The aqueous extract of polypodium leucotomos (Fernblock®) regulates opsin 3 and prevents photooxidation of melanin precursors on skin cells exposed to blue light emitted from digital devices

The effects of sun exposure on the skin and specifically those related to pigmentation disorders are well known. It has recently been shown that blue light leads to the induction of oxidative stress and long-lasting pigmentation. The protective effect of an aqueous extract of Poly-podium leucotomos (Fernblock®) is known. Our aim was to investigate the action mechanism of Fernblock® against pigmentation induced by blue light from digital devices. Human fibroblasts (HDF) and murine melanocytes (B16-F10) were exposed to artificial blue light (a 400–500 nm LED lamp). Cell viability, mitochondrial morphology, and the expression of the mitogen-activated protein kinase (MAPK) p38, known markers involved in the melanogenesis pathway, were evaluated. The activation of Opsin-3, a membrane protein sensitive to blue light that triggers the activation of the enzyme tyrosinase responsible for melanogenesis in melanocytes, was also analyzed. Our results demonstrated that pretreatment with Fernblock® prevents cell death, alteration of mitochondrial morphology, and phosphorylation of p38 in HDF exposed to blue light. In addition, Fernblock® significantly reduced the activation of Opsin-3 in melanocytes and the photo-oxidation of melanin, preventing its photodegradation. In sum, Fernblock® exerts beneficial effects against the detrimental impact of blue light from digital devices and could prevent early photoaging, while maintaining skin homeostasi

gec estro acrop recommendations in skin brachytherapy

Abstract Purpose The aim of this publication is to compile available literature data and expert experience regarding skin brachytherapy (BT) in order to produce general recommendations on behalf of the GEC-ESTRO Group. Methods We have done an exhaustive review of published articles to look for general recommendations. Results Randomized controlled trials, systemic reviews and meta-analysis are lacking in literature and there is wide variety of prescription techniques successfully used across the radiotherapy centers. BT can be delivered as superficial application (also called contact BT or plesiotherapy) or as interstitial for tumours thicker than 5 mm within any surface, including very irregular. In selected cases, particularly in tumours located within curved surfaces, BT can be advantageous modality from dosimetric and planning point of view when compared to external beam radiotherapy. The general rule in skin BT is that the smaller the target volume, the highest dose per fraction and the shortest overall length of treatment can be used. Conclusion Skin cancer incidence is rising worldwide. BT offers an effective non-invasive or minimally invasive and relative short treatment that particularly appeals to elder and frail population

Pathological changes of renal biopsy in Sjögren Syndrome

We are presenting the case of a 53-year-old woman with a history of Sjögren syndrome and a secondary antiphospholipid syndrome admitted at the Nephrology department for the evaluation of renal failure. The patient was initially diagnosed with tubulointerstitial nephritis and subsequently a membranoproliferative type I glomerulonephritis, secondary to cryoglobulins during the course of the disease. Repeated renal biopsies were required to confirm the diagnosis

Impaired Phagocytosis in Dendritic Cells From Pediatric Patients With Type 1 Diabetes Does Not Hamper Their Tolerogenic Potential

Type 1 diabetes (T1D) is prompted by defective immunological tolerance, an event in which dendritic cells (DCs) are crucial as immune response orchestrators. In fact, they contribute to maintaining tolerance to self-antigens, but they can also prompt an immunogenic response against them, leading to autoimmunity. Countless factors can potentially impact on the proper functionality of the DCs, which range from altered subset distribution, impaired phagocytic function to abnormal gene expression. Moreover, in T1D, metabolic dysregulation could impair DC functions as well. Indeed, since T1D clinical course is likely to be more aggressive in children and adolescents and entails severe dysglycemia, the aim of this study was to analyze circulating DCs subpopulations in pediatric T1D at different stages, as well as to characterize their phagocytosis ability and tolerance induction potential. Thus, pediatric patients newly diagnosed with T1D, with established disease and control subjects were recruited. Firstly, DCs subsets from peripheral blood were found quantitatively altered during the first year of disease, but recovered in the second year of progression. Secondly, to study the tolerogenic functionality of DCs, liposomes with phosphatidylserine (PS) were designed to mimic apoptotic beta cells, which are able to induce tolerance, as previously demonstrated by our group in DCs from adult patients with T1D. In this study, monocyte-derived DCs from pediatric patients with T1D and control subjects were assessed in terms of PS-liposomes capture kinetics, and transcriptional and phenotypic changes. DCs from pediatric patients with T1D were found to phagocyte PS-liposomes more slowly and less efficiently than DCs from control subjects, inversely correlating with disease evolution. Nonetheless, the transcription of PS receptors and immunoregulatory genes, cytokine profile, and membrane expression of immunological markers in DCs was consistent with tolerogenic potential after PS-liposomes phagocytosis. In conclusion, T1D progression in childhood entails altered peripheral blood DCs subsets, as well as impaired DCs phagocytosis, although tolerance induction could still function optimally. Therefore, this study provides useful data for patient follow-up and stratification in immunotherapy clinical trials

