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1.
Clin Cancer Res ; 26(21): 5598-5608, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32816890

RESUMEN

PURPOSE: Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment. PATIENTS AND METHODS: Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS). RESULTS: Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; P = 0.091). Higher baseline serum levels of CXCL10 (P = 0.0197) and CEACAM1 (P = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; P = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes CA9 (P = 0.084), HIF1A (P = 0.064), and IFNG (P = 0.073) showed trending associations with ORR, and AKT3 (P = 0.0145), DDX58 (P = 0.0726), GZMA (P = 0.0666), LCN2 (NGAL; P = 0.0267), and PTPN11 (P = 0.0287) with PFS. CONCLUSIONS: With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Axitinib/administración & dosificación , Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antígenos de Neoplasias/sangre , Axitinib/efectos adversos , Biomarcadores de Tumor/genética , Anhidrasa Carbónica IX/sangre , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Proteína 58 DEAD Box/sangre , Relación Dosis-Respuesta a Droga , Femenino , Granzimas/sangre , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/sangre , Interferón gamma/sangre , Lipocalina 2/sangre , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neovascularización Patológica/sangre , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Supervivencia sin Progresión , Proteína Tirosina Fosfatasa no Receptora Tipo 11/sangre , Receptores Inmunológicos/sangre , Resultado del Tratamiento
2.
Life Sci ; 231: 116570, 2019 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-31207307

RESUMEN

AIMS: Systemic inflammation is a main hallmark of chronic kidney disease (CKD), but the underlying mechanisms of pathogenesis of CKD-associated systemic inflammation is unclear. Current study was designed to investigate the relationship between indoxyl sulphate (IS) and CKD-associated systemic inflammation along with the protective effects of Klotho in CKD. METHODS: IS serum levels from patients were detected by high-performance liquid chromatography (HPLC), and Serum Klotho, IL-6 and TNF-α were measured separately by ELISA and Real-Time PCR analysis. Monocytes were incubated with or without Klotho, while the expressions of retinoic acid-inducible gene I (RIG-I) and NF-κB were analyzed through Western blot assay. Heterozygous kl/kl (kl/+) mice or WT mice were treated with 5/6 renal damage. Thereafter, the CKD mice were intraperitoneally injected with recombinant Klotho protein or PBS. KEY FINDINGS: It shows that in 286 CKD patients, the serum levels of inflammatory factors were positively related with IS, but negatively related with Klotho. Klotho significantly inhibited IS-induced RIG-I/NF-κB activation and productions of both IL-6 and TNF-α in cultured monocytes. In vivo, along with the increase of IS and decrease of Klotho in the serum, the activation of RIG-I/NF-κB signaling was observed in peripheral blood monocytes in both CKD mice and patients. Notably, higher levels of IL-6 and TNF-α were detected in kl+/- mice given CKD. Klotho administration has evidently attenuated RIG-I/NF-κB activation in monocytes and systemic inflammation in CKD mice. SIGNIFICANCE: The findings suggest that Klotho can suppress CKD-associated systemic inflammation through inhibiting IS-induced RIG-1/NF-κB activation and monocyte inflammatory factor release.


Asunto(s)
Proteína 58 DEAD Box/sangre , Glucuronidasa/farmacología , Indicán/sangre , Monocitos/metabolismo , FN-kappa B/sangre , Insuficiencia Renal Crónica/sangre , Uremia/sangre , Adulto , Animales , Western Blotting , Femenino , Glucuronidasa/sangre , Humanos , Inflamación/sangre , Inflamación/patología , Interleucina-6/sangre , Riñón/metabolismo , Proteínas Klotho , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Monocitos/patología , Receptores Inmunológicos , Insuficiencia Renal Crónica/patología , Transducción de Señal , Células THP-1 , Factor de Necrosis Tumoral alfa/sangre , Uremia/patología
3.
J Clin Lab Anal ; 33(5): e22886, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30924966

