一氧化氮、人乳头瘤病毒和宫颈癌之间相互关系的研究进展

人乳头瘤病毒感染是宫颈癌发生的重要始动原因,从HPV感染到宫颈癌发生,需要许多共刺激因子的参与。这些共刺激因子均可引起宫颈局部一氧化氮浓度的增高。而一氧化氮既可影响HPV的转录和翻译,又在肿瘤发生过程中具有重要调节作用。深入研究一氧化氮、人乳头瘤病毒感染及宫颈癌之间的关系,可为宫颈癌的防治提供新的重要理论基础和药物研制实验平台,通过使用一氧化氮合酶抑制剂降低宫颈局部NO浓度将为全面有效防治宫颈癌带来新的希望。     

Human papillomavirus infection in women with and without cervical cancer in Tbilisi, Georgia

Background: No accurate estimates of cervical cancer incidence or mortality currently exist in Georgia. Nor are there any data on the population-based prevalence of high-risk (HR) human papillomavirus (HPV) infection, which, in the absence of good-quality screening, is known to correlate with cervical cancer incidence. Methods: We obtained cervical cell specimens from 1309 women aged 18–59 years from the general population of Tbilisi, and also from 91 locally diagnosed invasive cervical cancers (ICC). DNA of 44 HPV types was tested for using a GP5+/6+-based PCR assay. Results: In the general population (of whom 2% reported a previous Pap smear) HPV prevalence was 13.5% (95% CI: 11.6–15.9), being highest in women aged 25–34 years (18.7%) and falling to between 8.6% and 9.5% for all age groups above 34 years. HR HPV prevalence was 8.6% overall, being 6.8% and 38.9% among women with normal and abnormal cytology, respectively. HPV45 (1.6%) was the most common type in women with normal cytology, whereas HPV16 predominated among women with cervical abnormalities (including 7 of 10 histologically confirmed cervical intraepithelial neoplasia 2/3) and among ICC (57.6%). The next most common types in ICC in Georgia were HPV45 and 18 (13.2 and 11.0%, respectively). Conclusions: We report a relatively high burden of HPV infection in Tbilisi, Georgia. Improving cervical cancer prevention, through screening and/or HPV vaccination, is an important public health issue in Georgia, where 70% of ICC are theoretically preventable by HPV16/18 vaccines.     

人乳头瘤病毒感染与宫颈癌的研究进展

人乳头瘤病毒(Human Papillomavirus HPV)感染是导致性传播疾病的常见原因,上世纪八十年代初,首次报道生殖器HPV感染与宫颈癌之间的联系,认为HPV感染是95%以上宫颈癌变的高危因素。随着分子生物学技术的发展,对HPV致癌机制的研究不断深入,取得大量有价值的成果,现就HPV的致癌途径与协同因素探讨宫颈癌的发病机制以及对HPV检测方法等方面的研究进行综述。     

A retrospective analysis of human papillomavirus (HPV) prevalence and genotype distribution among 25,238 women in Shanghai,China revealed the limitations of current HPV-based screening and HPV vaccine

BackgroundTo determine the human papillomavirus (HPV) type-specific prevalence and distribution among women with various age and cervical lesions in Shanghai, China. And to evaluate the carcinogenicity of different high-risk HPV (HR-HPV) and the efficacy of HR-HPV testing and HPV vaccine.MethodsThe clinical data from 25,238 participants who received HR-HPV testing (HPV GenoArray test kit, HybriBio Ltd) at the Affiliated Hospital of Tongji University from 2016 to 2019 were reviewed and analyzed using SPSS (version 20.0, Tongji University, China).ResultsThe overall prevalence of HPV was 45.57% in the study population, of which 93.51% were found HR-HPV infection. The three most prevalent HR-HPV genotypes were HPV 52 (22.47%), 16 (16.4%) and 58 (15.93%) among HPV-positive women, and HPV 16 (43.30%), 18 (9.28%) and 58 (7.22%) in women with histologically confirmed cervical cancer (CC). 8.25% of CC were found to be HPV negative. Only 83.51% of CC cases were related to the HPV genotypes covered by nine-valent HPV vaccine. HPV prevalence and genotype distribution varied with age and cervical histology. The odds ratios (OR) of HR-HPV for CC were also different, among which the top three types were HPV 45 [OR= 40.13, 95% confidence intervals (CI) 10.37–155.38], 16 (OR=33.98, 95%CI 15.90–72.60) and 18 (OR=21.11, 95%CI 8.09–55.09). The increase in the types of HPV infection did not increase the risk of CC correspondingly. As the primary cervical screening method, HR-HPV testing showed the high sensitivity (93.97%, 95%CI 92.00–95.49) but low specificity (42.82%, 95%CI 41.81–43.84).ConclusionsOur study provide the comprehensive epidemiological data on HPV prevalence and genotype distribution among Shanghai women with various cervical histology, which can not only serve as a significant reference for clinical practice, but also implicated the need of more effective CC screening methods and HPV vaccine covering more subtypes.     

