RESUMEN
The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generate spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T-cells in the BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC.
Asunto(s)
Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Carcinoma Epitelial de Ovario/inmunología , Cistadenocarcinoma Seroso/inmunología , Neoplasias Ováricas/inmunología , Microambiente Tumoral/inmunología , Proteína BRCA1/genética , Proteína BRCA2/genética , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Carcinoma Epitelial de Ovario/genética , Cistadenocarcinoma Seroso/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Genotipo , Recombinación Homóloga , Humanos , Mutación , Neoplasias Ováricas/genética , Pronóstico , ProteómicaRESUMEN
Ten patients with amyotrophic lateral sclerosis were treated during 5 consecutive days with intravenous infusion of high-dose human leukocyte interferon-alpha (IFN-alpha) or placebo in a single-blinded randomized trial. To assess the effect of IFN on the water and electrolyte balance, serum electrolytes, creatinine, and antidiuretic hormone as well as urine excretion of electrolytes, aldosterone, and cortisol were measured before the trial and during the fourth day of IFN infusion. Compared with placebo the results showed a significant reduction of the mean serum calcium level (from 2.28 +/- 0.03 mmole/liter to 2.01 +/- 0.06 mmole/liter; p less than 0.01), that of the mean serum osmolality (from 296 +/- 9.9 mosm/kgH2O to 281 +/- 2.5 mosm/kgH2O; p less than 0.05) and that of the mean urinary excretion of magnesium (from 5.32 +/- 2.04 mmoles/liter to 2.65 +/- 1.68 mmoles/liter; p less than 0.05). Careful observation of water and electrolyte balance is emphasized during high-dose IFN treatment.
Asunto(s)
Interferón Tipo I/efectos adversos , Desequilibrio Hidroelectrolítico/inducido químicamente , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Humanos , Infusiones Intravenosas , Interferón Tipo I/administración & dosificación , Interferón Tipo I/uso terapéutico , Distribución Aleatoria , Método Simple CiegoRESUMEN
Fatty acid patterns of plasma and platelet lipids, platelet aggregation and thromboxane A2 (TxA2) production were studied in young patients (n = 12) with brain infarction and in healthy controls (n = 13). Platelet arachidonic acid content was significantly reduced in the stroke patients, but in vitro platelet aggregation was similar in the two groups. A low dose of acetosalicylic acid (ASA) (100 mg) suppressed thromboxane production and normalized the platelet arachidonic acid values. The low arachidonic acid in platelets is probably due to its increased consumption, indicating platelet activation in vivo.
