RESUMEN
The objective of this study was to investigate the association between mRNA expression and single nucleotide polymorphisms (SNPs) of the ATP-binding cassette transporter (ABCA1) gene, apolipoprotein A1 (APOA1) gene, low-density lipoprotein (LDLR) gene and RNA gene located in the CDKN2B-CDKN2A cluster (CDKN2B-AS1) involved in lipid metabolism and the occurrence of intracranial aneurysm (IA). Fifty three IA patients, and 27 controls (IA-free) were enrolled in this study and were genotyped for seven single nucleotide polymorphisms. Increased expression of the LDLR gene in IA patients was observed. The A/G genotype and the A allele of the c. -113G>A polymorphism of the APOA1 gene were associated with increased occurrence of IA (ORs 12.36 and 14.14, respectively), while the G/G genotype and G allele showed the opposite tendency (ORs 0.06 and 0.07, respectively). We also detected that the A/A-G/A combined genotype of the c. -113G>A - APOA1 and g.46859A>G - LDLR SNPs was associated with a decreased occurrence of IA. Moreover, the A/G-G/G combined genotype of the c.656G>A - ABCA1 and c. -113G>A - APOA1 was associated with a decreased occurrence of IA. The results of our study suggest the association between expression and variability of lipid metabolism genes and occurrence of IA.
Asunto(s)
Regulación de la Expresión Génica , Variación Genética , Aneurisma Intracraneal/genética , Metabolismo de los Lípidos/genética , Adulto , Alelos , Estudios de Casos y Controles , Demografía , Epistasis Genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The product of the LIG3 gene encodes DNA ligase III, which is involved in the repair of oxidatively damaged DNA in the base excision repair pathway. We hypothesized that polymorphism in this gene may change susceptibility to oxidative stress and predispose individuals to the development of keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Therefore, we investigated the association between genotypes and haplotypes of the g.29661G>A polymorphism (rs1003918) and the g.29059C>T polymorphism (rs1052536) of the LIG3 gene and the occurrence of KC and FECD in patients with FECD (258 individuals) or KC (283) and ethnically matched controls (300). The A/A genotype and the A allele of the g.29661G>A polymorphism were associated with increased occurrence of KC, while the G allele of this polymorphism was positively correlated with a decreased occurrence of this disease. The T/C genotype of the g.29059C>T polymorphism was associated with decreased FECD occurrence. In addition, the AT haplotype was associated with increased occurrence of KC and FECD, while the GT haplotype was associated with decreased occurrence of these diseases. The g.29661G>A and g.29059C>T polymorphisms may play a role in the KC and FECD pathogenesis and can be considered as markers in these diseases.
Asunto(s)
ADN Ligasas/genética , Distrofia Endotelial de Fuchs/genética , Predisposición Genética a la Enfermedad/genética , Queratocono/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , ADN Ligasa (ATP) , Europa (Continente)/epidemiología , Femenino , Distrofia Endotelial de Fuchs/epidemiología , Distrofia Endotelial de Fuchs/etnología , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/etnología , Genotipo , Haplotipos/genética , Humanos , Queratocono/epidemiología , Queratocono/etnología , Masculino , Persona de Mediana Edad , Estrés Oxidativo/genética , Proteínas de Unión a Poli-ADP-Ribosa , Prevalencia , Proteínas de XenopusRESUMEN
Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia in chronic phase (CML-CP). Unfortunately, 25% of TKI-naive patients and 50-90% of patients developing TKI-resistance carry CML clones expressing TKI-resistant BCR-ABL1 kinase mutants. We reported that CML-CP leukemia stem and progenitor cell populations accumulate high amounts of reactive oxygen species, which may result in accumulation of uracil derivatives in genomic DNA. Unfaithful and/or inefficient repair of these lesions generates TKI-resistant point mutations in BCR-ABL1 kinase. Using an array of specific substrates and inhibitors/blocking antibodies we found that uracil DNA glycosylase UNG2 were inhibited in BCR-ABL1-transformed cell lines and CD34(+) CML cells. The inhibitory effect was not accompanied by downregulation of nuclear expression and/or chromatin association of UNG2. The effect was BCR-ABL1 kinase-specific because several other fusion tyrosine kinases did not reduce UNG2 activity. Using UNG2-specific inhibitor UGI, we found that reduction of UNG2 activity increased the number of uracil derivatives in genomic DNA detected by modified comet assay and facilitated accumulation of ouabain-resistant point mutations in reporter gene Na(+)/K(+)ATPase. In conclusion, we postulate that BCR-ABL1 kinase-mediated inhibition of UNG2 contributes to accumulation of point mutations responsible for TKI resistance causing the disease relapse, and perhaps also other point mutations facilitating malignant progression of CML.
Asunto(s)
Daño del ADN/genética , ADN de Neoplasias/genética , Proteínas de Fusión bcr-abl/metabolismo , Inestabilidad Genómica , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Células Madre Neoplásicas/metabolismo , Uracil-ADN Glicosidasa/metabolismo , Animales , Western Blotting , Núcleo Celular/genética , Ensayo Cometa , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Mutagénesis , Células Madre Neoplásicas/patología , Mutación Puntual/genética , Reacción en Cadena de la Polimerasa , Especies Reactivas de Oxígeno/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética , Células Tumorales Cultivadas , Uracil-ADN Glicosidasa/genéticaRESUMEN
BACKGROUND: Multidrug-resistant Acinetobacter baumannii (MRAB) is a serious nosocomial pathogen characterized by its survival on inanimate surfaces for long periods, making control of outbreaks difficult. AIM: To analyse two hospital outbreaks caused by MRAB, determine their epidemiology, carbapenem-resistance mechanisms and assess the effectiveness of surface disinfection by vaporized hydrogen peroxide (VHP). METHODS: MRAB strains were isolated from patients in two intensive care units (ICUs). Antimicrobial susceptibility testing was performed by E-test. Polymerase chain reaction (PCR) was used to detect the presence of the most common A. baumannii carbapenemases. Epidemiological typing was performed by rep-PCR (DiversiLab) and pulsed-field gel electrophoresis. VHP was used to decontaminate the affected ICUs. FINDINGS: MRAB was isolated from 28 patients between January 2009 and September 2010. All isolates were resistant to ciprofloxacin and gentamicin. Twenty-one were also resistant to carbapenems. Carbapenem resistance was associated primarily with the acquired OXA-23-like enzyme. Genotyping revealed three clones; the predominant clone corresponded to the international clone (IC) 2. Typing of the isolates pointed to a multifocal outbreak without a single source of infection, with horizontal spread of the dominating clone among ICU patients. A combination of rigorous infection control measures including strict isolation, education of staff, hand hygiene and surface decontamination using VHP halted the outbreak. CONCLUSION: The results of this study confirm the importance of rigorous infection prevention and control measures, combined with VHP decontamination in controlling an outbreak of MRAB.
