PURPOSE: The measuring Epstein-Barr virus (EBV) DNA is an important predictor of nasopharyngeal carcinoma (NPC). This study evaluated the predictive value of pretreatment serum amyloid A (SAA) and C-reactive protein (CRP) comparing with EBV DNA in patients with NPC. MATERIALS AND METHODS: In an observational study of 419 non-metastatic NPC patients, we prospectively evaluated the prognostic effects of pretreatment SAA, CRP, and EBV DNA on survival. The primary end-point was progress-free survival (PFS). RESULTS: The median level of SAA and CRP was 4.28 mg/L and 1.88 mg/L, respectively. For the high-SAA group (> 4.28 mg/L) versus the low-SAA (≤ 4.28 mg/L) group and the high-CRP group (> 1.88 mg/L) versus the low-CRP (≤ 1.88 mg/L) group, the 5-year PFS was 64.5% versus 73.1% (p=0.013) and 65.2% versus 73.3% (p=0.064), respectively. EBV DNA detection showed a superior predictive result, the 5-year PFS in the EBV DNA ≥ 1,500 copies/mL group was obviously different than the EBV DNA < 1,500 copies/mL group (62.2% versus 77.8%, p < 0.001). Multifactorial Cox regression analysis confirmed that in the PFS, the independent prognostic factors were including EBV DNA (hazard ratio [HR], 1.788; p=0.009), tumour stage (HR, 1.903; p=0.021), and node stage (HR, 1.498; p=0.049), but the SAA and CRP were not included in the independent prognostic factors. CONCLUSION: The results of SAA and CRP had a certain relationship with the prognosis of NPC, and the prognosis of patients with high level of SAA and CRP were poor. However, the predictive ability of SAA and CRP was lower than that of EBV DNA.
C-Reactive Protein* ; DNA* ; Herpesvirus 4, Human* ; Humans ; Observational Study ; Prognosis ; Prospective Studies* ; Serum Amyloid A Protein* ; Survival Analysis

PURPOSE: Little is known about combination of the circulating Epstein-Barr viral (EBV) DNA and tumor volume in prognosis of stage II nasopharyngeal carcinoma (NPC) patients in the intensity modulated radiotherapy (IMRT) era. We conducted this cohort study to evaluate the prognostic values of combining these two factors. MATERIALS AND METHODS: By Kaplan-Meier, we compare the differences of survival curves between 385 patients with different EBV DNA or tumor volume levels, or with the combination of two biomarkers mentioned above. RESULTS: Gross tumor volume of cervical lymph nodes (GTVnd, p < 0.001) and total tumor volume (GTVtotal, p < 0.001) were both closely related to pretreatment EBV DNA, while gross tumor volume of nasopharynx (GTVnx, p=0.047) was weakly related to EBV DNA. EBV DNA was significantly correlated with progress-free survival (PFS, p=0.005), locoregional-free survival (LRFS, p=0.039), and distant metastasis-free survival (DMFS, p=0.017), while GTVtotal, regardless of GTVnx and GTVnd, had a significant correlation with PFS and LRFS. The p-values of GTVtotal for PFS and LRFS were 0.008 and 0.001, respectively. According to GTVtotal and pretreatment EBV DNA level, patients were divided into a low-risk group (EBV DNA 0 copy/mL, GTVtotal < 30 cm³; EBV DNA 0 copy/mL, GTVtotal ≥ 30 cm³; or EBV DNA > 0 copy/mL, GTVtotal < 30 cm³) and a high-risk group (EBV DNA > 0 copy/mL, GTVtotal ≥ 30 cm³). When patients in the low-risk group were compared with those in the high-risk group, 3-year PFS (p=0.003), LRFS (p=0.010), and DMFS (p=0.031) rates were statistically significant. CONCLUSION: Pretreatment plasma EBV DNA and tumor volume were both closely correlated with prognosis of stage II NPC patients in the IMRT era. Combination of EBV DNA and tumor volume can refine prognosis and indicate for clinical therapy.
Biomarkers ; Cohort Studies* ; DNA* ; Herpesvirus 4, Human* ; Humans ; Lymph Nodes ; Nasopharynx ; Plasma ; Prognosis ; Radiotherapy* ; Tumor Burden*