Recommendations of the Spanish brachytherapy group of the Spanish Society of Radiation Oncology and the Spanish Society of Medical Physics for interstitial high-dose-rate brachytherapy for gynaecologic malignancies

The present document includes consensus-based recommendations from the Brachytherapy Group (GEB) of the Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM) for interstitial high-dose-rate (HDR) brachytherapy (BT) for gynaecologic malignancies. A nine-item survey-which included questions on experience with interstitial BT; indications and technique; applicator type; magnetic resonance imaging (MRI)-based planning; dose; fractionation schedule; and treatment planning-was sent to all radiation oncology departments (n = 174) in Spain in 2021. Responses were received from 36 centres (50% of all centres [n = 72] with a BT unit). The consensus-based recommendations presented here are based on a review of the available literature, professional experience among the group of experts, and in-person discussions held during the annual meeting of these two societies. We describe the results of the survey and the following: indications; contraindications; patient selection; description of applicators; role of imaging in planning; contouring; dose prescription; dosimetric reconstruction; optimisation; and dose indications for cancers of the cervix, vagina, and vulva. The various clinical scenarios in which interstitial BT is used in the treatment of gynaecological tumours are described in detail, including cervix intracavitary/interstitial hybrid HDR-BT; cervix perineal templates/freehand implants; primary vaginal malignancies/vaginal recurrences; and vulvar interstitial implants

Prenatal Betamethasone interferes with immune system development and alters target cells in autoimmune diabetes

Altres ajuts: This work has been co-financed with the European Regional Development funds (FEDER), and supported by the Deutsche Forschungsgemeinschaft (KFO296). CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III. SRF is supported by the Agency for Management of University and Research Grants (AGAUR) of the Generalitat de Catalunya.Non-genetic factors are crucial in the pathogenesis of type 1 diabetes (T1D), a disease caused by autoimmunity against insulin-producing β-cells. Exposure to medications in the prenatal period may influence the immune system maturation, thus altering self-tolerance. Prenatal administration of betamethasone -a synthetic glucocorticoid given to women at risk of preterm delivery- may affect the development of T1D. It has been previously demonstrated that prenatal betamethasone administration protects offspring from T1D development in nonobese diabetic (NOD) mice. The direct effect of betamethasone on the immature and mature immune system of NOD mice and on target β-cells is analysed in this paper. In vitro, betamethasone decreased lymphocyte viability and induced maturation-resistant dendritic cells, which in turn impaired γδ T cell proliferation and decreased IL-17 production. Prenatal betamethasone exposure caused thymus hypotrophy in newborn mice as well as alterations in immune cells subsets. Furthermore, betamethasone decreased β-cell growth, reduced C-peptide secretion and altered the expression of genes related to autoimmunity, metabolism and islet mass in T1D target tissue. These results support the protection against T1D in the betamethasone-treated offspring and demonstrate that this drug alters the developing immune system and β-cells. Understanding how betamethasone generates self-tolerance could have potential clinical relevance in T1D

Preclinical evaluation of antigen-specific nanotherapy based on phosphatidylserine-liposomes for type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing cells. Due to the ability of apoptotic cells clearance to induce tolerance, we previously generated liposomes rich in phophatidylserine (PS) -a feature of apoptotic cells- loaded with insulin peptides to mimic apoptotic beta-cells. PS-liposomes arrested autoimmunity in experimental T1D through the induction of tolerance. The aim of this study was to investigate the potential of several peptides from different T1D autoantigens encapsulated in (PS)-liposomes for T1D prevention and to assess its safety. T1D autoantigens (Insulin, C-peptide, GAD65 and IA2) were encapsulated in PS-liposomes. Liposomes were administered to the 'gold-standard' model for the study of autoimmune T1D, the Non-Obese Diabetic mouse, that spontaneously develop the disease. Safety and toxicity of liposomes were also determined. Only PS-liposomes encapsulating insulin peptides decrease T1D incidence in the Non-Obese Diabetic mouse model. Disease prevention correlates with a decrease in the severity of the autoimmune islet destruction driven by leukocytes. PS-liposomes neither showed toxic effect nor secondary complications. Among the here referred autoantigens, insulin peptides are the best candidates to be encapsulated in liposomes, like an artificial apoptotic cell, for the arrest of autoimmunity in T1D in a safe manner

Repurposed analog of GLP-1 ameliorates hyperglycemia in type 1 diabetic mice through pancreatic cell reprogramming

