INTRODUCTION

Cervical cancer is the leading cause of death in women worldwide. The prevalence is high in women in lowto middle-income countries[1]. In 2012, approximately 522000 women globally were diagnosed with cervical cancer, and the mortality rate due to cervical cancer was reported to be 266,000 cases/year[2]. The highest incidence occurred in sub-Saharan Africa while in Asia,cervical cancer remains the third most common cancer(after breast and lung cancer), with an estimated 285000 new cases and 144000 deaths in 2012[3]. The age-standardized incidence rates (ASRs) of cervical cancer estimated by GLOBOSCAN in 2012 indicated that the ASR is higher in less developed compared to more developed regions[4]. In Thailand, the age group with the highest incidence is 45-70 years[5].

Several studies had found that cervical cancer is preceded by a pre-invasive stage, in which abnormal cells are confined to the cervical epithelium. The preinvasive stage is also known as cervical intraepithelial neoplasia (CIN). The 2014 Bethesda System categorizes squamous epithelial cell abnormalities as atypical squamous cell of undetermined significance (AS-CUS);low-grade squamous intraepithelial lesion (LSIL), which was previously known as CIN Ⅰ; high-grade squamous intraepithelial lesion (HSIL), which was previously known as CIN Ⅱ and Ⅲ; or squamous cell carcinoma(SCC)[6]. SCC represents ＞ 80% of cervical cancers,while adenocarcinoma (AC) accounts for the rest.

The standard method for screening for early-stage cervical neoplasia is cytological morphologic assessment of cervical scrapings. The sensitivity of the conventional Pap smear for identifying CIN Ⅱ+ is 55.2%, while the sensitivity of liquid-based cytology is 57.1%[7]. Highrisk human papillomavirus (HPV) DNA testing in combination with the conventional Pap smear increases the sensitivity. Furthermore, biomarkers of oncogenic progression would improve the accuracy of cancer progression predictions. Epigenetic biomarkers may help to fulfil this role, and they have the additional benefit predicting the stage of cervical carcinogenesis progression[8].

GENOME OF HPV

HPV is a small, non-enveloped and circular doublestranded DNA virus with a genome of approximately 8 kb in length[9]. The HPV genome comprises eight proteincoding genes and a noncoding region that is referred to as the regulatory long control region[10]. Only one strand of the DNA carries the protein-coding sequence[11].Regarding the protein-coding genes, the genes are designated as early (E) or late (L) to indicate when the proteins are expressed in the viral life cycle[12]. The eight protein-coding gene consist of E1, E2, E4, E5,E6, E7, L1 and L2[9]. E1 and E2 are highly conserved and involved in viral DNA replication[13-15]. L1 and L2,which both have a high degree of sequence variation,encode for viral packaging proteins[16]. E4 releases the viral particle from the epithelial cells[17]. E6 and E7 are viral oncogenes that are involved in the integration of the HPV genome into the host genome[18]. There are more than 130 genotypes of HPV, which are categorized based on sequence variation in their L1 region[19]. Of the 130 genotypes, at least 40 genotypes infect the genital areas of humans via sexual transmission. HPV can also be classified into cutaneous or mucosal types[12].The mucosal type can be subdivided into high-,intermediate-, or low-risk types[20].

HPV AND CERVICAL CANCER

The most important risk factor for cervical cancer is HPV infection, which has been found in 90.7% of cervical cancer patients worldwide[21]. HPV infection is a sexually transmitted disease. It has been estimated that more than 80% of sexually active women become infected with HPV, while more than 50% of young women become infected after they first have sexual intercourse[22]. The oncogenic potential of HPV depends on the genotype. HPV 16 and 18 are the most common types associated with invasive cervical cancer[23]. Other HPV genotypes have been found to be related to cancer,but their oncogenic risk differs among the various populations, geographic regions, and age groups.

At the country level, collecting baseline data on the local burden of specific HPV genotypes related to cervical cancer is important. This information can impact the local HPV vaccination policies. A meta-analysis revealed that HPV 16, 18, 31, 33, 45, 52, and 58 are responsible for more than 90% of cervical cancers worldwide[20]. These genotypes represent the baseline genotypes to include in a vaccine targeting the genotypes circulating in the population[4]. The current HPV vaccines were developed to prevent HPV infection, and thus prevent cervical carcinoma. HPV vaccines have been implemented in routine vaccination programs in several developed and developing countries worldwide[24]. To date, there have been three HPV vaccines in clinical use:Bivalent, quadrivalent, and nanovalent vaccines[25].

