Asunto(s)
Enfermedades de la Uña , Psoriasis , Humanos , Cuero Cabelludo/patología , Uñas/patología , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Anticuerpos Monoclonales Humanizados/efectos adversos , Enfermedades de la Uña/inducido químicamente , Enfermedades de la Uña/tratamiento farmacológicoRESUMEN
[This corrects the article DOI: 10.3389/fneph.2023.1194989.].
RESUMEN
OBJECTIVES: Limited information is available on the clinical features, treatment modalities and outcomes of the juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA). This study was aimed to describe the characteristics of Italian children with ERA and JPsA and to compare them with those of patients with the other categories of JIA. METHODS: Patients were part of a multinational sample included in a study aimed to investigate the prevalence of disease categories, treatment approaches, and disease status in patients from across different geographical areas (EPOCA Study). All patients underwent a retrospective assessment, based on the review of clinical chart, and a cross-sectional evaluation, which included assessment of physician- and parent-reported outcomes and laboratory tests, and recording of ongoing therapies. RESULTS: Of the 9081 children with JIA enrolled in the EPOCA Study, 1300 were recruited at 18 paediatric rheumatology centres in Italy. 45 (3.5%) had ERA and 49 (3.8%) had JPsA. Several remarkable differences in demographic features and frequency of articular and extra-articular manifestations, disease damage, impairment in physical function and health-related quality of life, school-related problems, comorbidities, and ongoing treatments were observed between ERA and JPsA and the other JIA categories. CONCLUSIONS: We described the characteristics of Italian children with ERA and JPsA and highlighted their peculiarities and their differences from the other JIA subsets. These data provide useful insights for future revisions of JIA classification and a benchmarking against which the features from other cohorts may be compared.
Asunto(s)
Artritis Juvenil , Niño , Humanos , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/epidemiología , Estudios Retrospectivos , Estudios Transversales , Calidad de Vida , Resultado del TratamientoRESUMEN
Introduction: SARS-CoV-2 infection in the pediatric population can be associated with a multiorgan inflammatory syndrome called children's multisystem inflammatory syndrome (MIS-C). The kidneys can be affected by a broad spectrum of possible injuries, whose pathogenetic mechanisms are still unclear.Case report: We report the case of a 5-year-old boy with severe cardiac involvement in the context of MIS-C. After two weeks of hospitalization, an abdominal ultrasound showed massive bladder "debris", followed by the onset of normoglycemic glycosuria. Over time, there was a progressive increase in glycosuria, and the presence of a mat of amorphous phosphate crystals was evidenced on urinary sediment. Together with the findings of hypo-uricemia, increased urinary uric acid, and globally increased urinary amino acids, a clinical picture of kidney proximal tubular damage with secondary Fanconi-like syndrome took shape. Discussion: This case report describes the case of a patient with MIS-C with cardiac and kidney involvement characterized by proximal tubular damage, which slowly improved but still persisted at the 8-month follow-up. The pathogenesis of the damage is unclear and probably multifactorial.
RESUMEN
The ubiquitin-proteasome system (UPS) plays an important role in maintaining cellular homeostasis by degrading a multitude of key regulatory proteins. FBXW11, also known as b-TrCP2, belongs to the F-box family, which targets the proteins to be degraded by UPS. Transcription factors or proteins associated with cell cycle can be modulated by FBXW11, which may stimulate or inhibit cellular proliferation. Although FBXW11 has been investigated in embryogenesis and cancer, its expression has not been evaluated in osteogenic cells. With the aim to explore FBXW11gene expression modulation in the osteogenic lineage we performed molecular investigations in mesenchymal stem cells (MSCs) and osteogenic cells in normal and pathological conditions. In vitro experiments as well as ex vivo investigations have been performed. In particular, we explored the FBXW11 expression in normal osteogenic cells as well as in cells of cleidocranial dysplasia (CCD) patients or osteosarcoma cells. Our data showed that FBXW11 expression is modulated during osteogenesis and overexpressed in circulating MSCs and in osteogenically stimulated cells of CCD patients. In addition, FBXW11 is post-transcriptionally regulated in osteosarcoma cells leading to increased levels of beta-catenin. In conclusion, our findings show the modulation of FBXW11 in osteogenic lineage and its dysregulation in impaired osteogenic cells.
