RESUMEN
BACKGROUND/AIMS: Aquaporin-3 (AQP3) is an aquaglyceroporin and peroxiporin that plays a crucial role in skin barrier homeostasis. Dysregulated AQP3 expression has been observed in different inflammatory skin conditions. Hidradenitis Suppurativa (HS) is an autoinflammatory keratinization disease that typically appears between 10 and 21 years of age, characterized by alteration of skin barrier homeostasis. METHODS: To evaluate in vitro the role of AQP3 in the development of HS, we performed real-time PCR and Western blot to analyze gene and protein levels in human keratinocyte cell lines knock-out (KO) for NCSTN and PSENEN genes, simulating genetic-associated HS. Additionally, we investigated the impact of Glyceryl Glucoside (GG) on biological processes by performing MTT, scratch, proliferation assays and proteome studies. RESULTS: We detected a significant decrease of the levels of AQP3 gene and protein in KO cell lines. GG effectively elevated the levels of mRNA and protein, significantly decreased the hyperproliferation rate, and enhanced cell migration in our in vitro model of genetic Hidradenitis Suppurativa. Pathway enrichment analysis further confirmed GG's role in the migration and proliferation pathways of keratinocytes. CONCLUSION: Our results suggest that AQP3 may act as a new novel actor in HS etio-pathogenesis, and GG could be further explored as potential treatment option for managing HS in patients.
Asunto(s)
Acuaporina 3 , Movimiento Celular , Proliferación Celular , Glucósidos , Hidradenitis Supurativa , Queratinocitos , Humanos , Acuaporina 3/metabolismo , Acuaporina 3/genética , Hidradenitis Supurativa/metabolismo , Hidradenitis Supurativa/patología , Hidradenitis Supurativa/tratamiento farmacológico , Hidradenitis Supurativa/genética , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/patología , Queratinocitos/citología , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Glucósidos/farmacología , Glucósidos/uso terapéutico , Línea CelularRESUMEN
Ketamine provides the highest safety profile among sedatives for procedural sedation and analgesia in the pediatric emergency setting. However, it can cause vomiting and recovery agitation. No studies have examined epigenetic factors, such as microRNAs, for predicting the occurrence of these adverse events. Neuronal-derived extracellular vesicle microRNA profiles were studied to predict the occurrence of ketamine-induced vomiting and recovery agitation in children. For this aim, a single-center prospective pharmacoepigenetic study was performed and 50 children who underwent procedural sedation with intravenous ketamine as the only sedative drug were enrolled between October 2019 and November 2022. MiRNA profiling in plasma neural-derived extracellular vesicles was analyzed through next-generation sequencing and measured before treatment with ketamine. Twenty-two patients experienced vomiting or recovery agitation. Among the 16 differentially expressed microRNAs, the upregulated miR-15a-5p and miR-484 targeted genes related to N-methyl-D-aspartate (NMDA) receptor activity, including glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A). Preliminary data confirmed lower GRIN2A levels in patients who developed these events. Downregulated miR-126-3p and miR-24-3p targeted AMPA receptor-associated genes. Functional analyses of gene targets revealed the enrichment of glutamatergic and neurotrophins signaling. Recovery agitation was associated with this network. Vomiting was related to dopaminergic and cholinergic systems. Three miRNAs (miR-18a-3p, miR-484, and miR-548az-5p) were identified as predictive biomarkers (AUC 0.814; 95% CI: 0.632-0.956) for ketamine-induced vomiting and recovery agitation. MicroRNA profiles can predict the development of ketamine-induced vomiting or recovery agitation in children. This study contributes to the understanding of the mechanisms underlying ketamine-induced adverse events.
RESUMEN
Dowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT-1 and POFUT-1 genes have been associated with DDD, and loss-of-function mutations in PSENEN, a subunit of the gamma-secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma-secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four-generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma-secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co-occurrence in HS patients carrying a mutation in the NCSTN gene.
