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1.
Anesth Analg ; 132(4): 1156-1163, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33323783

RESUMO

BACKGROUND: Pain is one of the first presenting symptoms in patients with head and neck cancer, who often develop chronic and debilitating pain as the disease progresses. Pain is also an important prognostic marker for survival. Unfortunately, patients rarely receive effective pain treatment due to our limited knowledge of the mechanisms underlying head and neck cancer pain (HNCP). Pain is often associated with neuroinflammation and particularly interleukin (IL)-1 signaling. The purpose of this study is to develop a novel syngeneic model of HNCP in immunocompetent mice to examine the contribution of IL-1 signaling. METHODS: Male C57BL/6 mice were injected with a murine model of human papillomavirus (HPV+)-induced oropharyngeal squamous cell carcinoma in their right hindlimb to induce tumor growth. Pain sensitivity was measured via von Frey filaments. Spontaneous pain was assessed via the facial grimace scale. IL-1ß was measured by quantifying gene expression via quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Pain hypersensitivity and spontaneous pain develop quickly after the implantation of tumor cells, a time when tumor volume is still insignificant. Spinal and circulating IL-1ß levels are significantly elevated in tumor-bearing mice. Blocking IL-1 signaling either by intrathecal administration of interleukin-1 receptor antagonist (IL-1ra) or by genetic deletion (interleukin-1 receptor knockout [Il1r1-/-]) does not alleviate HNCP. CONCLUSIONS: We established the first syngeneic model of HNCP in immunocompetent mice. Unlike inflammatory or nerve-injured pain, HNCP is independent of IL-1 signaling. These findings challenge the common belief that pain results from tissue compression or IL-1 signaling in patients with head and neck cancer.


Assuntos
Dor do Câncer/etiologia , Interleucina-1beta/metabolismo , Neoplasias Orofaríngeas/complicações , Medula Espinal/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Animais , Comportamento Animal , Dor do Câncer/metabolismo , Dor do Câncer/fisiopatologia , Linhagem Celular Tumoral , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/virologia , Limiar da Dor , Papillomaviridae/patogenicidade , Transdução de Sinais , Medula Espinal/fisiopatologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
2.
Adv Exp Med Biol ; 1287: 105-122, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034029

RESUMO

The NOTCH pathway is critical for the development of many cell types including the squamous epithelium lining of cutaneous and mucosal surfaces. In genetically engineered mouse models, Notch1 acts as one of the first steps to commit basal keratinocytes to terminally differentiate. Similarly, in human head and neck squamous cell cancers (HNSCCs), NOTCH1 is often lost consistent with its essential tumor-suppressive role for initiating keratinocyte differentiation. However, constitutive NOTCH1 activity in the epithelium results in expansion of the spinous keratinocyte layers and impaired terminal differentiation is consistent with the role of NOTCH1 as an oncogene in other cancers, especially in T-cell acute lymphoblastic leukemia. We have previously observed that NOTCH1 plays a dual role as both a tumor suppressor and oncogene, depending on the mutational context of the tumor. Namely, gain or loss or NOTCH1 activity promotes the development of human papillomavirus (HPV)-associated cancers. The additional HPV oncogenes likely disrupt the tumor-suppressive activities of NOTCH and enable the oncogenic pathways activated by NOTCH to promote tumor growth. In this review, we detail the role of NOTCH pathway in head and neck cancers with a focus on HPV-associated cancers.


Assuntos
Carcinogênese , Neoplasias Bucais/metabolismo , Neoplasias Bucais/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Humanos , Infecções por Papillomavirus/virologia
3.
Recent Results Cancer Res ; 217: 141-155, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33200365

RESUMO

Human papillomaviruses (HPVs) are small DNA viruses that infect basal epithelial cells and are the causative agents of cervical, anogenital, as well as oral cancers. High-risk HPVs are responsible for nearly half of all virally induced cancers. Viral replication and amplification are intimately linked to the stratified epithelium differentiation program. The E6 and E7 proteins contribute to the development of cancers in HPV positive individuals by hijacking cellular processes and causing genetic instability. This genetic instability induces a robust DNA damage response and activating both ATM and ATR repair pathways. These pathways are critical for the productive replication of high-risk HPVs, and understanding how they contribute to the viral life cycle can provide important insights into HPV's role in oncogenesis. This review will discuss the role that differentiation and the DNA damage responses play in productive replication of high-risk HPVs as well as in the development of cancer.


