RESUMO
Poly(ADP ribose) polymerase inhibitors (PARPi) have efficacy in triple negative breast (TNBC) and ovarian cancers (OCs) harboring BRCA mutations, generating homologous recombination deficiencies (HRDs). DNA methyltransferase inhibitors (DNMTi) increase PARP trapping and reprogram the DNA damage response to generate HRD, sensitizing BRCA-proficient cancers to PARPi. We now define the mechanisms through which HRD is induced in BRCA-proficient TNBC and OC. DNMTi in combination with PARPi up-regulate broad innate immune and inflammasome-like signaling events, driven in part by stimulator of interferon genes (STING), to unexpectedly directly generate HRD. This inverse relationship between inflammation and DNA repair is critical, not only for the induced phenotype, but also appears as a widespread occurrence in The Cancer Genome Atlas datasets and cancer subtypes. These discerned interactions between inflammation signaling and DNA repair mechanisms now elucidate how epigenetic therapy enhances PARPi efficacy in the setting of BRCA-proficient cancer. This paradigm will be tested in a phase I/II TNBC clinical trial.
Assuntos
Recombinação Homóloga/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína BRCA1/genética , Proteína BRCA2/genética , Linhagem Celular Tumoral , Biologia Computacional , Metilases de Modificação do DNA/antagonistas & inibidores , Reparo do DNA/efeitos dos fármacos , Anemia de Fanconi/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Modelos Biológicos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Glutathione is an important biological molecule which can be an indicator of numerous diseases. A method for self-powered detection of glutathione levels in solution has been developed using an enzymatic biofuel cell. The device consists of a glucose oxidase anode and a bilirubin oxidase cathode. For the detection of glutathione, the inhibition of bilirubin oxidase leads to a measurable decrease in current and power output. The reported method has a detection limit of 0.043 mM and a linear range up to 1.7 mM. Being able to detect a range of concentrations can be useful in evaluating a patient's health. This method has the potential to be implemented as a quick, low-cost alternative to previously reported methods.
Assuntos
Técnicas Biossensoriais , Glutationa/análise , Fontes de Energia Bioelétrica , Eletrodos , Enzimas Imobilizadas , Glucose , Humanos , Oxirredutases atuantes sobre Doadores de Grupo CH-CHRESUMO
Enzymatic electrodes are becoming increasingly common for energy production and sensing applications. Research over the past several decades has addressed a major issue that can occur when using these biocatalysts, i.e., slow heterogeneous electron transfer, by incorporation of a redox active species to act as an electron shuttle. There are several advantages to immobilizing both the enzyme and mediator at the enzyme surface, including increased electron transfer rates, decreased enzyme leaching, and minimized diffusion limitations. Redox polymers consisting of a redox active center attached to a polymer backbone are a particularly attractive option because they have high self-exchange rates for electron transfer and tunable redox potential. Osmium (Os) polymers are the most well studied of this type of polymer for bioelectrocatalysis. Here, we describe the methods to synthesize one of the most common Os redox polymers and how it can be used to fabricate glucose oxidase electrodes. Procedures are also outlined for evaluating the enzymatic electrodes.