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Developmentally-programmed cellular senescence is conserved and widespread in zebrafish
No full textCellular senescence is considered a stress response imposing a stable cell cycle arrest to restrict the growth of damaged cells. More recently however, cellular senescence was identified during mouse embryo development at particular structures during specific periods of time. This programmed cell senescence has been proposed to serve developmental and morphogenetic functions and to potentially represent an evolutionary origin of senescence. Cellular senescence has also been described to take place during bird (chick and quail) and amphibian (xenopus and axoltl) development. Fish however, have been described to show a very narrow and restricted pattern of developmental cell senescence. Here we carried out a detailed characterization of senescence during zebrafish development and found it to be conserved and widespread. Apart from yolk and cloaca, previously described structures, we also identified senescence in the developing central nervous system, intestine, liver, pronephric ducts, and crystalline. Interestingly, senescence at these developing structures disappeared upon treatment with senolytic compound ABT-263, supporting their senescent identity and opening the possibility of studying the contribution of this process to development. In summary, our findings extend the description of developmentally-programmed cell senescence to lower vertebrates contributing to the notion of the relevance of this process for embryo development
A Novel Nanoproteomic Approach for the Identification of Molecular Targets Associated with Thyroid Tumors
Get PDFA thyroid nodule is the most common presentation of thyroid cancer; thus, it is extremely important to differentiate benign from malignant nodules. Within malignant lesions, classification of a thyroid tumor is the primary step in the assessment of the prognosis and selection of treatment. Currently, fine-needle aspiration biopsy (FNAB) is the preoperative test most commonly used for the initial thyroid nodule diagnosis. However, due to some limitations of FNAB, different high-throughput "omics" approaches have emerged that could further support diagnosis based on histopathological patterns. In the present work, formalin-fixed paraffin-embedded (FFPE) tissue specimens from normal (non-neoplastic) thyroid (normal controls (NCs)), benign tumors (follicular thyroid adenomas (FTAs)), and some common types of well-differentiated thyroid carcinoma (follicular thyroid carcinomas (FTCs), conventional or classical papillary thyroid carcinomas (CV-PTCs), and the follicular variant of papillary thyroid carcinomas (FV-PTCs)) were analyzed. For the first time, FFPE thyroid samples were deparaffinized using an easy, fast, and non-toxic method. Protein extracts from thyroid tissue samples were analyzed using a nanoparticle-assisted proteomics approach combined with shotgun LC-MS/MS. The differentially regulated proteins found to be specific for the FTA, FTC, CV-PTC, and FV-PTC subtypes were analyzed with the bioinformatic tools STRING and PANTHER showing a profile of proteins implicated in the thyroid cancer metabolic reprogramming, cancer progression, and metastasis. These proteins represent a new source of potential molecular targets related to thyroid tumors
Variation in antibiotic prescription rates in febrile children presenting to emergency departments across Europe (MOFICHE): A multicentre observational study
