Assessment of the association between the frequency of micronucleus and p16INK4a/Ki-67 co-expression in patients with cervical intraepithelial lesions

Human papilloma virus (HPV) infection is the main etiological factor for cervical intraepithelial lesions (CIN). An important characteristic of this process is the loss of genome stability. Therefore, it is imperative to use biomarkers of DNA damage caused by genomic instability to identify high risk individuals. We investigated the frequency of micronuclei (MN) in peripheral blood lymphocytes (PBL) of 20 patients, diagnosed as histologically CIN 1 and 10 healthy controls. We also examined the frequency of other nuclear anomalies including nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) in PBL of patients with CIN 1 and healthy controls, and evaluated the benefits of p16^INK4a and Ki-67 (p16^INK4a/Ki-67) immunohistochemical double staining for identifying cervical squamous cells that express HPV E6/E7 oncogenes. We analyzed the association between the frequency of MN in PBL and the amount of p16^INK4a/Ki-67 co-expression in CIN 1 patients to establish genomic instability. Among CIN 1 subjects, 15% exhibited diffuse p16^INK4a/Ki-67 co-expression and were considered high positive, 25% of the CIN 1 cases exhibited p16^INK4a/Ki-67 co-expression restricted to the lower part of the epithelium and were considered low positive and the remaining 60% of cases were negative. The frequency of MN, NPBs and NBUDs differed significantly among groups. We found a statistically significant positive correlation between p16^INK4a/Ki-67 co-expression and the frequency of MN, NPBs and NBUDs in PBL. Our findings demonstrate the efficacy of p16^INK4a/Ki-67 double immunostaining for histological samples with CIN 1. MN frequency in PBL might be useful for detecting genomic instability in cases of HPV infection and CIN.     

Dimethylhydrazine: a reliable positive control for the short sampling time in the UDS assay in vivo

Cervical cancer represents the second most common malignant neoplasia in women world-wide. In Mexico, cervical cancer is the most common female malignancy. It has been recently seen an increased frequencies of micronuclei (MN) lymphocytes and cervical epithelial cells of cervical cancer patients. The aim of this hospital-based unmatched case-control study was to investigate the association between progressive stages in development of cervical cancer and frequency of micronucleated cells in the cervical epithelium and peripheral lymphocytes of 40 women, grouped by disease stage. Women at the Obstetrics and Gynecology Hospital of the Instituto Mexicano del Seguro Social (IMSS) in Monterrey, Mexico were diagnosed and classified on the bases of the Papanicolaou (PAP) smear and colposcopy/biopsy into control, low-grade squamous intraepithelial lesions (LGSIL), high-grade squamous intraepithelial lesions (HGSIL), and invasive groups. Analysis of the MN data in both cell types revealed (a) homogeneity among women within each of the four groups with regard to MN frequency, (b) in general, a correlation between MN frequency and grade of cervical lesion, and (c) a positive linear trend between the MN frequency and increased cervical cancer risk. In conclusion, we suggest that MN are a useful biomarker of cancer risk. Nonetheless, these results should be validated by other researchers.     

Proteomics approaches in cervical cancer: focus on the discovery of biomarkers for diagnosis and drug treatment monitoring

Introduction: The HPV virus accounts for the majority of cervical cancer cases. Although a diagnostic tool (Pap Test) is widely available, cervical cancer incidence still remains high worldwide, and especially in developing countries, attributed to a large extent to suboptimal sensitivities of the Pap test and unavailability of the test in developing countries.

Areas covered: Proteomics approaches have been used in order to understand the HPV virus correlation to cervical cancer pathology, as well as to discover putative biomarkers for early cervical cancer diagnosis and drug mode of action.

Expert commentary: The present review summarizes the latest in vitro and in vivo proteomic studies for the discovery of putative cervical cancer biomarkers and the evaluation of available drugs and treatments.     

