宫颈病变与人乳头瘤病毒感染临床病例分析

目的评价人乳头瘤病毒(Human Papillomavirus,HPV)感染在宫颈病变早期筛查中的作用,为进一步诊断和判断预后提供依据。方法来我院进行宫颈癌筛查,因宫颈液基薄层细胞学检查存在异常细胞妇女413例,均进行阴道镜下组织活检和HPV-DNA分型。结果上皮内瘤样病变(CIN)I患者中以ASCUS检出符合率最高,CIN II患者中以LSIL检出符合率最高,CIN III患者中以HSIL检出符合率最高。慢性宫颈炎患者一种或多种高危型HPV(HR-HPV)感染率要低于CIN患者(χ2=32.105,P=0.000),宫颈癌HR-HPV感染率为100%;慢性宫颈炎患者与CIN患者低危型HPV(LR-HPV)感染率比较,差异无统计学意义(χ2=0.205,P=0.650)。宫颈病变患者以单一HR-HPV亚型感染更常见。结论宫颈癌及癌前病变与HPV感染密切相关,HR-HPV基因检测及分型在宫颈病变的预后判断、疗效监测等方面具有重要价值。     

Single Nucleotide Polymorphisms in the FADS Gene Cluster but not the ELOVL2 Gene are Associated with Serum Polyunsaturated Fatty Acid Composition and Development of Allergy (in a Swedish Birth Cohort)

Exposure to polyunsaturated fatty acids (PUFA) influences immune function and may affect the risk of allergy development. Long chain PUFAs are produced from dietary precursors catalyzed by desaturases and elongases encoded by FADS and ELOVL genes. In 211 subjects, we investigated whether polymorphisms in the FADS gene cluster and the ELOVL2 gene were associated with allergy or PUFA composition in serum phospholipids in a Swedish birth-cohort sampled at birth and at 13 years of age; allergy was diagnosed at 13 years of age. Minor allele carriers of rs102275 and rs174448 (FADS gene cluster) had decreased proportions of 20:4 n-6 in cord and adolescent serum and increased proportions of 20:3 n-6 in cord serum as well as a nominally reduced risk of developing atopic eczema, but not respiratory allergy, at 13 years of age. Minor allele carriers of rs17606561 in the ELOVL2 gene had nominally decreased proportions of 20:4 n-6 in cord serum but ELOVL polymorphisms (rs2236212 and rs17606561) were not associated with allergy development. Thus, reduced capacity to desaturase n-6 PUFAs due to FADS polymorphisms was nominally associated with reduced risk for eczema development, which could indicate a pathogenic role for long-chain PUFAs in allergy development.     

Association between SERPING1 rs2511989 polymorphism and age-related macular degeneration: Meta-analysis

AIM: To investigate the association between SERPING1 rs2511989 (G>A) polymorphism and age-related macular degeneration (AMD). METHODS: A number of electronic databases (up to July 15, 2014) were searched independently by two investigators. A Meta-analysis was performed on the association between SERPING1 rs2511989 polymorphism and AMD. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: Eight studies with 16 cohorts consisting of 9163 cases and 6813 controls were included in this Meta-analysis. There was no significant association between rs2511989 polymorphism and AMD under all genetic models in overall estimates (A vs G: OR= 0.938, 95%CI =0.858-1.025; AA vs GG:OR =0.871, 95%CI =0.719-1.056; AG vs GG: OR =0.944, 95%CI =0.845-1.054; AA+AG vs GG: OR =0.927, 95% CI =0.823-1.044; AA vs AG+GG: OR =0.890, 95%CI =0.780-1.034). Cumulative Meta-analyses also showed a trend of no association between rs2511989 polymorphism and AMD as information accumulated by year. Subgroup analysis and Meta-regression analysis indicated that age-matching status was the main source of heterogeneity. Sensitivity analysis found the results in overall comparisons and subgroup comparisons of white subjects under the allele model were found to have significantly statistical differences after studies deviating from Hardy-Weinberg equilibrium (HWE) were excluded (overall: OR=0.918, 95%CI = 0.844-0.999, P =0.049; whites: OR =0.901, 95%CI = 0.817-0.994, P =0.038). However, the results were not sufficiently robust for further sensitivity analysis and statistical differences disappeared on applying Bonferroni correction (with a significance level set at 0.05/25). CONCLUSION: This Meta-analysis indicates that SERPING1 rs2511989 polymorphism and AMD tend to have no association with each other. Age matching status is a big confounding factor, and more studies with subtle designs are warranted in future.     

高危型HPV感染宫颈病变中E6/E7 mRNA的表达水平

目的探讨人乳头状瘤病毒(HPV)E6/E7 m RNA检测对高危型人乳头瘤病毒(HR-HPV)感染宫颈病变筛查的临床价值。方法选择265例HR-HPV感染者,其中100例病理结果为正常宫颈/慢性炎症(对照组),88例宫颈上皮内瘤变(CIN)Ⅰ级,33例CINⅡ级,28例CINⅢ级,16例宫颈癌患者的宫颈脱落细胞标本,采用支链DNA(b-DNA)技术检测HPV E6/E7 m RNA的表达情况。结果 CINⅡ级(81.82%)、CINⅢ级(89.29%)、宫颈癌组(100.00%)的HPV E6/E7 m RNA阳性率高于对照组(20.00%)和CINⅠ级(35.23%),差异有统计学意义,其余各组间比较差异无统计学意义;CINⅡ级、CINⅢ级、宫颈癌组的HPV E6/E7 m RNA表达量也高于对照组和CINⅠ级,差异有统计学意义,其余各组间比较差异无统计学意义;高级别鳞状上皮内瘤变(HSIL)和癌组的HPV E6/E7 m RNA阳性率及表达量显著高于正常、非典型鳞状细胞(ASC)和低级别鳞状上皮内瘤变(LSIL)组(P<0.05)。结论 HPV E6/E7 m RNA的表达可能提示了病毒的活性和病变的进展程度,可能成为筛查出高级别宫颈病变的有效指标,可以作为宫颈癌前病变筛查的辅助方法。     

