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BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.
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Antineoplásicos , Neoplasias de la Mama , Femenino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Recombinación Homóloga , Mutación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Proteína 1 de Unión al Supresor Tumoral P53RESUMEN
BACKGROUND: The severity of facial telangiectasia or red veins is associated with many lifestyle factors. However, the genetic predisposition remains unclear. OBJECTIVES: We performed a genome-wide association study (GWAS) on facial telangiectasia in the Rotterdam Study (RS) and tested for replication in two independent cohorts. Additionally, a candidate gene approach with known pigmentation genes was performed. METHODS: Facial telangiectasia were extracted from standardized facial photographs (collected from 2010-2013) of 2842 northwestern European participants (median age 66.9, 56.8% female) from the RS. Our GWAS top hits (P-value <10-6 ) were tested for replication in 460 elderly women of the SALIA cohort and in 576 additional men and women of the RS. Associations of top single nucleotide polymorphisms (SNPs) with expression quantitative trait loci (eQTL) in various tissues were reviewed (GTEx database) alongside phenotype associations in the UK biobank database. SNP-based associations between known pigmentation genes and facial telangiectasia were tested. Conditional analysis on skin colour was additionally performed. RESULTS: Our most significant GWAS signal was rs4417318 (P-value 5.38*10-7 ), an intergenic SNP on chromosome 12 mapping to the SLC16A7 gene. Other suggestive SNPs tagged genes ZNF211, ZSCAN4, ICOS and KCNN3; SNP eQTLs and phenotype associations tagged links to the vascular system. However, the top signals did not pass significance in the two replication cohorts. The pigmentation genes KIAA0930, SLCA45A2 and MC1R, were significantly associated with telangiectasia in a candidate gene approach but not independently of skin colour. CONCLUSION: In this GWAS on telangiectasia in a northwestern European population, no genome-wide significant SNPs were found, although suggestive signals indicate genes involved in the vascular system might be involved in telangiectasia. Significantly associated pigmentation genes underline the link between skin colour and telangiectasia.
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Estudio de Asociación del Genoma Completo , Telangiectasia , Anciano , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Telangiectasia/genéticaRESUMEN
Macrovipera lebetina obtusa (MLO) is a venomous snake endemic to Middle East. Here we describe the therapeutic potential of the MLO snake venom. In S-180 sarcoma-bearing mouse model, we showed that the MLO snake venom inhibits tumour growth by 50%. In human dermal microvascular endothelial cells (HMVEC-D), treatment with the MLO snake venom lead to an increase of expression levels of the vascular endothelial growth factor (VEGF), while the level of the expression of caspase 8 did not change. In HMVEC-D cells MLO snake venom induces necroptosis, rather than apoptosis. In the chick embryo chorioallantoic membrane (CAM) assay, exposure to MLO snake venom inhibited bFGF-induced angiogenesis by 22%. Taken together, these results indicate that the MLO snake venom has a potent cytotoxic activity. Regulated necroptic cell death pathway, which is engaged by MLO snake venom, may become a promising novel target for antitumor therapies.