人乳头状瘤病毒感染与宫颈癌患者临床病理特征和Ki-67、PCNA的关系

目的:研究人乳头状瘤病毒(HPV)感染与宫颈癌患者临床病理特征和Ki-67、细胞增殖抗原(PCNA)的相关性,从而为临床宫颈癌的诊治提供参考依据。方法:选取2016年3月～2018年6月于我院接受手术治疗的宫颈病变患者130例为研究对象。其中宫颈癌患者30例记为宫颈癌组,宫颈上皮内瘤变患者68例记为宫颈上皮内瘤变组,慢性宫颈炎患者32例记为对照组。采用免疫组织化学法检测各组宫颈组织中HPV感染、Ki-67以及PCNA阳性表达情况,并分析HPV与宫颈癌患者临床病理特征的关系及其与Ki-67、PCNA的相关性。结果:宫颈癌组、宫颈上皮内瘤变组患者HPV、Ki-67以及PCNA阳性率均高于对照组,宫颈癌组高于宫颈上皮内瘤变组(均P0.05)。临床分期Ⅲ～Ⅳ期以及淋巴结转移宫颈癌患者HPV感染率均明显高于临床分期Ⅰ～Ⅱ期与无淋巴结转移患者(均P0.05)。经Spearman相关性分析可得:宫颈癌患者HPV感染与Ki-67、PCNA表达均呈正相关关系(均P0.05)。结论:宫颈癌患者存在明显的HPV感染,且HPV感染与宫颈癌患者临床分期、淋巴结转移、Ki-67、PCNA表达存在一定相关性,临床可通过对HPV、Ki-67、PCNA进行联合检测,从而有助于宫颈癌的早期诊断。     

生殖道感染与宫颈癌及宫颈癌前病变的相关性研究

目的:探讨生殖道感染与宫颈癌、宫颈癌前病变的相关性及危险因素分析。方法:选取我院收治的185例宫颈癌及宫颈癌前病变患者和同期206例健康体检者分为两组,对人乳头瘤病毒(HPV)、沙眼衣原体(CT)、细菌性阴道病(BV)、阴道滴虫进行检测,观察分析相应病原微生物导致的生殖道感染与宫颈癌及宫颈癌前病变的关系,同时根据HPV不同基因型在宫颈癌及宫颈癌前病变中的致癌作用和程度,判定危险程度。结果:宫颈癌及宫颈癌前病变患者上述指标感染检出率明显高于对照组,差异具有统计学意义(P=0.000、0.001、0.000、0.037),其中高危HPV感染率随宫颈上皮内瘤变级别的升高而呈明显上升趋势,CINⅠ～Ⅲ级感染率分别为57.1%、78.6%和82.9%,宫颈癌感染率最高达91.1%,高危HPV为高危因素。结论:生殖道HPV、CT、BV、滴虫感染与宫颈癌及CIN存在必然或一定相关性,加强对妇女生殖道病原体感染的重视和检测对防治宫颈癌及CIN具有积极意义。     

基于免疫组化和癌症基因组图谱数据分析的脾酪氨酸激酶在宫颈癌中的表达研究

摘要 目的：探讨Syk 在宫颈癌中的表达及其临床意义。方法：应用免疫组化检测Syk在宫颈癌、癌前病变(CIN)和相应的正常宫颈组织中的表达。借助R2生物信息平台挖掘Syk在TCGA数据库305例宫颈鳞癌中的mRNA表达及其与预后的关系。结果：免疫组化结果显示,Syk在宫颈癌巢分化较好的中心区表达较强,在分化较低的癌巢周边区表达较弱。Syk 染色主要定位在宫颈癌和正常宫颈组织的细胞质和细胞膜,正常宫颈组织基底细胞无 Syk 表达,8例CIN组织细胞核中可见Syk表达, 但宫颈癌组织细胞核中未见Syk表达。Syk在宫颈癌、CIN和正常宫颈组织中的阳性率分别是76%、54%、40%,三组间的表达差异具有统计学意义（P=0.001）。Syk 在深度浸润和淋巴结转移中表达较强。数据挖掘结果显示,Syk mRNA在305例不同临床分期的宫颈癌中均表达,Syk mRNA高表达组219例,Syk mRNA低表达组73例,其中13例生存数据缺失,Syk高表达组的患者预后较差。结论：Syk在宫颈癌中的表达提示Syk在宫颈癌中具有致癌蛋白的作用,Syk在某些CIN中的核表达可能与更好的预后相关。     

Cancer biomarker discovery and translation: proteomics and beyond

Introduction: Cancer is often diagnosed at late stages when the chance of cure is relatively low and although research initiatives in oncology discover many potential cancer biomarkers, few transition to clinical applications. This review addresses the current landscape of cancer biomarker discovery and translation with a focus on proteomics and beyond.

