Functional variant in the 3'-untranslated region of Toll-like receptor 4 is associated with nasopharyngeal carcinoma risk.

Signaling pathways activated by the Toll-like receptor 4 (TLR4) involve the induction of anti-cancer immunity. While screening for nasopharyngeal carcinoma (NPC) susceptibility genes, we isolated TLR4 and found that the 3'-untranslated region (3'-UTR) of exon 4 contained two polymorphisms that may alter its translation efficiency, potentially leading to NPC. To test this hypothesis, we conducted a hospital-based case-controlled study on NPC patients and cancer-free controls. We determined that the variant allele 11350C and the 11350GC genotype were associated with a significantly increased risk for NPC. We also determined significant differences between the male gender group and the remaining patient cases and controls, and between subjects equal to or younger than 47 years old and the cases and controls. Secondly, we cloned the entire 3'-UTR into a luciferase reporter system, and compared the luciferase activities between the wild-type 3'-UTR construct (WILD) and a construct containing the 11350C variant (MUT). Both constructs caused lower reporter gene activities, as compared to the positive control pGL3-promoter plasmid. Sixty hours after the transfections, the MUT construct reduced the reporter gene activity by 40% compared to that of the WILD construct (P<0.05). Functional analyses of the 11350C variant suggested that the TLR4 3'-UTR is a potent regulator of gene expression, as the mutated TLR4 3'-UTR was associated with decreased mRNA stability, and may down-regulate TLR4 expression resulting in EBV metainfective antiviral immunologic deficits and a high risk of NPC.

V-val subtype of Epstein-Barr virus nuclear antigen 1 preferentially exists in biopsies of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) has been suggested to be involved in pathogenesis of nasopharyngeal carcinoma (NPC). However, EBV infection is ubiquitous, whereas NPC occurs with strong geographic and racial distribution. Whether a substrain of EBV contributes to this phenomenon remains uncertain. Epstein-Barr virus nuclear antigen 1 (EBNA-1) is one of the most frequently detected EBV proteins in NPC tissues. Based on the polymorphism of amino acids at position 487, EBNA-1 is classified into five subtypes: P-ala, P-thr, V-val, V-leu and V-pro. To examine the relationship between subtypes of EBNA-1 and NPC, we determined the subtypes of EBNA-1 in biopsies of NPC, peripheral blood lymphocytes (PBL), and throat washings (TWs) obtained in endemic and non-endemic areas of NPC within China. The results revealed that V-val was the only subtype detected in NPC tissue, whereas three subtypes of EBNA-1, V-val, P-ala, and P-thr, were detected in PBL and TWs irrespective of origin, and mixed infection of V-val and P-ala was also observed. In addition, the variations of V-val derived from biopsies of NPC were identical to those derived from PBL and TWs in the context of N-terminus and C-terminus of EBNA-1. These facts indicate that a substrain of EBV with V-val subtype of EBNA-1 infects NPC preferentially and a susceptibility to a particular EBV isolate in the nasopharynx may exist during development of NPC.

[Effects of sustained release morphine hydrochloride tablets in management of cancer pain: a survey of 567 patients].

OBJECTIVE: To evaluate the effect and adverse effects of morphine hydrochloric sustained release for patients with cancer pain. METHODS: A total of 567 patients, 369 males (65.1%) and 198 females (34.9%), aged 65 - 90 with a mean age of 72.6, with cancer pain, 67.4% with severe pain, 28.2% with moderate pain, a and 4.4% with mild pain, that were treated in 25 hospitals from 13 provinces received oral morphine hydrochloric sustained release. The recommended initial dosage was 30 mg every 12 hours, and then the dosage was regulated according to the effects until the ideal anesthesia was achieved. All patients were asked to record the attacks of pain, quality of life, and any side effect of the treatment. RESULTS: The baseline mean pain intensity (NRS) was 7.0 +/- 1.8. On the day 1, 5, 10, 15, 20, 25 and 30, the mean pain scores were decreased to 4.6 +/- 2.6, 2.8 +/- 1.8, 2.7 +/- 1.8, 2.6 +/- 1.7, 2.5 +/- 1.6, 2.3 +/- 1.4, and 2.2 +/- 1.4 respectively (all P = 0.000). The general effective rate on day 30 was 89.8%. The mean dosages were 66 +/- 56 mg/d initially, 84 +/- 64 mg/d (10 - 800 mg/d) on day 15, and 92 +/- 67 mg/d (10 - 800 mg/d) on day 30. On the day 30, 55.1% of the patients received a dosage or= 241 mg/d. Ninety-one point six percent (89.4% - 95.8%) of the patients took morphine orally twice daily. The poor quality of life rate in the patients was 90.5% before treatment, and were 56.8% and 49.6% respectively on the day 15 and day 30 (P = 0.0000 and P = 0.0009). The incidence of side effects was 35.6% on day 1, and 15.1% on day 30. The common side effects were constipation (14.3%), nausea (13.4%), dizziness (3.4%), vomiting (2.8%), drowsiness (0.7%), dysuria (0.4%), mental symptoms (0.2%), and respiratory depression (0.2%). Sixty-eight point four percent of the patients preferred continuation of sustained release morphine hydrochloride treatment. CONCLUSION: Oral treatment with sustained release morphine hydrochloride for patients with cancer pain is effective, safe, and convenient, and can improve the quality of life. Sustained release morphine hydrochloride is worth recommending as a first-line drug for the treatment of patients with moderate to severe cancer pain, and the usually dosage is 120 mg or less per day.

Genome-wide scan for familial nasopharyngeal carcinoma reveals evidence of linkage to chromosome 4.

Nasopharyngeal carcinoma (NPC) occurs with high frequency in Asian populations, especially among people of Cantonese ancestry. In areas with high incidence, NPC clusters in families, which suggests that both geography and genetics may influence disease risk. Although the HLA-Bw46 locus is associated with increased risk of NPC, no predisposing genes have been identified so far. Here we report the results of a genome-wide search carried out in families at high risk of NPC from Guangdong Province, China. Parametric analyses provide evidence of linkage to the D4S405 marker on chromosome 4 with a logarithm of odds for linkage (lod) score of 3.06 and a heterogeneity-adjusted lod (hlod) score of 3.21. Fine mapping with additional markers flanking D4S405 resulted in a lod score of 3.54 and hlod score of 3.67 for the region 4p15.1-q12. Multipoint nonparametric linkage analysis gives lod scores of 3.54 at D4S405 (P = 5.4 x 10(-5)) and 4.2 at D4S3002 (P = 1.1 x 10(-5)), which is positioned 4.5 cM away from D4S405. When Epstein Barr virus antibody titer was included as a covariate, the lod scores reached 4.70 (P = 2.0 x 10(-5)) and 5.36 (P = 4.36 x 10(-6)) for D4S405 and D4S3002, respectively. Our findings provide evidence of a major susceptibility locus for NPC on chromosome 4 in a subset of families.