Non‐clinical safety evaluation of single and repeated intramuscular administrations of MAGE‐A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys

The MAGE‐A3 recombinant protein combined with AS15 immunostimulant (MAGE‐A3 Cancer Immunotherapeutic) is under development by GlaxoSmithKline for the treatment of lung cancer and melanoma. We performed non‐clinical safety studies evaluating potential local and systemic toxic effects induced by MAGE‐A3 Cancer Immunotherapeutic in rabbits (study 1) and cynomolgus monkeys (study 2). Animals were allocated to two groups to receive a single (rabbits) or 25 repeated (every 2 weeks) injections (monkeys) of MAGE‐A3 Cancer Immunotherapeutic (treatment groups) or saline (control groups). All rabbits were sacrificed 3 days post‐injection and monkeys 3 days following last injection (3/5 per gender per group) or after a 3‐month treatment‐free period (2/5 per gender per group). Local and systemic reactions and MAGE‐A3‐specific immune responses (monkeys) were assessed. Macroscopic and microscopic (for rabbits, injection site only) post‐mortem examinations were performed on all animals. No systemic toxicity or unscheduled mortalities were recorded. Single (rabbits) and repeated (monkeys; up to four times at the same site) injections were well tolerated. Following five to seven repeated injections, limb circumferences increased up to 26% (5 h post‐injection), but returned to normal after 1–8 days. Three days after the last injection, enlargements of iliac, popliteal, axillary and inguinal lymph nodes, and increased incidence or severity of mononuclear inflammatory cell infiltrates was observed in injected muscles of treated monkeys. No treatment‐related macroscopic findings were recorded after the treatment‐free period. MAGE‐A3‐specific antibody and T‐cell responses were raised in all treated monkeys, confirming test item exposure. Single or repeated intramuscular injections of MAGE‐A3 Cancer Immunotherapeutic were well tolerated in rabbits and monkeys. Copyright © 2014 GlaxoSmithKline Vaccines. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.     

The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer

Enhancer of zeste 2 (EZH2), a polycomb histone methyltransferase, is overexpressed in various cancers, including cervical cancer. Gene expression analysis revealed that increased expression of EZH2 is associated with cervical cancer progression, particularly the progression to invasive squamous cell carcinoma. Enhancer of zeste 2 is known to trimethylate lysine 27 on histone H3, leading to gene silencing that contributes to the progression of tumours into a more aggressive form of cancer. However, the specific molecular mechanisms by which EZH2 contributes to the development of cervical cancer remain largely unknown. Recently, an EZH2 inhibitor was reported to selectively inhibit trimethylated lysine 27 on histone H3 and to reactivate silenced genes in cancer cells. In this study, we found that GSK343 (a specific inhibitor of EZH2 methyltransferase) induces phenotypic reprogramming of cancer cells from mesenchymal to epithelial cells, reducing proliferation and cell motility and blocking the invasion of cervical cancer cell lines both in vitro and in vivo. Treatment with the EZH2 inhibitor led to increased levels of the epithelial marker E‐cadherin and decreased levels of mesenchymal markers such as N‐cadherin and vimentin. The observed reprogramming is associated with restrained cervical cancer progression and provides direct evidence in support of EZH2 as a therapeutic target.     

The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients

Aim

Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.

Methods

The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan–Meier analysis.

Results

The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HR_PFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HR_OS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.

Conclusions

Discrepancies between preclinical success and clinical failure may be due to the patients'' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.     

Alcohol policy impact on young risky drinkers and their support for proposed measures

Objective: To explore the impacts of existing policies on young Australian risky drinkers' access to alcohol and to gauge their support for proposed alcohol measures. Methods: The 16–19 year old participants were recruited from three Australian states using non‐random convenience sampling, for either a face‐to‐face or online quantitative survey (N=958). The sample was deliberately selected to represent drinkers whose consumption placed them in the riskiest drinking 20–25% of their age bracket. Results: Half (49%) the sample who were younger than the Australian legal purchase age reported it was ‘easy’ to buy alcohol from bottle stores, and 75% of those who had tried to purchase alcohol, said it was ‘easy’ the last time they tried. Half of those under 18, who had attempted to enter a licensed venue, reported they did not have their identification checked last time they gained access. Ninety per cent of all respondents drank within a private location at their last risky drinking session. Sixty‐five per cent supported ‘increasing the price of [alcohol by 20¢] a standard drink if the extra 20¢ was used to support prevention and treatment of alcohol problems'. Conclusions: Age‐ or intoxication‐based restrictions to alcohol were commonly bypassed. Implications: Point‐of‐sale alcohol controls require improvement to prevent under age access. Given that a significant proportion of drinking occasions for those under 18 were in private premises, prevention strategies need to target these locations. There were diverse levels of support for strategies to reduce harm, including potential community backing for an evidence‐based proposed price policy.