Jesús Mateos

Purpose: Adalimumab (ADA) is a systemic biological treatment option approved for the treatment of noninfectious uveitis (NIU); however, up to 40% of patients do not respond to the drug, either in a primary or secondary manner. Here, we evaluated the proteomic profile of patients with NIU who fail to ADA to identify proteins implicated in intraocular inflammation, as well as potential biomarkers for treatment response and novel therapeutic targets. Methods: Cross-sectional observational study of patients with NIU under ADA treatment for six or more months. Tears were collected with microcapillary tubes and protein analyzed by data-independent acquisition/sequential window acquisition of all theoretical mass spectra. Differentially expressed proteins (DEPs) were defined based on the fold change between their expression in nonresponders (NR) and responders (R). Protein network and gene ontology analysis were performed. The χ² test for trend and receiver operating characteristic (ROC) curves were used to evaluate potential biomarkers of treatment response. Results: Twenty-nine DEPs, 14 upregulated and 15 downregulated, were detected in NR. These proteins were mainly related to enhanced neutrophil effector functions and redox imbalance. ROC analysis identified defensin-1,3 (DEF-1,3), biotinidase, and ATP-binding cassette transporter A1 as potential biomarkers for treatment response. Conclusions: This is the first study on a clinical cohort of patients with noninfectious uveitis that identifies tear proteins related to neutrophil hyperactivation as drivers of the persistent intraocular inflammation observed in NR to ADA and provides evidence that targeting interleukin 6, Janus kinases, or the complement cascade could be potential alternative therapeutic strategies in these patients. Our results indicate the potential of high-throughput proteomics to provide insights into the underlying pathological mechanisms of persistent intraocular inflammation observed in patients who do not adequately respond to anti-TNF treatment and the value of tear proteomics as a tool for personalized medicine.

Background: A challenging new branch of research related to aging-associated diseases is the identification of miRNAs capable of modulating the senescence-associated secretory phenotype (SASP) which characterizes senescent cells and contributes to driving inflammation. Methods: Mesenchymal stem cells (MSC) from human umbilical cord stroma were stable modified using lentivirus transduction to inhibit miR-21-5p and shotgun proteomic analysis was performed in the MSC-derived extracellular vesicles (EV) to check the effect of miR-21 inhibition in their protein cargo. Besides, we studied the paracrine effect of those modified extracellular vesicles and also their effect on SASP. Results: Syndecan-1 (SDC1) was the most decreased protein in MSC-miR21⁻-derived EV, and it was involved in inflammation and EV production. MSC-miR21⁻-derived EV were found to produce a statistically significant inhibitory effect on SASP and inflammaging markers expression in receptor cells, and in the opposite way, these receptor cells increased their SASP and inflammaging expression statistically significantly when treated with MSC-miR-21⁺-derived EV. Conclusion: This work demonstrates the importance of miR-21 in inflammaging and its role in SASP through SDC1. Graphical

Outpatient parenteral antimicrobial therapy (OPAT) with continuous infusion pumps is postulated as a very promising solution to treat complicated infections, such as endocarditis or osteomyelitis, that require patients to stay in hospital during extended periods of time, thus reducing their quality of life and increasing the risk of complications. However, stability studies of drugs in elastomeric devices are scarce, which limits their use in OPAT. Therefore, we evaluated the stability of ampicillin in sodium chloride 0.9% at two different concentrations, 50 and 15 mg/mL, in an elastomeric infusion pump when stored in the refrigerator and subsequently in real-life conditions at two different temperatures, 25 and 32 °C, with and without the use of a cooling device. The 15 mg/mL ampicillin is stable for up to 72 h under refrigeration, allowing subsequent dosing at 25 °C for 24 h with and without a cooling device, but at 32 °C its concentration drops below 90% after 8 h. In contrast, 50 mg/mL ampicillin only remains stable for the first 24 h under refrigeration, and subsequent administration at room temperature is not possible, even with the use of a cooling system. Our data support that 15 mg/mL AMP is suitable for use in OPAT if the volume and rate of infusion are tailored to the dosage needs of antimicrobial treatments.

Age-related macular degeneration (AMD) is a common ocular disease characterized by degeneration of the central area of the retina in the elderly population. Progression and response to treatment are influenced by genetic and non-genetic factors. Proteomics is a powerful tool to study, at the molecular level, the mechanisms underlying the progression of the disease, to identify new therapeutic targets and to establish biomarkers to monitor progression and treatment effectiveness. In this work, we systematically review the use of proteomics-based approaches for the study of the molecular mechanisms underlying the development of AMD, as well as the progression of the disease and on-treatment patient monitoring. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines were followed. Proteomic approaches have identified key players in the onset of the disease, such as complement components and proteins involved in lipid metabolism and oxidative stress, but also in the progression to advanced stages, including factors related to extracellular matrix integrity and angiogenesis. Although anti-vascular endothelial growth factor (anti-VEGF)-based therapy has been crucial in the treatment of neovascular AMD, it is necessary to deepen our understanding of the underlying disease mechanisms to move forward to next-generation therapies for later-stage forms of this multifactorial disease.

Age-related macular degeneration (AMD) is a common ocular disease characterized by the de-generation of the central area of the retina in elderly population. Progression and response to treatment is influenced by genetic and non-genetic factors. Proteomics is a powerful tool to study, at the molecular level, the mechanisms underlaying the progression of the diseases, to identify new therapeutical targets and to establish biomarkers to monitor progression and treatment ef-fectiveness. In this work we pursue to systematically review the use of proteomic-based ap-proaches for the study of the molecular mechanisms underlying the development of AMD, as well as the progression of the disease and the on-treatment patient monitoring. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed. Proteomic approaches have identified key players on the onset of the disease, such as proteins involved in lipid metabolism and oxidative stress, but also in the progression to advanced stages, including factors related to extracellular matrix integrity and angiogenesis. Although an-ti-vascular endothelial growth factor (anti-VEGF)-based therapy has been crucial in the treatment of neovascular AMD it is necessary to get deeper into the underlying disease mechanisms to move forward to next-generation therapies of the later-stage forms of this multifactorial disease.