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Sarcoma , Viperidae , Animales , Embrión de Pollo , Células Endoteliales , Ratones , Sarcoma/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular , Venenos de VíborasRESUMEN
BACKGROUND: Patients with actinic keratosis (AK) are at increased risk for developing keratinocyte carcinoma (KC) but predictive factors and their risk rates are unknown. OBJECTIVES: To develop and internally validate a prediction model to calculate the absolute risk of a first KC in patients with AK. METHODS: The risk-prediction model was based on the prospective population-based Rotterdam Study cohort. We hereto analysed the data of participants with at least one AK lesion at cohort baseline using a multivariable Cox proportional hazards model and included 13 a priori defined candidate predictor variables considering phenotypic, genetic and lifestyle risk factors. KCs were identified by linkage of the data with the Dutch Pathology Registry. RESULTS: Of the 1169 AK participants at baseline, 176 (15·1%) developed a KC after a median follow-up of 1·8 years. The final model with significant predictors was obtained after backward stepwise selection and comprised the presence of four to nine AKs [hazard ratio (HR) 1·68, 95% confidence interval (CI) 1·17-2·42], 10 or more AKs (HR 2·44, 95% CI 1·65-3·61), AK localization on the upper extremities (HR 0·75, 95% CI 0·52-1·08) or elsewhere except the head (HR 1·40, 95% CI 0·98-2·01) and coffee consumption (HR 0·92, 95% CI 0·84-1·01). Evaluation of the discriminative ability of the model showed a bootstrap validated concordance index (c-index) of 0·60. CONCLUSIONS: We showed that the risk of KC in patients with AK can be calculated with the use of four easily assessable predictor variables. Given the c-index, extension of the model with additional, currently unknown predictor variables is desirable. Linked Comment: Kim et al. Br J Dermatol 2020; 183:415-416.
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Carcinoma , Queratosis Actínica , Humanos , Queratinocitos , Queratosis Actínica/epidemiología , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: The underlying phenotypic correlations between wrinkles, pigmented spots (PS), telangiectasia and other related facial-ageing subphenotypes are not well understood. OBJECTIVES: To analyse the underlying phenotypic correlation structure between seven features for facial ageing: global wrinkling, perceived age (PA), Griffiths photodamage grading, PS, telangiectasia, actinic keratosis (AK) and keratinocyte cancer (KC). METHODS: This was a cross-sectional study. Facial photographs and a full-body skin examination were used. We used principal component analysis (PCA) to derive principal components (PCs) of common variation between the features. We performed multivariable linear regressions between age, sex, body mass index, smoking and ultraviolet radiation exposure and the PC scores derived from PCA. We also tested the association between the main PC scores and 140 single-nucleotide polymorphisms (SNPs) previously associated with skin-ageing phenotypes. RESULTS: We analysed data from 1790 individuals with complete data on seven features of skin ageing. Three main PCs explained 73% of the total variance of the ageing phenotypes: a hypertrophic/wrinkling component (PC1: global wrinkling, PA and Griffiths grading), an atrophic/skin colour component (PC2: PS and telangiectasia) and a cancerous component (PC3: AK and KC). The associations between lifestyle and host factors differed per PC. The strength of SNP associations also differed per component with the most SNP associations found with the atrophic component [e.g. the IRF4 SNP (rs12203592); P-value = 1·84 × 10-22 ]. CONCLUSIONS: Using a hypothesis-free approach, we identified three major underlying phenotypes associated with extrinsic ageing. Associations between determinants for skin ageing differed in magnitude and direction per component. What's already known about this topic? Facial ageing is a complex phenotype consisting of different features including wrinkles, pigmented changes, telangiectasia and cancerous-related growths; it is not clear how these phenotypes are related to each other and to other phenotypes. A few studies have described two main clinical phenotypes for photoageing, namely hypertrophic ageing and atrophic ageing, which have been based solely on the clinical assessment of photoageing characteristics. What does this study add? We are the first to use epidemiology data to identify three main components associated with photoageing, namely a hypertrophic component (global wrinkling; perceived age; Griffiths grading) and atrophic component (pigmented spots; telangiectasia) and a cancer component (actinic keratosis; keratinocyte cancer). Association analysis showed different effects and direction of environmental determinants and genetic associations with the three components, with the most significant gene variants associations found for the atrophic component.
