• Obstetrics & gynecology science
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• 제61권6호
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• pp.662-668
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• 2018

Objective This study was to identify the risk factors for cytological progression in women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). Methods We analyzed data from women infected with the human papillomavirus (HPV) who participated in the Korean HPV cohort study. The cohort recruited women aged 20-60 years with abnormal cervical cytology (ASC-US or LSIL) from April 2010. All women were followed-up at every 6-month intervals with cervical cytology and HPV DNA testing. Results Of the 1,158 women included, 654 (56.5%) and 504 (43.5%) women showed ASC-US and LSIL, respectively. At the time of enrollment, 143 women tested positive for HPV 16 (85 single and 58 multiple infections). Cervical cytology performed in the HPV 16-positive women showed progression in 27%, no change in 23%, and regression in 50% of the women at the six-month follow-up. The progression rate associated with HPV 16 infection was higher than that with infection caused by other HPV types (relative risk [RR], 1.75; 95% confidence interval [CI], 1.08-2.84; P=0.028). The cytological progression rate in women with persistent HPV 16 infection was higher than that in women with incidental or cleared infections (P<0.001). Logistic regression analysis showed a significant relationship between cigarette smoking and cytological progression (RR, 4.15; 95% CI, 1.01-17.00). Conclusion The cytological progression rate in HPV 16-positive women with ASC-US or LSIL is higher than that in women infected with other HPV types. Additionally, cigarette smoking may play a role in cytological progression.

• Molecules and Cells
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• 제44권3호
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• pp.146-159
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• 2021

DNA methylation, and consequent down-regulation, of tumour suppressor genes occurs in response to epigenetic stimuli during cancer development. Similarly, human oncoviruses, including human papillomavirus (HPV), up-regulate and augment DNA methyltransferase (DNMT) and histone deacetylase (HDAC) activities, thereby decreasing tumour suppressor genes (TSGs) expression. Ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), an epigenetic regulator of DNA methylation, is overexpressed in HPV-induced cervical cancers. Here, we investigated the role of UHRF1 in cervical cancer by knocking down its expression in HeLa cells using lentiviral-encoded short hairpin (sh)RNA and performing cDNA microarrays. We detected significantly elevated expression of thioredoxin-interacting protein (TXNIP), a known TSG, in UHRF1-knockdown cells, and this gene is hypermethylated in cervical cancer tissue and cell lines, as indicated by whole-genome methylation analysis. Up-regulation of UHRF1 and decreased TXNIP were further detected in cervical cancer by western blot and immunohistochemistry and confirmed by Oncomine database analysis. Using chromatin immunoprecipitation, we identified the inverted CCAAT domain-containing UHRF1-binding site in the TXNIP promoter and demonstrated UHRF1 knockdown decreases UHRF1 promoter binding and enhances TXNIP expression through demethylation of this region. TXNIP promoter CpG methylation was further confirmed in cervical cancer tissue by pyrosequencing and methylation-specific polymerase chain reaction. Critically, down-regulation of UHRF1 by siRNA or UHRF1 antagonist (thymoquinone) induces cell cycle arrest and apoptosis, and ubiquitin-specific protease 7 (USP7), which stabilises and promotes UHRF1 function, is increased by HPV viral protein E6/E7 overexpression. These results indicate HPV might induce carcinogenesis through UHRF1-mediated TXNIP promoter methylation, thus suggesting a possible link between CpG methylation and cervical cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8063-8067
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• 2014

Background: Cervical cancer is a major public health problem in Bangladesh. Persistence of high risk human papillomavirus (HRHPV) influences the progression of the disease, with an important role in followup for cervical intraepithelial neoplasia (CIN). Objective: To establish application of high risk HPV DNA test in the follow-up of women after treatment of CIN. Materials and Methods: This cross-sectional and hospital based study was carried out among 145 CIN treated women during the previous six months to three years at the colposcopy clinic of Bangabandhu Sheikh Mujib Medical University, Dhaka, between January 2011 and June 2012. Pap smear and HPV samples were collected and colposcopy was performed to find out the persistence of the disease. Cervical samples obtained were tested for HPV DNA using the Hybrid Capture II (HC-II) test. A cervical biopsy was collected whenever necessary. The results were compared to assess the efficacy of different methods during follow up such as Pap smear, HPV test and colposcopy. Results: Mean age of the recruited women (n=145) was 33.6 (${\pm}7.6$), mean age of marriage was 16.8 (${\pm}2.9$) and mean age of 1st delivery was 18.8 (${\pm}3.5$) years. More than half had high grade CIN before treatment and 115 (79.3%) women were managed by LEEP and 20.7% were managed by cold coagulation. Among the 145 treated women, 139 were negative for HPV DNA and six of them (4.1%) were HPV positive. Sensitivity of Pap smear (40.0) and HPV DNA test (40.0) was poor, but specificity was quite satisfactory (>93.0) for all the tests. Conclusions: The high risk HPV DNA test can be an effective method of identifying residual disease. It can be added to colposcopy and this should be applied to all treated women attending for their first or second post-treatment follow-up visit at 6 months to one year, irrespective of the grade of treated CIN.

