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1.
Fam Community Health ; 44(4): 245-256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34397570

RESUMO

We compared the effectiveness of an educational intervention at reducing stigma and improving knowledge of human papillomavirus (HPV) and cervical cancer among Nigerian men and women. We used a pre-/posttest design to deliver 2 educational interventions to 266 adults. Low knowledge was observed at baseline, which improved significantly post-intervention with no difference between groups. No significant changes were observed between groups in 5 out the 6 stigma domains. Health education was effective in improving knowledge. However, the lack of positive change in stigma shows urgent need for HPV and cervical cancer stigma reduction interventions.


Assuntos
Alphapapillomavirus , Educação em Saúde , Infecções por Papillomavirus , Adulto , Alphapapillomavirus/fisiologia , Feminino , Educação em Saúde/normas , Educação em Saúde/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Nigéria , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus , Aceitação pelo Paciente de Cuidados de Saúde , Neoplasias do Colo do Útero/prevenção & controle
2.
Am J Pathol ; 191(10): 1774-1786, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34303699

RESUMO

Viruses are the second leading cause of cancer worldwide, and human papillomavirus (HPV)-associated head and neck cancers are increasing in incidence in the United States. HPV preferentially infects the crypts of the tonsils rather than the surface epithelium. The present study sought to characterize the unique microenvironment within the crypts to better understand the viral tropism of HPV to a lymphoid-rich organ. Laser-capture microdissection of distinct anatomic areas (crypts, surface epithelium, and germinal centers) of the tonsil, coupled with transcriptional analysis and multiparameter immunofluorescence staining demonstrated that the tonsillar crypts are enriched with myeloid populations that co-express multiple canonical and noncanonical immune checkpoints, including PD-L1, CTLA-4, HAVCR2 (TIM-3), ADORA2A, IDO1, BTLA, LGALS3, CDH1, CEACAM1, PVR, and C10orf54 (VISTA). The resident monocytes may foster a permissive microenvironment that facilitates HPV infection and persistence. Furthermore, the myeloid populations within HPV-associated tonsil cancers co-express the same immune checkpoints, providing insight into potential novel immunotherapeutic targets for HPV-associated head and neck cancers.


Assuntos
Alphapapillomavirus/fisiologia , Células Mieloides/patologia , Células Mieloides/virologia , Tonsila Palatina/patologia , Tonsila Palatina/virologia , Tropismo Viral/fisiologia , Antígenos CD/metabolismo , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Moléculas de Adesão Celular/metabolismo , Epitélio/patologia , Epitélio/virologia , Centro Germinativo/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Microdissecção e Captura a Laser , Monócitos/patologia , Receptores Virais/metabolismo , Transcriptoma/genética
3.
Int J Cancer ; 149(10): 1833-1844, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34310698

RESUMO

Human papillomavirus (HPV)-induced anal intraepithelial neoplasia (AIN, graded 1-3) is highly prevalent in HIV-positive (HIV+) men who have sex with men (MSM), but only a minority of lesions progresses to cancer. Our study aimed to characterise comprehensively anal tissue samples from a cross-sectional series (n = 104) of HIV+ MSM and longitudinal series (n = 40) of AIN2/3 progressing to cancer using different biomarkers. The cross-sectional series consisted of 8 normal, 26 AIN1, 45 AIN2, 15 AIN3 and 10 anal squamous cell carcinoma. Tissue sections were immunohistochemically (IHC) stained for p16 (viral transformation marker), Ki-67 (cellular proliferation marker) and HPV-E4 (viral production marker). We evaluated the expression of IHC markers and compared it with DNA methylation, a marker for malignant transformation. E4 positivity decreased, whereas p16 and Ki-67 scores and methylation marker positivity increased (P values < .001) with increasing severity of anal lesions. Within AIN2, a heterogeneous biomarker pattern was observed concerning E4, p16 and methylation status, reflecting the biological heterogeneity of these lesions. In the longitudinal series, all AIN2/3 and carcinomas showed high p16 and Ki-67 expression, strong methylation positivity and occasional E4 positivity. We earlier showed that high methylation levels are associated with progression to cancer. The observed E4 expression in some AIN2/3 during the course of progression to cancer and absence of E4 in a considerable number of AIN1 lesions make the potential clinical significance of E4 expression difficult to interpret. Our data show that IHC biomarkers can help to characterise AIN; however, their prognostic value for cancer risk stratification, next to objective methylation analysis, appears to be limited.