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Envejecimiento de la Piel , Estudios Transversales , Humanos , Análisis de Componente Principal , Envejecimiento de la Piel/genética , Pigmentación de la Piel/genética , Rayos Ultravioleta/efectos adversosRESUMEN
BACKGROUND: Telangiectasia or red veins are one of the prominent features of facial skin ageing. To date, there are few studies investigating the determinants of telangiectasia. OBJECTIVES: We investigated lifestyle and physiological factors associated with facial telangiectasia in a large prospective Dutch cohort study. METHODS: Telangiectasia was quantified digitally from standardized facial photographs of 2842 North European participants (56.8% female, median age 66.9) from the Rotterdam Study, collected in 2010-2013. Effect estimates from multivariable linear regressions are presented as the percentage difference in the mean value of telangiectasia area per unit increase of a determinant (%Δ) with corresponding 95% CI. RESULTS: Significant determinants were older age [1.7%Δ per year (95% CI 1.4, 2.0)], female sex [18.3%Δ (95% CI 13.2, 23.6)], smoking [current versus never 38.4%Δ (95% CI 30.3, 47.0); former versus never 11.6%Δ (95% CI 6.6, 16.9)], a high susceptibility to sunburn [10.2%Δ (95% CI 5.4, 15.3)] and light skin colour [pale versus white-to-olive 31.4%Δ (95% CI 19.7, 44.1]; white vs. white-to-olive 9.2%Δ (95% CI 2.8, 16.0)]. CONCLUSIONS: In this large cohort study, we confirmed known and described new determinants of facial telangiectasia.
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Cara/irrigación sanguínea , Telangiectasia/epidemiología , Telangiectasia/etiología , Factores de Edad , Anciano , Estudios Transversales , Femenino , Humanos , Estilo de Vida , Masculino , Países Bajos/epidemiología , Estudios Prospectivos , Factores de Riesgo , Factores SexualesRESUMEN
BACKGROUND: Alterations of the skin microbiome have been associated with atopic dermatitis (AD) and its severity. The nasal microbiome in relation to AD severity is less well studied. OBJECTIVES: We aimed to characterize the nasal and skin microbiomes in children with AD in relation to disease severity. In addition, we explored the differences and correlations between the nasal and skin communities. METHODS: We characterized the microbial composition of 90 nasal and 108 lesional skin samples cross-sectionally from patients with AD, using 16S-rRNA sequencing. In addition, a quantitative polymerase chain reaction was performed for Staphylococcus aureus and Staphylococcus epidermidis on the skin samples, and AD severity was estimated using the self-administered Eczema Area and Severity Index. RESULTS: We found an association between the microbial composition and AD severity in both the nose and skin samples (R2 = 2·6%; P = 0·017 and R2 = 7·0%; P = 0·004), strongly driven by staphylococci. However, other species also contributed, such as Moraxella in the nose. Skin lesions were positive for S. aureus in 50% of the children, and the presence and the load of S. aureus were not associated with AD severity. Although the nose and skin harbour distinct microbial communities (n = 48 paired samples; P < 0·001), we found that correlations exist between species in the nose and (other) species on the skin. CONCLUSIONS: Our results indicate that both the nasal and the skin microbiomes are associated with AD severity in children and that, next to staphylococci, other species contribute to this association.