• Radiation Oncology Journal
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• 제33권3호
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• pp.198-206
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• 2015

Purpose: We evaluated the prognostic factors and clinical outcomes of 56 patients with vulvar cancer treated with curative radiotherapy (RT) or concurrent chemoradiotherapy. Materials and Methods: Overall survival (OS) and disease-free survival (DFS) were assessed retrospectively. Prognostic factors evaluated included age, International Federation of Gynecology and Obstetrics (FIGO) stage, TNM classification, tumor size, treatment modality, RT duration, and RT field. The association between the tumor human papillomavirus (HPV) status and survival was analyzed in 35 patients. Results: During the median follow-up of 2.8 years (range, 0.3 to 18.9 years), 21 patients (37.5%) experienced treatment failure. Fifteen patients (27%) had local failure: nine (16%) local failure only, three (5%) locoregional failure, two (4%) local and distant failure, and one (2%) locoregional and distant failure. Of 56 patients, seven (13%) had persistent disease at the first follow-up at 2 months and all but one died within a year after completing RT. The 5-year OS and DFS were 51.6% and 44.0%, respectively. In multivariate analysis, clinical size ${\geq}3$ cm predicted a poor prognostic factor for DFS (p = 0.040) and age (${\geq}70years$) was poor prognostic for DFS (p = 0.032) and OS (p = 0.048). Patients with HPV-positive tumors tended to have better 5-year OS and DFS, but the differences were not significant statistically. Conclusion: Clinical size ${\geq}3$ cm was a significant prognostic factor for DFS. However, age was the most important prognostic factor for DFS and OS in patients treated with curative RT. Further studies are needed to determine which treatment should be considered for old age ${\geq}70years$.

• 한국발생생물학회:학술대회논문집
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• 한국발생생물학회 2003년도 제3회 국제심포지움 및 학술대회
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• pp.106-106
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• 2003

Human papillomavirus type 16(HPV16) has been known to the major factor for the development of uterine cervical carcinomas. We have extended these studies to investigate the in vivo activities of HPV-16 E6/E7 when expressed in squamous epithelia of transgenic mice. Grossly, hK14HPV16E6/E7 transgenic mice had multiple phenotypes, including wrinkled skin that was apparent prior to the appearance of hair on neonates, thickened ears, and loss of hair in adults. In the transgenic mice, the wrinkled skin phenotype on the body and legs died at the age of 3-4 weeks. Histological analysis of demonstrated that E6/E7 causes epidermal hyperplasia in multiple transgenic lineages with high penetrance. This epithelial hyperplasia was characterized by an expansion of the proliferating compartment and an expansion of the keratinocyte and was associated with hyperkeratosis. These transgenic mice expressed E6/E7 transgene mainly in skin, heart, pancreas and kidney. Hyperplasia was found at the skin. The enzyme activities of GR, GPx and CuZnSOD were measured from the transgene cause keratinocyte at the skin. The specific enzyme activities were significantly higher in transgenic mice skin compared to the normal mice skin. Thus these transgenic mice may be useful for the develpment of antioxidant enzymes or other therapies for HPV-associated hyperkeratosis.