Assuntos
Canal Anal/metabolismo , Neoplasias do Ânus/metabolismo , Biomarcadores Tumorais/biossíntese , Carcinoma in Situ/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Infecções por HIV/metabolismo , Homossexualidade Masculina/estatística & dados numéricos , Antígeno Ki-67/biossíntese , Adulto , Alphapapillomavirus/metabolismo , Alphapapillomavirus/fisiologia , Canal Anal/patologia , Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/genética , Biomarcadores Tumorais/genética , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/genética , Estudos Transversais , Metilação de DNA , Infecções por HIV/genética , Infecções por HIV/virologia , Humanos , Imuno-Histoquímica/métodos , Masculino , Proteínas Oncogênicas Virais/biossíntese , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Estudos Retrospectivos
4.
PLoS Pathog ; 17(5): e1009580, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33974675

RESUMO

Human papillomaviruses (HPVs) utilize an atypical mode of nuclear import during cell entry. Residing in the Golgi apparatus until mitosis onset, a subviral complex composed of the minor capsid protein L2 and viral DNA (L2/vDNA) is imported into the nucleus after nuclear envelope breakdown by associating with mitotic chromatin. In this complex, L2 plays a crucial role in the interactions with cellular factors that enable delivery and ultimately tethering of the viral genome to mitotic chromatin. To date, the cellular proteins facilitating these steps remain unknown. Here, we addressed which cellular proteins may be required for this process. Using label-free mass spectrometry, biochemical assays, microscopy, and functional virological assays, we discovered that L2 engages a hitherto unknown protein complex of Ran-binding protein 10 (RanBP10), karyopherin alpha2 (KPNA2), and dynein light chain DYNLT3 to facilitate transport towards mitotic chromatin. Thus, our study not only identifies novel cellular interactors and mechanism that facilitate a poorly understood step in HPV entry, but also a novel cellular transport complex.


Assuntos
Alphapapillomavirus/fisiologia , Proteínas do Capsídeo/metabolismo , Núcleo Celular/metabolismo , DNA Viral/metabolismo , Genoma Viral/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Infecções por Papillomavirus/virologia , Transporte Ativo do Núcleo Celular , Alphapapillomavirus/genética , Proteínas do Capsídeo/genética , Cromatina/genética , Dineínas/genética , Dineínas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Proteínas Associadas aos Microtúbulos/genética , Mitose , Internalização do Vírus , alfa Carioferinas/genética , alfa Carioferinas/metabolismo
5.
OMICS ; 25(6): 358-371, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34037476

RESUMO

About a tenth of all cancers are caused by viruses or associated with viral infection. Recent global events including the coronavirus disease-2019 (COVID-19) pandemic means that human encounter with viruses is increased. Cancer development in individuals with viral infection can take many years after infection, demonstrating that the involvement of viruses in cancer development is a long and complex process. This complexity emanates from individual genetic heterogeneity and the many steps involved in cancer development owing to viruses. The process of tumorigenesis is driven by the complex interaction between several viral factors and host factors leading to the creation of a tumor microenvironment (TME) that is ideal and promotes tumor formation. Viruses associated with human cancers ensure their survival and proliferation through activation of several cellular processes including inflammation, migration, and invasion, resistance to apoptosis and growth suppressors. In addition, most human oncoviruses evade immune detection and can activate signaling cascades including the PI3K-Akt-mTOR, Notch and Wnt pathways associated with enhanced proliferation and angiogenesis. This expert review examines and synthesizes the multiple biological factors related to oncoviruses, and the signaling cascades activated by these viruses contributing to viral oncogenesis. In particular, I examine and review the Epstein-Barr virus, human papillomaviruses, and Kaposi's sarcoma herpes virus in a context of cancer pathogenesis. I conclude with a future outlook on therapeutic targeting of the viruses and their associated oncogenic pathways within the TME. These anticancer strategies can be in the form of, but not limited to, antibodies and inhibitors.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Neoplasias/virologia , Infecções por Papillomavirus/virologia , Infecções por Retroviridae/virologia , Retroviridae/fisiologia , Sarcoma de Kaposi/virologia , Infecções Tumorais por Vírus/virologia , Alphapapillomavirus/fisiologia , Carcinogênese , Transformação Celular Viral , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/fisiologia , Herpesvirus Humano 8/fisiologia , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Neoplasias/terapia , Infecções por Papillomavirus/patologia , Infecções por Retroviridae/patologia , Sarcoma de Kaposi/patologia , Transdução de Sinais , Microambiente Tumoral , Infecções Tumorais por Vírus/patologia
6.
J Gen Virol ; 102(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33427604

