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2.
J Mol Diagn ; 20(3): 279-288, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29471114

RESUMO

Cancer genome copy number alterations (CNAs) assist clinicians in selecting targeted therapeutics. Solid tumor CNAs are most commonly evaluated in formalin-fixed, paraffin-embedded (FFPE) tissue by fluorescence in situ hybridization. Although fluorescence in situ hybridization is a sensitive and specific assay for interrogating preselected genomic regions, it provides no information about coexisting clinically significant copy number changes. Chromosomal microarray analysis is an alternative DNA-based method for interrogating genome-wide CNAs in solid tumors. However, DNA extracted from FFPE tumor tissue produces an essential, yet problematic, sample type. The College of American Pathologists/American Society of Clinical Oncology guidelines for optimal tumor tissue handling, published in 2007 for breast cancer and in 2016 for gastroesophageal adenocarcinomas, are lacking for other solid tumors. Thus, cold ischemia times are seldom monitored in non-breast cancer and non-gastroesophageal adenocarcinomas, and all tumor biospecimens are affected by chemical fixation. Although intended to preserve specimens for long-term storage, formalin fixation causes loss of genetic information through DNA damage. Herein, we describe a reference size matching, whole-genome amplification, and fluorescent labeling method for FFPE-derived DNA designed to improve chromosomal microarray results from suboptimal nucleic acids and salvage highly degraded samples. With this technological advance, whole-genome copy number analysis of tumor DNA can be reliably performed in the clinical laboratory for a wide variety of tissue conditions and tumor types.


Assuntos
Cromossomos Humanos/genética , Variações do Número de Cópias de DNA/genética , Corantes Fluorescentes/química , Genoma Humano , Análise em Microsséries/normas , Neoplasias/genética , Inclusão em Parafina/métodos , Fixação de Tecidos/métodos , Linhagem Celular , DNA/genética , Formaldeído , Deleção de Genes , Dosagem de Genes , Humanos , PTEN Fosfo-Hidrolase/genética , Controle de Qualidade , Receptor ErbB-2/genética , Padrões de Referência
3.
Chem Biol Drug Des ; 74(4): 343-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19751419

RESUMO

Beta-lactam antibiotics are among the most important drugs used to fight bacterial infection. Overuse and misuse of beta-lactam antibiotics has caused the evolution of resistance mechanisms, allowing pathogenic bacteria to survive antibiotic treatment. The major source of resistance to beta-lactam antibiotics occurs through production of enzymes called beta-lactamases capable of catalyzing hydrolysis of the beta-lactam rings in these drug compounds. The metallo-beta-lactamases have become a major threat due to their broad substrate specificities; there are no clinically useful inhibitors for these metalloenzymes. We have obtained single-stranded DNA's that are potent inhibitors of the Bacillus cereus 5/B/6 metallo-beta-lactamase. These are rapid, reversible, non-competitive inhibitors of the metalloenzyme, with K(i) and K(i)' values in the nanomolar range. The inhibition patterns and metal ion dependence of their inhibition suggest that the oligonucleotides alter the coordination of the active site metal ion(s); inhibition is efficient and highly specific. Microbiological growth experiments, using combinations of ssDNA with the beta-lactam antibiotic cephalexin, reveal that the inhibitor is capable of causing cell death in liquid cultures of both Gram-positive and Gram-negative metallo-beta-lactamase producing bacteria in the micromolar concentration range.


Assuntos
Resistência beta-Lactâmica , Inibidores de beta-Lactamases , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Bacillus cereus/enzimologia , Sequência de Bases , DNA de Cadeia Simples/química , DNA de Cadeia Simples/farmacologia , Cinética , Técnica de Seleção de Aptâmeros/métodos , beta-Lactamases/metabolismo
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