• Asian Pacific Journal of Cancer Prevention
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• 제15권10호
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• pp.4197-4201
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• 2014

Minor trauma to the uterine cervix is supposed to induce local immunity to prevent cervical lesions caused by human papillomavirus (HPV) infection. This study aimed to investigate the local cervical immunity in women with low grade squamous intraepithelial lesion (LSIL) and effects of abrasion after cryosurgery or Pap smear. One hundred women with LSIL and known results of HPV detection were recruited. HPV positive women were randomly divided according to abrasion into cryotherapy and Pap smear observation groups. Cervical tissues and cervico-vaginal lavage (CVL) were collected at 6 and 12 months after allocation. The levels of cytokines at first recruitment were compared with cytokine levels at 6 months after abrasions. The mRNA of IFN-${\gamma}$, TNF-${\alpha}$ and IL-10 in cervical tissues and these cytokines secreted in CVL were determined using real time PCR and ELISA, respectively. Anti-HPV16 IgG and IgA antibodies in CVL were assessed by western blotting. At first recruitment of women with LSIL (100 cases), IL-10 mRNA and cytokine in HPV positive group (60 cases) was significantly higher than negative group (40 cases). IFN-${\gamma}$ and TNF-${\alpha}$ mRNA level in both groups were comparable but their secretions in CVL were significantly increased in HPV negative group. After abrasion for 6 months in HPV-positive women, all mRNA and secreted cytokines were changed, but no significant difference was observed between cryotherapy and observation groups. When individuals were compared between first recruitment and after abrasion for 6 months, IFN-${\gamma}$ mRNA and anti-HPV16 L1 IgA antibodies were significantly increased in the cryotherapy group. The results suggest that modulation of local cervical immunities by abrasion might promote different effects in clearance of HPV-related cytological abnormalities.

• Asian Pacific Journal of Cancer Prevention
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• 제14권1호
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• pp.121-126
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• 2013

Background: Significance of HPV infection and genic mutation of APC and K-ras in rectal cancer has been investigated but not clarified. The objective of our study was to investigate these parameters in patients with rectal cancer to analyze correlations with biological behaviour, to determine relationships among the three, and also to demonstrate survival prognosis effects. Methods: From December 2007 to September 2008, 75 rectal cancer cases confirmed by histopathology in the Tumor Hospital of Xinjiang Medical University were enrolled. The control group consisted of normal rectal mucous membrane taken simultaneously, a least 10 cm distant from the carcinoma fringe. HPV DNA, the MCR of APC and exon-1 of K-ras were detected by PCR and PCR-SSCP. All results were analyzed in relation to clinical pathological material, using chi-square and correlation analysis via SPSS.13 and Fisher's Exact Probability via STATA. 9.0. All 75 patients were followed up for survival analysis using Kaplan-Meier and Log-rank tests. Results: 55 out of 75 cases demonstrated gene HPV L1 while it was notdetected in normal rectal mucosa tissue. HPV infection was correlated with age and lymphatic metastasis (P<0.05) but not other characteristics, such as ethnicity, tumor size, histological type, tumor type, Duke's stage and infiltration depth. Some 43 cases exhibited APC genic mutation (57.3%) and 34 K-ras genic mutation (45.3%). APC genic mutation was correlated with gender(P<0.05), but not age, histological type, infiltration depth, lymphatic metastasis and Duke's stage. In 55 cases of rectal cancer with HPV infection, there were 31 cases with genic mutation of APC (56.4%) and 24 with genic mutation of K-ras (43.6%). For the 20 cases of rectal cancer with non-HPV infection, the figures were 12 cases (60%) and 10 (50.0%), respectively, with no significant relation. Survival analysis showed no statistical significance for K-ras genic mutation, APC genic mutation or HPV infection (P>0.05). However, the survival time of the patients with HPV infection was a little shorter than in cases without HPV infection. Conclusions: Our results suggest that HPV infection might be an important factor to bring about malignant phenotype of rectal cancer and influence prognosis. Genic mutation of APC and K-ras might be common early molecular events of rectal cancer, but without prognostic effects on medium-term or early stage patients with rectal cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제14권3호
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• pp.1755-1760
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• 2013

