Globally,about 70% of cervical cancers are associated with human papillomavirus (HPV)-16 or HPV-18 infection.A meta-analysis of epidemiologic studies in China showed that HPV was present in 98% of cervical cancer samp...Globally,about 70% of cervical cancers are associated with human papillomavirus (HPV)-16 or HPV-18 infection.A meta-analysis of epidemiologic studies in China showed that HPV was present in 98% of cervical cancer samples.The HPV-16/18 AS04-adjuvanted vaccine Cervarix has shown a high level of protection against HPV-16/18 infections and associated cervical lesions.This phase Ⅰ trial (NCT00549900) assessed the safety,tolerability,and immunogenicity of the vaccine in Chinese.Thirty healthy Chinese females,aged 15 to 45 years with a median age of 29.5 years,received three doses of Cervarix in Months 0,1,and 6.Safety was assessed via recording solicited local and systemic symptoms within 7 days and unsolicited symptoms within 30 days after each vaccination.Serious adverse events,new onset of chronic diseases,and other medically significant conditions were recorded throughout this trial.As an exploratory objective,HPV-16/18 antibody titers were determined by enzyme-linked immunosorbent assay in serum samples collected in Months 0 and 7.Pain at the injection site was the most frequently reported local symptom.Two subjects reported medically significant adverse events.Both cases were assessed as unrelated to vaccination by the investigator.In Month 7,100% seroconversion was observed for both anti-HPV-16 and anti-HPV-18 with high geometric mean antibody titers.HPV-16/18 AS04-adjuvanted vaccine,evaluated for the first time in Chinese females,was generally well tolerated and immunogenic,as previously shown in global studies.展开更多
The development of esophageal cancer accompanied by the presence of human papillomavirus (HPV) DNA into the host genome. By evaluating the expression of this virus for tumor cell origin and also their cell grows and m...The development of esophageal cancer accompanied by the presence of human papillomavirus (HPV) DNA into the host genome. By evaluating the expression of this virus for tumor cell origin and also their cell grows and migrations, we examined esophageal cancer clonality in the context of intra-tumor heterogeneity. In this research, we have checked the expression of HPV18 E6 and E7 in different single cell clones by the manual cell picking method in the HPV positive esophageal cancer (EC109), EC109 cell line used as a negative control, and Hela cell line used as the positive control. Quantitative real-time PCR (QRT-PCR) was run to detect the expression levels of HPV E6 and E7, Cell Counting Kit-8 (CCK-8) assay was used to examine cell proliferation, invasion assays performed using Costar chambers and wounding assay to study cell migrations in vitro. We investigated the intra-tumor heterogeneity of HPV E6 and E7 in esophageal cancer and the evaluation of the growth and migrations at the clonal level, using 10 single cell clones. In particular clones, C7 & C10 displayed a highly variable expression in both HPV E6 and E7 and weak in four clones (C1, C3, C4, and C9) consequently, the cell invasion, proliferation, and migration increase with increasing the level of HPV expression and inverse. In conclusion, the resulting based on single cell cloning showed the relationship between HPV and cell growth and migration in esophageal cancer. Future study in HPV DNA integration needed to explore the mains specific integration site of HPV DNA in esophageal cancer and molecular monitoring of the HPV for future prevention researches and also effective therapeutic strategies.展开更多