Areas covered: The review examines proteomic and genomic techniques for cancer biomarker detection and outlines advantages and challenges of integrating multiple omics approaches to achieve optimal sensitivity and address tumor heterogeneity. This discussion is based on a systematic literature review and direct participation in translational studies.

Expert commentary: Identifying aggressive cancers early on requires improved sensitivity and implementation of biomarkers representative of tumor heterogeneity. During the last decade of genomic and proteomic research, significant advancements have been made in next generation sequencing and mass spectrometry techniques. This in turn has led to a dramatic increase in identification of potential genomic and proteomic cancer biomarkers. However, limited successes have been shown with translation of these discoveries into clinical practice. We believe that the integration of these omics approaches is the most promising molecular tool for comprehensive cancer evaluation, early detection and transition to Precision Medicine in oncology.     

血清Hmga1、M-CSF及AFP与宫颈癌患者肿瘤病理特征及预后的关系

摘要 目的：探讨血清Hmga1、M-CSF、AFP与宫颈癌患者肿瘤病理特征及预后的关系。方法：选择2019年8月到2020年6月在本院妇产科诊治的120例宫颈癌患者作为宫颈癌组,同期选择宫颈良性病变患者120例作为良性组。检测两组患者的血清高迁移率族蛋白A1（Hmga1）、巨噬细胞集落刺激因子（M-CSF）、甲胎蛋白（AFP）含量,调查宫颈癌患者的肿瘤病理特征、预后情况并进行相关性分析。结果：宫颈癌组的血清Hmga1、M-CSF、AFP含量高于良性组（P<0.05）。在宫颈癌患者中,不同组织学分化、临床分期、淋巴结转移患者的血清Hmga1、M-CSF、AFP含量对比有差异（P<0.05）;随访到2022年1月1日,平均随访时间17.28±1.25个月,死亡18例,死亡率为15.0 %。Spearsman分析显示：患者预后死亡与Hmga1、M-CSF、AFP等存在相关性（P<0.05）。Cox比例风险模型分析显示Hmga1、M-CSF、AFP为影响患者预后死亡的重要因素（P<0.05）。结论：宫颈癌患者多存在血清Hmga1、M-CSF、AFP的高表达,且与患者的肿瘤病理特征存在相关性,宫颈癌患者的预后与血清Hmga1、M-CSF、AFP表达存在相关性,预测宫颈癌患者死亡具有很好的价值。     

An exosome-related lncRNA signature correlates with prognosis,immune microenvironment,and therapeutic responses in hepatocellular carcinoma

BackgroundExosomes act as essential modulators of cancer development and progression in hepatocellular carcinoma. However, little is known about the potential prognostic value and underlying molecular features of exosome-related long non-coding RNAs.MethodsGenes associated with exosome biogenesis, exosome secretion, and exosome biomarkers were collected. Exosome-related lncRNA modules were identified using PCA and WGCNA analysis. A prognostic model based on data from the TCGA, GEO, NODE, and ArrayExpress was developed and validated. A comprehensive analysis of the genomic landscape, functional annotation, immune profile, and therapeutic responses underlying the prognostic signature was performed on multi-omics data, and bioinformatics methods were also applied to predict potential drugs for patients with high risk scores. qRT-PCR was used to validate the differentially expressed lncRNAs in normal and cancer cell lines.ResultsTwenty-six hub lncRNAs were identified as highly correlated with exosomes and overall survival and were used for prognosis modeling. Three cohorts consistently showed higher scores in the high-risk group, with an AUC greater than 0.7 over time. These higher scores implied poorer overall survival, higher genomic instability, higher tumor purity, higher tumor stemness, pro-tumor pathway activation, lower anti-tumor immune cell and tertiary lymphoid structure infiltration, and poor responses to immune checkpoint blockade therapy and transarterial chemoembolization therapy.ConclusionThrough developing an exosome-related lncRNA predictor for HCC patients, we revealed the clinical relevance of exosome-related lncRNAs and their potential as prognostic biomarkers and therapeutic response predictors.     