Human papillomavirus genotype distribution in cervical intraepithelial neoplasia grades 1 or worse among 4215 Chinese women in a population-based study

PurposeTo estimate the burden of human papillomavirus (HPV) infection and cervical disease among sexually active women in a sample of Chinese women.MethodsA multicenter, population-based study was conducted between May 2006 and April 2007. A total of 4215 sexually active women aged 17–54 years were surveyed from five geographical sites representing both urban and rural areas: Beijing, Shanghai, Shanxi, Henan and Xinjiang. Women were referred for colposcopy on the basis of results of Pap testing and HPV screening. HPV genotyping of the CIN1+ specimens was performed with INNO-LiPA. Attribution of HPV types to lesions was estimated using a fractional contribution approach.Results13.3% of the women (559/4215) were referred for colposcopy; 4.3% (183/4215) of these were diagnosed with CIN1+. Of the latter, 88.5% (162/183) were typed and 94.4% (153/162) were HPV-positive. HPV16 was the most prevalent type in lesions in both urban and rural settings. Combined, HPV16 and 18 were attributable to 71.4% of HPV-positive CIN2+ lesions. In addition, HPV31, 33, 52 and 58 were prevalent in CIN1+ lesions, with HPV33, 52, and 58 combined accounting for 24.1% CIN2+ lesions. Though prevalent, HPV31 always occurred as a co-infection with another HPV type and therefore was attributed minimal causality.ConclusionsHPV16 and 18 are associated with the majority of cervical lesions in Chinese women from which this population-based sample was drawn. In addition, other HPV types, such as 33, 52, and 58, also play an important role in cervical disease.     

STAT3基因多态性与女性人乳头瘤病毒感染及宫颈病变的关系

目的探究女性人乳头瘤病毒(HPV)感染及转录活化因子3(STAT3)单核苷酸基因多态性(SNPs)的改变。方法2016年9月至2019年9月经病理组织学确定的健康子宫者60例(NC组)、低度鳞状上皮内病变(LSIL)50例(LSIL组)、高度鳞状上皮内病变(HSIL)55例(HSIL组)和宫颈鳞状细胞癌(CSCC)57例(CSCC组),PCR测定HPV感染情况,同时采用PCR 限制片段长度多态性(RFLP)测定各组STAT3基因C1697G多态性。结果HSIL组、LSIL组及CSCC组高危HPV与NC组比较阳性率显著升高,CSCC组(98.24%)显著高于HSIL组(72.73%)和LSIL组(5.8%),HSIL组显著高于LSIL组,结果均具有统计学差异(P<0.05)。LSIL组、HSIL组及CSCC组中与NC组比较显著升高的基因比例为C/C型,CSCC组C/C型基因比例为70.18%,HSIL组(58.18%)C/C型基因比例显著高于LSIL组(0.18%)(P<0.05)。与HPV阴性比较,C/C型基因比例在HPV阳性中显著升高(P<0.05)。通过调整年龄因素,C/G基因型HPV感染风险上升到3.120(95％CI:0.847～4.995),发生宫颈癌的风险上升到3.876(95％CI为0.935～5.336);C/C型基因HPV感染风险上升到3.574(95％CI为0.893～4.912),发生宫颈癌的风险上升到5.137(95％CI为0.967～5.776)。结论STAT3基因C1697G多态性与HPV易感性及宫颈病变的发生发展有密切关系。     

Prevalence and correlation of human papillomavirus genotypes with clinical factors in cervical samples from Mexican women