Histological low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 （LSIL/CIN1） preceded by normal or mildly abnormal cytology is recommended for conservative follow-up, with no separat...Histological low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 （LSIL/CIN1） preceded by normal or mildly abnormal cytology is recommended for conservative follow-up, with no separated management. In this study, we assessed the triage value of human papillomavirus （HPV） 16/18 genotyping in 273 patients with LSIL/CINI. HPV16/18 genotyping was performed at baseline and follow-up was at 6-monthly intervals for up to 2 years. At each follow-up, women positive for cytology or high-risk HPV （hrHPV） were referred for colposcopy. Enrollment cytology, HPV16/18 genotyping, and questionnaire-obtained factors were linked to the 2-year cumulative progression rate. Univariate and multivariate analyses were performed taking into account time-to-event with Cox proportional hazard regression. The results showed that 190 cases （69.6%） regressed, 37 （13.6%） persisted, and 46 （16.8%） progressed. HPV16/18 positivity （hazard ratio （HR）, 2.708; 95% confidence interval （CI）, 1.432-5.121; P=-0.002） is significantly associated with higher 2-year cumulative progression rate. Sub-analysis by enrollment cytology and age restricted the positive association among patients preceded by mildly abnormal cytology and aged 30 years or older. Immediate treatment is a rational recommendation for the high-risk subgroup, when good compliance is not assured.展开更多
Human papillomavirus 18(HPV18) E6 and E7 oncogenes are transcribed as a single bicistronic E6 E7 pre-mRNA. The E6 ORF region in the bicistronic E6 E7 pre-mRNA contains an intron. Splicing of this intron disrupts the E...Human papillomavirus 18(HPV18) E6 and E7 oncogenes are transcribed as a single bicistronic E6 E7 pre-mRNA. The E6 ORF region in the bicistronic E6 E7 pre-mRNA contains an intron. Splicing of this intron disrupts the E6 ORF integrity and produces a spliced E6*I RNA for efficient E7 translation. Here we report that the E6 intron has two overlapped branch point sequences(BPS) upstream of its 30 splice site, with an identical heptamer AACUAAC, for E6*I splicing. One heptamer has a branch site adenosine(underlined) at nt 384 and the other at nt 388. E6*I splicing efficiency correlates to the expression level of E6 and E7 proteins and depends on the selection of which branch site. In general, E6*I splicing prefers the 30 ss-proximal branch site at nt 388 over the distal branch site at nt 384. Inactivation of the nt 388 branch site was found to activate a cryptic acceptor site at nt 636 for aberrant RNA splicing. Together, these data suggest that HPV18 modulates its production ratio of E6 and E7 proteins by alternative selection of the two mapped branch sites for the E6*I splicing, which could be beneficial in its productive or oncogenic infection according to the host cell environment.展开更多
文摘Globally,about 70% of cervical cancers are associated with human papillomavirus (HPV)-16 or HPV-18 infection.A meta-analysis of epidemiologic studies in China showed that HPV was present in 98% of cervical cancer samples.The HPV-16/18 AS04-adjuvanted vaccine Cervarix has shown a high level of protection against HPV-16/18 infections and associated cervical lesions.This phase Ⅰ trial (NCT00549900) assessed the safety,tolerability,and immunogenicity of the vaccine in Chinese.Thirty healthy Chinese females,aged 15 to 45 years with a median age of 29.5 years,received three doses of Cervarix in Months 0,1,and 6.Safety was assessed via recording solicited local and systemic symptoms within 7 days and unsolicited symptoms within 30 days after each vaccination.Serious adverse events,new onset of chronic diseases,and other medically significant conditions were recorded throughout this trial.As an exploratory objective,HPV-16/18 antibody titers were determined by enzyme-linked immunosorbent assay in serum samples collected in Months 0 and 7.Pain at the injection site was the most frequently reported local symptom.Two subjects reported medically significant adverse events.Both cases were assessed as unrelated to vaccination by the investigator.In Month 7,100% seroconversion was observed for both anti-HPV-16 and anti-HPV-18 with high geometric mean antibody titers.HPV-16/18 AS04-adjuvanted vaccine,evaluated for the first time in Chinese females,was generally well tolerated and immunogenic,as previously shown in global studies.