Get PDFBACKGROUND: The prescription rate of antibiotics is high for febrile children visiting the emergency department (ED), contributing to antimicrobial resistance. Large studies at European EDs covering diversity in antibiotic and broad-spectrum prescriptions in all febrile children are lacking. A better understanding of variability in antibiotic prescriptions in EDs and its relation with viral or bacterial disease is essential for the development and implementation of interventions to optimise antibiotic use. As part of the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) project, the MOFICHE (Management and Outcome of Fever in Children in Europe) study aims to investigate variation and appropriateness of antibiotic prescription in febrile children visiting EDs in Europe. METHODS AND FINDINGS: Between January 2017 and April 2018, data were prospectively collected on febrile children aged 0-18 years presenting to 12 EDs in 8 European countries (Austria, Germany, Greece, Latvia, the Netherlands [n = 3], Spain, Slovenia, United Kingdom [n = 3]). These EDs were based in university hospitals (n = 9) or large teaching hospitals (n = 3). Main outcomes were (1) antibiotic prescription rate; (2) the proportion of antibiotics that were broad-spectrum antibiotics; (3) the proportion of antibiotics of appropriate indication (presumed bacterial), inappropriate indication (presumed viral), or inconclusive indication (unknown bacterial/viral or other); (4) the proportion of oral antibiotics of inappropriate duration; and (5) the proportion of antibiotics that were guideline-concordant in uncomplicated urinary and upper and lower respiratory tract infections (RTIs). We determined variation of antibiotic prescription and broad-spectrum prescription by calculating standardised prescription rates using multilevel logistic regression and adjusted for general characteristics (e.g., age, sex, comorbidity, referral), disease severity (e.g., triage level, fever duration, presence of alarming signs), use and result of diagnostics, and focus and cause of infection. In this analysis of 35,650 children (median age 2.8 years, 55% male), overall antibiotic prescription rate was 31.9% (range across EDs: 22.4%-41.6%), and among those prescriptions, the broad-spectrum antibiotic prescription rate was 52.1% (range across EDs: 33.0%-90.3%). After standardisation, differences in antibiotic prescriptions ranged from 0.8 to 1.4, and the ratio between broad-spectrum and narrow-spectrum prescriptions ranged from 0.7 to 1.8 across EDs. Standardised antibiotic prescription rates varied for presumed bacterial infections (0.9 to 1.1), presumed viral infections (0.1 to 3.3), and infections of unknown cause (0.1 to 1.8). In all febrile children, antibiotic prescriptions were appropriate in 65.0% of prescriptions, inappropriate in 12.5% (range across EDs: 0.6%-29.3%), and inconclusive in 22.5% (range across EDs: 0.4%-60.8%). Prescriptions were of inappropriate duration in 20% of oral prescriptions (range across EDs: 4.4%-59.0%). Oral prescriptions were not concordant with the local guideline in 22.3% (range across EDs: 11.8%-47.3%) of prescriptions in uncomplicated RTIs and in 45.1% (range across EDs: 11.1%-100%) of prescriptions in uncomplicated urinary tract infections. A limitation of our study is that the included EDs are not representative of all febrile children attending EDs in that country. CONCLUSIONS: In this study, we observed wide variation between European EDs in prescriptions of antibiotics and broad-spectrum antibiotics in febrile children. Overall, one-third of prescriptions were inappropriate or inconclusive, with marked variation between EDs. Until better diagnostics are available to accurately differentiate between bacterial and viral aetiologies, implementation of antimicrobial stewardship guidelines across Europe is necessary to limit antimicrobial resistance
Pancreatic Cancer Malnutrition and Pancreatic Exocrine Insufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer
Get PDFBackground: Malnutrition and cachexia are common in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and have a significant influence on the tolerance and response to treatments. If timely identified, malnourished PDAC patients could be treated to increase their capacity to complete the planned treatments and, therefore, possibly, improve their efficacy. Aims: The aim of this study is to assess the impact of nutritional status, pancreatic exocrine insufficiency (PEI), and other clinical factors on patient outcomes in patients with advanced PDAC. Methods: PAncreatic Cancer MAlnutrition and Pancreatic Exocrine INsufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer (PAC-MAIN) is an international multicenter prospective observational cohort study. The