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1.
Acta Cytol ; 64(1-2): 63-70, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30889579

RESUMO

The association between high-risk genotypes of human papillomavirus (hr-HPV) and cervical cancer is well established. As hr-HPV testing is rapidly becoming a part of routine cervical cancer screening, either in conjunction with cytology or as primary testing, the management of hr-HPV-positive women has to be tailored in a way that increases the detection of cervical abnormalities while decreasing unnecessary colposcopic biopsies or other invasive procedures. In this review, we discuss the overall utility and strategies of hr-HPV testing, as well as the advantages and limitations of potential triage strategies for hr-HPV-positive women, including HPV genotyping, p16/Ki-67 dual staining, and methylation assays.


Assuntos
Citodiagnóstico/métodos , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Detecção Precoce de Câncer/métodos , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Papillomaviridae/fisiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Triagem , Neoplasias do Colo do Útero/complicações
2.
Acta Cytol ; 64(1-2): 30-39, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30783052

RESUMO

Human papilloma virus (HPV)-related squamous cell carcinoma (SCC) is biologically unique and has a better prognosis than conventional SCC of the head and neck. p16 immunohistochemistry emerged as a valuable surrogate marker for HPV in oropharyngeal SCC. The criteria for a positive p16 result in tissue specimens are well established. However, there is no consensus regarding interpreting p16 staining in cell blocks and other cytology specimens. This review discusses the current evidence on p16 testing in cytology specimens and also highlights other methods for HPV testing, including DNA and RNA in situ hybridization, as well as other molecular HPV tests.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Imuno-Histoquímica/métodos , Infecções por Papillomavirus/metabolismo , Biópsia por Agulha Fina/métodos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hibridização In Situ/métodos , Papillomaviridae/genética , Papillomaviridae/fisiologia , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Sensibilidade e Especificidade
3.
Acta Cytol ; 64(1-2): 155-165, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30982025

RESUMO

The Papanicolaou (PAP) test is widely used to screen for cervical cancer. All high-grade lesions such as atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H), and high-grade squamous intraepithelial lesion, identified on a PAP test should be followed-up by a confirmatory cervical biopsy. In this review, we discuss the challenges in interpreting cervical tissue specimens and the various ancillary techniques used in the evaluation of cervical dysplasia. Ancillary studies include deeper levels, p16 immunohistochemistry (IHC), human papillomavirus (HPV) testing, and, importantly, cyto-histologic correlation. Of these, p16 IHC is consistently sensitive and specific for detecting HSIL. HPV RNA in situ hybridization (ISH) is a newer technique with excellent sensitivity and specificity for detecting virally infected cells and it may be more broadly applicable to both low- and high-grade squamous intraepithelial lesions.


Assuntos
Células Escamosas Atípicas do Colo do Útero/patologia , Neoplasia Intraepitelial Cervical/patologia , Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Biópsia , Neoplasia Intraepitelial Cervical/diagnóstico , Curetagem , Feminino , Humanos , Teste de Papanicolaou/métodos , Papillomaviridae/fisiologia , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/diagnóstico
4.
BJOG ; 127(2): 171-180, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237400

RESUMO

BACKGROUND: Persistent infection with high-risk human papillomavirus can lead to cervical dysplasia and cancer. Recent studies have suggested associations between the composition of the vaginal microbiota, infection with human papillomavirus (HPV) and progression to cervical dysplasia and cancer. OBJECTIVE: To assess how specific cervico-vaginal microbiota compositions are associated with HPV infection, cervical dysplasia and cancer, we conducted a systematic review and network meta-analysis (registered in PROSPERO: CRD42018112862). SEARCH STRATEGY: PubMed, Web of science, Embase and Cochrane database. SELECTION CRITERIA: All original studies describing at least two community state types of bacteria (CST), based on molecular techniques enabling identification of bacteria, and reporting the association with HPV infection, cervical dysplasia and/or cervical cancer. DATA COLLECTION AND ANALYSIS: For the meta-analysis, a network map was constructed to provide an overview of the network relationships and to assess how many studies provided direct evidence for the different vaginal microbiota compositions and HPV, cervical dysplasia or cancer. Thereafter, the consistency of the model was assessed, and forest plots were constructed to pool and summarise the available evidence, presenting odds ratios and 95% confidence intervals. MAIN RESULTS: Vaginal microbiota dominated by non-Lactobacilli species or Lactobacillus iners were associated with three to five times higher odds of any prevalent HPV and two to three times higher for high-risk HPV and dysplasia/cervical cancer compared with Lactobacillus crispatus. CONCLUSIONS: These findings suggest an association between certain bacterial community types of the vaginal microbiota and HPV infection and HPV-related disease. This may be useful for guiding treatment options or serve as biomarkers for HPV-related disease. TWEETABLE ABSTRACT: This network meta-analysis suggests an association between different vaginal bacterial community types and the risk of HPV.