In the last decade, the inclusion of HPV DNA testing in cervical cancer screening has provided one of the best strategies for the prevention and timely detection of HPV. We conducted a high-throughput HPV genotyping study based on MALDI-TOF mass spectrometry to determine the prevalence of 24 HPV genotypes, including oncogenic genotypes, in Mexican women and correlated the results with cytological findings and clinical variables. We likewise identified the risk factors in patients with the HPV infection. Our study included 1000 women from Sonora, Mexico, who participated in cervical cancer screening campaigns and who underwent a Pap smear and HPV DNA test. The results showed that the overall prevalence of HPV was 27.2%, 18.5% with single, and 8.7% multiple infections. The low-risk HPV genotype 6 (8.5%) and oncogenic genotypes 31 (8.1%) and 53 (4.4%) were the most prevalent in the study population. The number of lifetime sexual partners, previous STIs, and age at first intercourse was significantly associated with HPV infection (P ≤ 0.05). Smoking (OR = 1.5609; 95% IC 1.062–2.292) and more than three lifetime sexual partners (OR = 1.609; 95% IC = 1.124–2.303) represented risk factors for HPV infection. Cytological abnormalities were found in 3.4% of the HPV-positive samples. CIN 1–3 occurred in 0.6% of high-risk HPV cases. In general, the prevalence of the HPV genotypes is high in Mexican women with normal cytological findings. This issue highlights the importance of HPV research in seemingly healthy women and could help guide screening strategies for cervical cancer prevention in Mexico.Impact statementWe are submitting data regarding the prevalence and type distribution of the HPV infection and the risk factors associated with it, which may provide a valuable reference to reinforce screening strategies, and to maintain HPV genotype surveillance in Mexico. We discuss the overall prevalence of HPV infection as detected in normal cytological samples stratified by age, different types of infection, and oncogenic capacity. One of the most important findings was that common HPV genotypes detected in healthy women were the genotype numbers: 6, 31, 16, and 56, likewise, smoking and having a history of more than three sexual partners over their lifetime, represented the main risk factors in this study. Furthermore, we found a low frequency of cytological abnormalities and CIN 1–3 in women with HR-HPV.     

Human papillomavirus type 16 viral load in relation to HIV infection,cervical neoplasia and cancer in Senegal

Background: The importance of human papillomavirus (HPV) viral load in the pathogenesis of cervical cancer among HIV-infected and HIV-uninfected women has not yet been established. Methods: In this cross-sectional study, HPV-16 viral loads were measured using previously-collected and frozen cervical swab samples from 498 HPV-16 positive Senegalese women (368 HIV-seronegative, 126 HIV-1 and/or HIV-2 seropositive). The real-time polymerase chain reaction assay was used to quantify HPV-16 E7 copy number normalized by human cellular DNA (β-actin), and viral loads were log₁₀ transformed. Associations between HPV-16 viral load, degree of cervical abnormality, and HIV status were assessed using multinomial and linear regression methods. Results: Compared to women with normal cytology, the likelihood of CIN1 (OR_a: 1.21, 95% CI 0.93–1.57), CIN2-3 (OR_a: 2.38, 95% CI 1.72–3.29) and cancer (OR_a: 2.12, 95% CI 1.52–2.96) was found to increase for each 1-unit log₁₀ increase in HPV-16 viral load. Compared to HIV-negative women, HIV-positive women had higher average HPV-16 viral load values (β_a: 0.39, 95% CI 0.03–0.75), even after accounting for degree of cervical abnormality. Conclusion: In our study of women including those with cancer, HPV-16 viral load was associated with a higher likelihood of cervical abnormalities. However, substantial overlaps across categories of disease severity existed. Higher viral load among HIV-infected individuals may indicate that HIV infection influences HPV viral replication factors.     