Asunto(s)
Hidradenitis Supurativa , Papulosis Atrófica Maligna , Humanos , Secretasas de la Proteína Precursora del Amiloide/genética , Codón sin Sentido , Hidradenitis Supurativa/complicaciones , Hidradenitis Supurativa/genética , Proteínas de la Membrana/genética , Mutación , Factores de Transcripción/genéticaRESUMEN
The remarkable variability of response to vaccines against SARS-CoV-2 is apparent. The present study aims to estimate the extent to which the host genetic background contributes to this variability in terms of immune response and side effects following the administration of the BNT162b2 vaccine. We carried out a genome wide association study (GWAS) by genotyping 873 Italian healthcare workers who underwent anti-SARS-CoV-2 vaccination with the BNT162b2 vaccine and for whom information about anti-SARS-CoV-2 spike antibodies titers and vaccine side effects were available. The GWAS revealed a significant association between the HLA locus and the anti-SARS-CoV-2 Spike antibodies level at 2 months following the first dose of vaccine (SNP: rs1737060; p = 9.80 × 10-11 ). In particular, we observed a positive association between the antibody levels and the presence of the HLA-A*03:01 allele. The same allele was found associated with a 2-2.4-fold increased risk of experiencing specific side effects such as fever, chills and myalgia and a 1.5-1.8-fold increased risk of joint pain, nausea, fatigue, headache and asthenia, independently of age and sex. This study confirms that the heterogeneity in the immune response to the BNT162b2 vaccine and in its side effects are at least partially influenced by genetic variants. This information, integrated with individual biological and lifestyle-related correlates, could be of use in the definition of algorithms aimed at the identification of subjects in which the administration of additional vaccine doses would be particularly beneficial to maintain immunity against the virus.
Asunto(s)
Estudio de Asociación del Genoma Completo , Vacunas , Humanos , Alelos , Vacuna BNT162 , Vacunas contra la COVID-19/efectos adversos , Anticuerpos Antivirales , Personal de Salud , Antígenos HLA-ARESUMEN
Primary complement system (C) deficiencies are rare but notably associated with an increased risk of infections, autoimmunity, or immune disorders. Patients with terminal pathway C-deficiency have a 1,000- to 10,000-fold-higher risk of Neisseria meningitidis infections and should be therefore promptly identified to minimize the likelihood of further infections and to favor vaccination. In this paper, we performed a systematic review about clinical and genetic patterns of C7 deficiency starting from the case of a ten-year old boy infected by Neisseria meningitidis B and with clinical presentation suggestive of reduced C activity. Functional assay via Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum. Sanger sequencing of genomic DNA extracted from peripheral blood of the patient allowed the identification of two pathogenetic variants in the C7 gene: the already well-characterized missense mutation G379R and a novel heterozygous deletion of three nucleotides located at the 3'UTR (c.*99_*101delTCT). This mutation resulted in an instability of the mRNA; thus, only the allele containing the missense mutation was expressed, making the proband a functional hemizygote for the expression of the mutated C7 allele.
Asunto(s)
Autoinmunidad , Bioensayo , Masculino , Humanos , Niño , Regiones no Traducidas 3' , AlelosRESUMEN
Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder, which typically occurs during puberty or early adulthood. The pathogenesis of HS is complex and multifactorial; a close interaction between hormonal, genetic, epigenetics factors, host-specific aspects, and environmental influences contributes to the susceptibility, onset, severity, and clinical course of this disease, although the exact molecular mechanisms are still being explored. Epigenetics is currently emerging as an interesting field of investigation that could potentially shed light on the molecular intricacies underlying HS, but there is much still to uncover on the subject. The aim of this work is to provide an overview of the epigenetic landscape involved in HS. Specifically, in this in-depth review we provide a comprehensive overview of DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs (such as microRNA-miRNA-132, miRNA-200c, miRNA-30a-3p, miRNA-100-5b, miRNA-155-5p, miRNA-338-5p) dysregulation in HS patients. An interesting element of epigenetic regulation in HS is that the persistent inflammatory milieu observed in HS lesional skin could be exacerbated by an altered methylation profile and histone acetylation pattern associated with key inflammatory genes. Deepening our knowledge on the subject could enable the development of targeted epigenetic therapies to potentially restore normal gene expression patterns, and subsequentially ameliorate, or even reverse, the progression of the disease. By deciphering the epigenetic code governing HS, we strive to usher in a new era of personalized and effective interventions for this enigmatic dermatological condition.