Assuntos
Neoplasia Intraepitelial Cervical/patologia , Lactobacillus/fisiologia , Microbiota/fisiologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/patologia , Neoplasias do Colo do Útero/patologia , Vagina/patologia , Neoplasia Intraepitelial Cervical/microbiologia , Feminino , Humanos , Meta-Análise em Rede , Infecções por Papillomavirus/microbiologia , RNA Ribossômico 16S , Neoplasias do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/virologia , Vagina/microbiologia , Vagina/virologia
5.
Adv Virus Res ; 104: 97-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31439154

RESUMO

Viruses must navigate the complex endomembranous network of the host cell to cause infection. In the case of a non-enveloped virus that lacks a surrounding lipid bilayer, endocytic uptake from the plasma membrane is not sufficient to cause infection. Instead, the virus must travel within organelle membranes to reach a specific cellular destination that supports exposure or arrival of the virus to the cytosol. This is achieved by viral penetration across a host endomembrane, ultimately enabling entry of the virus into the nucleus to initiate infection. In this review, we discuss the entry mechanisms of three distinct non-enveloped DNA viruses-adenovirus (AdV), human papillomavirus (HPV), and polyomavirus (PyV)-highlighting how each exploit different intracellular transport machineries and membrane penetration apparatus associated with the endosome, Golgi, and endoplasmic reticulum (ER) membrane systems to infect a host cell. These processes not only illuminate a highly-coordinated interplay between non-enveloped viruses and their host, but may provide new strategies to combat non-enveloped virus-induced diseases.


Assuntos
Adenoviridae/fisiologia , Interações Hospedeiro-Patógeno , Papillomaviridae/fisiologia , Polyomavirus/fisiologia , Internalização do Vírus , Endocitose , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/virologia , Endossomos/metabolismo , Endossomos/virologia , Complexo de Golgi/metabolismo , Complexo de Golgi/virologia , Humanos
6.
Presse Med ; 48(7-8 Pt 1): 756-766, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31307878

RESUMO

Human oncogenic papillomaviruses (HPV) have an increasingly prominent role in the genesis of many cancers. The oncogenic mechanisms associated with HPV are now better known and make it possible to explain the etiopathogenesis of the association. HPV status is now sought for certain cancers and conditions both prognosis and management of patients. Preventive antiviral vaccination has become a real public health issue and aims to effectively reduce the prevalence of cervical, anal and oropharynx cancer, HPV-associated. However, vaccination against HPV still lags behind. The purpose of this review is to redefine the involvement of HPV in several cancers as well as current therapeutic challenges of HPV-related cancers, notably in term of prevention.


Assuntos
Transformação Celular Viral/fisiologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/prevenção & controle , Medicina Preventiva/métodos , Vacinação , Neoplasias do Ânus/prevenção & controle , Neoplasias do Ânus/virologia , Carcinogênese , Feminino , Humanos , Masculino , Neoplasias Orofaríngeas/prevenção & controle , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/uso terapêutico , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia , Vacinação/métodos , Vacinação/psicologia , Vacinação/tendências
7.
J Cancer Res Clin Oncol ; 145(8): 2061-2069, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31309301

RESUMO

PURPOSE: Cervical cancer metastases to the ovary may occur with advanced tumor stage, deep cervical stromal involvement and corpus involvement. Endocervical adenocarcinoma in situ (AIS) with ovarian involvement is exceptionally rare with about twelve reported cases. METHODS: Here we present a case of endocervical AIS with ovarian and pulmonary involvement 39 months after the initial diagnosis. The characteristics of that case were compared and summarized with the eleven previously published cases. RESULTS: The patients' age ranged between 30 and 40 years (median 37.4 years). The time interval between the diagnosis of AIS and ovarian involvement was 26.7 months (range 2-84 months). Majority of the patients are alive without evidence of disease after a median time of 63.4 months (range 9-156 months). All reported cases were positive for high-risk HPV which was associated with strong p16 expression on immunohistochemistry. CONCLUSIONS: The ovarian involvement by endocervical AIS suggests the concept of a transtubal spread of the neoplastic cervical cells with or without previous colonization within the endometrium without evidence of invasive growth, suggesting a seed and soil spread of the disease. In cases with ovarian involvement by the AIS and without additional extragenital spread, the prognosis may be favorable.


