RESUMO
A strictly defined subset of gonococci (n = 65) isolated in Italy from 2011 to 2014 was characterized by antimicrobial susceptibility for cefixime (CFM) and ceftriaxone (CRO) and by sequencing of resistance determinant genes (penA, mtrR, porB1b, ponA) for extended-spectrum cephalosporins and Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST). The penA mosaic alleles XXXIV and XXXV were found in all resistant (R) and decreased susceptibility (DS) gonococci to CFM, except for one. They were associated with an adenine deletion in the mtrR promoter plus amino acid substitutions, H105Y or G45D, in the coding region and ponA L421P. The penA mosaic allele XXXIV, and one variant, was found exclusively among genogroup (G) 1407 and its closely related sequence types (STs), as in CFM-DS as well as in CFM-R isolates. Single or combined mutation patterns in penA, mtrR, porB1b, and ponA genes were associated with different CFM susceptibility patterns and NG-MAST STs. Genotyping and antimicrobial resistance (AMR) determinant analyses can be valuable to enhance the gonococcal AMR surveillance.
Assuntos
Antibacterianos/uso terapêutico , Cefixima/uso terapêutico , Farmacorresistência Bacteriana/genética , Gonorreia/tratamento farmacológico , Gonorreia/microbiologia , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/genética , Alelos , Substituição de Aminoácidos/genética , Proteínas de Bactérias/genética , Ceftriaxona/uso terapêutico , Cefalosporinas/uso terapêutico , Genótipo , Humanos , Itália , Testes de Sensibilidade Microbiana/métodos , Mutação/genética , Neisseria gonorrhoeae/isolamento & purificação , Regiões Promotoras Genéticas/genéticaRESUMO
Human malignant pleural mesothelioma (MPM) is a dreadful disease and there is still no standard therapy available for a consistent therapeutic approach. This research is aimed at the evaluation of the potential therapeutic effect of a specific nicotinic receptor (nAChR) antagonist, namely alpha-Cobratoxin (alpha-CbT). Its effectiveness was tested in mesothelioma cell lines and in primary mesothelioma cells in vitro, as well as in vivo, in orthotopically xenotransplanted NOD/SCID mice. Cells showed alpha7-nAChR expression and their growth was significantly inhibited by alpha-CbT. Severe induction of apoptosis was observed after exposure to alpha-CbT [IC(80-90)]. Apoptosis was characterised by: change in mitochondrial potential, caspase-3 cleavage, down-regulation of mRNA and protein for survivin, XIAP, IAP1, IAP2 and Bcl-XL, inhibition by caspase-3 inhibitor. In vivo, the alpha-CbT acute LD(50) was 0.15 mg/kg. The LD(100) [0.24 mg/kg] induced fatal respiratory failure and massive kidney necrosis. Phase II experiments with 0.12 ng/kg alpha-CbT (1/1000 of LD(10)) were done in 53 xenotransplanted mice, inhibiting tumour development as confirmed by chest X-ray examinations, autopsy and microscopical findings. The growth of human proliferating T lymphocytes and of mesothelial cells in primary culture was not affected by alpha-CbT. Non-immunogenic derivatives of the alpha-CbT molecule need to be developed for possible human use.