RESUMEN
BACKGROUND: Fibrosis progression in hepatitis C virus (HCV)-infected patients varies greatly between individuals. Chemokines recruit immune cells to the infected liver and may thus play a role in the fibrosis process. AIM: To investigate plasma levels of a diverse chemokine panel in relation to liver fibrosis. METHODS: African-American and Caucasian HCV genotype 1 infected patients were treated with peginterferon (pegIFN) and ribavirin (RBV) for 48 weeks (VIRAHEP-C cohort). Plasma levels of 13 cytokines were studied at baseline (n = 386). Subsequently, GROα levels were assessed in a sub cohort (n = 99) at baseline, and at 4 and 12 weeks after start of pegIFN/RBV treatment. RESULTS: Increased severity of fibrosis (Ishak fibrosis score 0-2 vs. 3-6) was associated with increased plasma IP-10 (CXCL10) and IL-8 (CXCL8) levels, and decreased plasma levels of the chemokine growth-related oncogene (GRO, CXCL1-3). Plasma GRO levels were also positively correlated with platelet counts, and were higher in African-American as compared to Caucasian patients. In response to pegIFN/RBV treatment, GROα levels increased in Caucasian but not African-American patients from week 4 onwards. CONCLUSIONS: The association with severity of fibrosis and platelet count positions plasma GRO as a potential biomarker for liver fibrosis in HCV-infected patients. The secretion of GRO by platelets may explain the correlation between GRO plasma level and platelet count. The ethnic difference in GRO levels both pre-treatment and in response to pegIFN/RBV might be driven by a genetic polymorphism in GROα associated with higher plasma levels and more common in the African-American population.
Asunto(s)
Antivirales/uso terapéutico , Quimiocinas/sangre , Hepatitis C/complicaciones , Interferón-alfa/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/fisiopatología , Recuento de Plaquetas , Ribavirina/uso terapéutico , Adulto , Negro o Afroamericano/genética , Anciano , Biomarcadores , Quimiocina CXCL1 , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Humanos , Interferón alfa-2 , Interleucina-8 , Interleucinas , Cirrosis Hepática/etiología , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Polimorfismo Genético , Proteínas Recombinantes , Población Blanca/genética , Adulto JovenRESUMEN
Neurodegenerative diseases are difficult to study due to unavailability of human neurons. Cell culture systems and primary rodent cultures have shown to be indispensable to clarify disease mechanisms and provide insights into gene functions. Nevertheless, it is hard to translate new findings into new medicines. The discovery of human induced pluripotent stem cells (iPSC) might partially overcome this problem. Commercially available human iPSC-derived neurons, when thoroughly characterized and suitable for viral transduction, might represent a faster model for drugs screening than the time-consuming derivation and differentiation of iPSC from patient samples. In this study we show that iCell® neurons are primarily immature GABAergic neurons within the tested time frame. Addition of C6 glioma conditioned medium improved the bursting frequency of cells without further maturation or evidence for glutamatergic responses. Furthermore, cells were suitable for lentiviral transduction within the tested time frame. Altogether, iCell® neurons might be useful to model neurodegenerative diseases in which young GABAergic subtypes are affected.
