NP. However, O83:H1strain induced an increased expression of CEACAM6, ICAM1, HLA-DR and higher levels mRNA levels of TNF-alpha transcripts when compared with LF82 strain; on the contrary, LF82 strain induced an increased expression of LAMP1. Conclusions: Our data show that O83:H1 is more adherent and pathogenic than LF82, inducing increased expression of CEACAM6, ICAM-1, HLA-DR, and TNF-alpha. On the other hand, LF82 is more invasive but less pathogenic inducing higher expression of LAMP1. Taken together these data suggest the involvement of both LF82 and O83:H1 AIEC strains in CD pathogenesis and that their role might be played by different pathways.
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