RESUMEN

BACKGROUND: Innate immunity plays a crucial role in host-virus interactions and greatly influences viral replication including HBV infection. However, few studies have investigated the possible antiviral immune roles played by TLRs, RIG-I, and long no-coding RNA NEAT1 in chronic HBV infection (CHB) patients in clinical samples and their relationships among immune responses. In this study, we sought to investigate the mRNA expression levels of TLR1-10, RIG-I, and NEAT1 expression in HBeAg-positive CHB treatment-naïve patients with the active phase. METHODS: The expression levels of TLR1-10, RIG-I, and NEAT1 of CHB patients with the active phase and healthy controls were measured by qPCR. Serum HBV DNA and routine liver biochemistry including ALT, etc were also measured to evaluate the impaired physiological function of the liver affected by CHB. RESULTS: The expression levels of TLR1 and TLR6 in CHB with active phase were remarkably lower than that in healthy controls. The levels of TLR3 in CHB patients with active phase were remarkably higher than that in healthy controls. The total NEAT1 expression was abnormally decreased in CHB patients as compared with healthy controls. The levels of RIG-I were significantly decreased in CHB patients in the active phase when compared to healthy controls. The expression of TLR6 and RIG-I was closely correlated with NEAT1 expression. TLR6 level was positively correlated with RIG-I level. CONCLUSION: Chronic HBV infection can alter the innate immune response by downregulating functional expression of TLR1, TLR6, NEAT1.


Asunto(s)
Proteína 58 DEAD Box/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/etiología , ARN Largo no Codificante/sangre , Receptores Toll-Like/sangre , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Proteína 58 DEAD Box/genética , Regulación hacia Abajo/genética , Femenino , Regulación de la Expresión Génica , Humanos , Inmunidad Innata/genética , Masculino , Receptores Inmunológicos , Receptores Toll-Like/genética
4.
J Vasc Surg ; 68(6S): 39S-46S, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29567028

RESUMEN

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a vascular disease relatively common in the elderly population. Although some events that contribute to the development and progression of AAA are known, there are limited data examining the association of Toll-like receptor 3 (TLR3) and RIG-I-like receptor expression with the pathogenesis of AAAs. In this study, we investigated the gene and protein expression of TLR3 and RIG-I-like receptors (RIG-I and MDA5) in aortic wall and blood of AAA patients and examined the relationship between their expression and immune response. METHODS: Total RNA was extracted from aortic wall tissues and blood samples collected from 20 patients with AAA and blood samples of 17 healthy volunteers without aortic aneurysm. To evaluate the DDX58 (RIG-I), IFIH1 (MDA5), and TLR3 gene expression level, quantitative real-time polymerase chain reaction was used. Extracellular cytokine and pattern recognition receptor levels were quantified by enzyme-linked immunosorbent assays. RESULTS: TLR3, RIG-I, and MDA5 were constitutively expressed in both aortic tissues and blood samples from AAA patients and healthy volunteers. In patients with AAA, higher TLR3 expression in aortic tissues than in blood was found (P = .004). The DDX58 messenger RNA expression was higher in blood of patients with AAA compared with healthy subjects (P = .021). A significantly higher level of plasma interleukin 4 was noticed in patients with AAA than in healthy individuals (P = .008). CONCLUSIONS: This study suggests that RIG-I and TLR3 seem to be important factors in the pathogenesis of AAA.


Asunto(s)
Aorta Abdominal/química , Aneurisma de la Aorta Abdominal/genética , Proteína 58 DEAD Box/genética , Receptor Toll-Like 3/genética , Anciano , Aorta Abdominal/inmunología , Aorta Abdominal/virología , Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/inmunología , Aneurisma de la Aorta Abdominal/virología , Estudios de Casos y Controles , Proteína 58 DEAD Box/sangre , Femenino , Papillomavirus Humano 11/aislamiento & purificación , Humanos , Helicasa Inducida por Interferón IFIH1/sangre , Helicasa Inducida por Interferón IFIH1/genética , Interleucina-4/sangre , Masculino , Persona de Mediana Edad , Receptores Inmunológicos , Receptor Toll-Like 3/sangre
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