Asunto(s)
Osteogénesis , Osteosarcoma , Ubiquitina-Proteína Ligasas , Proteínas con Repetición de beta-Transducina , Humanos , Proteínas con Repetición de beta-Transducina/metabolismo , Diferenciación Celular/genética , Proliferación Celular/genética , Osteogénesis/genética , Osteosarcoma/genética , Factores de Transcripción/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
AIMS: To assess whether, besides "traditional" risk factors, overall oxidative stress, oxidized lipoproteins, and glycemic variability are associated with early macro-vascular damage in type 1 diabetes (T1D). METHODS: In 267 children/adolescents with T1D (130 girls, age 9.1-23.0 years) we evaluated: derivatives of reactive oxygen metabolites [d-ROMs], serum total antioxidant capacity [TAC] and oxidized LDL-cholesterol [oxLDL]; markers of early vascular damage (Lipoprotein-associated phospholipase A2 [Lp-PLA2], z-score of carotid intima-media thickness [z-cIMT] and carotid-femoral pulse wave velocity [z-PWV]); CGM metrics of four weeks preceding the visit, central systolic/diastolic blood pressures (cSBP/cDBP), and HbA1c, z-score of BP (z-SBP/z-DBP) and circulating lipids longitudinally collected since T1D onset.. Three general linear models were built with z-cIMT, z-PWV adjusted for current cDBP, and Lp-PLA2 as independent variables. RESULTS: The z-cIMT was associated with male gender (B = 0.491, η2 = 0.029, p = 0.005), cSBP (B = 0.023, η2 = 0.026, p = 0.008) and oxLDL (B = 0.022, η2 = 0.022, p = 0.014). The z-PWV was associated with diabetes duration (B = 0.054, η2 = 0.024, p = 0.016), daily insulin dose (B = 0.52, η2 = 0.018, p = 0.045), longitudinal z-SBP (B = 0.18, η2 = 0.018, p = 0.045) and dROMs (B = 0.003, η2 = 0.037, p = 0.004). Lp-PLA2 was associated with age (B = 0.221, η2 = 0.079, p = 3*10-6), oxLDL (B = 0.081, η2 = 0.050, p = 2*10-4), longitudinal LDL-cholesterol (B = 0.031, η2 = 0.043, p = 0.001) and male gender (B = -1.62, η2 = 0.10, p = 1.3*107). CONCLUSIONS: Oxidative stress, male gender, insulin dose, diabetes duration and longitudinal lipids and blood pressure, contributed to the variance of early vascular damage in young patients with T1D.
Asunto(s)
Aterosclerosis , Diabetes Mellitus Tipo 1 , Insulinas , Femenino , Niño , Humanos , Masculino , Adolescente , Adulto Joven , Adulto , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Grosor Intima-Media Carotídeo , Análisis de la Onda del Pulso , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Factores de Riesgo , Aterosclerosis/epidemiología , Aterosclerosis/etiología , ColesterolRESUMEN
We describe the unique case of a patient in whom two ciliopathies with autosomal recessive transmission were clinically and molecularly diagnosed: Nephronophthisis type1 (NPHP1) and Alström Syndrome (AS). NPHP1 is one of the main genetic causes of terminal kidney failure in childhood. AS is an ultra-rare multi-systemic disease, characterized by progressive kidney disease, hepatic failure, dystrophy of the rods and cones to blindness, slowly progressive neuro-sensory deafness, dilated cardiomyopathy, obesity, insulin resistance / type 2 diabetes mellitus. The coexistence in the same patient of two rare syndromes with overlapping clinical manifestations but genetically different is an eventuality to be considered. This case report would describe the onset and progression of the multi-organ manifestations of both syndromes to highlight that ciliopathies present a strong phenotype overlap but also specific peculiarities. Therefore, to make a correct diagnosis, that is essential to achieve the best clinical management, could be challenging.