Assuntos
Adenocarcinoma in Situ/patologia , Suscetibilidade a Doenças , Neoplasias Pulmonares/secundário , Neoplasias Ovarianas/secundário , Neoplasias do Colo do Útero/patologia , Adenocarcinoma in Situ/virologia , Adulto , Suscetibilidade a Doenças/etiologia , Suscetibilidade a Doenças/patologia , Suscetibilidade a Doenças/virologia , Feminino , Humanos , Neoplasias Pulmonares/virologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/virologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/virologia
8.
mSphere ; 4(4)2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315968

RESUMO

Jason Bodily works in the field of tumor virology. In this mSphere of Influence article, he reflects on how "Inactivation of Rb in stromal fibroblasts promotes epithelial cell invasion" by Adam Pickard et al. (EMBO J 31:3092-3103, 2012, https://doi.org/10.1038/emboj.2012.153) has impacted his work by making him think about the role of stromal cells in human papillomavirus infections.


Assuntos
Células Epiteliais/virologia , Oncogenes , Papillomaviridae/genética , Células Estromais/virologia , Humanos , Narração , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia
9.
Emerg Microbes Infect ; 8(1): 1108-1121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31340720

RESUMO

Human papillomaviruses (HPV) contribute to most cervical cancers and are considered to be sexually transmitted. However, papillomaviruses are often found in cancers of internal organs, including the stomach, raising the question as to how the viruses gain access to these sites. A possible connection between blood transfusion and HPV-associated disease has not received much attention. Here we show, in rabbit and mouse models, that blood infected with papillomavirus yields infections at permissive sites with detectable viral DNA, RNA transcripts, and protein products. The rabbit skin tumours induced via blood infection displayed decreased expression of SLN, TAC1, MYH8, PGAM2, and APOBEC2 and increased expression of SDRC7, KRT16, S100A9, IL36G, and FABP9, as seen in tumours induced by local infections. Furthermore, we demonstrate that blood from infected mice can transmit the infection to uninfected animals. Finally, we demonstrate the presence of papillomavirus infections and virus-induced hyperplasia in the stomach tissues of animals infected via the blood. These results indicate that blood transmission could be another route for papillomavirus infection, implying that the human blood supply, which is not screened for papillomaviruses, could be a potential source of HPV infection as well as subsequent cancers in tissues not normally associated with the viruses.


Assuntos
Sangue/virologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/transmissão , Infecções por Papillomavirus/virologia , Animais , DNA Viral/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/sangue , Infecções por Papillomavirus/genética , Coelhos
10.
Cancer Immunol Immunother ; 68(8): 1263-1272, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31240326

RESUMO

BACKGROUND: An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC. MATERIALS AND METHODS: A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels. CONCLUSION: Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Orofaríngeas/diagnóstico , Papillomaviridae/fisiologia , Infecções por Papillomavirus/diagnóstico , Inibidor Tecidual de Metaloproteinase-1/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Metaloproteinase 8 da Matriz/sangue , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/epidemiologia , Neoplasias Orofaríngeas/mortalidade , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/mortalidade , Prognóstico , Análise de Sobrevida
11.
Cells ; 8(6)2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234354

RESUMO

Cervical cancer develops through persistent infection with high-risk human papilloma virus (hrHPV) and is a leading cause of death among women worldwide and in the United States. Periodic surveillance through hrHPV and Pap smear-based testing has remarkably reduced cervical cancer incidence worldwide and in the USA. However, considerable discordance in the occurrence and outcome of cervical cancer in various populations exists. Lack of adequate health insurance appears to act as a major socioeconomic burden for obtaining cervical cancer preventive screening in a timely manner, which results in disparate cervical cancer incidence. On the other hand, cervical cancer is aggressive and often detected in advanced stages, including African American and Hispanic/Latina women. In this context, our knowledge of the underlying molecular mechanism and genetic basis behind the disparate cervical cancer outcome is limited. In this review, we shed light on our current understanding and knowledge of racially disparate outcomes in cervical cancer.