RESUMO

Persistent infection with high-risk human papillomaviruses (HR-HPVs) is the causal factor in over 99 % of cervical cancer cases, and a significant proportion of oropharyngeal and anogenital cancers. The key drivers of HPV-mediated transformation are the oncoproteins E5, E6 and E7. Together, they act to prolong cell-cycle progression, delay differentiation and inhibit apoptosis in the host keratinocyte cell in order to generate an environment permissive for viral replication. The oncoproteins also have key roles in mediating evasion of the host immune response, enabling infection to persist. Moreover, prolonged infection within the cellular environment established by the HR-HPV oncoproteins can lead to the acquisition of host genetic mutations, eventually culminating in transformation to malignancy. In this review, we outline the many ways in which the HR-HPV oncoproteins manipulate the host cellular environment, focusing on how these activities can contribute to carcinogenesis.


Assuntos
Alphapapillomavirus/fisiologia , Transformação Celular Viral , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/virologia , Alphapapillomavirus/genética , Alphapapillomavirus/patogenicidade , Apoptose , Carcinogênese , Pontos de Checagem do Ciclo Celular , Diferenciação Celular , Proliferação de Células , Reprogramação Celular , Epigênese Genética , Genoma Viral , Humanos , Evasão da Resposta Imune , Proteínas Oncogênicas Virais/genética , Domínios PDZ , RNA não Traduzido/genética , Transdução de Sinais , Replicação Viral
7.
EBioMedicine ; 63: 103165, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33422988

RESUMO

BACKGROUND: Recent publications from a single research group have suggested that aldehyde-based high-level disinfectants (HLDs), such as ortho-phthalaldehyde (OPA), are not effective at inactivating HPVs and that therefore, patients may be at risk of HPV infection from medical devices. These results could have significant public health consequences and therefore necessitated evaluation of their reproducibility and clinical relevance. METHODS: We developed methods and used standardised controls to: (1) quantify the infectious levels of clinically-sourced HPVs from patient lesions and compare them to laboratory-derived HPVs, (2) evaluate experimental factors that should be controlled to ensure consistent and reproducible infectivity measurements of different HPV genotypes, and (3) determine the efficacy of select HLDs. FINDINGS: A novel focus forming unit (FFU) infectivity assay demonstrated that exfoliates from patient anogenital lesions and respiratory papillomas yielded infectious HPV burdens up to 2.7 × 103 FFU; therefore, using 2.2 × 102 to 1.0 × 104 FFU of laboratory-derived HPVs in disinfection assays provides a relevant range for clinical exposures. RNase and neutralising antibody sensitivities were used to ensure valid infectivity measures of tissue-derived and recombinant HPV preparations. HPV infectivity was demonstrated over a dynamic range of 4-5 log10; and disinfection with OPA and hypochlorite was achieved over 3 to >4 log10 with multiple genotypes of tissue-derived and recombinant HPV isolates. INTERPRETATION: This work, along with a companion publication from an independent lab in this issue, address a major public health question by showing that HPVs are susceptible to HLDs. FUNDING: Advanced Sterilization Products; US NIH (R01CA207368, U19AI084081, P30CA118100).


