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Fundoscopy is the standard method for diagnosis and follow‐up of intraocular retinoblastoma, but it is sometimes insufficient to discern whether tumors are inactivated following treatments. In this work, we hypothesized that the amount of conserved nuclear DNA sequences in the cell‐free DNA (cfDNA) fraction of the aqueous humor (AH) might complement fundoscopy for retinoblastoma follow‐up. To address our hypothesis, we developed highly sensitive droplet digital polymerase chain reaction (ddPCR) methods to quantify highly conserved DNA sequences of nucleus‐encoded genes (GAPDH and B4GALNT1) and of a mitochondrial gene, MT‐ATP6. We obtained AH samples during intravitreal treatments. We analyzed 42 AH samples from 25 patients with intraocular retinoblastoma and 11 AH from controls (non‐cancer patients). According to clinical criteria, we grouped patients as having progression‐free or progressive retinoblastoma. cfDNA concentration in the AH was similar in both retinoblastoma groups. Copy counts for nucleus‐derived sequences of GAPDH and B4GALNT1 were significantly higher in the AH from patients with progressive disease, compared to the AH from progression‐free patients and control non‐cancer patients. The presence of mitochondrial DNA in the AH explained that both retinoblastoma groups had similar cfDNA concentration in AH. The optimal cut‐off point for discriminating between progressive and progression‐free retinoblastomas was 108 GAPDH copies per reaction. Among patients having serial AH samples analyzed during their intravitreal chemotherapy, GAPDH copies were high and decreased below the cut‐off point in those patients responding to chemotherapy. In contrast, one non‐responder patient remained with values above the cut‐off during follow‐up, until enucleation. We conclude that the measurement of conserved nuclear gene sequences in AH allows follow‐up of intraocular retinoblastoma during intravitreal treatment. The method is applicable to all patients and could be relevant for those in which fundoscopy evaluation is inconclusive.

Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project. Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines. None.

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.

The development of nanofibrous membranes with tunable wettability, degradation, and biocompatibility is highly keen for biomedical applications, including drug delivery and wound dressing. In this study, biocompatible and biodegradable nanofibrous membranes with antioxidant properties were successfully prepared by the electrospinning technique. The membranes were developed using polylactic acid (PLA) and polyethylene oxide (PEO) as the matrix, with the addition of grape seed extract (GSE), a rich source of natural antioxidants. The nanofibrous membranes were thoroughly characterized both from the materials and from the biocompatibility point of view. PLA and PLA/PEO nanofibers showed high encapsulation efficiency, close to 90%, while the encapsulated GSE retained its antioxidant capacity in the membranes. In vitro release studies showed that GSE diffuses from PLA/GSE and PLA/PEO/GSE membranes in a Fickian diffusion manner, whose experimental data were well fitted using the Korsmeyer-Peppas model. Furthermore, a higher controlled release of GSE was observed for the PLA/PEO/GSE membrane. Moreover, culturing experiments with human foreskin fibroblast (HFF1) cells demonstrated that all samples are biocompatible and showed that the GSE-loaded PLA/PEO nanofibrous membranes support better cell attachment and proliferation compared to the PLA/GSE nanofibrous membranes, owing to the superior hydrophilicity. In summary, the results suggested that the GSE-loaded membranes are a promising topical drug delivery system and have a great potential for wound dressing applications.

Background Research published to date on the relationship between insulin resistance (IR) and fructose consumption is scarce, has used different methods, and has yielded sometimes contradictory results. This study aims to determine whether a low-fructose and/or low-sucrose diet supervised by a physician or nurse decreases IR compared to a standard diet. Methods/design This field trial is located at primary care centers. The participants are adults aged 29 to 66 years, with a Body mass Index (BMI) between 29 and 40.99 kg/m 2 and without diabetes. To date, 245 participants have been assigned randomly to the low-fructose diet intervention group (LFDI) at health centers in the western health service zone of Tenerife island, and 245 to the standard-diet control group (SDC) at health centers in the eastern health service zone. Recruitment is opportunistic and is carried out by physicians and nurses at participating health centers. Initially (baseline), and after 24 weeks of intervention, dietary records, physical activity, waist circumference, BMI, blood pressure, fasting blood glucose and insulin concentrations (HOMA2-IR) and lipid profile are recorded; blood glucose and insulin and lipid profile are also recorded 2 h after a 75-g glucose overload. After 48 weeks (24 weeks after the intervention), fasting blood samples are again obtained and a physical examination is performed. All tests and measures are repeated and recorded except dietary records, physical activity and oral glucose overload. Low-fructose diets are designed by calculating free and total (free + fructose associated with sucrose) fructose contents in standard diets, and removing foods with a fructose content in the highest quartile for the amounts in the standard diet. Participants in both groups are prescribed a diet that contains 30 to 40% less than the participant’s energy requirements. The primary endpoint is change in HOMA2-IR between baseline and week 24, and other outcomes are change in HDL-cholesterol, LDL-cholesterol, triglycerides , waist circumference to height ratio and BMI. The secondary endpoint is change in HOMA2-IR between week 24 and week 48 together with the outcomes noted above. Comparisons between groups for variables used to indicate IR levels are done with a Student’s t test for unpaired variables or the Mann-Whitney U test if the distribution is not normal. Multivariate regression models will be used to control for confounding factors not accounted for in the study design, and for independent prognostic factors. Discussion If the dietary intervention being tested, i.e., a diet low in fructose/sucrose, is able to reduce IR, the results – if translated into regular clinical practice – could provide a hitherto unavailable tool to prevent type-2 diabetes mellitus. Trial registration ISRCTN, ID: ISRCTN41579277 . Registered retrospectively on 15 November 2016.

La resolución de problemas geométricos de la estereometría como habilidad de carácter general en los programas de la asignatura Matemática presenta bajos niveles de desarrollo en los estudiantes. En este trabajo, a partir del estudio realizado por diferentes didactas de la Matemática tanto del ámbito nacional como internacional, se precisa un sistema de habilidades del pensamiento geométrico espacial a desarrollar en los estudiantes para una mejor aprensión de los contenidos geométricos.