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Dermatitis Atópica/diagnóstico , Microbiota/inmunología , Mucosa Nasal/microbiología , Índice de Severidad de la Enfermedad , Piel/microbiología , Adolescente , Niño , Preescolar , Estudios Transversales , ADN Bacteriano/aislamiento & purificación , Dermatitis Atópica/inmunología , Dermatitis Atópica/microbiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Microbiota/genética , Mucosa Nasal/inmunología , ARN Ribosómico 16S/genética , Piel/inmunología , Staphylococcus aureus/genética , Staphylococcus aureus/inmunología , Staphylococcus aureus/aislamiento & purificación , Staphylococcus epidermidis/genética , Staphylococcus epidermidis/inmunología , Staphylococcus epidermidis/aislamiento & purificaciónRESUMEN
In glass-forming substances, the addition of water tends to produce the effect of lowering the glass transition temperature, Tg. In a previous work by some of us (Ruiz et al., Sci. Rep., 2017, 7, 7470) we reported on a rare anti-plasticizing effect of water on the molecular dynamics of a simple molecular system, the pharmaceutically active prilocaine molecule, for which the addition of water leads to an increase of Tg. In the present work, we study pure and hydrated prilocaine confined in 0.5 nm and 1 nm pore size molecular sieves, and carry out a comparison with the bulk compounds in order to gain a better understanding of the microscopic mechanisms that result in this rare effect. We find that the Tg of the drug under nanometric confinement can be lower than the bulk value by as much as 17 K. Through the concurrent use of differential scanning calorimetry and broadband dielectric spectroscopy we are able to observe the antiplasticizing effect of water in prilocaine also under nanometric confinement, finding an increase of Tg of up to almost 6 K upon hydration. The extension of our analysis to nanoconfined systems provides a plausible explanation for the very uncommon antiplasticizing effect, based on the formation of water-prilocaine molecular complexes. Moreover, this study deepens the understanding of the behavior of drugs under confinement, which is of relevance not only from a fundamental point of view, but also for practical applications such as drug delivery.
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Simulación de Dinámica Molecular , Prilocaína/química , Agua/química , NanoestructurasRESUMEN
BACKGROUND: Several observational studies have suggested differences in the risk factor profile between patients with superficial basal cell carcinomas (BCCs) and non-superficial BCCs. OBJECTIVE: To test the reproducibility of previous study findings and to find new genetic and non-genetic predictors for patients with a superficial first BCC. METHODS: A total of 14.628 participants of northwestern European descent aged 45 years or older from a prospective population-based cohort study (Rotterdam Study) were linked with the Dutch Pathology Registry (PALGA) of whom 1528 were identified as BCC patients. After exclusion, 948 eligible BCC patients remained for further non-genetic analyses and 1014 for genetic analyses. We included 11 phenotypic, environmental and tumour-specific characteristics, and 20 candidate single nucleotide polymorphisms (SNP) as potential predictors for patients with a superficial first BCC. We performed binary logistic multivariable regression analyses. RESULTS: We found that patients with a superficial first BCC were significantly younger, almost two times more often female and 12-18 times more likely to have their BCC on the trunk or extremities than patients with a non-superficial first BCC. One SNP (rs12203592), mapped to IRF4, looked promising (OR 1.83, 95% CI 1.13-2.97, P-value <0.05), but after adjustment for multiple testing, no significant differences in genetic make-up between superficial BCC and non-superficial BCC patients were found. CONCLUSION: We conclude that patients with a superficial BCC differ from non-superficial BCC patients with respect to environmental factors (tumour localization as a proxy for UVR exposure) and phenotypic characteristics (age and sex), but we found no difference in genotype. As superficial BCC patients develop their first BCCs at a younger age, they could be at higher lifetime risk for subsequent skin cancers and therefore be an important group for secondary prevention.
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Carcinoma Basocelular/etiología , Neoplasias Cutáneas/etiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma Basocelular/genética , Carcinoma Basocelular/patología , Estudios de Cohortes , Exposición a Riesgos Ambientales/efectos adversos , Extremidades , Femenino , Genotipo , Humanos , Factores Reguladores del Interferón/genética , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Sistema de Registros , Reproducibilidad de los Resultados , Factores de Riesgo , Factores Sexuales , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Torso , Rayos Ultravioleta/efectos adversosRESUMEN
BACKGROUND: Seborrhoeic dermatitis is a chronic relapsing inflammatory skin disease with unclear pathophysiological mechanisms. OBJECTIVES: To establish which lifestyle and physiological determinants are associated with seborrhoeic dermatitis. METHODS: Seborrhoeic dermatitis was diagnosed by a trained physician during a full-body skin examination within the Rotterdam Study, a prospective population-based cohort study in middle-aged and elderly people. The current design is a comparative cross-sectional study embedded in the Rotterdam Study. Potential factors were identified from the literature and analysed in a multivariable logistic regression, including: age, sex, obesity, skin colour, stress, depression, education level, hypertension, climate, xerosis cutis, alcohol and tobacco use. RESULTS: Of the 5498 participants, 788 participants were diagnosed with seborrhoeic dermatitis (14·3%). We found associations between seborrhoeic dermatitis and male sex [adjusted odds ratio (OR) 2·09, 95% confidence interval (CI) 1·77-2·47], darker skin (adjusted OR 0·39, 95% CI 0·22-0·69), season (summer vs. winter: adjusted OR 0·63, 95% CI 0·48-0·82) and generalized xerosis cutis (adjusted OR 1·41, 95% CI 1·11-1·80). CONCLUSIONS: Seborrhoeic dermatitis is one of the most common inflammatory dermatoses in middle-aged and elderly individuals, especially during winter. Men, and people with a light and dry skin were most likely to have seborrhoeic dermatitis.