Assuntos
Alphapapillomavirus/efeitos dos fármacos , Alphapapillomavirus/fisiologia , Desinfetantes/farmacologia , Infecções por Papillomavirus/virologia , Carga Viral , Alphapapillomavirus/classificação , Alphapapillomavirus/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linhagem Celular , Células Cultivadas , Desinfecção/métodos , Feminino , Genoma Viral , Genótipo , Humanos , Masculino , Testes de Neutralização
8.
Int J Cancer ; 148(8): 1850-1857, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33070318

RESUMO

Attendance at early recall and colposcopy is crucial to attaining the benefits of primary high-risk human papillomavirus (HR-HPV)-based screening. Within the English HPV pilot, we analysed deprivation- and age-related patterns of attendance at colposcopy and 12- and 24-month early recall of HR-HPV positive women screened in 2013 to 2015 (N = 36 466). We fitted logistic regression models for adjusted odds ratios (OR). Despite high overall attendance, area deprivation had a small but significant impact at both early recalls, for example, attendance at 24 months was 86.3% and 83.0% in less vs more deprived areas, respectively (ORadj : 0.76; 95% CI: 0.67-0.87). Older women (≥30 years) were more likely to attend early recall than younger women (<30 years), for example, attendance at 24 months was 86.1% vs 82.3%, respectively (ORadj : 1.32, 95% CI: 1.16-1.51). Most women attended colposcopy following a baseline referral, with 96.9% attendance among more deprived and 97.8% among less deprived areas (ORadj : 0.70; 95% CI: 0.55-0.88). Differences in colposcopy attendance by deprivation level at 12 and 24 months were of approximately the same magnitude. In conclusion, attendance at early recall and colposcopy was reassuringly high. Although there were statistically significant differences by deprivation and age group, these were small in absolute terms.


Assuntos
Neoplasia Intraepitelial Cervical/diagnóstico , Colposcopia/estatística & dados numéricos , Detecção Precoce de Câncer/estatística & dados numéricos , Programas de Rastreamento/estatística & dados numéricos , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Fatores Etários , Alphapapillomavirus/fisiologia , Neoplasia Intraepitelial Cervical/virologia , Colo do Útero/virologia , Colposcopia/métodos , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Projetos Piloto , Encaminhamento e Consulta/estatística & dados numéricos , Neoplasias do Colo do Útero/virologia , Esfregaço Vaginal/métodos , Esfregaço Vaginal/estatística & dados numéricos , Adulto Jovem
9.
Cancer Immunol Immunother ; 70(5): 1227-1237, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33125511

RESUMO

Approximately 15% of advanced head and neck squamous cell carcinomas (HNSCC) respond to anti-PD-(L)1 monotherapies. Tumor PD-L1 expression and human papillomavirus (HPV) status have been proposed as biomarkers to identify patients likely to benefit from these treatments. We aimed to understand the potential immune effects of HPV in HNSCC and to characterize additional potentially targetable immune-regulatory pathways in primary, treatment-naïve tumors. CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, PD-L2, LAG-3, IDO-1, and GITR cell densities were determined in 27 HNSCC specimens. IHC for PD-L1 assessed percentage of positive tumor cells and immune cells separately or as a combined positive score (CPS), and whether PD-L1 was expressed in an adaptive or constitutive pattern (i.e., PD-L1+ tumor cells juxtaposed to TILs or in the absence of TILs, respectively). HPV testing with p16 IHC was confirmed by HPV genotyping. When compared to HPV(-) tumors (n = 14), HPV+ tumors (n = 13) contained significantly higher densities of CD3+, CD4+, CD8+, CD20+, and PD-1+ cells (P < 0.02), and there was a trend towards increased density of FoxP3 + cells. PD-L1 expression patterns did not vary by tumor viral status, suggesting possible heterogeneous mechanisms driving constitutive vs adaptive PD-L1 expression patterns in HNSCC. IDO-1 expression was abundant (> 500 IDO-1+ cells/mm2 in 17/27 specimens) and was found on tumor cells as well as immune cells in 12/27 (44%) cases (range 5-80% tumor cells+). Notably, the studied markers varied on a per-patient basis and were not always related to the degree of T cell infiltration. These findings may inform therapeutic co-targeting strategies and raise consideration for a personalized treatment approach.