nutritional status will be determined by means of Mini-Nutritional Assessment score and laboratory blood tests. PEI will be defined by reduced fecal elastase levels. MAIN OUTCOME: adherence to planned chemotherapy in the first 12 weeks following the diagnosis, according to patients' baseline nutritional status and quantified and reported as "percent of standard chemotherapy dose delivered." SECONDARY OUTCOMES: rate of chemotherapy-related toxicity, progression-free survival, survival at 6 months, overall survival, quality of life, and the number of hospitalizations. ANALYSIS: chemotherapy dosing over the first 12 weeks of therapy (i.e., percent of chemotherapy received in the first 12 weeks, as defined above) will be compared between well-nourished and malnourished patients. SAMPLE SIZE: based on an expected percentage of chemotherapy delivered of 70% in well-nourished patients, with a type I error of 0.05 and a type II error of 0.20, a sample size of 93 patients per group will be required in case of a percentage difference of chemotherapy delivered of 20% between well-nourished and malnourished patients, 163 patients per group in case of a difference of 15% between the groups, and 356 patients per group in case of a 10% difference. Centers from Russia, Romania, Turkey, Spain, Serbia, and Italy will participate in the study upon Local Ethics Committee approval. Discussion: PAC-MAIN will provide insights into the role of malnutrition and PEI in the outcomes of PDAC. The study protocol was registered at clinicaltrials.gov as NCT04112836
Changes in Physical Activity Patterns from Childhood to Adolescence: Genobox Longitudinal Study
Get PDFLongitudinal changes of physical activity (PA) from childhood into adolescence have not been accurately described yet for the Spanish population. The aim of this study is to evaluate the changes of PA, assessed by accelerometry and anthropometric measures in a cohort of 213 children from the prepubertal to pubertal period, focusing on those with valid data from both time points (n = 75). Sedentary time (ST) increased about 50%, while all PA intensities declined from the pre-pubertal to pubertal period. Light PA (LPA) was the major contributor, decreasing by about 30%. Boys were more active than girls in both periods, but they showed a higher decline in PA, especially moderate-to-vigorous PA (MVPA). The proportion who reached the recommendation of 60 min of MVPA decreased by 33.3% in boys and 4.6% in girls. Children with obesity or overweight had lower MVPA than those with normal-weight in the pre-pubertal period, but no differences were found in the pubertal period. This study shows a decrease of PA and an increase of sedentarism in the transition from childhood to adolescence, particularly in boys. Regardless of body weight, adolescents tend to be less active. Therefore, prevention programs should be implemented to achieve optimal PA and reduce sedentarism during infancy considering the differences found by sex
Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome
Get PDFMutations in non-coding DNA regions are increasingly recognized as cancer drivers. These mutations can modify gene expression in cis or by inducing high-order chormatin structure modifications with long-range effects. Previous analysis reported the detection of recurrent and functional non-coding DNA mutations in the chronic lymphocytic leukemia (CLL) genome, such as those in the 3' untranslated region of NOTCH1 and in the PAX5 super-enhancer. In this report, we used whole genome sequencing data produced by the International Cancer Genome Consortium in order to analyze regions with previously reported regulatory activity. This approach enabled the identification of numerous recurrently mutated regions that were frequently positioned in the proximity of genes involved in immune and oncogenic pathways. By correlating these mutations with expression of their nearest genes, we detected significant transcriptional changes in genes such as PHF2 and S1PR2. More research is needed to clarify the function of these mutations in CLL, particularly those found in intergenic regions
How to perform EUS-guided tattooing?