阴道微生态与高危型人乳头瘤病毒感染及宫颈病变的相关性

目的 探究阴道微生态与高危型人乳头瘤病毒(HR HPV)感染以及宫颈病变之间的相关性,为后续研究提供参考。 方法 选择2018年1月至2019年6月就诊于石河子大学医学院第一附属医院妇科门诊,同时行爱必维(细菌性阴道病五项联合测定试剂盒)检测、HR HPV检测及宫颈组织病理检查的343名妇女作为研究对象,分析相关检测数据并探究阴道微生态与HR HPV感染以及宫颈病变的相关性。 结果 过氧化氢阳性、唾液酸苷酶阳性、白细胞酯酶阳性、乳杆菌数量减少及阴道清洁度3~4度的妇女感染HR HPV及发生宫颈病变的可能性显著大于过氧化氢阴性、唾液酸苷酶阴性、白细胞酯酶阴性、乳杆菌数量较多及阴道清洁度1~2度的妇女,差异均有统计学意义(均P结论 阴道微生态失衡与HR HPV感染以及宫颈病变有一定关联,纠正阴道微生态失衡可一定程度上预防HR HPV感染及宫颈病变。     

阴道微生态改变与人乳头瘤病毒感染和宫颈病变相关研究

目的 探讨阴道微生态变化对人乳头瘤病毒(Human papillomavirus, HPV)感染和宫颈病变的影响。 方法 收集我院2018年11月至2019年7月门诊患者1 529例,进行阴道微生态和宫颈HPV检测,根据筛查结果阴道镜下多点活检,应用卡方检验分析阴道微生态变化在HPV阴性组和阳性组之间差异以及对宫颈病变程度的影响。 结果 pH值>4.6、白细胞计数增高、清洁度级别增高、乳杆菌消失、BV和滴虫感染能增加HPV感染(χ2值分别为12.281、17.692、79.999、192.700、48.863和16.758,均P结论 阴道微生态变化能增加HPV感染概率,但与HPV相关性宫颈病变关系不密切。     

高危型人乳头瘤病毒感染与宫颈癌中miR-218表达的关系

目的观察高危型人乳头瘤病毒(HPV)感染与宫颈癌中miR-218表达的关系。方法收集2015年6月至2018年12月我院手术切除的宫颈癌组织并检测高危型HPV感染情况和miR-218表达量。培养HPV16阳性的SiHa细胞株并进行分组,阴性对照(NC)组转染NC模拟物、miR-218组转染miR-218模拟物,检测两组细胞凋亡率、B淋巴细胞瘤-2基因(Bcl-2)、Bcl-2相关x蛋白(Bax)、Bcl-2相互作用细胞死亡介导因子(Bim)、含半胱氨酸的天冬氨酸蛋白水解酶(Caspase)-9、Caspase-3的mRNA表达量及凋亡通路分子c-Jun氨基末端激酶(JNK)、c-Jun基因(c-Jun)、磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B(AKT)、哺乳动物雷帕霉素靶蛋白(mTOR)的蛋白表达量。结果高危型HPV阳性的宫颈癌组织中miR-218表达量减少。转染24 h后,miR-218组细胞凋亡率、细胞中Bax、Bim、Caspase-9、Caspase-3的mRNA表达量及JNK、c-Jun的蛋白表达量均明显高于NC组,而细胞中Bcl-2的mRNA表达量及PI3K、AKT、mTOR的蛋白表达量均低于NC组,差异均有统计学意义(均P<0.05)。结论miR-218在高危型HPV感染的宫颈癌组织中表达减少。增加miR-218的表达能够促进HPV感染宫颈癌细胞的凋亡。该调控作用与JNK/c-Jun通路的激活及PI3K/AKT/mTOR通路的抑制有关。     

阴道微生态异常与高危型人乳头瘤病毒感染及宫颈病变的关系

目的 探讨阴道微生态异常与高危型人乳头瘤病毒（HR-HPV）感染及宫颈病变的相关性。方法 选取2015年1月至2017年6月在十堰市妇幼保健院妇科门诊接受宫颈病变筛查的562例患者为研究对象,分别进行阴道微生态、HR-HPV检测、宫颈脱落细胞检查和组织病理学活检,对检查结果进行分析。结果 562例患者中,宫颈病变发生率为16.01%,液基薄层细胞检测（TCT）阳性率为19.93%,HR-HPV感染率为28.47%,阴道微生态失调发生率为30.78%,其中细菌性阴道病（BV）、滴虫性阴道炎（TV）、外阴阴道假丝酵母菌病（VVC）、需氧菌性阴道炎（AV）和乳杆菌减少检出率分别为24.02%、3.20%、12.28%、8.54%和28.47%。宫颈病变患者微生态失调率为67.78%,明显高于正常组的23.73%（P<0.05）。宫颈病变患者其BV、VVC、AV和乳杆菌减少检出率分别为66.67%、30.0%、22.22%和75.56%,均明显高于正常者的15.89%、8.90%、5.93%和19.49%（P<0.05）;宫颈病变患者HR-HPV阳性率为75.56%,明显高于正常者的19.49%（P<0.05）。HR-HPV阳性患者BV、VVC、AV和乳杆菌减少的检出率分别为51.88%、24.38%、16.88%和62.5%,明显高于HR-HPV阴性患者的12.94%、7.46%、5.22%和14.93%（P<0.05）。结论 阴道微生态环境的改变与高危型HPV感染及宫颈病变的发生具有一定关系。     