Other independent risk factors such as immunosuppression, individual lifestyle, and smoking have been found to be associated with the development of HPV-related cervical cancer[21,26]. Most HPV infection is transient,and clearance of the virus can occur spontaneously over a 3-year period[27]. However, in some cases, persistent infection can result in cervical cancer development. The transition from dysplasia to invasive carcinoma may take several years to decades to develop. HPV initially infects the basal layers of the epithelium through micro-wounds.The virus begins to replicate, and when infected daughter cells migrate to the upper layers of the epithelium, the viral late genes are activated, and viral DNA is packaged into capsids. Progeny virions are released to re-initiate infection, which can result in persistent and/or asymptomatic infection[28]. The integration of HPV into the host genome can lead to carcinogenic transformation. Certain regions of the human genome are favored for viral DNA insertion such as fragile sites, rupture points, translocation points, and transcriptionally active regions[29]. Moreover,the virus can induce epigenetic modification of viral and cellular genes, which affect their expression, leading to malignant cell transformation[30,31].

HOST GENETIC FACTORS AND CERVICAL CANCER

Diverse immunogenetic associations with HPV infection,persistence, and transformation have been extensively investigated. Recent studies have looked at multiple genes in various populations with different environment interactions[32]. HPV infection alone might not be sufficient for the development of cervical carcinoma, and certain antigen-processing machinery (APM) and singlenucleotide polymorphisms (SNPs) may lead to a smaller immunogenic peptide repertoire for presentation to local immune cells. This can result in further attenuation of cytokine and receptor expression, which leads to an ineffective overall immune response and progression to carcinoma[33]. The Genome-Wide Association Study(GWAS) for polymorphisms of host immune response genes showed that variation in several genes contributes to different risks of cervical cancer. The integrative approach, which is also known as systems biology, could help explain the complexity of host-virus interactions and provide a better understanding that may eventually lead to personalized prevention, diagnosis, and treatment[34-36].

The detection of methylated genes in cervical specmens is a feasible technique and represents a potential source of biomarkers that are of relevance to carcinogenesis. In particular, there are methylation markers that, among HPV-infected women, indicate the presence of CIN Ⅱ+and risk of cancer[37].

High expression levels of certain oncoproteins in cervical cells have been found to be associated with cervical carcinoma. One study found a strong correlation between centromere protein H (CENP-H) expression and cervical carcinoma in a Chinese population[38]. Another study found that expression of the B-cell-specific Moloney leukemia virus insert site 1 (Bmi-1), P16, and CD44v6(a CD44 variant) were significantly higher in cervical carcinoma tissues compared with precancerous lesions and normal tissues[39]. In addition, abnormalities in the phosphatidylinositide 3-kinase (PI3K) pathway induced by mutations in PI3K catalytic subunit α (PIK3CA)were associated with shorter survival in cervical cancer patients[40]. Recently, deep sequencing of somatic mutations has identified several novel mutations in carcinoma cells, including E322K in the mitogenactivated protein kinase 1 (MAPK1) gene, inactivating mutations in the major histocompatibility complex, class I, B (HLA-B) gene, and mutations in F-box and WD repeat domain containing 7 (FBXW7), tumor protein p53 (TP53), and Erb-B2 receptor tyrosine kinase 2(ERBB2)[41].

EPIGENETIC MECHANISMS AND RISK OF CANCER DEVELOPMENT

Recent studies also investigated epigenetic mechanisms related to HPV infection, including methylation of the host and viral genes, and chromatin modification in host cells[42]. Epigenetic mechanisms affect gene regulation without changing the genetic sequences,and these mechanisms have been increasingly found to be associated with cancer development[43]. The main epigenetic mechanism is methylation patterning,which occurs to various extents in different DNA and proteins. DNA methylation is a mechanism of gene regulation that typically occurs in CpG dinucleotide contexts, resulting in genomic instability. Methylation of heterochromatin and promoter regions is associated with decreased gene transcription. Several studies have found that DNA methylation frequently occurs in cervical cells but rarely in normal cells, suggesting that their methylation is highly related to the severity of cervical neoplasia[44]. Several markers have been evaluated extensively in studies involving women with precancerous and cancerous cervical lesions[44-46].Epigenetic methylation in the promoter region of several tumor suppressor genes (TSGs) has been detected in precancerous cervical cells[47,48]. Genes that were found to be significantly associated with promoter methylation were RASSF1A and MGMT (involved in DNA repair),CDKN2A (involved in cell cycle control), PYCARD (involved in apoptosis), and APC and SFRP1 (involved in Wnt signaling)[49].