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Dermatitis Seborreica/epidemiología , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Estaciones del AñoRESUMEN
BACKGROUND: An altered immune response against Staphylococcus aureus might contribute to inflammation and barrier damage in atopic dermatitis (AD). OBJECTIVES: To profile IgG antibodies against 55 S. aureus antigens in sera of children with mild-to-severe AD and to evaluate the association between IgG levels and disease severity. METHODS: In this cross-sectional study, we included children with AD from two interventional study cohorts, the Shared Medical Appointment (SMA) cohort (n = 131) and the older DAVOS cohort (n = 76). AD severity was assessed using the Self-Administered Eczema Area and Severity Index (SA-EASI) and levels of thymus and activation-regulated chemokine (TARC) in serum. IgG antibody levels against 55 S. aureus antigens were quantified simultaneously using a Luminex assay. Pair-wise correlations were calculated between the 55 IgG levels using the Spearman rank correlation test. Linear regression analysis was performed to test for associations between 55 IgG levels and SA-EASI and TARC, adjusting for age, sex and S. aureus colonization. RESULTS: In the SMA cohort, 16 antigens were associated with SA-EASI and 12 with TARC (10 overlapping antigens; P-values 0·001-0·044). The associated IgG antibodies targeted mainly secreted proteins with immunomodulatory functions. In the DAVOS study, IgG levels against only four and one S. aureus antigen(s) were associated with SA-EASI and TARC, respectively (no overlap). CONCLUSIONS: In young children, severity of AD is associated with an IgG response directed against S. aureus antigens with mainly immunomodulatory functions. These findings encourage further evaluation of the role of S. aureus in the pathogenesis of AD.
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Dermatitis Atópica/inmunología , Inmunoglobulina G/metabolismo , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Adolescente , Anticuerpos Antibacterianos/metabolismo , Antígenos Bacterianos/metabolismo , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Inmunoglobulina G/inmunología , Lactante , Recién Nacido , MasculinoRESUMEN
In his comment on a recent publication by us, G. Graziano claims that solubility differences of indole in methanol and water can be rationalized by the reversible work needed to create a cavity in the solvent of the size of the solute, in this case indole. This quantity, he argues, is closely related to the solvent accessible surface area, which is greater for methanol compared with water, thus making indole more soluble in the former solvent. G. Graziano asserts that it is this property which is responsible for the large difference between the solubilities of indole in methanol and water. Further, G. Graziano claims that the differences in excess entropies and in distance distribution functions of indole in methanol and water and in methanol and water as a cosolvent found in our original work (Henao, et al., Phys. Chem. Chem. Phys., 2016, 18, 23006) are too "small" to be able to account for the differences in solubility of the indole molecule. We show in this work that the differences found by us are not small, by displaying some selected distance distribution functions in an alternative way to that described in our original paper. In fact we conclude that the differences in these functions are quantitatively greater than those found by Graziano in his comment. Secondly, we show in this reply that although the increase of the solvent accessible surface area may rationalize the differences in the indole-methanol and indole-water binary systems, and thus the work required for cavity creation, it is insufficient to fully account for the increase of indole solubility in water by the addition of very small quantities of methanol in the ternary system indole-methanol-water. In other words, as stated in our original paper, methanol is actively changing the solvation shell and not just passively increasing the solvent accessible surface area around indole. As a result of these additional analyses, we conclude that our work on the solvation differences of indole in water and methanol successfully captures differences in the solvation shells of both solvents around indole in both binary and ternary systems. Finally, while we do agree that Graziano's calculations are able to capture the role of cavity creation to explain differences in solubility, we think that our results concerning the quantification of changes in molecular interaction should be added to the calculations suggested by him to lead to a full description of the solubility.