文摘The development of esophageal cancer accompanied by the presence of human papillomavirus (HPV) DNA into the host genome. By evaluating the expression of this virus for tumor cell origin and also their cell grows and migrations, we examined esophageal cancer clonality in the context of intra-tumor heterogeneity. In this research, we have checked the expression of HPV18 E6 and E7 in different single cell clones by the manual cell picking method in the HPV positive esophageal cancer (EC109), EC109 cell line used as a negative control, and Hela cell line used as the positive control. Quantitative real-time PCR (QRT-PCR) was run to detect the expression levels of HPV E6 and E7, Cell Counting Kit-8 (CCK-8) assay was used to examine cell proliferation, invasion assays performed using Costar chambers and wounding assay to study cell migrations in vitro. We investigated the intra-tumor heterogeneity of HPV E6 and E7 in esophageal cancer and the evaluation of the growth and migrations at the clonal level, using 10 single cell clones. In particular clones, C7 & C10 displayed a highly variable expression in both HPV E6 and E7 and weak in four clones (C1, C3, C4, and C9) consequently, the cell invasion, proliferation, and migration increase with increasing the level of HPV expression and inverse. In conclusion, the resulting based on single cell cloning showed the relationship between HPV and cell growth and migration in esophageal cancer. Future study in HPV DNA integration needed to explore the mains specific integration site of HPV DNA in esophageal cancer and molecular monitoring of the HPV for future prevention researches and also effective therapeutic strategies.
基金Project supported by the Zhejiang Provincial Natural Science Foundation of China(No.LQ14H160007)the National Natural Science Foundation of China(No.81402364)+2 种基金the Zhejiang Provincial Medical & Hygienic Science and Technology Project of China(No.2013KYA104)the Special Fund for Scientific Research in the Public Interest from the National Health and Family Planning Commission of the People’s Republic of China(No.2015SQ00243)the National Key Research and Development Program of China(No.2016YFC1302900)
文摘Histological low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 （LSIL/CIN1） preceded by normal or mildly abnormal cytology is recommended for conservative follow-up, with no separated management. In this study, we assessed the triage value of human papillomavirus （HPV） 16/18 genotyping in 273 patients with LSIL/CINI. HPV16/18 genotyping was performed at baseline and follow-up was at 6-monthly intervals for up to 2 years. At each follow-up, women positive for cytology or high-risk HPV （hrHPV） were referred for colposcopy. Enrollment cytology, HPV16/18 genotyping, and questionnaire-obtained factors were linked to the 2-year cumulative progression rate. Univariate and multivariate analyses were performed taking into account time-to-event with Cox proportional hazard regression. The results showed that 190 cases （69.6%） regressed, 37 （13.6%） persisted, and 46 （16.8%） progressed. HPV16/18 positivity （hazard ratio （HR）, 2.708; 95% confidence interval （CI）, 1.432-5.121; P=-0.002） is significantly associated with higher 2-year cumulative progression rate. Sub-analysis by enrollment cytology and age restricted the positive association among patients preceded by mildly abnormal cytology and aged 30 years or older. Immediate treatment is a rational recommendation for the high-risk subgroup, when good compliance is not assured.
基金fully supported by Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (1ZIASC010357 to ZMZ)a part of Brant AC Ph.D thesis being developed at the Post-graduate program in Genetics (PGGEN) of Rio de Janeiro Federal University (UFRJ), Rio de Janeiro, Brazil+2 种基金the National Cancer Institute of USAsupported by the PDSE program of Coordenacao de Aperfeicoamento de Pessoal de Nível Superior (Capes, Brazil)the National Cancer Institute of USA
文摘Human papillomavirus 18(HPV18) E6 and E7 oncogenes are transcribed as a single bicistronic E6 E7 pre-mRNA. The E6 ORF region in the bicistronic E6 E7 pre-mRNA contains an intron. Splicing of this intron disrupts the E6 ORF integrity and produces a spliced E6*I RNA for efficient E7 translation. Here we report that the E6 intron has two overlapped branch point sequences(BPS) upstream of its 30 splice site, with an identical heptamer AACUAAC, for E6*I splicing. One heptamer has a branch site adenosine(underlined) at nt 384 and the other at nt 388. E6*I splicing efficiency correlates to the expression level of E6 and E7 proteins and depends on the selection of which branch site. In general, E6*I splicing prefers the 30 ss-proximal branch site at nt 388 over the distal branch site at nt 384. Inactivation of the nt 388 branch site was found to activate a cryptic acceptor site at nt 636 for aberrant RNA splicing. Together, these data suggest that HPV18 modulates its production ratio of E6 and E7 proteins by alternative selection of the two mapped branch sites for the E6*I splicing, which could be beneficial in its productive or oncogenic infection according to the host cell environment.