Get PDFRecently, we introduced a series of papers describing on how to perform certain techniques and controversies in EUS. In the first paper, "What should be known before performing EUS examinations, Part I," the authors discussed clinical information and whether other imaging modalities should be needed before embarking in EUS examination. In Part II, some technical controversies on how EUS is performed are discussed from different points of view by providing the relevant available evidence. Herewith, we describe on how to perform EUS-guided fine needle tattooing (FNT) in daily practice. The aim of this paper is to discuss pros and cons for several issues including historical remarks, injecting material, technical approach, and how to perform EUS-FNT including argues in favor and against
Antioxidants and Oxidative Stress in Children: Influence of Puberty and Metabolically Unhealthy Status
Get PDFOxidative stress could help explain the relationship between childhood obesity and a metabolically unhealthy (MU) status. Moreover, puberty could also influence this relationship, since it entails physiological cardiometabolic changes. We aimed to evaluate plasma antioxidants and oxidative stress biomarkers in MU and metabolically healthy (MH) prepubertal and pubertal children and their associations with pro-inflammatory and endothelial damage biomarkers, taking puberty into account. A total of 1444 Spanish children aged 3-17 years (48.9% males, 66% prepubertal, 47.1% with obesity) were recruited. Blood pressure, anthropometric and biochemical parameters were measured, and children were categorized as having a MU or MH status according to risk factors. Retinol, carotenes, tocopherols, total antioxidant capacity (TAC), oxidized low-density lipoprotein and selected pro-inflammatory and endothelial damage biomarkers were analyzed. General linear models adjusted for age, sex, recruitment center and body mass index, partial correlations and stepwise linear regressions were performed. Lower carotenes and tocopherols levels were found in MU than in MH children. Plasma TAC was lower in prepubertal and higher in pubertal children with obesity compared to normal-weight children. Antioxidants and oxidative stress biomarkers showed novel associations with several pro-inflammatory and endothelial damage biomarkers, with pubertal differences, supporting the importance of considering both the antioxidant and oxidative stress status and puberty in the prevention of metabolic diseases in childhood
Relationship Between Clinical Control, Respiratory Symptoms and Quality of Life for Patients with COPD
Get PDFBackground: The concept of clinical control has been proposed as an instrument for evaluating patients with COPD. However, the possible association between clinical control, reduced symptom severity and HRQoL has yet to be confirmed. Methods: This multicentre, prospective and observational study was carried out in 15 pulmonology clinics in Spain. The patients were followed up for six months, with a baseline visit (V0), followed by visits at three months (V1) and six months (V2). Clinical control was determined at V1, with the application of both clinical criteria and the COPD assessment test (CAT). All patients reported their symptoms by a validated symptom diary (E-RS) using a portable device, and their HRQoL was assessed using the EQ5D questionnaire. The relationship between clinical control and E-RS and HRQoL during follow-up was assessed with t-test. Results: A total of 126 patients were screened. After application of the inclusion/exclusion criteria, 93 were finally included (mean age 66 +/- 8 years, 84.9% male), with a mean FEV1 predicted of 49.8% +/- 16.5%. Of these patients, 44 (47.3%) achieved clinical control at V1, according to CAT criteria, and 50 (53.8%), according to clinical criteria. The E-RS scores differed between controlled and uncontrolled patients at all time points, both according to CAT (mean differences of -4.6, -5.6 and -6.2 units at V0, V1 and V2, respectively, p<0.005 for all comparisons) and to clinical criteria (mean differences of -3.3, -5-6 and -4.99 units, respectively, p<0.005 for all comparisons). The controlled patients also presented a significantly better HRQoL, measured by the EQ5D questionnaire (mean difference 0.13 and 0.10 at V2 by CAT or clinical criteria, respectively, p<0.05). Conclusion: Clinical control in patients with COPD, whether measured by CAT or by clinical criteria, is associated with a lower symptom load and a better HRQoL
Polymorphisms in the BER and NER pathways and their influence on survival and toxicity in never-smokers with lung cancer
Get PDFPolymorphisms in DNA repair pathways may play a relevant role in lung cancer survival in never-smokers. Furthermore, they could be implicated in the response to chemotherapy and toxicity of platinum agents. The aim of this study was to evaluate the influence of various genetic polymorphisms in the BER and NER DNA repair pathways on survival and toxicity in never-smoker LC patients. The study included never-smokers LC cases diagnosed from 2011 through 2019, belonging to the Lung Cancer Research In Never Smokers study. A total of 356 never-smokers cases participated (79% women; 83% adenocarcinoma and 65% stage IV). Survival at 3 and 5 years from diagnosis was not associated with genetic polymorphisms, except in the subgroup of patients who received radiotherapy or chemo-radiotherapy, and presented with ERCC1 rs3212986 polymorphism. There was greater toxicity in those presenting OGG1 rs1052133 (CG) and ERCC1 rs11615 polymorphisms among patients treated with radiotherapy or chemo-radiotherapy, respectively. In general, polymorphisms in the BER and NER pathways do not seem to play a relevant role in survival and response to treatment among never-smoker LC patients