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Astrocytic excitability relies on cytosolic calcium increases as a key mechanism, whereby astrocytes contribute to synaptic transmission and hence learning and memory. While it is a cornerstone of neurosciences that experiences are remembered, because transmitters activate gene expression in neurons, long-term adaptive astrocyte plasticity has not been described. Here, we investigated whether the transcription factor CREB mediates adaptive plasticity-like phenomena in astrocytes. We found that activation of CREB-dependent transcription reduced the calcium responses induced by ATP, noradrenaline, or endothelin-1. As to the mechanism, expression of VP16-CREB, a constitutively active CREB mutant, had no effect on basal cytosolic calcium levels, extracellular calcium entry, or calcium mobilization from lysosomal-related acidic stores. Rather, VP16-CREB upregulated sigma-1 receptor expression thereby increasing the release of calcium from the endoplasmic reticulum and its uptake by mitochondria. Sigma-1 receptor was also upregulated in vivo upon VP16-CREB expression in astrocytes. We conclude that CREB decreases astrocyte responsiveness by increasing calcium signalling at the endoplasmic reticulum-mitochondria interface, which might be an astrocyte-based form of long-term depression.
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Astrocitos/metabolismo , Señalización del Calcio , Calcio/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Receptores sigma/metabolismo , Envejecimiento/metabolismo , Animales , Citosol/metabolismo , Ratones Transgénicos , Mitocondrias/metabolismo , Neurotransmisores/metabolismo , Ratas Sprague-Dawley , Fracciones Subcelulares/metabolismo , Transcripción Genética , Regulación hacia Arriba , Receptor Sigma-1RESUMEN
BACKGROUND: Melanoma is rare in the first two decades of life. Trends in incidence differ across countries. OBJECTIVE: To describe incidence and relative survival of children and adolescents with melanoma in the Netherlands for children (0 through 11 years) and adolescents (12 through 19 years) separately. We hypothesized that adolescent melanoma increased in contrast to childhood melanoma, possibly due to a difference in cancer biology and sun exposure patterns. METHODS: Data on all patients of 0-19 years diagnosed between 1989 and 2013 with histologically confirmed cutaneous invasive melanoma were retrieved from the Netherlands Cancer Registry (NCR). Incidence trends were analysed with Joinpoint regression. Relative survival analysis was performed. RESULTS: Between 1989 and 2013, 80 children and 544 adolescents with melanoma were registered in the NCR. Median age at diagnosis was 17 years (IQR 15-18); the female-to-male ratio was 1.7 : 1 Statistically significant incidence trends were found in the older age group (12-19 years): an increasing incidence since 1991 [annual percentage change (APC) 3.2%, 95%CI 1.3-5.1] followed by a decrease from 2005 to 2013 (APC -4.9%, 95%CI -9.6-0.0). No incidence trends for childhood melanoma were observed (APC 0.3%, 95% CI -3.0-3.8). Relative survival at 1, 5 and 10 years was 98% (95% CI 97-99), 94% (95% CI 92-96) and 90% (95% CI 87-92), respectively. Survival was worse in males and higher Breslow thickness. CONCLUSIONS: Melanoma is very rare under the age of 12 with stable incidence rates. In comparison with childhood melanoma, melanomas in adolescents are more common with a decreasing trend in the past decade. Male sex and increasing Breslow thickness are associated with worse survival in paediatric melanoma patients.