川西高原地区妇女人乳头瘤病毒感染现状及其与阴道微环境改变的关系

【背景】人乳头瘤病毒(human papillomavirus,HPV)感染与宫颈癌及癌前病变的发生密切相关,HPV疫苗是预防感染的重要手段,但HPV亚型分布具有明显的区域差异。【目的】了解川西高原地区妇女宫颈HPV感染现状,探讨其与阴道微环境改变之间的关系,为该人群HPV疫苗使用和宫颈癌预防工作提供指导。【方法】选取2017年11月至2019年5月在成都三六三医院体检和就诊的3 816例川西高原地区妇女,进行HPV基因分型、薄层液基细胞学检测(thinprep cytologic test,TCT)和阴道微环境检查,分析HPV感染率和基因型分布,并探讨高危型HPV (high risk HPV,hrHPV)感染与阴道微环境改变之间的关系。【结果】3 816例妇女的HPV总感染率为19.81%(756/3 816),hrHPV感染率为16.48%(629/3 816),HPV52在hrHPV感染中占比最高,达17.20%(135/785),后面依次为HPV58 (92/11.72%)、HPV16 (89/11.34%)、HPV53 (88/11.21%)、HPV18 (55/7.01%...     

Detection of human papillomavirus types by the polymerase chain reaction and the differentiation between high-risk and low-risk cervical lesions

By means of a consensus polymerase chain reaction (PCR) method, the prevalence of HPV types was determined in cervical biopsies from 137 women referred to the gynecological outpatient clinic for colposcopy because of an abnormal cervical smear. The prevalence of HPV was 80.3%. There was a statistically highly significant rise in the prevalence of the oncogenic HPV types (16, 18, 31, 33) with increasing severity of cervical intraepithelial neoplasia (CIN I to III), indicating a role for these HPV types in the pathogenesis of cervical cancer. The prevalence of other HPV types decreased significantly with the severity of the lesion, suggesting that these HPV types play a less significant role in this process. These data indicate that HPV typing with PCR may be a valuable tool for distinguishing between highrisk and low-risk cervical lesions. Furthermore, our results suggest that the detection of HPV types by consensus PCR in the cervix of patients with an abnormal smear but without histologically detectable CIN is a useful tool for predicting which of these patiens will eventually develop CIN. Finally, a relatively low percentage (3%) of HPV double infections is reported in this study.     

人乳头瘤病毒的致瘤性及机制

高危型人乳头瘤病毒(HPV)可能引发多种癌症,公认的如宫颈癌和宫颈上皮内瘤变.近年来的研究表明,HPV还与头颈部鳞癌、食管癌及乳房癌等的发生密切相关.HPV引起头颈部鳞癌的机制在某种程度上与宫颈癌相似,但又有所不同.因此,阐明HPV的致癌机制对于HPV相关肿瘤的治疗具有重要意义.     

Inter-laboratory variability in the presence of human papillomavirus in normal and abnormal cervical cytology samples

Introduction: Treatment of cervical carcinoma is affected by the stage of the disease, being most likely curable with early detection. High-risk human papillomavirus (HPV) infection and persistency are necessary to the development of precancerous and cancerous lesions leaving the possibility to detect in time cells progressing in at risk behaviour. Methods: This study documents the proportion of HPV DNA positivity in 906 samples with cytological result negative for intraepithelial lesion and malignancy (NILM), 220 atypical squamous cells of undetermined significance (ASC-US) samples and 211 low grade intraepithelial lesions (LSIL) samples collected from various pathological laboratories in Brussels, Belgium. Results: The proportion of samples harbouring one or more HPV types was 10.8% (95% confidence interval, 95% CI: 8.8–12.8) in NILM, 34.5% (95% CI: 27.6–40.3) in ASC-US, 54.3% (95% CI: 47.5–61.1) in LSIL, with significant variability of HPV proportion in ASC-US and LSIL between laboratories. Conclusion: This study provides an on-site picture, confirming an added value of HPV DNA detection.     