Assuntos
Disparidades em Assistência à Saúde , Papillomaviridae/fisiologia , Neoplasias do Colo do Útero/virologia , Epigênese Genética , Feminino , Humanos , Modelos Biológicos , Fatores de Risco , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/terapia
12.
Gynecol Oncol ; 154(2): 345-353, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31242966

RESUMO

OBJECTIVE: Cervical HR-HPV persistence is the main risk factor for cervical cancer. We aimed to investigate the association of age and viral factors with HR-HPV persistence. METHODS: From 2010 to 2017, 343,128 women underwent 390,411 tests performed by the Cervista HR-HPV assay (Data C3) and 157,123 women underwent 206,505 tests performed by the GenoArray HR-HPV assay (Data G14) in nine medical centers located in central and eastern China. We combined the test results and identified 9234 HPV-specific baseline-negative records for time-to-event analyses. The study endpoint event was defined as clearance of type/group-specific HPV. Therefore, hazard ratio (HR) < 1 indicated a higher risk of HPV persistence, which is contrary to the common meaning of HR. RESULTS: The median persistence time was 375 and 541.5 days for Data C3 and Data G14, respectively. For every 5-year increase in age, a 15% (95% confidence interval [CI], 11%-19%) decrease in the clearance rate was observed only after 400 days of infection. For each additional co-infected HPV, the HR was 1.80 (95% CI, 1.63-1.97) on infection initiation but decreased by 22% (95% CI, 18%-26%) every 100 days. The HR of infection recurrence was 0.48 (95% CI, 0.32-0.72). The findings were consistent across different populations and test methods and were robust in sensitivity analysis. CONCLUSIONS: We found a time-dependent association of age and viral factors with HPV clearance. Older age reduced HPV clearance only after 400 days of infection. Co-infection promoted HPV clearance in the beginning, but the effect attenuated and reversed as infection persisted. Recurrent same-type infection cleared slower than the previous one.


Assuntos
Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Adulto , Fatores Etários , Idoso , Neoplasia Intraepitelial Cervical/virologia , China , Feminino , Seguimentos , Humanos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Tempo , Neoplasias do Colo do Útero/virologia
13.
J Cancer Res Clin Oncol ; 145(8): 1919-1937, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31236668

RESUMO

PURPOSE: This review is devoted to assessing the prevalence of human papillomavirus (HPV) in lung cancer (LC) in the world. HPV is recognized as the etiological factor of cervical cancer, however, there is widespread evidence that this virus is detected not only in gynecological carcinomas, but also in tumors of other organs, in particular the upper respiratory tract and digestive tract. MATERIALS AND METHODS:  A search was conducted to a depth of 29 years in the PubMed, Web of Science, Scopus, databases. The review includes 95 articles. RESULTS: Of all the analyzed studies (9195 patients), 12 works showed a complete absence of HPV in the biological material in patients with LC. The absence of a virus among lung cancer patients has been established for Canada, the Netherlands and Singapore. The highest average percent of occurrence of this virus is shown for such countries as: Brazil, Korea, Greece and Taiwan (more than 40%). But the highest percentage of HPV occurrence by region is observed in Latin America (33.5%), followed by the Asian countries (31%), in European countries the frequency is 18%. Interestingly, the highest occurrence of high oncogenic types (16 and 18) is observed in Asia (40.3%), then in Latin America (33.6%), Europe (25.6%) and North America (15.4%). Low-oncogenic types (6 and 11) are also predominantly observed in Asia (39.9%), while in Europe and North America 30% and 12.8%, respectively. A meta-analysis of the prevalence of HPV was conducted using Comprehensive Meta-Analysis 3.0. Program, which included 26 studies, the results of which revealed: the prevalence of HPV infection in tumor lung tissue was compared with normal lung tissue OR (95% CI) = 5.38 (3.21-9.00) p < 0.0001, significance was also found for Chinese studies OR = 6.3, 95% CI 3.42-11.53, p < 0.0001, I2 = 71.8% and for nine studies in Europe OR = 6.3, 95% CI 1.8-22.18, p = 0.004, I2 = 51.0%. However, given the fact that the frequency of occurrence of HPV in lung tumor tissue varies greatly, a question may arise about the real role of HPV in LC carcinogenesis, which makes further research relevant and promising.