Asunto(s)
Hidradenitis Supurativa , MicroARNs , Humanos , Adulto , Epigénesis Genética , Hidradenitis Supurativa/genética , MicroARNs/genética , Acetilación , Código de HistonasRESUMEN
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin's physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach.
Asunto(s)
Antiinfecciosos , Dermcidinas , Hidradenitis Supurativa , Niño , Humanos , Antiinfecciosos/metabolismo , Hidradenitis Supurativa/genética , Hidradenitis Supurativa/metabolismo , Mutación , Péptidos/genética , Péptidos/metabolismo , Piel/metabolismo , Masculino , FemeninoRESUMEN
(1) Background: We find the incidence of clubfoot in Italy from "Certificate of Delivery Care Registry (CeDAP)", a database of the Italian Ministry of Health, the most comprehensive public data available for this purpose. (2) Methods: The CeDAP registry is a web system that provides epidemiological and sociodemographic information about newborns. It started on 1 January 2002, following the ministerial Decree no. 349 of 16 July 2001. The certificate is structured into six sections; each collects specific information referring to the birthplace, parents, pregnancy, childbirth, newborn, and the possible presence of congenital malformations or the causes of neonatal mortality. The midwife or the doctor draws up the certificate no later than ten days after birth. Each region transmits the data every six months to the Ministry of Health. The period between 2013 and 2017 has been selected for the study, with every Italian region's data. We conducted a retrospective descriptive study. (3) Results: The overall rate in northern Italy is 1.09 (with some exceptions described), but we think it is essential to reevaluate this number again, given more accurate data collections by every Italian hospital. (4) Conclusions: This study intends to build a framework for future epidemiologic studies about clubfoot in Italy.
Asunto(s)
Pie Equinovaro , Pie Equinovaro/epidemiología , Femenino , Humanos , Incidencia , Recién Nacido , Italia/epidemiología , Embarazo , Datos Preliminares , Sistema de Registros , Estudios RetrospectivosRESUMEN
BACKGROUND: Despite consolidated guidelines, the clinical diagnosis and prognosis of cystic fibrosis (CF) is still challenging mainly because of the extensive phenotypic heterogeneity and the high number of CFTR variants, including their combinations as complex alleles. RESULTS: We report a family with a complicated syndromic phenotype, which led to the suspicion not only of CF, but of a dominantly inherited skeletal dysplasia (SD). Whereas the molecular basis of the SD was not clarified, segregation analysis was central to make a correct molecular diagnosis of CF, as it allowed to identify three CFTR variants encompassing two known maternal mutations and a novel paternal microdeletion. CONCLUSION: This case well illustrates possible pitfalls in the clinical and molecular diagnosis of CF; presence of complex phenotypes deflecting clinicians from appropriate CF recognition, and/or identification of two mutations assumed to be in trans but with an unconfirmed status, which underline the importance of an in-depth molecular CFTR analysis.
Asunto(s)
Fibrosis Quística , Alelos , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Humanos , Mutación , FenotipoRESUMEN
OBJECTIVES: Progressive familial intrahepatic cholestasis is an expanding group of autosomal recessive intrahepatic cholestatic disorders. Recently, next-generation sequencing allowed identifying new genes responsible for new specific disorders. Two biochemical phenotypes have been identified according to gamma-glutamyltransferase (GGT) activity. Mutations of the myosin 5B gene (MYO5B) are known to cause microvillus inclusion disease. Recently, different mutations in MYO5B gene have been reported in patients with low-GGT cholestasis. METHODS: A multicenter retrospective and prospective study was conducted in 32 children with cryptogenic intrahepatic cholestasis. Clinical, biochemical, histological, and treatment data were analyzed in these patients. DNA from peripheral blood was extracted, and all patients were studied by whole exome sequencing followed by Sanger sequencing. RESULTS: Six patients out of 32 had mutations in the MYO5B gene. Of these six patients, the median age at disease onset was 0.8âyears, and the median length of follow-up was 4.2âyears. The most common signs were pruritus, poor growth, hepatomegaly, jaundice, and hypocholic stools. Two patients also showed intestinal involvement. Transaminases and conjugated bilirubin were moderately increased, serum bile acids elevated, and GGT persistently normal. At anti-Myo5B immunostaining, performed in liver biopsy of two patients, coarse granules were evident within the cytoplasm of hepatocytes while bile salt export pump was normally expressed at the canalicular membrane. Six variants in homozygosity or compound heterozygosity in the MYO5B gene were identified, and three of them have never been described before. All nucleotide alterations were located on the myosin motor domain except one missense variant found in the isoleucine-glutamine calmodulin-binding motif. CONCLUSIONS: We identified causative mutations in MYO5B in 18.7% of a selected cohort of patients with intrahepatic cholestasis confirming a relevant role for the MYO5B gene in low-GGT cholestasis.
