Gustavo J. Melen

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelicCOL7A1gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 10⁶cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6–9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-β, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies.

Venous leg ulcers (VLU) represent an uphill economic, health and social burden, aggravated in the elderly. Best-practice care interventions are often insufficient and alternative therapies need to ... Lay abstract Elderly people suffering from leg ulcers often have a reduced quality of life for a number of reasons. These include persistent pain, difficulty moving, depression and social isolation... Graphical abstract

Introduction and Objectives: Acute bronchiolitis (AB) is the leading cause of hospitalization in infants and around 5% require intensive care treatment. Early identification of children diagnosed with AB at a high risk of severe progression is of great interest. The receptor for advanced glycation end products (RAGE), highly expressed in lung tissue, regulates immune responses and inflammation, and its soluble form, sRAGE, is believed to have an anti‐inflammatory role. We hypothesized serum sRAGE might be a major determinant of AB severity and prognosis. This study was conducted to measure serum sRAGE in infants with severe AB and to assess its correlation with clinical severity, immediate complications, and outcome.Methods: Single‐center, prospective, observational study of hospitalized children with severe bronchiolitis admitted to the Pediatric Intensive Care Unit (PICU), from September 2015 to September 2016.Results: A total of 52 children and 27 controls were included. The cases age ranged from 11 days to 21 months, resulting in a significant age difference with controls (11.85 vs 4.84 months, P < .01). Serum levels of sRAGE were lower but not significant in severe AB patients than in controls (1350.93 vs 1450.42 pg/mL; P = .399). No correlation was found between serum sRAGE and causative viruses, clinical symptoms, Wood‐Downes score (a clinical severity score) on admission, respiratory support, or length of hospital stay. Serum sRAGE was also lower in the cases having had a previous respiratory disease (1463.84 vs 1072.43 pg/mL; P = .049). However, it was higher in patients with any lung consolidation on the chest X‐ray (1584.79 vs 1131.62 pg/mL; P = .044) and weakly positively correlated with classical biomarkers (maximum C‐reactive protein, +0.295, P = .034; maximum procalcitonin, +0.309; P = .029).Conclusion: This single‐center study reveals that sRAGE couldn't predict AB severity or outcome in children hospitalized at PICU. Nevertheless, it significantly increased in the presence of any lung consolidation and had a positive correlation with classical biomarkers. The utility of sRAGE in this population could be probably elucidated with a better understanding of AGE‐RAGE axis.

Little is known about the effect of oncolytic adenovirotherapy on pediatric tumors. Here we present the clinical case of a refractory neuroblastoma that responded positively to Celyvir (ICOVIR-5 oncolytic adenovirus delivered by autologous mesenchymal stem cells) for several months. We analyzed samples during tumor evolution in order to identify molecular and mutational features that could explain the interactions between treatment and tumor and how the balance between both of them evolved. We identified a higher adaptive immune infiltration during stabilized disease compared to progression, and also a higher mutational rate and T-cell receptor (TCR) diversity during disease progression. Our results indicate an initial active role of the immune system controlling tumor growth during Celyvir therapy. The tumor eventually escaped from the control exerted by virotherapy through acquisition of resistance by the tumor microenvironment that exhausted the initial T cell response.

The selective delivery of therapeutic and imaging agents to tumoral cells has been postulated as one of the most important challenges in the nanomedicine field. Meta‐iodobenzilguanidine (MIBG) is widely used for the diagnosis of neuroblastoma (NB) due to its strong affinity for the norepinephrine transporter (NET), usually overexpressed on the membrane of malignant cells. Herein, a family of novel Y‐shaped scaffolds has been synthesized, which have structural analogues of MIBG covalently attached at each end of the Y‐structure. The cellular uptake capacity of these double‐targeting ligands has been evaluated in vitro and in vivo, yielding one specific Y‐shaped structure that is able to be engulfed by the malignant cells, and accumulates in the tumoral tissue, at significantly higher levels than the structure containing only one single targeting agent. This Y‐shaped ligand can provide a powerful tool for the current treatment and diagnosis of this disease.

(2015). Effects of local administration of allogenic adipose tissue-derived mesenchymal stem cells on functional recovery in experimental traumatic brain injury. Brain Injury: Vol. 29, No. 12, pp. 1497-1510. doi: 10.3109/02699052.2015.1053525