阴道菌群失调与宫颈癌发病的研究进展

宫颈癌是世界女性第四大常见恶性肿瘤,严重危害女性身体健康。为此,国内外学者和临床医生进行了大量的科学研究和临床实践,不断探索有效预防、筛查、干预和治疗宫颈癌及癌前病变的新举措。研究表明,阴道菌群影响HPV感染持续状态或病毒清除率,由此参与宫颈癌和癌前病变发生和发展过程,甚至可能在HPV感染→癌前病变→宫颈癌进程中起主导作用。特定的阴道菌群具有预测HPV持续感染的潜力,有望成为筛查宫颈癌和癌前病变以及指示疾病高风险的生物标志物,这为宫颈病变乃至宫颈癌的筛查和诊断提供了新契机。本文就阴道菌群在HPV相关宫颈癌中的作用进行综述。

     

Association of sexually transmitted infections and human papillomavirus co-infection with abnormal cervical cytology among women in Saudi Arabia

Human papillomavirus (HPV) is a causative agent of cervical and other cancers. Sexually transmitted Infections (STIs) may play a crucial role in HPV persistence, leading to serious complications, including cervical cancer. This study investigated the association of HPV/STI co-infection in cervical samples with cervical dysplasia among women in Saudi Arabia. HPV-positive cervical samples (n = 142) were obtained from previous studies and newly collected samples (n = 209) were obtained from women aged 19–83 years. For HPV detection and genotyping, PCR and Genoflow HPV assay kits were used. STIs were detected using a Genoflow STD array kit. Of 351 samples, 94 (27%) were positive for STIs. Among HPV-positive samples, 36 (25%) were positive for STIs; the most common pathogens were Ureaplasma urealyticum/Ureaplasma parvu (13%) and Mycoplasma hominis (6%). A global significant correlation was detected between HPV and STIs with progression of abnormal cervical cytology (χ² = 176, P < 0.0001). Associations between cervical cytology diagnosis and HPV status, STI types (opportunistic and pathogenic), and the presence of Ureaplasma spp., and Mycoplasma hominis were significant (P < 0.05). Our results suggest that additional study in a larger population is warranted to determine the association between HPV/STI co-infection and cervical neoplasia in Saudi women.     

高危型人乳头瘤病毒持续感染患者阴道菌群与 宫颈局部免疫功能改变

目的研究高危型人乳头瘤病毒(hr-HPV)持续感染患者阴道菌群及宫颈免疫功能的变化特点,为宫颈癌的防治提供临床研究资料。方法选择286例连续2年同一型别hr-HPV阳性女性患者为观察组,124例hr-HPV阴性女性患者为对照组,比较两组患者阴道乳杆菌、支原体、衣原体、霉菌检出情况及细菌性阴道病、滴虫感染的差异,并比较两组患者宫颈分泌物物CD~+_4 T、CD~+_8 T细胞检测情况。结果观察组患者中单一型别感染214例(74.83%),2种及2种以上hr-HPV型别复合感染者72例(25.17%)。观察组患者中检出HPV16型165例(45.21%)、HPV18型36例(9.86%)、HPV31型31例(8.49%)、HPV33型22例(6.03%)、HPV51型12例(3.29%)、HPV52型75例(20.54%)、HPV53型15例(4.11%)、HPV58型9例(2.47%)。观察组患者阴道乳杆菌检出率低于对照组,而沙眼衣原体、解脲支原体、细菌性阴道病检出率均高于对照组,差异有统计学差异(P0.05)。观察组患者CD~+_4 T细胞水平(%)及CD~+_4/CD~+_8水平均低于对照组,差异有统计学意义(P0.05)。结论 hr-HPV病毒持续感染患者阴道菌群发生改变,导致宫颈微环境稳态被打破,宫颈局部免疫防御能力降低而成为宫颈癌变的主要促进因素。