RESUMEN
Circular RNAs (circRNAs) are emerging as new players in leukemogenic mechanisms. In patients with T-cell Acute Lymphoblastic Leukemia (T-ALL), the recent report of a remarkable dysregulation of circRNAs incited further functional investigation. Here we focus on circFBXW7, highly expressed in T-cells, with a notably high abundance of the circular compared to linear transcript of FBXW7. Two T-ALL patient cohorts profiled with RNA-seq were analyzed in comparison with five populations of developing thymocytes as normal counterpart, quantifying circRNA and gene expression. CircFBXW7 expression was very heterogeneous in T-ALL patients allowing their stratification in two groups with low and high expression of this circRNA, not correlated with FBXW7 mutation status and T-ALL molecular subgroups. With a loss-of-function study in T-ALL in vitro, we demonstrate that circFBXW7 depletion increases leukemic cell viability and proliferation. Microarray profiling highlighted the effect of the circFBXW7 silencing on gene expression, with activation of pro-proliferative pathways, supporting a tumor suppressor role of circFBXW7 in T-ALL. Further, MYC and intracellular NOTCH1 protein levels, as well as expression of MYC target and NOTCH signaling genes were elevated after circFBXW7 depletion, suggesting an inhibitory role of circFBXW7 in these oncogenic axes. Plus, low circFBXW7 levels were associated with a particular gene expression profile in T-ALL patients, which was remarkably mirrored by the effects of circFBXW7 loss-of-function in vitro. CircFBXW7 depletion notably emerges as a new factor enhancing a proliferative phenotype and the activation of the MYC signaling pathway, key players in this aggressive malignancy.
RESUMEN
INTRODUCTION: Type 1 diabetes (T1D) is associated with an increased risk of cardiovascular disease. Insulin resistance is an important cardiovascular risk factor (CVRF), also in subjects with T1D, but the influence of the genetic predisposition of insulin resistance on cardiovascular risk is still unknown in T1D. We aimed to determine whether a genetic score composed of six variants, previously associated with insulin resistance and type 2 diabetes (T2D) risk, associates with insulin sensitivity and known CVRFs in children and adolescents with T1D. MATERIALS AND METHODS: 330 children and adolescents (174 males; mean age 15.7 ± 3.5 years) with T1D were genotyped for the following genetic variants: rs1801278 (IRS1), rs1044498 (ENPP1), rs2295490 (TRIB3), rs1801282 (PPARG), rs780094 (GCKR), and rs35767 (IGF1). An additive genetic risk score (GRS) and cardiovascular risk score (CVRS) were calculated. Anthropometric, glycemic control, insulin sensitivity, blood pressure, and biochemical parameters were assessed. Multivariate regression between evaluated phenotypes and GRS was performed. RESULTS: We found a significant association between the GRS and estimated insulin sensitivity (ß = -0.027 [-0.040 to -0.013], R2 = 0.86, p≤ 0.001), diastolic blood pressure (ß = 0.68 [0.08-1.27], R2 = 0.20, p = 0.026), triglycerides (ß = 4.26 [1.74-6.77], R2 = 0.13, p = 0.001), waist to height ratio (ß = 0.003 [0.001-0.006], R2 = 0.75, p = 0.010), non-HDL-cholesterol (ß = 3.63 [1.39-5.87], R2 = 0.12, p = 0.002), and CVRS (ß = 0.063 [0.008-0.118], R2 = 0.19, p = 0.025), independent of age, sex, BMI, pubertal stage, diabetes duration, glycated hemoglobin, type of treatment, and total insulin requirement. The addition of the GRS to established clinical risk factors significantly improved the discriminatory capability of the regression model for predicting subjects with more CVRFs (C-statistic 0.89 [95% CI: 0.84-0.95] versus 0.83 (0.73-0.93); p = 0.037). CONCLUSIONS: Insulin resistance and T2D risk-associated genetic variants influence insulin sensitivity and known CVRFs in children and adolescents with T1D.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Masculino , Niño , Humanos , Resistencia a la Insulina/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/complicaciones , Factores de Riesgo , Diabetes Mellitus Tipo 2/genética , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/complicaciones , Factores de Riesgo de Enfermedad CardiacaRESUMEN
Cleidocranial dysplasia (CCD), a dominantly inherited skeletal disease, is characterized by a variable phenotype ranging from dental alterations to severe skeletal defects. Either de novo or inherited mutations in the RUNX2 gene have been identified in most CCD patients. Transcription factor RUNX2, the osteogenic master gene, plays a central role in the commitment of mesenchymal stem cells to osteoblast lineage. With the aim to analyse the effects of RUNX2 mutations in CCD patients, we investigated RUNX2 gene expression and the osteogenic potential of two CCD patients' cells. In addition, with the aim to better understand how RUNX2 mutations interfere with osteogenic differentiation, we performed string analyses to identify proteins interacting with RUNX2 and analysed p53 expression levels. Our findings demonstrated for the first time that, in addition to the alteration of downstream gene expression, RUNX2 mutations impair p53 expression affecting osteogenic maturation. In conclusion, the present work provides new insights into the role of RUNX2 mutations in CCD patients and suggests that an in-depth analysis of the RUNX2-associated gene network may contribute to better understand the complex molecular and phenotypic alterations in mutant subjects.
