RESUMO
We developed a high-throughput mass spectrometry-based method to simultaneously quantify numerous small-molecule thiols and disulfides in blood plasma. Application of this assay to analyze plasma from patients with known oxidative stress (sickle cell disease and sepsis) and from a patient with sickle cell disease treated with the antioxidant N-acetylcysteine suggests that cysteine disulfides, in particular protein-bound cysteine, serve as sensitive plasma biomarkers for the extent of oxidative stress and effectiveness of antioxidant treatment.
Assuntos
Anemia Falciforme/sangue , Cisteína/sangue , Dissulfetos/sangue , Estresse Oxidativo , Sepse/sangue , Acetilcisteína/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Humanos , Sepse/tratamento farmacológico , Sepse/metabolismoAssuntos
Infarto/diagnóstico por imagem , Rim/irrigação sanguínea , Trombocitemia Essencial/complicações , Doença Aguda , Adulto , Anticoagulantes/uso terapêutico , Biópsia , Medula Óssea/patologia , Meios de Contraste/administração & dosagem , Feminino , Taxa de Filtração Glomerular , Humanos , Hidroxiureia/uso terapêutico , Infarto/sangue , Infarto/tratamento farmacológico , Infarto/etiologia , Rim/diagnóstico por imagem , Rim/fisiopatologia , Trombocitemia Essencial/sangue , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/patologia , Tomografia Computadorizada por Raios X/métodosRESUMO
Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404-19. ©2017 AACR.See related commentary by Mackall and Miklos, p. 1371This article is highlighted in the In This Issue feature, p. 1355.