This study was designed to investigate the inhibitory effects of sciadopitysin on the catalytic activities of human 12 kinds of UDP-glucuronosyltransferases (UGTs) in vitro. The risk of drug-drug interactions (DDI) is predicted by in vitro-in vivo extrapolation (IV-IVE). Methods A panel of recombinant human UGT isoforms and human liver microsome (HLM) as well as a series substrates including 4-methyl umbelliferone (4-MU), trifluoperazine (TFP) and N-3-carboxypropyl-4-hydroxy-1, 8-naphthalimide (NCHN) (UGT1A1 specific fluorescent probe substrates) were used to characterize the inhibitory effects of sciadopitysin on human UGTs in vitro. The half maximum inhibitory concentration (IC₅₀) and the constant of inhibition kinetics (K_i) were obtained by nonlinear regression using GraphPad Prism 6.0 software. The potential risk of DDI induced by UGT1A1 was predicted based on in vitro parameters. The results demonstrated that sciadopitysin had strong inhibitory effects on UGT1A1, UGT1A3, UGT1A8 and UGT1A10, with the remaining activity being below 30% at a final concentration of 10 μmol·L^-1. For UGT1A1, UGT1A3, UGT1A8 and UGT1A10, the IC₅₀ was 0.20 μmol·L^-1 to 1.34 μmol·L^-1, the inhibition kinetic constant K_i was 0.07 μmol·L^-1 to 2.12 μmol·L^-1. The AUC ratio of UGT1A1 can be increased by 19% to 147% at the oral dose of 240 mg·d^-1. The sciadopitysin competitively inhibited the formation of 4-MU-O-glucuronide by UGT1A1, UGT1A3, UGT1A8, and UGT1A10. At the same time, the inhibition of NCHN-O-glucuronidation by UGT1A1 was consistent with the competitive inhibition. The strong inhibition of sciadopitysin on UGT1A1 led to reduction of the metabolism of UGT1A1 substrates, and increased the risk of DDI. When co-administrated with other drugs, special attentions should be given to the DDI from inhibition of drug metabolism enzymes to prevent serious clinical consequences.

Objective Benzothiazole derivative BD960 has immunosuppressive activity after cell -based assays for high-throughput screening.The paper aimed to investigate the involved mechanism of BD960 on T cell proliferation. Methods Human peripheral blood T-lymphocytes were isolated and purified by the immunomagnetic microbeads.Then the T cells were activated by anti-CD3/anti-CD28 mAbs or alloantigen.The effect of BD960 on activa-ted T cell proliferation, the cytotoxic effect BD960 on resting T cells and the expression of activated T cells marker CD25 were measured by flow cytometer.Cytokine levels, including IL-2, IL-4, IL-6, IL-10, IL-17A and IFN-γ, were determined by ELISA. Results BD960 significantly inhibited the proliferation of T cells stimulated by anti-CD3/anti-CD28 mAb or alloantigen in a dose-dependent manner.The IC50 value is (2.3 ±0.3)μmol/L or (2.5 ±0.3)μmol/L, respectively.Moreover, BD960 had no obvious cytotoxic effects on rest-ing T cells and peripheral blood mononuclear cells, even at a high concentration ( up to 100μmol/L) .The ratio of CD25 expression on T cell was 69.7%after stimulated by Anti-CD3/CD28 mAbs with 72 h, the concentration (0.625、2.5、10)μmol/L of BD960 also had no potent effects on the ratio, but 0.1μmol/L FK506 could inhibit CD25 expression as low as 9.4%.The G0/G1 phase of activated T cells was 58.5%after stimulated by BD960 with 96 h.BD960 could induce cell cycle arrest at the G0/G1 phase in activated T cells with the increase of concentration and RAPA in the concentration of 0.1 μmol/L was 91.5%.In addition, BD960 (0.625、2.5、10)μmol/L could inhibit the secretion of IFN-γ, IL-6 and IL-17 in activated T cells with the increase of concentration, without any effects on the secretion of IL-2, IL-4 and IL-10. Conclusion BD960 not only exerts the inhibition on the late stage of T cell activation of cell proliferation but also inhibits the secretion of inflammatory cytokines, such as IL-6, IL-17 and IFN-γ, while the mechanism of BD960 on T cell proliferation was not the same as FK506.As a result, BD960 has the potential to be the lead compound to develop a new immunosuppressant.