Asunto(s)
Colestasis Intrahepática , Colestasis , Miosina Tipo V , Colestasis/genética , Colestasis Intrahepática/diagnóstico , Humanos , Mutación , Cadenas Pesadas de Miosina/genética , Miosina Tipo V/genética , Miosinas/genética , Fenotipo , Estudios Prospectivos , Estudios Retrospectivos , gamma-Glutamiltransferasa/genéticaRESUMEN
Among chronic skin autoinflammatory diseases, Hidradenitis Suppurativa (HS) stands out for its chronicity, highly variable condition, and profound impact on the patients' quality of life. HS is characterized by suppurative skin lesions in diverse body areas, including deep-seated painful nodules, abscesses, draining sinus, and bridged scars, among others, with typical topography. To date, HS is considered a refractory disease and medical treatments aim to reduce the incidence, the infection, and the pain of the lesions. For this purpose, different classes of drugs, including anti-inflammatory molecules, antibiotics and biological drugs are being used. Antimicrobial peptides (AMPs), also called defense peptides, emerge as a new class of therapeutic compounds, with broad-spectrum antimicrobial action, in addition to reports on their anti-inflammatory, healing, and immunomodulating activity. Such peptides are present in prokaryotes and eukaryotes, as part of the innate eukaryotic immune system. It has been proposed that a deregulation in the expression of AMPs in human epithelial tissues of HS patients may be associated with the etiology of this skin disease. In this scenario, plant AMPs stand out for their richness, diversity of types, and broad antimicrobial effects, with potential application for topical systemic use in patients affected by HS.
RESUMEN
BACKGROUND AND OBJECTIVES: The treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. Change in methylation pattern is a crucial event in human cancer, including lung cancer. We therefore studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy. METHODS: The DNA extracted from resected congenital lung malformations and control lung tissue was screened using Illumina MethylationEPIC arrays. Comparisons between the group of malformed samples or the malformed samples of same histology or each malformed sample and the controls and between a pleuropulmonary blastoma (PPB) and controls were performed. Moreover, each malformed sample was pairwise compared with its respective control. All differentially methylated regions (DMRs) with an adjusted p-value <0,05 were studied. RESULTS: Every comparison highlighted a number of DMRs closed to genes involved either in cell proliferation or in embryonic development or included in the Cancer Gene Census. Their abnormal methylation had been already described in lung tumors. CONCLUSIONS: Methylation anomalies already described in lung tumors and also shared by the PPB were found in congenital lung malformations, regardless the histology. The presence of methylation abnormalities is suggestive of a correlation between congenital lung malformations and some step of malignant transformation.
Asunto(s)
Hiperinsulinismo Congénito/tratamiento farmacológico , Hiperinsulinismo Congénito/cirugía , Fármacos Gastrointestinales/uso terapéutico , Octreótido/uso terapéutico , Diazóxido/administración & dosificación , Humanos , Lactante , Recién Nacido , Masculino , Páncreas/cirugía , Resultado del TratamientoRESUMEN
The CRISPR/Cas9 bacterial system has proven to be an powerful tool for genetic manipulation in several organisms, but the efficiency of sequence replacement by homologous direct repair (HDR) is substantially lower than random indel creation. Many studies focused on improving HDR efficiency using double sgRNA, cell synchronization cycle, and the delivery of single-stranded oligo DNA nucleotides (ssODN) with a rational design. In this study, we evaluate these three methods' synergistic effects to improve HDR efficiency. For our tests, we have chosen the TNFα gene (NM_000594) for its crucial role in various biological processes and diseases. For the first time, our results showed how the use of two sgRNA with asymmetric donor design and triple transfection events dramatically increase the HDR efficiency from an undetectable HDR event to 39% of HDR efficiency and provide a new strategy to facilitate CRISPR/Cas9-mediated human genome editing. Besides, we demonstrated that the TNFα locus could be edited with CRISPR/Cas9 methodology, an opportunity to safely correct, in the future, the specific mutations of each patient.