One striking conclusion of previous studies was that methylation frequencies for the same gene vary widely between studies. It was difficult to identify highly consistent results for most genes even when restricting analyses to studies of similar size or those that used common specimen sources or similar assays.This suggests that the frequency of certain methylation markers may also vary for reasons related to differences in populations, specific features of assay protocols,chance, or other unidentified factors. The most important prerequisite for a potential biomarker is that it must be reliable in its measurement. There is a possibility that the wide range of frequencies reported for some genes (in contrast to the more consistent measurement of a few other genes in similar studies) could be related to unreliable assays for these specific genes rather than biological variation. Another prerequisite for a good biomarker is that it has high sensitivity and high specificity for disease detection, resulting in a high positive predictive value. Several studies have proposed the use of methylated gene panels in order to obtain optimal assessment performance for cervical cancer screening[47,50].

Retinoic acid (RA) is an essential regulator of normal epithelial cell differentiation. The effect of RA is mediated by two types of nuclear receptors, the retinoic-acid receptor (RAR) family and retinoid-X receptor (RXR)family. Both of these receptor families have three members (alpha, beta, and gamma), which are encoded by distinct genes in vertebrates. The retinoic acid receptor beta (RARβ) gene encodes a nuclear receptor that binds RA and mediates cellular signaling. It is important during differentiation of stratified squamous epithelium, including cervical epithelium. It is considered to be a potential TSG. The RARβ gene is usually expressed in normal epithelial tissue. The direct roles of the RARβ protein include regulating gene expression and differentiation, immune modulation, and inducing apoptosis. Previous studies revealed that the RARβ gene is downregulated in high-grade lesions[51]. RARβ gene silencing was observed in carcinoma cells[52]. Recent research suggested that the RARβ protein can suppress cervical carcinogenesis and may play a role in the early development of cancer[51]. CpG methylation of the 5’region of the RARβ gene contributes to gene silencing,and this methylation is associated with increased grades of SIL and invasive cervical cancer. Many studies have revealed that methylation of CpG islands in the promoter region of the RARβ gene induces repression of RARβ expression in several epithelial carcinomas,including cervical cancer[53-55].

The risk of cervical cancer due to RARβ methylation remains inconsistent across different studies[51,52,56].Therefore, we reviewed previously published articles and summarized the relationship between RARβ promoter methylation and cervical cancer (Table 1).

Among the 14 articles reviewed, the majority of them (11/14) demonstrated that the frequency of RARβ promoter methylation was significantly correlated with severity of cervical epithelium abnormalities. Three studies did not concur with this finding. The first study was conducted in 2003 with a small sample size and no cancer patients were involved[37]. The other two studies were conducted in 2010 and 2015. Both studies found that normal tissue also had RARβ promoter methylation,which made it a poor predictor of progression to severe disease[62,64]. However, one of the two studies also investigated the level of methylation using quantitative methylation-specific PCR and found that although normal cells were methylated, the level of methylation increased in LSIL, HSIL, and invasive cancer tissue[62].

In addition, both Narayan et al[56] and Choi et al[60]found that RARβ promoter methylation was associated with cervical cancer prognosis. Narayan et al[56] found that 80% of the patients with RARβ methylation either died of cancer or only partly responded to treatment,while Choi et al[60] found that absence or reduction of RARβ protein expression was associated with a higher level of SCC antigen (P = 0.04) and more frequent lymph node metastasis (P = 0.023).