Asunto(s)
Displasia Cleidocraneal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Secuencia de Aminoácidos , Secuencia de Bases , Diferenciación Celular/genética , Niño , Femenino , Redes Reguladoras de Genes/genética , Humanos , Masculino , Osteoblastos/fisiología , Osteogénesis/genéticaRESUMEN
AIMS: We assessed whether oxidative stress (OS) is increased in children/adolescents with type 1 diabetes (T1D) compared to healthy peers. Moreover, we searched for OS predictors in the T1D population. METHODS: We compared the concentration of serum derivatives of reactive oxygen metabolites (d-ROMs) in 412 children/adolescents with T1D (3.6-23.5 years old) to that of 138 healthy children/adolescents (1.2-19.2 years old) by ANOVA adjusted for age, gender, and BMI z-score (z-BMI). Applying a general linear model, in a subgroup of 331 patients using continuous glucose monitoring, we searched for predictors of d-ROMs among 3-day, 2-week, and 4-week metrics of glucose control and variability, such as mean blood glucose, percent time in range (70-180 mg/dl,TIR70-180), coefficient of variation, and others, as well as among conventional cardiovascular risk factors like current and average HbA1c, z-BMI, blood pressure percentiles, and lipid concentrations recorded retrospectively over the entire follow-up period. RESULTS: D-ROMs levels were significantly higher in children/adolescents with T1D compared to controls [371.9 (64.2) versus 324.9 (46.3), p < 10-16]. Sex (B = 49.1, Æ2 = 0.14, p = 1.3 * 10-9), age < 12 years in boys (B = 79.4, Æ2 = 0.074, p = 10-7),3-day TIR70-180 (B = -0.87, Æ2 = 0.048, p = 6.5 * 10-5), and z-BMI (B = 7.4, Æ2 = 0.016, p = 0.022) predicted d-ROMs with an overall R2 of 0.278. CONCLUSIONS: OS is increased in youth with T1D and only partially predicted by gender, age, glucose control, and anthropometry. Other potential determinants of OS in this population should be targeted in future studies.
Asunto(s)
Diabetes Mellitus Tipo 1 , Adolescente , Adulto , Glucemia , Automonitorización de la Glucosa Sanguínea , Niño , Preescolar , Diabetes Mellitus Tipo 1/epidemiología , Control Glucémico , Humanos , Lactante , Masculino , Estrés Oxidativo , Estudios Retrospectivos , Adulto JovenRESUMEN
Essential to the design of genetic bioreactors used in the human body is a consideration of how the properties of biomaterials can combine to envelope, spatially guide, reprogramme by gene transfer, and then release cells. In order to approach this goal, poly(ethylene glycol) (PEG) matrices with modulated structural features and defined spatial patterns of bioactive signals have been designed and produced. In particular, within such PEG matrices, both an adhesive RGD peptide gradient, to directionally attract NIH3T3 cells, and a designed spatial distribution of immobilized poly(ethylenimine) (PEI)/DNA complexes, to obtain a localized transfection, have been realized. These bioactive biomaterials have been designed bearing in mind that cells following an RGD gradient migrate through the matrix, in which they find the bound DNA and become transfected. Both cell migration and transfection have been monitored by fluorescence microscopy. Results show that this system is able to envelope cells, spatially guide them towards the immobilized gene complexes and locally transfect them. Therefore, the system, acting as a genetic bioreactor potentially useful for the regulation of biology at a distance, could be used to directly control cell trafficking and activation in the human body, and has many potential biomedical applications.
Asunto(s)
Movimiento Celular , ADN/química , Oligopéptidos/química , Polietilenglicoles/química , Activación Transcripcional , Animales , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Microscopía Electrónica de Rastreo , Microscopía Fluorescente , Células 3T3 NIH , TransfecciónRESUMEN
The ability to genetically modify cells seeded inside synthetic hydrogel scaffolds offers a suitable approach to induce and control tissue repair and regeneration guiding cell fate. In fact the transfected cells can act as local in vivo bioreactor, secreting plasmid encoded proteins that augment tissue regeneration processes. We have realized a DNA bioactivated high porous poly(ethylene glycol) (PEG) matrix by polyethyleneimine (PEI)/DNA complexes adsorption. As the design of the microarchitectural features of a scaffold also contributes to promote and influence cell fate, we appropriately designed the inner structure of gene activated PEG hydrogels by gelatine microparticles templating. Microarchitectural properties of the scaffold were analysed by scanning electron microscopy. 3D cell migration and transfection were monitored through time-lapse videomicroscopy and confocal laser scanning microscopy.