Assuntos
Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/virologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/virologia , Feminino , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/virologia , Geografia , Humanos , Infecções por Papillomavirus/complicações , Prevalência , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia
14.
Virchows Arch ; 475(5): 537-549, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31209635

RESUMO

Endocervical adenocarcinomas (ECAs) are currently classified according to the 2014 World Health Organization (WHO) system, which is predominantly based on descriptive morphologic characteristics, considers factors bearing minimal etiological, clinical, or therapeutic relevance, and lacks sufficient reproducibility. The 2017 International Endocervical Adenocarcinoma Criteria and Classification (IECC) system was developed by a group of international collaborators to address these limitations. The IECC system separates ECAs into two major groups-those that are human papillomavirus-associated (HPVA) and those that are non-HPV-associated (NHPVA)-based on morphology (linked to etiology) alone, precluding the need for an expensive panel of immunohistochemical markers for most cases. The major types of HPVA ECA include the usual (with villoglandular and micropapillary architectural variants) and mucinous types (not otherwise specified [NOS], intestinal, signet-ring, and invasive stratified mucin-producing carcinoma). Invasive adenocarcinoma NOS is morphologically uninformative, yet considered part of this group when HPV positive. NHPVA ECAs include gastric, clear cell, endometrioid, and mesonephric types. The IECC system is supported by demographic and clinical features (HPVA ECAs develop in younger patients, are smaller, and are diagnosed at an earlier stage), p16/HPV status (almost all HPVA ECAs are p16 and/or HPV positive), prognostic parameters (NHPVA ECAs more often have lymphovascular invasion, lymph node metastases, and are Silva pattern C), and survival data (NHPVA ECAs are associated with worse survival). A move from the morphology-based WHO system to the IECC system will likely provide clinicians with an improved means to diagnose and classify ECAs, and ultimately, to better personalize treatment for these patients.


Assuntos
Adenocarcinoma/classificação , Papillomaviridae/fisiologia , Neoplasias do Colo do Útero/classificação , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Colo do Útero/patologia , Feminino , Humanos , Metástase Linfática , Infecções por Papillomavirus , Prognóstico , Reprodutibilidade dos Testes , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia
15.
PLoS One ; 14(6): e0217108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31199811

RESUMO

AIM: Many cervical cancers occurs among women over 65 and prevalence of HPV genotypes in this age cohort is sparingly studied. One aim of this study was to study the prevalence and distribution of HPV genotypes in women 55-59 years, with normal cytology when exiting the screening program. Secondly, HPV clearance as well as the value of HPV genotyping and/or liquid based cytology as triage tests for identifying histological dysplasia among women with persistent HPV was studied. METHODS: Women that exited the screening program with normal cytology, between the years 2012-2014, in Örebro County, Sweden, were invited to this study. A total of 2946 samples were analyzed with a broad-spectrum assay to detect both hrHPV and lrHPV in order to investigate the distribution of genotypes. In the consent group, women with a positive hrHPV test were offered a follow-up test and a cone biopsy for histological confirmation, and a follow up sample 6 months post cone. RESULTS: The overall prevalence of hrHPV was 7.4% and 59% of them remained hrHPV positive in a follow-up test after 12 months. A total of 99 women had a cone biopsy done, where 19% showed histological dysplasia. HPV 53 was the most common genotype, and among women with histology confirmed LSIL or HSIL, HPV 31 was most common. A positive hrHPV result showed a PPV of 25% for LSIL+ and 12.5%for HSIL+. Using detection of HPV 16/18 genotypes as a triage test for hrHPV positive tests, indicated FNR for histological LSIL+ and HSIL+ of 94% and 87.5% respectively, whilst triage based on cervical cytology had a FNR of 69% for LSIL+ and 37.5% for HSIL+. CONCLUSION: The most common hrHPV genotypes among women 55-59 years of age were non HPV16/18 genotypes, and in this population, these genotypes represented most of the histological verified HSIL lesions. This result does not support the proposition of a HPV 16/18 triaging test after a positive hrHPV test as a marker of histological HSIL+ cervical lesions in women over 55 years of age. Similarly, cytological triage after a positive hrHPV showed no additional benefit in this population. Specific triaging tests should be validated to follow post-menopausal women with a positive hrHPV test.