Current status of proteomics of esophageal carcinoma

Introduction: Esophageal cancer (EC) is one of the most common causes of cancer-related death worldwide. Identifying suitable biomarkers for early diagnosis as well as predicting lymph node metastasis, prognosis and the therapeutic response of EC is essential for the effective and efficient management for EC. There is an urgent need to develop effective, novel approaches for patients who do not respond to conventional treatment.

Areas covered: EC is characterized by the presence of two main histological types such as squamous cell carcinoma and adenocarcinoma, which differ in their response to treatments and prognosis. Thus, this review describes the latest research into biomarkers and novel treatment targets generated by cancer proteomics for the two main histological types. Finally, the main difficulties facing the translation of biomarkers and novel treatment targets into the clinical settings are discussed.

Expert commentary: EC proteomics have provided useful results and, after their validation, novel clinical tools should be developed to improve the clinical outcomes for EC patients.     

基于基因组不稳定性相关lncRNA的宫颈癌患者预后模型

结合TCGA数据库中宫颈癌的lncRNA表达谱和体细胞突变谱,构建基于突变假设的计算框架,鉴定出36个与宫颈癌基因组不稳定性相关的lncRNA;对其共表达的基因功能进行分析,发现与36个lncRNA共表达的基因在2-氧代戊二酸代谢过程和2-氧羧酸代谢通路中富集。构建了基于基因组不稳定性衍生的两个lncRNA的基因特征(GILncSig),将Train组患者分为高风险组和低风险组,两组患者生存率显著不同,这一结果在Test组患者中得到进一步验证。通过独立预后分析,结果显示GILncSig可独立于其他临床性状,作为宫颈癌患者的整体生存相关独立预后因子。总之,本研究为进一步探讨lncRNA在基因组不稳定性中的作用提供了关键的方法和资源,为识别基因组不稳定性相关的肿瘤标志物提供了新的预测方法。     

共刺激分子B7-H4在宫颈癌中的表达及意义

目的:肿瘤微环境中免疫共刺激分子B7-H4与其配体结合后可提供免疫抑制信号,调控肿瘤组织中的免疫应答。本研究探讨B7-H4、Fas及Caspase-3裂解片段在宫颈鳞状细胞癌中的表达及其与临床病理因素的关系,分析其参与肿瘤免疫逃逸的机制。方法:应用免疫组织化学SP法检测23例正常宫颈上皮、38例宫颈上皮内瘤变(CIN)和132例宫颈鳞状细胞癌组织中B7-H4、Fas及Caspase-3裂解片段的表达水平,分析其与宫颈癌各临床病理因素的相关性。结果:B7-H4在正常宫颈上皮组织中不表达,在CIN组织中微弱表达,在宫颈鳞状细胞癌组织中高表达。B7-H4表达与肿瘤的临床分期、淋巴结转移、原发肿瘤大小和肿瘤浸润深度有关,B7-H4与Fas蛋白表达呈现负相关,与Caspase-3裂解片段存在共表达关系。结论:B7-H4在宫颈鳞状细胞癌中过表达可引起Fas蛋白表达下调和Caspase-3裂解片段增多,抑制肿瘤细胞发生凋亡,参与肿瘤逃避宿主的免疫监视,从而促发宫颈癌的发生和发展。阻断B7-H4通路途径,有望成为宫颈鳞状细胞癌治疗的新靶点。     

Downregulation of ERp57 expression is associated with poor prognosis in early-stage cervical cancer

Abstract

Objective: We investigated the clinical significance of ERp57 in the progression of cervical cancer.