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Melanoma/epidemiología , Neoplasias Cutáneas/epidemiología , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Melanoma/fisiopatología , Países Bajos/epidemiología , Neoplasias Cutáneas/fisiopatología , Tasa de SupervivenciaRESUMEN
The KCNH1 gene encodes the Kv10.1 (Eag1) ion channel, a member of the EAG (ether-à-go-go) family of voltage-gated potassium channels. Recent studies have demonstrated that KCHN1 mutations are implicated in Temple-Baraitser and Zimmermann-Laband syndromes and other forms of developmental deficits that all present with mental retardation and epilepsy, suggesting that Kv10.1 might be important for cognitive development in humans. Although the Kv10.1 channel is mainly expressed in the mammalian brain, its ectopic expression occurs in 70% of human cancers. Cancer cells and tumors expressing Kv10.1 acquire selective advantages that favor cancer progression through molecular mechanisms that involve several cellular pathways, indicating that protein-protein interactions may be important for Kv10.1 influence in cell proliferation and tumorigenesis. Several studies on transcriptional and post-transcriptional regulation of Kv10.1 expression have shown interesting mechanistic insights about Kv10.1 role in oncogenesis, increasing the importance of identifying the cellular factors that regulate Kv10.1 expression in tumors.
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Encéfalo/metabolismo , Canales de Potasio Éter-A-Go-Go/metabolismo , Neoplasias/metabolismo , Animales , HumanosRESUMEN
We present a dynamic and thermodynamic study of the orientational glass former Freon 113 (1,1,2-trichloro-1,2,2-trifluoroethane, CCl_{2}F-CClF_{2}) in order to analyze its kinetic and thermodynamic fragilities. Freon 113 displays internal molecular degrees of freedom that promote a complex energy landscape. Experimental specific heat and its microscopic origin, the vibrational density of states from inelastic neutron scattering, together with the orientational dynamics obtained by means of dielectric spectroscopy have revealed the highest fragility value, both thermodynamic and kinetic, found for this orientational glass former. The excess in both Debye-reduced specific heat and density of states (boson peak) evidences the existence of glassy low-energy excitations. We demonstrate that early proposed correlations between the boson peak and the Debye specific heat value are elusive as revealed by the clear counterexample of the studied case.
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BACKGROUND: Epithelial barrier dysfunction is a central feature in the pathogenesis of allergic disease. Epithelial-to-mesenchymal transition (EMT) has been proposed as one mechanism afflicting barrier in asthma. However, genes and pathways involved in aberrant epithelial-mesenchymal signaling, and their relationship to asthma severity, are poorly understood. METHODS: We used unbiased gene network analysis to evaluate functional convergence in epithelial gene expression signatures across multiple public access transcriptomics datasets of human asthma, followed by text mining to evaluate functional marker relevance of discovered genes. We objectively confirmed these findings in epithelial brushings and primary asthmatic epithelial cells cultured in different biological contexts. RESULTS: We found a striking suppression of epithelial differentiation in asthma, overrepresented by insufficiency in insulin and Notch signaling, but with the absence of conventional EMT markers. We identified EFNB2, FGFR1, FGFR2, INSR, IRS2, NOTCH2, TLE1, and NTRK2 as novel markers central to dysregulation of epithelial-mesenchymal signaling, but surprisingly overlooked in asthma research. We found that this "core" signature of asthma is shared by mild, moderate, and severe forms of disease, progressing with severity. Loss of epithelial differentiation induced by insulin deprivation in normal human bronchial epithelial cells cultured in organotypic conditions closely approximated gene expression in asthmatic epithelial brushings. CONCLUSIONS: The comparative analysis of publically available transcriptomes demonstrated that epithelial barrier dysfunction in asthma is characterized by persistent underlying de-differentiation program with complex etiology. The lasting alteration of the asthmatic epithelial cell transcriptome implicates regulation involving metabolism and epigenetics, beyond EMT driven by injury and repair in chronic inflammation.