Assuntos
Programas de Rastreamento , Papillomaviridae/isolamento & purificação , Papillomaviridae/fisiologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/virologia , Estudos de Coortes , Detecção Precoce de Câncer , Feminino , Seguimentos , Genótipo , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Neoplasias do Colo do Útero/patologia
16.
J Mass Spectrom ; 54(8): 693-703, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31116903

RESUMO

Cervicovaginal fluid (CVF) is a valuable source of clinical information about the female reproductive tract in both nonpregnant and pregnant women. The aim of this study is to specify the CVF proteome at different stages of cervix neoplastic transformation by label-free quantitation approach based on liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The proteome composition of CVF from 40 women of reproductive age with human papillomavirus (HPV)-associated cervix neoplastic transformation (low-grade squamous intraepithelial lesion [LSIL], high-grade squamous intraepithelial lesion [HSIL], and CANCER) was investigated. Hierarchical clustering and principal component analysis (PCA) of the proteomic data obtained by a label-free quantitation approach show the distribution of the sample set between four major clusters (no intraepithelial lesion or malignancy [NILM], LSIL, HSIL and CANCER) depending on the form of cervical lesion. Multisample ANOVA with subsequent Welch's t test resulted in 117 that changed significantly across the four clinical stages, including 27 proteins significantly changed in cervical cancer. Some of them were indicated as promising biomarkers previously (ACTN4, VTN, ANXA1, CAP1, ANXA2, and MUC5B). CVF proteomic data from the discovery stage were analyzed by the partial least squares-discriminant analysis (PLS-DA) method to build a statistical model, allowing to differentiate severe dysplasia (HSIL and CANCER) from the mild/normal stage (NILM and LSIL), and receiver operating characteristic (ROC) area under the curve (AUC) were obtained on an independent set of 33 samples. The sensitivity of the model was 77%, and the specificity was 94%; AUC was equal to 0.87. CVF proteome proved to be reflect the stage of cervical epithelium neoplastic process.


Assuntos
Líquidos Corporais/metabolismo , Transformação Celular Neoplásica/metabolismo , Colo do Útero/metabolismo , Proteoma/análise , Neoplasias do Colo do Útero/diagnóstico , Vagina/metabolismo , Adulto , Biomarcadores/análise , Transformação Celular Neoplásica/patologia , Colo do Útero/patologia , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Papillomaviridae/fisiologia , Infecções por Papillomavirus/metabolismo , Gravidez , Proteoma/metabolismo , Espectrometria de Massas em Tandem , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Vagina/patologia , Esfregaço Vaginal
17.
PLoS Pathog ; 15(5): e1007755, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31083694

RESUMO

Human papillomaviruses (HPV) have genotype-specific disease associations, with high-risk alpha types causing at least 5% of all human cancers. Despite these conspicuous differences, our data show that high- and low- risk HPV types use similar approaches for genome maintenance and persistence. During the maintenance phase, viral episomes and the host cell genome are replicated synchronously, and for both the high- and low-risk HPV types, the E1 viral helicase is non-essential. During virus genome amplification, replication switches from an E1-independent to an E1-dependent mode, which can uncouple viral DNA replication from that of the host cell. It appears that the viral E2 protein, but not E6 and E7, is required for the synchronous maintenance-replication of both the high and the low-risk HPV types. Interestingly, the ability of the high-risk E6 protein to mediate the proteosomal degradation of p53 and to inhibit keratinocyte differentiation, was also seen with low-risk HPV E6, but in this case was regulated by cell density and the level of viral gene expression. This allows low-risk E6 to support genome amplification, while limiting the extent of E6-mediated cell proliferation during synchronous genome maintenance. Both high and low-risk E7s could facilitate cell cycle re-entry in differentiating cells and support E1-dependent replication. Despite the well-established differences in the viral pathogenesis and cancer risk, it appears that low- and high-risk HPV types use fundamentally similar molecular strategies to maintain their genomes, albeit with important differences in their regulatory control. Our results provide new insights into the regulation of high and low-risk HPV genome replication and persistence in the epithelial basal and parabasal cells layers. Understanding the minimum requirement for viral genome persistence will facilitate the development of therapeutic strategies for clearance.