Assuntos
Alphapapillomavirus/fisiologia , Neoplasias de Cabeça e Pescoço/imunologia , Infecções por Papillomavirus/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Infecções por Papillomavirus/virologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Transcriptoma , Microambiente Tumoral
10.
Int J Cancer ; 148(8): 1964-1972, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320983

RESUMO

Oral infection with human papillomavirus (HPV) is likely to underpin the rapidly rising incidence of oropharyngeal squamous cell carcinoma; however, there are few data describing the natural history of oral HPV infection. We recruited 704 participants aged 20 to 70 years from worksites, universities and primary care practices in Brisbane, Australia. Participants completed questionnaires at baseline, 12 and 24 months and donate four saliva samples at baseline, 6, 12 and 24 months for HPV polymerase chain reaction testing and typing. We estimated the prevalence of oral HPV infection at baseline, incidence of new infections among those HPV-negative at baseline, clearance rate and persistent infections. At baseline, 10.7% of participants had oral HPV infections from 26 different HPV types. Sexual behaviours were associated with oral HPV infection, including more partners for passionate kissing (29 or more; odds ratio [OR] 3.4, 95% confidence interval [CI] 1.5-8.0), and giving and receiving oral sex (16 or more; OR 5.4, 95% CI 1.6-17.7 and OR 5.6, 95% CI 1.6-18.7, respectively). Of 343 participants, HPV-free at baseline and with subsequent saliva samples, 87 (25%) acquired new infections over the 24 months. Sixty-eight of 87 people included in the clearance analysis (78%) cleared their oral HPV infections. Clearance was associated with being a nonsmoker (OR 12.7, 95% CI 1.3-122.8), and no previous diagnosis of a sexually transmitted infection (OR 6.2, 95% CI 2.0-19.9). New oral infections with HPV in this sample were not rare. Although most infections were cleared, clearance was not universal suggesting a reservoir of infection exists that might predispose to oropharyngeal carcinogenesis.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Doenças da Boca/diagnóstico , Neoplasias Orofaríngeas/diagnóstico , Infecções por Papillomavirus/diagnóstico , Inquéritos e Questionários , Adulto , Idoso , Alphapapillomavirus/classificação , Alphapapillomavirus/fisiologia , Austrália/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças da Boca/epidemiologia , Doenças da Boca/virologia , Neoplasias Orofaríngeas/epidemiologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Prevalência , Estudos Prospectivos , Saliva/virologia , Comportamento Sexual/estatística & dados numéricos , Fatores de Tempo , Adulto Jovem
11.
Appl Immunohistochem Mol Morphol ; 29(3): 209-217, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33264105

RESUMO

Immunohistochemistry (IHC) improves the diagnosis of cervical adenocarcinoma but is not adequately studied. The performance of 16 antibodies previously reported as potentially discriminating between some histotypes was investigated in 184 tumors comprised of 12 histotype groups collapsed into 3 categories [47 adenocarcinomas in situ (AIS), 121 probable human papillomavirus-dependent adenocarcinomas (HPVD), and 16 of probable independence (HPVI)]. IHC sections from 5 tissue microarrays were scanned, and 3 pathologists independently reviewed images to assess staining percentages and intensities. Biomarker expression was based on published positive and negative cutoffs and agreement between any 2 pathologists. Differences between the 3 categories in the hierarchical ranking of biomarker positivity were analyzed by Random Forest classification, and between select groups by Unsupervised Hierarchical Clustering. Important category discriminants were combined in logistic regression models and the area under the curve (AUC) computed. Potential group discriminants were terminal cluster biomarkers with a 50% or more difference in positivity. Strong associations occurred between the lower expression of carcinoembryonic antigen and stromal actin in AIS compared with HPVD [AUC=0.70, 95% confidence interval (CI), 0.59-0.80] and in the higher expression of p16 and estrogen receptor in comparison to HPVI (AUC=0.86, 95% CI, 0.73-0.98), and between the higher expression of p16, carcinoembryonic antigen and estrogen receptor in HPVD compared with HPVI (AUC=0.88, 95% CI, 0.77-0.99). Between select groups, 9 biomarkers emerged as potential discriminants. Select IHC biomarkers can discriminate AIS from invasive adenocarcinomas, and invasive adenocarcinomas stratified by human papillomavirus dependency from each other. Independent replication in larger studies is needed, and to confirm discriminants of histotype groups.