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Asma/patología , Transición Epitelial-Mesenquimal , Mucosa Respiratoria/patología , Asma/diagnóstico , Asma/etiología , Asma/metabolismo , Células Cultivadas , Biología Computacional/métodos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/inmunología , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Reproducibilidad de los Resultados , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , TranscriptomaRESUMEN
BACKGROUND AND PURPOSE: For patients with acute ischaemic stroke due to large-vessel occlusion, it has recently been shown that mechanical thrombectomy (MT) with stent retrievers is better than medical treatment alone. However, few hospitals can provide MT 24 h/day 365 days/year, and it remains unclear whether selected patients with acute stroke should be directly transferred to the nearest MT-providing hospital to prevent treatment delays. Clinical scales such as Rapid Arterial Occlusion Evaluation (RACE) have been developed to predict large-vessel occlusion at a pre-hospital level, but their predictive value for MT is low. We propose new criteria to identify patients eligible for MT, with higher accuracy. METHODS: The Direct Referral to Endovascular Center criteria were defined based on a retrospective cohort of 317 patients admitted to a stroke center. The association of age, sex, RACE scale score and blood pressure with the likelihood of receiving MT were analyzed. Cut-off points with the highest association were thereafter evaluated in a prospective cohort of 153 patients from nine stroke units comprising the Madrid Stroke Network. RESULTS: Patients with a RACE scale score ≥ 5, systolic blood pressure <190 mmHg and age <81 years showed a significantly higher probability of undergoing MT (odds ratio, 33.38; 95% confidence interval, 12-92.9). This outcome was confirmed in the prospective cohort, with 68% sensitivity, 84% specificity, 42% positive and 94% negative predictive values for MT, ruling out 83% of hemorrhagic strokes. CONCLUSIONS: The Direct Referral to Endovascular Center criteria could be useful for identifying patients suitable for MT.
Asunto(s)
Isquemia Encefálica/diagnóstico , Isquemia Encefálica/terapia , Servicios Médicos de Urgencia/métodos , Procedimientos Endovasculares , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Transferencia de Pacientes , Proyectos Piloto , Estudios Retrospectivos , España , Stents , Trombectomía , Tiempo de TratamientoRESUMEN
Globular molecules of 1-chloroadamantane form a plastic phase in which the molecules rotate in a restrained way, but with their centers of mass forming a crystalline ordered lattice. Plastic phases can be regarded as test cases for the study of disordered phases since, contrary to what happens in the liquid phase, there is a lack of stochastic translational degrees of freedom. When the temperature is increased, a hump in the specific heat curve is observed indicating a change in the energetic footprint of the dynamics of the molecules. This change takes place without a change in the symmetry of the crystalline lattice, i.e. no first-order transition is observed between temperatures below and above the calorimetric hump. This implies that subtle changes in the dynamics of the disordered plastic phase concerning purely orientational degrees of freedom should appear at the thermodynamic anomaly. Accordingly, we describe, for the first time, the microscopic mechanisms behind a disorder-disorder transition through the analysis of neutron diffraction and QENS experiments. The results evince a change in the molecular rotational dynamics accompanied by a continuous change in density.
RESUMEN
The treatment of antihistamine and steroid resistant Chronic Idiopathic Urticaria (CIU) during pregnancy poses a challenge due to teratogenicity of immunosuppressants. Omalizumab is a recently FDA approved therapy for CIU and is classified as pregnancy category B. We present an initial series of subjects treated at a tertiary care center for antihistamine and steroid resistant CIU with omalizumab who became pregnant during therapy.