RESUMEN
BACKGROUND AND AIM: The German NPC-GPOH trials introduced treatment including neoadjuvant chemotherapy, radiochemotherapy (RCT) and antiviral treatment in patients aged 25 years or younger with nasopharyngeal cancer (NPC). We conducted a retrospective study on outcomes of patients at the age of ≥26 years treated accordingly at our institution. METHODS: Consecutive patients who received primary RCT for NPC were included. The Kaplan-Meier method was used to calculate survival probabilities, and the Cox regression analysis was used to test for an influence of the variables on outcomes. Acute and late toxicity were evaluated via CTCAE criteria and LENT/SOMA criteria, respectively. RESULTS: In total, 30 patients were included. Diagnosis was made from 09/1994 to 11/2016. The median 5 year overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS) and locoregional recurrence-free survival (LRC) were 75%, 56%, 83%, and 85%, respectively. We found a negative impact on outcomes (p < .05) in case of older age (OS), history of smoking (OS), and T4 stage/ UICC stage IV (DFS). WHO histologic type significantly influenced outcomes, with best outcomes for type III and worst outcomes for type I. The rates of acute and late toxicities were acceptable. CONCLUSION: We found excellent outcomes and good feasibility of the NPC-GPOH trials regimen in adult patients. Additionally, we identified patients with outcomes which need to be improved (smokers, histologic type I tumors) and with particularly excellent outcomes (histologic type III tumors). This stimulates further studies on treatment intensification or de-escalation aiming at reduced side effects with optimal tumor control in NPC.
Asunto(s)
Quimioradioterapia , Neoplasias Nasofaríngeas , Terapia Neoadyuvante , Humanos , Masculino , Femenino , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Quimioradioterapia/métodos , Terapia Neoadyuvante/métodos , Adulto Joven , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estadificación de Neoplasias , Anciano , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Supervivencia sin Enfermedad , Terapia Combinada/métodos , Tasa de SupervivenciaRESUMEN
Viral infections in tubular epithelial cells lead to the production of inflammatory cytokines by innate immunity, causing tubulointerstitial nephritis. TLR3 recognizes viral infections and acts via the activation of interferon (IFN)/IFN-stimulated genes (ISGs). This study investigates the role of ISG56, a representative ISG, in TLR3 signaling in cultured human renal proximal tubular epithelial cells (hRPTECs). To this end, hRPTECs were stimulated by a synthetic TLR3 ligand, polyinosinic-polycytidylic acid (poly IC), recombinant human interferon-ß [r(h)IFN-ß] or Japanese encephalitis virus (JEV) infection and assayed for inflammatory cytokine mRNA expression by RT-qPCR, and protein expression via western blotting or ELISA. ISG56 was expressed by poly IC or r(h)IFN-ß and IFN-ß knockdown reduced poly IC-induced expression of ISG56 and CXCL10. Moreover, ISG56 knockdown reduced poly IC- or r(h)IFN-ß-induced expression of CXCL10 at the same time as increasing JEV growth and reducing CXCL10 expression induced by JEV infection. Overall, TLR3 signaling induced IFN-ß-dependent expression of ISG56 and CXCL10. We show that ISG56 possibly plays a critical role in antiviral immunity of hRPTECs by positive regulation of IFN-ß-mediated CXCL10 expression downstream of TLR3.
Asunto(s)
Quimiocina CXCL10 , Células Epiteliales , Interferón beta , Túbulos Renales Proximales , Receptor Toll-Like 3 , Humanos , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 3/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/citología , Células Epiteliales/metabolismo , Interferón beta/metabolismo , Interferón beta/genética , Poli I-C/farmacología , Transducción de Señal , Células Cultivadas , Inmunidad Innata , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Péptidos y Proteínas de Señalización Intracelular , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
BACKGROUND: Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-ß (IFNß), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti-inflammatory properties and well-characterized safety profile suggest that IFNß has therapeutic potential for the treatment of ischemic stroke. METHODS AND RESULTS: We investigated the therapeutic effect of IFNß in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNß not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNß modulates ischemic brain inflammation were identified. IFNß reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. CONCLUSIONS: Our results demonstrate that IFNß exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNß is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator.
Asunto(s)
Antiinflamatorios/farmacología , Encéfalo/efectos de los fármacos , Infarto de la Arteria Cerebral Media/prevención & control , Interferón beta/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Moléculas de Adhesión Celular/metabolismo , Línea Celular , Quimiotaxis de Leucocito/efectos de los fármacos , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Infarto de la Arteria Cerebral Media/inmunología , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Mediadores de Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Receptor de Interferón alfa y beta/deficiencia , Receptor de Interferón alfa y beta/genéticaRESUMEN
Viral infection triggers innate immune signaling, which in turn induces interferon-ß (IFN-ß) production to establish innate antiviral immunity. Previous studies showed that Gcn5 (Kat2a), a histone acetyltransferase (HAT) with partial functional redundancy with PCAF (Kat2b), and Gcn5/PCAF-mediated histone H3K9 acetylation (H3K9ac) are enriched on the active IFNB gene promoter. However, whether Gcn5/PCAF and H3K9ac regulate IFN-ß production is unknown. Here, we show that Gcn5/PCAF-mediated H3K9ac correlates well with, but is surprisingly dispensable for, the expression of endogenous IFNB and the vast majority of active genes in fibroblasts. Instead, Gcn5/PCAF repress IFN-ß production and innate antiviral immunity in several cell types in a HAT-independent and non-transcriptional manner: by inhibiting the innate immune signaling kinase TBK1 in the cytoplasm. Our results thus identify Gcn5 and PCAF as negative regulators of IFN-ß production and innate immune signaling.