Asunto(s)
Sistemas CRISPR-Cas , Edición Génica/métodos , Genoma Humano , Reparación del ADN por Recombinación/genética , Factor de Necrosis Tumoral alfa/genética , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades/genética , ADN de Cadena Simple/genética , Células HEK293 , Humanos , Mutación , Nucleótidos/genética , ARN Guía de Kinetoplastida/genética , Transfección , Repeticiones de Trinucleótidos/genéticaRESUMEN
MED13-related disorder is a new neurodevelopmental disorder recently described in literature, which belongs to the group of CDK8-kinase module genes-associated conditions. It is characterized by variable intellectual disability and/or developmental delays, especially in language. Autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), eye or vision problems, hypotonia, mild congenital hearth abnormalities and dysmorphisms have been described among individuals with MED13 mutations. We report the case of a 13-year-old girl who received a previous clinical diagnosis of Kabuki syndrome (KS) without mutations in classic KS genes. After a whole exome sequencing (WES) analysis a de novo missense mutation in MED13 (c.C979T; p.Pro327Ser) was found. This variant has been once described in literature as accountable for a novel neurodevelopmental disorder. The aim of this report is to improve clinical delineation of MED13-related condition and to explore differences and similarities between KS spectrum and MED13-related disorders.
Asunto(s)
Anomalías Múltiples/genética , Cara/anomalías , Predisposición Genética a la Enfermedad , Enfermedades Hematológicas/genética , Complejo Mediador/genética , Enfermedades Vestibulares/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/patología , Adolescente , Quinasa 8 Dependiente de Ciclina/genética , Cara/patología , Femenino , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/patología , Humanos , Mutación/genética , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/patologíaRESUMEN
Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.
Asunto(s)
Enfermedades Autoinflamatorias Hereditarias/genética , Inflamación/genética , Receptores Notch/genética , Animales , Síndrome de Behçet/genética , Síndrome de Behçet/patología , Diferenciación Celular/genética , Arteritis de Células Gigantes/genética , Arteritis de Células Gigantes/patología , Enfermedades Autoinflamatorias Hereditarias/clasificación , Enfermedades Autoinflamatorias Hereditarias/patología , Hidradenitis Supurativa/genética , Hidradenitis Supurativa/patología , Humanos , Inflamación/patología , Mutación/genética , Transducción de Señal/genéticaRESUMEN
BACKGROUND: FBLIM1 gene has been recently demonstrated to be involved in the pathogenesis of bone sterile inflammation. The aim of the study is to evaluate the prevalence of FBLIM1 gene variants in a cohort of 80 Italian patients with Chronic Non-bacterial Osteomyelitis (CNO). METHODS: The coding regions of FBLIM1 gene were sequenced in a cohort of 80 patients with CNO using DNA extracted from blood lymphocytes, and PCR products were sequenced. Only rare (global MAF < 2%), coding variants detected were considered. Clinical evaluation of patients with rare variants and those without was performed. Fisher's exact test was used to compare categorical and ordinal data, and Student's t-test was used to analyze continuous data. RESULTS: Eighteen out of 80 patients (~ 22%) presented at least one rare coding variant in FBLIM1. Eight patients presented a variant never associated before with CNO. All patients presented classical features of CNO and no statistical difference between patients with presence of FBLMI1 variants and those without were found in terms of clinical manifestation, treatment, and outcome. CONCLUSION: Considering the high frequency of rare variants in our CNO cohort, our data seem to confirm a possible role of FBLIM1 in the pathogenesis of CNO suggesting that CNO is a disorder of chronic inflammation and imbalanced bone remodeling.
Asunto(s)
Moléculas de Adhesión Celular/genética , Proteínas del Citoesqueleto/genética , Osteomielitis , Remodelación Ósea/genética , Niño , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Humanos , Italia/epidemiología , Masculino , Osteomielitis/diagnóstico , Osteomielitis/epidemiología , Osteomielitis/genética , Polimorfismo Genético , PrevalenciaRESUMEN
The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelialâ»mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.
RESUMEN
HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.