Objective: To investigate the prevalence of genital high-risk human papillomavirus (HR-HPV) in male sexual partners of HR-HPV infected women and the concordance of viral types in couples in China, and comprehend the role of men play in HPV transmission to women. Methods/Materials: 94 asymptomatic women and their husbands from rural Chaozhou participated in epidemiologic screening for HPV infection. Cervical cells from females were collected for high risk HPV screening by real time-PCR, and they were positive for at least 1 of 13 HR-HPV subtypes, then these samples were genotyped. Approximately one mouth later, penile epithelial cells from 94 asymptomatic husbands were collected for HPV genotyping. At the same time, a cross-sectional study was conducted in 366 male patients from sexually transmitted disease (STD) outpatient clinic in China for the prevalence of genital HR-HPV infection in men having frequent sex behavior. Penial epithelial cells were collected for HPV 6/11 and HPV 16/18 detection by fluorescent real-time quantified PCR. Results: Among 94 couples, the prevalence of genital HR-HPV infection in men whose wife was positive for cervical HR-HPV was 5.32% (5/94). Only 2.63% (2/76) had the same high risk viral type presented by their wife. HPV 16 proved to be the most prevalent viral type in men and in couples. Of 366 male patients from STD outpatient clinic, the prevalence of HPV 16/18 infection in men with or without HPV 6/11 was 6.85% and 8.16%, respectively. The incidence of HPV 16/18 was higher in men aged more than 35 years than the young men (18-35 years). Conclusion: The prevalence of genital HR-HPV infection in male sexual partners of HPV-positive women in China was lower than that expected, and the concordance of high risk viral type between couples was extremely low. These data suggested that infected men consitute an important viral reservoir, contributing to transmission of HR-HPV to women and maintenance of infection, but HR-HPV infection may be less likely to persist in men than in women.

• Asian Pacific Journal of Cancer Prevention
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• 제17권9호
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• pp.4353-4356
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• 2016

Purpose: To study the prevalence of CIN2+ diagnosis in women with atypical Papaniculoau (Pap) smears to suggest appropriate management option for Thai health care. Materials and Methods: Data from all patients with liquid based cytology with human papillomavirus (HPV) testing between May 2013 - May 2016 were collected from medical records. Women with atypical cervical Pap smears were recruited. Results for age, HPV testing, HPV 16, 18, 45 and other genotypes tested, colposcopic examination and histopathological assessment were all collected. Atypical smears were defined as atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells cannot be exclude high grade squamous intraepithelial lesion (ASC-H). Results: A total of 2,144 cases were recruited. Twenty six women with ASC-US on cytology had high risk (HR) HPV detection while eight cases with ASC-H had HR-HPV (40.0% VS 72.7%, p=0.005). Among the 26 women with ASC-US cytology and positive HR-HPV, HPV type 16 (n=8, 30.8%), type 18 (n=1, 3.8%), type 45 (n=1, 3.8%) and other HPV types (n=17, 65.4%) were found. Eight women with ASC-H and positive HR-HPV demonstrated type 16 (n=6, 75%) and other HPV types (n=2, 25%). Fifty seven women with ASC-US had normal colposcopy, CIN1 and CIN2+ at percentages of 80.7 (46/57), 14.0 (8/57) and 5.3 (3/57), respectively. In the ASC-H group, 7 out of 10 women had normal colposcopy and three (30%) had CIN2+ results. Conclusions: In women with ASC-US cytology, immediate colposcopy is highly recommended. HPV testing can be performed if colposcopy is not an available option because there was high prevalence (5.3%) of CIN2+ in our findings. ASCCP recommendations for ASC-H that colposcopy should be performed on all ASC-H cases regardless of HPV result are thereby supported by the findings of this investigation.

• 대한임상검사과학회지
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• 제52권3호
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• pp.237-244
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• 2020

현재 성병은 성매개 질환(sexually transmitted disease, STD)은 무증상 감염도 포함하는 의미에서 "성매개 감염"(sexually transmitted infections, STI)이라고 표현하고 있다. STI는 다양한 상호 관계를 가지고 있다. 본 연구는 보건복지부 장관이 고시하는 STI로 매독, 임질, 클라미디아 감염증, 연성하감, 성기단순포진, 첨규콘딜로마, 사람유두종바이러스 감염증과 비임균성요도염(non-gonococcal urethritis, NGU)을 대상으로 하였다. 따라서 다발성 및 동시성 STI를 확인하여 요인을 특성화하는 것을 목적으로 하였다. 본 연구는 2014년부터 2019년까지 서울에 위치한 일개 수탁검사기관의 검사실정보시스템(laboratory information system)의 자료를 활용하였다. 본 연구에서 다발성 STI로 두 가지 감염균의 중복 STI는 10 종류, 세 가지 감염균의 다중 STI는 6 종류로 나타났다. 이러한 16 종류의 다발성 STI 중 가장 많은 비중을 차지하는 균은 U. urealyticum (9가지), HSV-2 (8가지), C. trachomatis (7가지), HPV 6, 11 (7가지), N. gonorrhoeae (6가지), T. pallidum (1가지)에 포함되었다. 따라서 본 연구 결과에서 다발성 STI에 가장 비중이 높은 STI 등 상호 관계연구의 추가연구가 필요할 것으로 사료된다.