Assuntos
Genoma Viral , Queratinócitos/virologia , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Proteína Supressora de Tumor p53/metabolismo , Replicação Viral , Células Cultivadas , DNA Viral/genética , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Plasmídeos , Proteína Supressora de Tumor p53/genética
18.
PLoS Pathog ; 15(5): e1007788, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31091289

RESUMO

Inhibition of human papillomavirus (HPV) replication is a promising therapeutic approach for intervening with HPV-related pathologies. Primary targets for interference are two viral proteins, E1 and E2, which are required for HPV replication. Both E1 and E2 are phosphoproteins; thus, the protein kinases that phosphorylate them might represent secondary targets to achieve inhibition of HPV replication. In the present study, we show that CX4945, an ATP-competitive small molecule inhibitor of casein kinase 2 (CK2) catalytic activity, suppresses replication of different HPV types, including novel HPV5NLuc, HPV11NLuc and HPV18NLuc marker genomes, but enhances the replication of HPV16 and HPV31. We further corroborate our findings using short interfering RNA (siRNA)-mediated knockdown of CK2 α and α' subunits in U2OS and CIN612 cells; we show that while both subunits are expressed in these cell lines, CK2α is required for HPV replication, but CK2α' is not. Furthermore, we demonstrate that CK2α acts in a kinase activity-dependent manner and regulates the stability and nuclear retention of endogenous E1 proteins of HPV11 and HPV18. This unique feature of CK2α makes it an attractive target for developing antiviral agents.


Assuntos
Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Fosfoproteínas/metabolismo , Proteínas Virais/metabolismo , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/virologia , Caseína Quinase II/genética , Caseína Quinase II/metabolismo , Humanos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/virologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Fosfoproteínas/genética , Fosforilação , Células Tumorais Cultivadas , Proteínas Virais/genética
19.
J Biomed Sci ; 26(1): 28, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014351

RESUMO

Cervical cancer is the fourth most frequent cancer in women worldwide and a major cause of mortality in developing countries. Persistent infection with high-risk human papillomavirus (HPV) is a necessary cause for the development of cervical cancer. In addition, genetic and epigenetic alterations in host cell genes are crucial for progression of cervical precancerous lesions to invasive cancer. Although much progress has been made in understanding the life cycle of HPV and it's role in the development of cervical cancer, there is still a critical need for accurate surveillance strategies and targeted therapeutic options to eradicate these cancers in patients. Given the widespread nature of HPV infection and the type specificity of currently available HPV vaccines, it is crucial that molecular details of the natural history of HPV infection as well as the biological activities of viral oncoproteins be elucidated. A better understanding of the mechanisms involved in oncogenesis can provide novel insights and opportunities for designing effective therapeutic approaches against HPV-associated malignancies. In this review, we briefly summarize epigenetic alterations and events that cause alterations in host genomes inducing cell cycle deregulation, aberrant proliferation and genomic instability contributing to tumorigenesis.


Assuntos
Carcinogênese , Papillomaviridae/fisiologia , Infecções por Papillomavirus , Carcinogênese/genética , Ciclo Celular , Proliferação de Células , Epigênese Genética , Feminino , Instabilidade Genômica/genética , Humanos , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/fisiopatologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/fisiopatologia
20.
Acta Cytol ; 63(2): 124-142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30861518

RESUMO

BACKGROUND: The association of human papillomavirus (HPV) with head and neck squamous cell carcinoma (HNSCC) was first described in 1982-1983 by the authors of this review. Prompted by this discovery 35 years ago, an entirely new field of HPV research has emerged, resulting in a paradigm shift from smoking and alcohol as the only etiological factors to confirmation of HNSCC as an important group of HPV-related human malignancies. SUMMARY: In this review, the authors first describe the scope (i.e., HNSCC) by the anatomic sites of the tumors. Their important site-specific differences in epidemiology are emphasized, and the misconceptions caused by the adopted practice of pooling all tumors from these divergent anatomic sites as a single entity (HNSCC) are pinpointed. The convincing evidence of the established risk factors (smoking and alcohol) is briefly addressed, before entering in the discussion on the causal role of HPV in HNSCC pathogenesis. The global HPV prevalence in different subsets of HNSCC is summarized using the data extracted from all meta-analyses published since 2010. Of all HNSCC subsets, oropharyngeal SCC has an HPV profile distinct form all the other subsets, and the possible mechanisms explaining this intimate association with HPV are discussed. Key Messages: Recent global trends show a constant increase in HNSCC rates particularly among younger age groups. The evidence on cigarette smoking and alcohol consumption as the prime risk factors of HNSCC is overwhelming. During the past 35 years, however, increasing evidence has accumulated implicating an important causal role of HPV in HNSCC. These data have important clinical implications, HPV detection and tailored treatment strategies for HPV-positive HNSCCs currently being an integral part of the oncological management practices of HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/virologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/fisiologia , Genoma Humano , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Prognóstico , Fatores de Risco
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