A study of the frequency of RARβ promoter methylation in urine and cervical samples from Senegalese women and cervical epithelial cell abnormalities found that methylation was significantly greater in abnormal specimens (and the results from the urine samples correlated with the results from the cervical swab samples)[58,65]. Another study by Zhang et al[52] compared the frequency of methylation with RARβ mRNA expression. The authors found that in normal cervical cells, the RARβ gene was highly expressed. In contrast, among 17 samples from patients with invasive cervical carcinoma, RARβ2 expression was completely repressed in 13 samples,highly repressed in 2 samples, and moderately downregulated in 2 samples. Among the 13 samples with completely repressed RARβ2 expression, the RARβ promoter region was methylated in 9 samples and unmethylated in 4 samples. The authors then further investigated the silencing mechanism and discovered that apart from methylation, repressive histone modifications also played a role in gene silencing, which could contribute to the development of cervical carcinoma.

7 Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol 2008; 111: 167-177 [PMID: 18165406 DOI: 10.1097/01.AOG.0000296488.85807.b3]

In addition, two studies performed immunohistochemistry staining of the RARβ protein in cervical cells.Narayan et al[56] found that in the LSIL group, 11% hadlow RARβ expression whereas, in the HSIL group, 60%had a complete lack of RARβ expression. This finding suggested that the downregulation of the RARβ gene occurs early in the development of cervical carcinoma[56].The second study was carried out by Choi et al[60], who discovered that all normal tissues highly expressed the RARβ protein, whereas no staining was detected in 43%of the SCC tissues.

Almost of cancer cell lines and primary cancer tissues examined, the RARβ2 was repressed. The repression was frequently associated with promoter methylation, which causes lack of gene expression. These results strongly support the hypothesis that promoter methylation is the epigenetic cause of RARβ2 repression in cervical cancers harboring methylated RARβ2 promoters. A DNA demethylating reagent can reactivate gene expression by inducing drastic demethylation of the promoter in repressed cells carrying a methylated promoter[44]. This consistency between promoter demethylation and RARβ2 derepression strongly suggests that the primary cause of RARβ2 repression is indeed promoter methylation.

Several hypotheses have been proposed regarding the mechanisms of DNA methylation that lead to silencing of genes. In some cancer cells and tissues examined, RARβ2 was repressed without promoter methylation. These facts indicate that although DNA methylation is the major epigenetic mechanism for gene silencing, there are other epigenetic silencing pathways independent of DNA methylation. RARβ2 is frequently silenced in cervical cancers by one of two epigenetic mechanisms. One is DNA methylation, a well-known epigenetic mechanism leading to transcriptional silencing of genes, while the other involves the formation of repressive histone modifications near the promoter, by unknown mechanisms independent of DNA methylation.At present, the initial causes of these epigenetic changes during carcinogenesis are unclear. RARβ2 silenced by promoter methylation can be reactivated by promoter hypomethylation. This result indicates the importance of examining promoter methylation if epigenetic modulation drugs are to be used for chemotherapy in patients with cervical cancers.

In conclusion, DNA methylation of TSGs likely contributes to the development of cancer. Although DNA methylation of only one gene may not represent the complete process of epigenetic silencing, it has been shown to be significantly correlated with cervical cancer. Analyzing combinations of aberrant hyper- or hypo-methylation of multiple genes may increase the sensitivity of prognoses. Thus, this approach may serve as a better tool for predicting disease progression. Risk factors should also be further characterized to better understand the pathogenesis of cervical carcinoma.

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1.4 观察及评价指标 采用CU和RT-3DE分别对患者右心功能进行评估检查，观察比较右心功能指标，包括RAA、RVDd、ΔIVC、RVESV、RVEDV、RVEF等。RVEF=RVESV/RVEDV;ΔIVC=(下腔静脉呼气末内径-下腔静脉吸气末内径)/下腔静脉呼气末内径×100%[3-5]。

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②根据物质的量与微粒(分子、原子、离子、电子、质子、中子等)数目、物质的质量、气体体积(标准状况)之间的相互关系进行有关计算。

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任何一种好的教学方法的实施，都需要教师来完成。能否得到学生的欢迎，受到学生认可，关键在教师，没有教师的组织与引导，以学习者为中心就是一句空话。以学习者为中心，需要教师付出更多的艰辛劳动，要始终把学习者放在中心地位，设身处地为学习者着想，帮助他们解决学习上的问题，教给他们制定学习计划、完成学习任务的方法，让学生在学习中获得愉悦的情感体验。教师首先要向学生清晰地阐述，由以教师为中心向以学习者为中心转变的必要性，明确参加继续教育的目的和任务，帮助学生认同、接受这样一种教学模式的转变。

