RESUMO
Species belonging to the Mycobacterium kansasii complex (MKC) are frequently isolated from humans and the environment and can cause serious diseases. The most common MKC infections are caused by the species M. kansasii (sensu stricto), leading to tuberculosis-like disease. However, a broad spectrum of virulence, antimicrobial resistance and pathogenicity of these non-tuberculous mycobacteria (NTM) are observed across the MKC. Many genomic aspects of the MKC that relate to these broad phenotypes are not well elucidated. Here, we performed genomic analyses from a collection of 665 MKC strains, isolated from environmental, animal and human sources. We inferred the MKC pangenome, mobilome, resistome, virulome and defence systems and show that the MKC species harbours unique and shared genomic signatures. High frequency of presence of prophages and different types of defence systems were observed. We found that the M. kansasii species splits into four lineages, of which three are lowly represented and mainly in Brazil, while one lineage is dominant and globally spread. Moreover, we show that four sub-lineages of this most distributed M. kansasii lineage emerged during the twentieth century. Further analysis of the M. kansasii genomes revealed almost 300 regions of difference contributing to genomic diversity, as well as fixed mutations that may explain the M. kansasii's increased virulence and drug resistance.
Assuntos
Genoma Bacteriano , Genômica , Infecções por Mycobacterium não Tuberculosas , Mycobacterium kansasii , Filogenia , Mycobacterium kansasii/genética , Mycobacterium kansasii/classificação , Mycobacterium kansasii/isolamento & purificação , Humanos , Infecções por Mycobacterium não Tuberculosas/microbiologia , Animais , Virulência/genéticaRESUMO
BACKGROUND: The evaluation of procedures for drug susceptibility prediction of Mycobacterium tuberculosis based on genomic data against the conventional reference method test based on culture is realistic considering the scenario of growing number of tools proposals based on whole-genome sequences (WGS). OBJECTIVES: This study aimed to evaluate drug susceptibility testing (DST) outcome based on WGS tools and the phenotypic methods performed on isolates of M. tuberculosis Lineage 1 from the state of Pará, Brazil, generally associated with low levels of drug resistance. METHODOLOGY: Culture based DST was performed using the Proportion Method in Löwenstein-Jensen medium on 71 isolates that had been submitted to WGS. We analysed the seven main genome sequence-based tools for resistance and lineage prediction applied to M. tuberculosis and for comparison evaluation we have used the Kappa concordance test. FINDINGS: When comparing the WGS-based tools against the DST, we observed the highest level of agreement using TB-profiler. Among the tools, TB-profiler, KvarQ and Mykrobe were those which identified the largest number of TB-MDR cases. Comparing the four most sensitive tools regarding resistance prediction, agreement was observed for 43 genomes. MAIN CONCLUSIONS: Drug resistance profiling using next-generation sequencing offers rapid assessment of resistance-associated mutations, therefore facilitating rapid access to effective treatment.
Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/genética , Antituberculosos/uso terapêutico , Brasil , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Preparações Farmacêuticas , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Sequenciamento Completo do GenomaRESUMO
BACKGROUND The evaluation of procedures for drug susceptibility prediction of Mycobacterium tuberculosis based on genomic data against the conventional reference method test based on culture is realistic considering the scenario of growing number of tools proposals based on whole-genome sequences (WGS). OBJECTIVES This study aimed to evaluate drug susceptibility testing (DST) outcome based on WGS tools and the phenotypic methods performed on isolates of M. tuberculosis Lineage 1 from the state of Pará, Brazil, generally associated with low levels of drug resistance. METHODOLOGY Culture based DST was performed using the Proportion Method in Löwenstein-Jensen medium on 71 isolates that had been submitted to WGS. We analysed the seven main genome sequence-based tools for resistance and lineage prediction applied to M. tuberculosis and for comparison evaluation we have used the Kappa concordance test. FINDINGS When comparing the WGS-based tools against the DST, we observed the highest level of agreement using TB-profiler. Among the tools, TB-profiler, KvarQ and Mykrobe were those which identified the largest number of TB-MDR cases. Comparing the four most sensitive tools regarding resistance prediction, agreement was observed for 43 genomes. MAIN CONCLUSIONS Drug resistance profiling using next-generation sequencing offers rapid assessment of resistance-associated mutations, therefore facilitating rapid access to effective treatment.
Assuntos
Humanos , Tuberculose Resistente a Múltiplos Medicamentos/genética , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Antituberculosos/farmacologia , Brasil , Preparações Farmacêuticas , Testes de Sensibilidade Microbiana , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sequenciamento Completo do Genoma , Mycobacterium tuberculosis/isolamento & purificação , Antituberculosos/uso terapêuticoRESUMO
In this review, we report on breast cancer's molecular features and on how high throughput technologies are helping in understanding the dynamics of tumorigenesis and cancer progression with the aim of developing precision medicine methods. We first address the current state of the art in breast cancer therapies and challenges in order to progress towards its cure. Then, we show how the interaction of high-throughput technologies with in silico modeling has led to set up useful inferences for promising strategies of target-specific therapies with low secondary effect incidence for patients. Finally, we discuss the challenge of pharmacogenetics in the clinical practice of cancer therapy. All these issues are explored within the context of precision medicine.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Medicina de Precisão/métodos , Mama/patologia , Neoplasias da Mama/prevenção & controle , Proliferação de Células , Biologia Computacional , DNA/metabolismo , Feminino , Redes Reguladoras de Genes , Hormônios/uso terapêutico , Humanos , Imunoterapia/métodos , Incidência , Inflamação , Estimativa de Kaplan-Meier , Modelos Biológicos , Farmacogenética , Mapeamento de Interação de Proteínas , Proteoma , Transdução de Sinais , Células-Tronco/citologia , TranscriptomaRESUMO
AIM: Hydralazine, a vasodilator used in resistant hypertension (RH) treatment is metabolized by an acetylation reaction mediated by N-acetyltransferase 2, the activity of which depends on NAT2 polymorphisms. Our aim was to evaluate whether different acetylation phenotypes influenced the antihypertensive effect of hydralazine in patients with RH. PATIENTS & METHODS: DNA samples from 169 RH patients using hydralazine were genotyped by sequencing the NAT2 coding region, and acetylation phenotypes were defined. RESULTS: Sixty-five patients (38.5%) were intermediate, 60 (35.5%) slow and 21 (12.4%) fast acetylators. Twenty-three (13.6%) patients were indeterminate. Upon association analysis, only slow acetylators had significant blood pressure reductions after hydralazine use, with mean 24-h systolic and diastolic blood pressure reductions of 9.2 and 5.5 mmHg. Four patients presented hydralazine adverse effects resulting in drug withdrawal, three of them were slow acetylators. CONCLUSION: The slow acetylation phenotype, determined by polymorphisms within NAT2, influenced both the antihypertensive and adverse effects of hydralazine in RH.