Asunto(s)
Polietilenglicoles/química , Polietileneimina/química , Adsorción , Animales , Linaje de la Célula , Movimiento Celular , Fibroblastos/metabolismo , Hidrogeles/química , Ratones , Microscopía Confocal/métodos , Microscopía Electrónica de Rastreo/métodos , Microscopía por Video/métodos , Células 3T3 NIH , Porosidad , Propiedades de SuperficieRESUMEN
Realization of systems able to both recruit cells and influence their fate (affecting their processes) represents a new approach for tissue regeneration. We investigated the potency of gene activated matrix (GAM) and implemented the GAM strategy in order to achieve a control of gene expression, as well as a specific cell recruitment. To this aim we developed a 3D DNA bio-activated collagen matrix by Poly (ethylenimine) (PEI)/DNA complex immobilization in the matrix through biotin/avidin bond. Moreover, we realised a serum based chemotactic gradient within the matrix in order to directionally attract NIH3T3 cells. In this system, cells are recruited and forced to migrate through the matrix where they find the bound PEI/DNA complexes and are transfected. The transfected cells can act as local in vivo bioreactors, secreting plasmid encoded proteins that augment tissue repair and regeneration. 3D cell migration and cell transfection were monitored through time-lapse video microscopy and fluorescence microscopy. Cell transfection was also quantified through FACS analysis. Results show that our engineered matrix is able to recruit external cells and transfect them once internalized, therefore it could help in tissue repairing strategy.
Asunto(s)
Movimiento Celular , Colágeno/química , ADN/metabolismo , Matriz Extracelular/metabolismo , Transfección/métodos , Animales , Avidina/química , Colágeno/metabolismo , ADN/genética , Matriz Extracelular/química , Ensayo de Materiales , Ratones , Estructura Molecular , Células 3T3 NIH , Regeneración/fisiología , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Advanced tissue engineering approaches rely upon the employment of biomaterials that integrate biodegradable scaffolds with growth factor delivery devices to better guide cellular activities and enhance tissue neogenesis. Along these lines, here we proposed a bottom-up approach for the realization of bioactive scaffolds with controllable pore size and interconnection, combined with protein-loaded polymeric microcarriers acting as local chrono-programmed point source generation of bioactive signals. Bioactive scaffolds are obtained through the thermal assembly of protein activated poly(epsilon-caprolactone) (PCL) microspheres prepared by double emulsion and larger protein free PCL microspheres obtained by single emulsion. It is shown that the pore dimension, interconnectivity and mechanical properties in compression of the scaffold could be predefined by an appropriate choice of the size of the protein-free microparticles and process conditions. Protein-loaded microparticles were successfully included within the scaffold and provided a sustained delivery of a model protein (BSA). These matrices offer the possibility to concurrently modulate and control the size and extension of the porosity, mechanical properties and the spatial-temporal distribution of multiple bioactive signals.
Asunto(s)
Sistemas de Liberación de Medicamentos , Microesferas , Poliésteres/química , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Animales , Bovinos , Emulsiones , Ensayo de Materiales , Microscopía Electrónica de Rastreo , Porosidad , Albúmina Sérica Bovina/metabolismoRESUMEN
Drug delivery applications using biodegradable polymeric microspheres are becoming an important means of delivering therapeutic agents. The aim of this work was to modulate the microporosity of poly(epsilon-caprolactone) (PCL) microcarriers to control protein loading capability and release profile. PCL microparticles loaded with BSA (bovine serum albumin) have been de novo synthesized with double emulsion solvent evaporation technique transferred and adapted for different polymer concentrations (1.7 and 3% w/v) and stabilizer present in the inner aqueous phase (0.05, 0.5 and 1% w/v). SEM (scanning electron microscope) and CLSM (confocal laser scanning microscope) analysis map the drug distribution in homogeneously distributed cavities inside the microspheres with dimensions that can be modulated by varying double emulsion process parameters. The inner structure of BSA-loaded microspheres is greatly affected by the surfactant concentration in the internal aqueous phase, while a slight influence of polymer concentration in the oil phase was observed. The surfactant concentration mainly determines microspheres morphology, as well as drug release kinetics, as confirmed by our in-vitro BSA release study. Moreover, the entrapped protein remained unaltered during the protein encapsulation process, retaining its bio-activity and structure, as shown through a dedicated gel chromatographic analytical method.