Assuntos
Adenocarcinoma/metabolismo , Alphapapillomavirus/fisiologia , Antígeno Carcinoembrionário/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Infecções por Papillomavirus/metabolismo , Receptores de Estrogênio/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/metabolismo , Análise por Conglomerados , Feminino , Humanos , Imuno-Histoquímica , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico
12.
Int J Cancer ; 148(2): 277-284, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-32638362

RESUMO

The age-standardised incidence of cervical cancer in Europe varies widely by country (between 3 and 25/100000 women-years) in 2018. Human papillomavirus (HPV) vaccine coverage is low in countries with the highest incidence and screening performance is heterogeneous among European countries. A broad group of delegates of scientific professional societies and cancer organisations endorse the principles of the WHO call to eliminate cervical cancer as a public health problem, also in Europe. All European nations should, by 2030, reach at least 90% HPV vaccine coverage among girls by the age of 15 years and also boys, if cost-effective; they should introduce organised population-based HPV-based screening and achieve 70% of screening coverage in the target age group, providing also HPV testing on self-samples for nonscreened or underscreened women; and to manage 90% of screen-positive women. To guide member states, a group of scientific professional societies and cancer organisations engage to assist in the rollout of a series of concerted evidence-based actions. European health authorities are requested to mandate a group of experts to develop the third edition of European Guidelines for Quality Assurance of Cervical Cancer prevention based on integrated HPV vaccination and screening and to monitor the progress towards the elimination goal. The occurrence of the COVID-19 pandemic, having interrupted prevention activities temporarily, should not deviate stakeholders from this ambition. In the immediate postepidemic phase, health professionals should focus on high-risk women and adhere to cost-effective policies including self-sampling.


Assuntos
Alphapapillomavirus/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Saúde Pública/métodos , Neoplasias do Colo do Útero/prevenção & controle , Adolescente , Adulto , Alphapapillomavirus/fisiologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/virologia , Detecção Precoce de Câncer , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Saúde Pública/normas , Saúde Pública/estatística & dados numéricos , SARS-CoV-2/fisiologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/imunologia , Vacinação/métodos , Organização Mundial da Saúde , Adulto Jovem
13.
Biomed Res Int ; 2020: 4542320, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33274212

RESUMO

According to their oncogenic properties, Human Papillomaviruses (HPVs) are classified into two types: Low-Risk (LR-HPVs) and High-Risk Human Papillomaviruses (HR-HPVs). The immune system naturally controls the majority of HPV infections; however, when the HR-HPV infection is persistent, the risk of developing cervical cancer increases. Previous studies indicate that multiple-infection or coinfection with HR-HPV occurs frequently and can potentiate the development of cervical lesions. This study aimed to establish the HPV coinfection rate in squamous intraepithelial lesions from Mexican patients. For HPV detection, we performed PCR on 55 cervical lesions diagnosed by colposcopy. We detected the presence of HPV infection in 87.27% (48/55) of the lesions; interestingly, HPV coinfection was observed in 70.83% (34/48) of these samples. We also evaluated HPV infection in adjacent areas without morphological changes from 25 samples. The results showed that 80% (20/25) of these were HPV-positive and, curiously, all presented HPV-16 infection. In conclusion, our results revealed a high prevalence of HPV coinfection in cervical lesions in Mexican patients, and these results contribute to future research focused on the role that HPV coinfection plays in the development of cervical cancer.


Assuntos
Alphapapillomavirus/fisiologia , Neoplasia Intraepitelial Cervical/virologia , Coinfecção/virologia , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/virologia , Adulto , Neoplasia Intraepitelial Cervical/epidemiologia , Coinfecção/epidemiologia , Feminino , Humanos , México , Infecções por Papillomavirus/epidemiologia , Prevalência , Neoplasias do Colo do Útero/epidemiologia
14.
Sci Rep ; 10(1): 19450, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173155