Methods: mRNA and protein expression of ERp57 in cervical neoplasias were examined.

Results: ERp57 mRNA expression was significantly decreased in cervical cancers. Immunohistochemistry revealed that ERp57 expression in 123 cervical cancers was down-regulated compared to cervical intraepithelial neoplasias or normal tissues (p?<?0.001). Low ERp57 expression was significantly associated with worse overall survival (HR?=?12.19, p?=?0.018).

Conclusions: Low ERp57 expression independently predicts a poor outcome for patients with cervical cancer, supporting the notion that ERp57 may be a promising novel cancer target.     

MiRNAs roles in the diagnosis,prognosis and treatment of colorectal cancer

ABSTRACT

Introduction: The liver is the main location for metastasization in stage IV colorectal cancers.

Areas covered: This review intends to comprehensively present the most important studies conducted in the past few years concerning the role of miRNAs in colorectal cancer liver metastases, trying to clarify some aspects regarding tumor biology and favorite liver metastasization site.

Expert commentary: Recent advances in tissue and serum RNA extraction has considerably improved the field of microRNAs studies. These molecules known to play a crucial role in the metastatic stage indicate a starting point in the development of clinical biomarkers with a possible role in the stratification of high-risk patients for adequate treatment.     

Loss of FBXW7 is related to the susceptibility and poor prognosis of cervical squamous carcinoma

Objective: To investigate the relationship between F box/WD-40 domain protein 7 (FBXW7) and cervical squamous cancer.

Methods: We investigated the FBXW7 expression in 136 cervical squamous carcinoma cases through immunohistochemistry and Western-blot analysis to evaluate the clinical significance of FBXW7 and to elucidate the relationship of FBXW7 expression with progression-free survival (PFS) and overall survival (OS).

Results: Low FBXW7 expression was associated with high histologic grade, lymphovascular space invasion and lymph node metastasis, among other parameters. Patients with low FBXW7 expression exhibited poor OS and PFS.

Conclusions: FBXW7 is related to the susceptibility and prognosis of cervical squamous carcinoma, indicating FBXW7 may be a potentially important target for the prediction of prognosis.     

术前预后营养指数、全身免疫炎症指数联合血清TFF3对宫颈癌术后复发转移的预测价值

摘要 目的：探讨术前预后营养指数（PNI）、全身免疫炎症指数（SII）联合血清三叶因子3（TFF3）对宫颈癌术后复发转移的预测价值。方法：选取2018年1月～2020年1月在江苏省人民医院行手术治疗的宫颈癌患者176例,随访3年根据是否出现复发转移将宫颈癌患者分为复发转移组（38例）和无复发转移组（138例）。计算术前PNI、SII和检测术前血清TFF3水平。宫颈癌术后复发转移的影响因素采用多因素Logistic回归模型分析,绘制受试者工作特征（ROC）曲线分析PNI、SII、TFF3单独及PNI、SII联合血清TFF3预测宫颈癌术后复发转移的价值。结果：随访3年,176例宫颈癌患者复发转移率为21.59%（38/176）。与无复发转移组比较,复发转移组PNI降低,SII和血清TFF3水平升高（P＜0.05）。多因素Logistic回归分析显示,低分化、国际妇产科联盟（FIGO）分期Ⅱ期、盆腔淋巴结转移、切缘阳性、鳞状细胞癌抗原升高、SII升高、TFF3升高为影响宫颈癌术后复发转移的独立危险因素,PNI升高为独立保护因素（P＜0.05）。ROC曲线分析显示,PNI、SII联合血清TFF3预测宫颈癌术后复发转移的曲线下面积为0.906,大于PNI、SII、TFF3、PNI+SII、PNI+TFF3、SII+TFF3预测的0.795、0.785、0.772、0.860、0.874、0.860。结论：术前PNI降低和SII、血清TFF3水平降低与宫颈癌术后复发转移密切相关,术前PNI、SII联合血清TFF3对宫颈癌术后复发转移的预测价值较高。     

Epidermal growth factor receptor (EGFR) mutations as biomarker for head and neck squamous cell carcinomas (HNSCC)

Abstract

Context: Mutations in tyrosine kinase domain (TK) of epidermal growth factor receptor (EGFR) lead to signalling interruptions in several cancers.