This work has been funded by Fundació La Marató de TV3 (project 201632_10). CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation. SR-F was supported by the Generalitat de Catalunya (AGAUR grant).Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to β-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the β-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic β-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing β-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD- Scid IL2rg −/− (NSG) mice with type 1 diabetes. Liraglutide significantly improved the blood glucose levels in diabetic NSG mice. During the treatment, a significant increase in β-cell mass was observed due to a boost in β-cell number. Both parameters were reduced after withdrawal. Interestingly, islet bihormonal glucagon + insulin + cells and insulin + ductal cells arose during treatment. In vitro experiments showed an increase of insulin and glucagon gene expression in islets cultured with liraglutide in normoglycemia conditions. These results point to β-cell replacement, including transdifferentiation and neogenesis, as aiding factors and support the role of liraglutide in β-cell mass restoration in type 1 diabetes. Understanding the mechanism of action of this drug could have potential clinical relevance in this autoimmune disease

NK Cell Subsets Changes in Partial Remission and Early Stages of Pediatric Type 1 Diabetes

Type 1 diabetes (T1D) is a chronic metabolic disease characterized by the autoimmune destruction of β-cells in the pancreatic islets. T1D is preceded by islet-specific inflammation led by several immune cells. Among them, natural killer (NK) cells are emerging as important players in T1D development. Human NK cells are characterized by CD56 and CD16 expression, which allows classifying NK cells into four subsets: 1) CD56 dim CD16 + or effector NK cells (NK); 2) CD56 bright CD16 − or regulatory NK cells (NK); 3) intermediate CD56 bright CD16 + NK cells; and 4) CD56 dim CD16 − NK cells, whose function is not well determined. Since many studies have shown that T1D progression is associated with changes in various immune cell types, we hypothesize that the kinetics of NK cell subsets in the blood could correlate with different stages of T1D. To that aim, pediatric patients newly diagnosed with T1D were recruited, and peripheral NK cell subsets were analyzed by flow cytometry at several disease checkpoints: disease onset, partial remission (PR), 8 months (for non-remitters), and 12 months of progression. Our results showed that total NK cells and their four subsets are altered at the early stages of T1D. A decrease in the counts and percentage of total NK cells and NK cells at the different disease stages was found when compared to controls. These results suggest the extravasation of these cells into the islets at disease onset, which is maintained throughout the follow-up. By contrast, NK cells increased during the early stages after T1D onset, and both intermediate NK cells and CD56 dim CD16 - NK cells diminished at the PR stage, which might reflect the immunoregulatory attempts and could be candidate biomarkers for this stage. Also, CD56 dim CD16 - NK cells increased during T1D progression. Finally, changes in CD16 expression were identified in the different T1D stages, highlighting a CD16 expression reduction in total NK cells and NK cells 1 year after diagnosis. That may reflect a state of exhaustion after multiple cell-to-cell interactions. Altogether, our preliminary data provide a longitudinal picture of peripheral NK cell subpopulations during the different T1D stages, which could be potential candidate biomarkers indicators of disease progression

Phosphatidylserine-Liposomes promote tolerogenic features on dendritic cells in human type 1 diabetes by apoptotic mimicry

Type 1 diabetes (T1D) is a metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. With its incidence increasing worldwide, to find a safe approach to permanently cease autoimmunity and allow β-cell recovery has become vital. Relying on the inherent ability of apoptotic cells to induce immunological tolerance, we demonstrated that liposomes mimicking apoptotic β-cells arrested autoimmunity to β-cells and prevented experimental T1D through tolerogenic dendritic cell (DC) generation. These liposomes contained phosphatidylserine (PS)-the main signal of the apoptotic cell membrane-and β-cell autoantigens. To move toward a clinical application, PS-liposomes with optimum size and composition for phagocytosis were loaded with human insulin peptides and tested on DCs from patients with T1D and control age-related subjects. PS accelerated phagocytosis of liposomes with a dynamic typical of apoptotic cell clearance, preserving DCs viability. After PS-liposomes phagocytosis, the expression pattern of molecules involved in efferocytosis, antigen presentation, immunoregulation, and activation in DCs concurred with a tolerogenic functionality, both in patients and control subjects. Furthermore, DCs exposed to PS-liposomes displayed decreased ability to stimulate autologous T cell proliferation. Moreover, transcriptional changes in DCs from patients with T1D after PS-liposomes phagocytosis pointed to an immunoregulatory prolife. Bioinformatics analysis showed 233 differentially expressed genes. Genes involved in antigen presentation were downregulated, whereas genes pertaining to tolerogenic/anti-inflammatory pathways were mostly upregulated. In conclusion, PS-liposomes phagocytosis mimics efferocytosis and leads to phenotypic and functional changes in human DCs, which are accountable for tolerance induction. The herein reported results reinforce the potential of this novel immunotherapy to re-establish immunological tolerance, opening the door to new therapeutic approaches in the field of autoimmunity