RESUMO

Extracellular RNAs (exRNAs) have attracted great attention due to their essential role in cell-to-cell communication as well as their potential as non-invasive disease biomarkers. However, at present, there is no consensus on the best method to profile exRNA expression, which leads to significant variability across studies. To address this issue, we established an experimental pipeline for comprehensive profiling of small exRNAs isolated from cell culture. By evaluating six RNA extraction protocols, we developed an improved method for robust recovery of vesicle-bound exRNAs. With this method, we performed small RNA sequencing of exosomes (EXOs), microvesicles (MVs) and source cells from 14 cancer cell lines. Compared to cells, EXOs and MVs were similarly enriched in tRNAs and rRNAs, but depleted in snoRNAs. By miRNA profiling analysis, we identified a subset of miRNAs, most noticeably miR-122-5p, that were significantly over-represented in EXOs and MVs across all 14 cell lines. In addition, we also identified a subset of EXO miRNAs associated with cancer type or human papillomavirus (HPV) status, suggesting their potential roles in HPV-induced cancers. In summary, our work has laid a solid foundation for further standardization on exRNA analysis across various cellular systems.


Assuntos
Vesículas Extracelulares/genética , Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Neoplasias/genética , Pequeno RNA não Traduzido/genética , Análise de Sequência de RNA/métodos , Alphapapillomavirus/genética , Alphapapillomavirus/fisiologia , Linhagem Celular Tumoral , Exossomos/genética , Células HeLa , Humanos , Neoplasias/patologia , Neoplasias/virologia , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , RNA Nucleolar Pequeno/genética , RNA de Transferência/genética
15.
Front Immunol ; 11: 561843, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33154746

RESUMO

Persistent infection with high-risk human papillomavirus (hrHPV) genotypes results in a large number of anogenital and head and neck cancers worldwide. Although prophylactic vaccination coverage has improved, there remains a need to develop methods that inhibit viral transmission toward preventing the spread of HPV-driven disease. Defensins are a class of innate immune effector peptides that function to protect hosts from infection by pathogens such as viruses and bacteria. Previous work utilizing α and ß defensins from humans has demonstrated that the α-defensin HD5 is effective at inhibiting the most common high-risk genotype, HPV16. A third class of defensin that has yet to be explored are θ-defensins: small, 18-amino acid cyclic peptides found in old-world monkeys whose unique structure makes them both highly cationic and resistant to degradation. Here we show that the prototype θ-defensin, rhesus theta defensin 1, inhibits hrHPV infection through a mechanism involving capsid clustering that inhibits virions from binding to cell surface receptor complexes.


Assuntos
Alphapapillomavirus/fisiologia , Capsídeo/metabolismo , Defensinas/metabolismo , Interações Hospedeiro-Patógeno , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Alphapapillomavirus/efeitos dos fármacos , Alphapapillomavirus/ultraestrutura , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Membrana Celular/virologia , Defensinas/farmacologia , Relação Dose-Resposta a Droga , Genoma Viral , Genótipo , Humanos , Imunidade Inata , Infecções por Papillomavirus/imunologia , Peptídeos Cíclicos/metabolismo , Ligação Proteica , Vírion/ultraestrutura , alfa-Defensinas/metabolismo
16.
PLoS Pathog ; 16(11): e1009028, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33253291

RESUMO

Oncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection.


Assuntos
Alphapapillomavirus/fisiologia , Genoma Viral/genética , Fator Regulador 3 de Interferon/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Infecções por Papillomavirus/virologia , Alphapapillomavirus/genética , Alphapapillomavirus/imunologia , Transporte Biológico , Capsídeo/metabolismo , Endossomos/virologia , Humanos , Mutação , Vírion , Internalização do Vírus
17.
Viruses ; 12(9)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899142

RESUMO

Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.


Assuntos
Alphapapillomavirus/patogenicidade , Janus Quinases/metabolismo , Neoplasias/virologia , Infecções por Papillomavirus/virologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Alphapapillomavirus/fisiologia , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Carcinogênese , Feminino , Humanos , Evasão da Resposta Imune , Interferons/metabolismo , Janus Quinases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/imunologia , Fatores de Transcrição STAT/antagonistas & inibidores , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/virologia , Proteínas Virais/genética , Proteínas Virais/metabolismo
18.
Viruses ; 12(9)2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32917014