Objective: To understand EGFR mutations in head and neck squamous cell carcinomas (HNSCC), and their role as biomarkers.

Methods: Screened 129 HNSCC patients and 150 controls for mutations in the TK domain using polymerase chain reaction (PCR), single strand confirmatory polymorphism (SSCP) and sequencing.

Results: 81.39% of HNSCC had four mutations: G2155C, G2176A, C2188G and G2471A among these two mutations were also reported in other cancers where as two novel mutations are being reported for the first time in HNSCC. Mutational frequency was significantly associated with an advanced stage of HNSCC, habits of tobacco/alcohol and ages above 49 years.

Conclusion: EGFR single nucleotide polymorphisms could be useful biomarkers of HNSCC.     

半乳糖凝集素-3与程序性死亡受体-1在宫颈鳞癌组织中的表达及其临床意义

目的:探讨半乳糖凝集素-3(Gal-3)和程序性死亡受体-1(PD-1)在宫颈鳞癌组织中的表达及其临床意义。方法:选择2016年1月-2017年12月期间我院收治的宫颈鳞癌患者80例纳入观察组,宫颈上皮内瘤变(CIN)患者60例纳入CIN组,取同期在我院进行治疗的宫颈炎患者50例纳入对照组。采集三组患者的宫颈组织标本,采用免疫组化SP法对各组织标本中的Gal-3、PD-1的阳性率、表达水平进行检测,并分析Gal-3、PD-1与宫颈鳞癌临床病理特征的关系以及各指标表达水平的相关性。结果:观察组、CIN组的Gal-3、PD-1的阳性表达率、表达水平均高于对照组,且观察组高于CIN组(P0.05)。Gal-3、PD-1的表达与宫颈鳞癌患者的年龄、病灶大小、分化程度无关(P0.05),而与宫颈鳞癌肿瘤的分期、淋巴结转移有关(P0.05)。经Spearman相关性分析显示,宫颈鳞癌组织中Gal-3与PD-1间表达水平呈正相关性(r=0.496,P=0.000)。结论:Gal-3、PD-1的表达水平与宫颈鳞癌的发生、发展有密切关联,并且两种指标间呈明显正相关。     

超声造影定量与动态增强MRI定量在宫颈癌诊断中的应用价值

摘要 目的：探究超声造影定量与动态增强MRI定量在宫颈癌诊断中的应用价值。方法：选择2016年1月至2019年1月于我院接受治疗的86例疑似宫颈癌患者为实验组,另选取同期于我院接受治疗的50例宫颈良性病变患者为对照组,分别对两组患者实施超声造影定量检测及动态增强MRI检查,对比两组患者各参数组间差异性,同时以病理学检测结果为金标准,分析两种检查手段对宫颈癌的筛查效果并实施组间比较。结果：（1）比较显示实验组患者的峰值强度（peak intensity,PI）及时间-曲线下面积（area under curve,AUC）均高于对照组,达峰时间（time to peak,TTP）及平均渡越时间（mean transit time,MTT）均低于对照组（P<0.05）;（2）比较显示实验组患者的容积转移常数（volume transfer constant,K ^trans ）、速率常数（rate constant,k _ep ）以及血管外细胞外容积分数（extravascular extracellular volume fraction,V _e ）均高于对照组,表观扩散系数（apparent diffusion coefficient,ADC）低于对照组（P<0.05）;（3）以病理学检测结果为金标准,超声造影定量检测对宫颈癌检测一致性为93.02 %,灵敏度为94.44 %,特异度为85.71 %,增强MRI对宫颈癌检测一致性为96.51%,灵敏度为98.61%,特异度为85.71%。结论：宫颈癌患者实施超声造影定量与增强MRI检测时检测参数与正常宫颈组织相比会出现明显的差异性,可将上述两种检测方式用于宫颈癌患者的筛查诊断中。