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（169）鳞叶疣鳞苔 Cololejeunea longifolia（Mitt.）Benedix ex Mizut.彭丹等（2002）；熊源新等（2006）；杨志平（2006）

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像CRISPR、锌指和TALENs这样的新技术也面临着同样的文化阻力，或者像第一代转基因生物一样，也要面临各种繁文缛节。不过，美国农业部于2018年3月宣布，不再对基因编辑技术导致突变的农作物进行监管，因为这类突变类似传统育种过程，只要没有远距离引入遗传物质，就可不用监管。

不久，叶霭玲语言暧昧地敲打我，含沙射影地攻击我，你与白丽筠之间是不是有了那种事呀？其实，我是先与叶霭玲发生了两性关系的。我在找不到工作，穷极无聊之际，通过与叶霭玲的性关系得以发泄内心的紧张情绪。而她通过我近来在这方面表现，与以前对比出现的差异变化，敏感地觉得我是有问题了。我解释说，那是因为最近工作比较累。可是叶霭玲恼怒地说，你是糊弄鬼吧？就是糊弄鬼也需要找出一个稍微像样点的理由来呢。

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1.3 评定标准 3组患儿主要照顾者于治疗前、治疗1个月及3个月时填写SAS及SDS评定量表。SAS以标准分≥50分为阳性，SDS以标准分≥53分为阳性。比较3组治疗前后SAS、SDS评分及SAS、SDS阳性率。

1．对创新创业教育的认识有偏差。创新创业教育的核心和本质是面向全体学生的、为其终身可持续发展奠定基础的素质教育。［6］创新创业教育是“完人”教育、培养开创性的教育，而非提高就业率的“缓兵之计”，更非创收的”孵化器”，不能简单地计算学生参加了多少创新创业活动，从事了多少创业项目，获取了多少创业资金。［6］创新创业教育的实质是素质教育，不能仅限于技能教育、技术教育、就业能力教育。只有认识到创新创业教育的本质特点，才能从总体上把握全局，定好创新创业的主基调，注重开发学生的思维能力。

生产是企业生产的基础，设备是为生产服务的。电气从二个方面为生产提供服务：一个是提供电力，一个是参与操作控制。而电气点检员必须熟悉生产工艺。生产工艺确定以后，运转方案就是决定性因素，电气控制及电气拖动的设置紧紧围绕运转方案展开，使电气设备能够按照运转方案的规定正常运转。运转方案是机械设备动作、操作要领及电气控制三方相组合的图纸资料。

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40年来，从“真理标准大讨论”出发，改革开放始终是响彻神州大地的时代呼声。从农村到城市，从试点到推广，从经济体制改革到全面深化改革，改革的精神一脉相承；从沿海到内陆，从“打开国门”到“全方位开放”，从加入世贸组织到共建“一带一路”，开放的步伐一往无前。今天，这个希望回答“社会主义中国向何处去”的执政党，成功开辟出一条通往现代化的中国道路；这个曾经面临“被开除球籍的危险”的国家，已经跃升为世界第二大经济体；这个近代以来矢志伟大复兴的民族，终于实现了从“赶上时代”到“引领时代”的伟大跨越。

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一个企业的运营与管理合理与否，终究还是人起作用。企业中人力资源部门作为管理员工的专职部门，更要在企业的经济管理中发挥出激励员工的作用。这要求企业要进行人力资源培训，培养人资部门员工的责任道德意识和管理能力，使他们积极主动的进行人力资源工作。企业在进行人力资源管理时，一定要按照员工的优势以及自身意愿将其安排在最适当的位置，使人员分布合理，使人资部门结构严谨，这样才便于让不同岗位的员工发挥各自的作用。

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老福放下笔，摁灭了烟头，关灯睡觉了。他决定，无论如何要办完这个案子，至于组织的决定和自己的选择都以后再说。

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“中国特色社会主义”是何时提出的？目前，绝大多数学者一致认为这一命题是在党的第十六次代表大会被正式提出和使用的，而邓小平在党的第十二次代表大会开幕词中的讲话则被普遍认为是中国特色社会主义内涵的首次铺垫。此后，党的历次代表大会均围绕“中国特色社会主义”的主题开展，并对其内涵进行不断的丰富与发展。

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