RESUMO

Recent reports have pointed to the link between persistent inflammation, oxidative stress, and carcinogenesis; however most of the studies concerning the role of viruses in head and neck cancer (HNC) are focused mainly on one type of virus. Our present study aimed to study the relationship between Epstein-Barr virus/human papilloma virus (EBV/HPV) coinfection and glutathione peroxidase (GPx) and superoxide dismutase (SOD) level in oropharyngeal cancer. Fresh-frozen tumor tissue samples were collected from 128 patients with oropharyngeal cancer infected with EBV or HPV or with EBV/HPV coinfection. After DNA extraction, EBV and HPV DNA was detected using a polymerase chain reaction (PCR) assay. GPx and SOD activity was determined in homogenates of cancer tissue using diagnostic kits produced by Randox Laboratories. Both GPx and SOD activity was statistically lower in patients with EBV/HPV coinfection than in a single EBV or HPV infection. Analysis of GPx and SOD activity in relation to histological grading and tumor, node (TN) classification revealed that in poorly-differentiated tumors, the level of antioxidant enzymes was lower compared with well-differentiated lesions and in cases with greater tumor dimensions and lymph-node involvement, both GPx and SOD activity was decreased. Further studies are necessary to clarify the influence of interplay between EBV, HPV, and oxidative stress on malignant transformation of upper aerodigestive tract epithelial cells.


Assuntos
Alphapapillomavirus/fisiologia , Coinfecção/enzimologia , Infecções por Vírus Epstein-Barr/epidemiologia , Glutationa Peroxidase/metabolismo , Herpesvirus Humano 4/fisiologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/virologia , Superóxido Dismutase/metabolismo , Adulto , Idoso , Coinfecção/genética , Coinfecção/virologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Glutationa Peroxidase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/enzimologia , Neoplasias Orofaríngeas/genética , Infecções por Papillomavirus/enzimologia , Infecções por Papillomavirus/genética , Superóxido Dismutase/genética
19.
Eur J Med Chem ; 204: 112556, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32739649

RESUMO

Human papillomavirus (HPV) is a well-established etiological factor for cervical cancer, and the expression of oncogenic protein E7 is crucial for carcinogenesis. Herein, virtual screening was performed and 2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives were designed, synthesized as antineoplastic agents, and evaluated for their anti-tumor activities. Among them, the most promising compound H1 showed specific anti-proliferation ability against HeLa cells (IC50 = 380 nM) as well as excellent inhibition of tumor growth in the HeLa xenograft model without inducing obvious side effects. It is interesting that compound H1 displayed significant inhibition against HPV18-positive cervical cell lines (HeLa) but not for HPV16-positive cervical cell lines (SiHa). Further study demonstrated that a low concentration of compound H1 could lead to a cell cycle blockage at the G1 phase and promote cell apoptosis slightly (8.77%). Compound H1 also exhibited transcription repression, especially those associated with the oncoprotein E7 cellular pathway like E7/Rb/E2F-1/DNMT1, which were essential in tumorigenesis. Proteomics analysis revealed that E7 might be degraded through E3 ubiquitin ligases, which aligned with decreasing expression of E7 following the treatment of compound H1. Taken together, it indicated that compound H1 could be a promising potential agent for cervical cancer treatment.


Assuntos
Alphapapillomavirus/fisiologia , Desenho de Fármacos , Oxazóis/química , Oxazóis/farmacologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Fase G1/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Oxazóis/síntese química , Proteínas E7 de Papillomavirus/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Front Immunol ; 11: 1434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754157

RESUMO

The human papillomavirus (HPV) vaccine plays an important role in preventing a series of diseases caused by HPV. Recent studies have shown that as a primary prevention measure, it can considerably prevent HPV infection and HPV-associated cervical cancer. However, studies on the safety, efficacy, and coverage of the HPV vaccine remain insufficient, especially in developing countries. Therefore, in this review, we outlined the recent studies of the HPV vaccine in terms of immunogenicity, safety, efficacy, latest vaccination concepts, and strategies. This review may provide a theoretical basis for use of the HPV vaccine.


Assuntos
Alphapapillomavirus/fisiologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Feminino , Humanos , Imunogenicidade da Vacina , Infecções por Papillomavirus/complicações , Resultado do Tratamento , Neoplasias do Colo do Útero/etiologia , Vacinação
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