RESUMEN
BACKGROUND: Because to date there is no available study on STAT3 polymorphism and gastric cancer in Western populations and taking into account that Helicobacter pylori CagA EPIYA-C segment deregulates SHP-2/ERK-JAK/STAT3 pathways, we evaluated whether the two variables are independently associated with gastric cancer. METHODS: We included 1048 subjects: H. pylori-positive patients with gastric carcinoma (n = 232) and with gastritis (n = 275) and 541 blood donors. Data were analyzed using logistic regression model. RESULTS: The rs744166 polymorphic G allele (p = 0.01; OR = 1.76; 95 % CI = 1.44-2.70), and CagA-positive (OR = 12.80; 95 % CI = 5.58-19.86) status were independently associated with gastric cancer in comparison with blood donors. The rs744166 polymorphism (p = 0.001; OR = 1.64; 95 % CI = 1.16-2.31) and infection with H. pylori CagA-positive strains possessing higher number of EPIYA-C segments (p = 0.001; OR = 2.28; 95 % CI = 1.41-3.68) were independently associated with gastric cancer in comparison with gastritis. The association was stronger when host and bacterium genotypes were combined (p < 0.001; OR = 3.01; 95 % CI = 2.29-3.98). When stimulated with LPS (lipopolysaccharide) or Pam3Cys, peripheral mononuclear cells of healthy carriers of the rs744166 GG and AG genotypes expressed higher levels of STAT3 mRNA than those carrying AA genotype (p = 0.04 for both). The nuclear expression of phosphorylated p-STAT3 protein was significantly higher in the antral gastric tissue of carriers of rs744166 GG genotype than in carriers of AG and AA genotypes. CONCLUSIONS: Our study provides evidence that STAT3 rs744166 G allele and infection with CagA-positive H. pylori with higher number of EPIYA-C segments are independent risk factors for gastric cancer. The odds ratio of having gastric cancer was greater when bacterium and host high risk genotypes were combined.
Asunto(s)
Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Gastritis/microbiología , Infecciones por Helicobacter/genética , Polimorfismo de Nucleótido Simple , Factor de Transcripción STAT3/genética , Neoplasias Gástricas/microbiología , Adulto , Antígenos Bacterianos/sangre , Proteínas Bacterianas/sangre , Biomarcadores , Femenino , Gastritis/genética , Estudios de Asociación Genética , Infecciones por Helicobacter/sangre , Infecciones por Helicobacter/microbiología , Helicobacter pylori/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/genéticaRESUMEN
Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis (PCM), a chronic granulomatous mycosis prevalent in Latin America, and cell-mediated immunity represents the main mode of protection against this fungal infection. The conventional treatment for this mycosis involves long periods of therapy resulting in sequels and a high frequency of relapse. The search for new alternative methods of treatment is thus necessary. With this aim, the objective of this work was to evaluate the potential of rPb27 and rPb40 immunization to reduce treatment length and the frequency of relapse when used as an adjuvant to fluconazole chemotherapy in experimental PCM. Combined treatment with the drug and the two proteins reduced CFUs in the lung, liver and spleen to undetectable levels and largely preserved the tissue structure of these organs. At the same time, IFN-γ and TNF-α levels were higher in mice treated as described above than in infected-only mice, while very low production of IL-10 and TGF-ß was observed in this treated group. Thus, the combined treatment, using immunization with the two recombinant proteins in addition to fluconazole chemotherapy, showed an additive protective effect after intratracheal challenge. These results provide new prospects for immunotherapy as a treatment for PCM.
Asunto(s)
Antifúngicos/farmacología , Proteínas Fúngicas/inmunología , Paracoccidioides/inmunología , Paracoccidioidomicosis/prevención & control , Adyuvantes Inmunológicos , Animales , Antifúngicos/uso terapéutico , Antígenos Fúngicos/genética , Antígenos Fúngicos/inmunología , Terapia Combinada , Citocinas/metabolismo , Epítopos de Linfocito T/inmunología , Escherichia coli/genética , Escherichia coli/metabolismo , Fluconazol/farmacología , Fluconazol/uso terapéutico , Proteínas Fúngicas/genética , Humanos , Hígado/microbiología , Hígado/patología , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Paracoccidioides/genética , Paracoccidioidomicosis/tratamiento farmacológico , Paracoccidioidomicosis/inmunología , Paracoccidioidomicosis/microbiología , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Bazo/microbiología , Bazo/patología , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
Paracoccidioidomycosis, PCM, the major systemic mycosis in Latin America, is caused by the termally dimorphic fungus Paracoccidioides brasiliensis and requires extended periods of chemotherapy with a significant frequency of relapsing disease. The search for new alternatives of treatment is necessary. rPb27 is an antigenic protein from P. brasiliensis that already showed a significant protective activity as a vaccine for PCM in experimental models. The cDNA of rPb27 was subcloned into a pET-DEST 42 plasmid, expressed in E. coli with a his-tag and purified by affinity chromatography. Immunization with this recombinant protein and chemotherapy were used together in an attempt to improve treatment of PCM. For this, BALB/c mice were challenged with pathogenic P. brasiliensis strain and after immunized with rPb27, in the presence of Corynebacterium parvum and Al(OH)(3), some groups were also treated with fluconazole. After 40 days of treatment, the combined drug/rPb27 administration controlled PCM in the liver and spleen, with long lasting protection, and largely preserved tissues structures of these organs. Additionally, in the lungs after 40 days of treatment there was a significant reduction in the fungal load and size of lesions. At the same time, the levels of TNF-α were higher than infected-only mice. Moreover, significant levels of anti-rPb27 specific IgG1, IgG2a and IgG2b isotypes were detected in the sera of mice immunized with rPb27 fluconazole treated or not. These results showed an additive protective effect of rPb27 immunization and chemotherapy, suggesting that an rPb27-based vaccine can be used to enhance PCM antifungal treatment.