Assuntos
Alphapapillomavirus , Reparo do DNA , Proteínas Oncogênicas Virais , Papillomaviridae , Infecções por Papillomavirus , Humanos , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Papillomaviridae/patogenicidade , Replicação Viral
4.
Anticancer Res ; 40(11): 6355-6366, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109573

RESUMO

BACKGROUND/AIM: p16 and PTEN are tumor suppressor genes. Loss of these molecules in oral squamous cell carcinoma (OSCC) has been studied worldwide. In this study, we explored whether p16 cooperates with inactive PTEN during the pathogenesis of OSCC, especially in regard to tumor aggressiveness and proliferation. MATERIALS AND METHODS: Immunocytochemistry and western blot analysis were used to examine the levels of p16 and PTEN. Sequencing analysis was performed to identify mutations in the PTEN gene and HPV infection. Fluorescence in situ hybridization was used to examine the presence of the PTEN locus. RESULTS: PTEN analysis showed high positivity in T4 samples. HPV-positive tumors correlated with tabagism, tumor size 3 and 4, disease stages 3 and 4, presence of lymph node metastasis (N1) and poor differentiation. Immunoexpression of p16 was strongly correlated with the presence of HPV. CONCLUSION: PTEN demonstrated a higher reactivity in advanced disease stages and p16 was strongly associated with HPV. Viral presence decreases tumor aggressiveness. Patients with advanced stage lesions demonstrated lower survival rate.


Assuntos
Carcinoma de Células Escamosas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Perda de Heterozigosidade/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia
5.
Anticancer Res ; 40(10): 5621-5630, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988886

RESUMO

BACKGROUND: Targeted therapies in the treatment of head and neck squamous cell carcinoma (HNSCC) are subject to extensive research. Different mutations of genes belonging to the fibroblast growth factor (FGF) family have been detected in HNSCC. In this study, we examined the expression of FGF1 and FGF2 after treatment with small-molecule tyrosine kinase inhibitors (TKIs) and an inhibitor of mechanistic target of rapamycin (mTOR) in vitro using human papillomavirus (HPV)-positive and -negative SCC lines. MATERIALS AND METHODS: Cells of two human HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with 20 µmol/l of erlotinib, gefitinib, nilotinib, dasatinib, or everolimus for 24-96 h. Cell proliferation was assessed by proliferation assay and the protein concentrations of FGF1 and FGF2 by sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those for untreated HPV-negative SCC cells. RESULTS: FGF1 and FGF2 were detected in all three tested cell lines. The tested TKIs significantly (p<0.05 reduced) FGF1 expression in the UMSCC-11A cell line within the first 24 h. At later time points, the tested TKIs and everolimus significantly (p<0.05) increased FGF1 and FGF2 expression in HPV-negative and -positive cancer cell lines. The effect was stronger in the HPV-positive cell line. CONCLUSION: Alterations in FGF signalling are considered to be relevant drivers of tumourigenesis in some HNSCCs. Our results show that the expression of FGF1 and -2 can be influenced effectively by small-molecule TKIs and everolimus. Based on our data, future research should include combinations of specific FGF inhibitors, mTOR inhibitors and other TKIs in the treatment of HNSCC and research on FGF-mediated drug escape mechanisms.


Assuntos
Everolimo/farmacologia , Fatores de Crescimento de Fibroblastos/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Serina-Treonina Quinases TOR/genética , Linhagem Celular Tumoral , Dasatinibe/farmacologia , Cloridrato de Erlotinib/farmacologia , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Gefitinibe/farmacologia , Papillomavirus Humano 16/efeitos dos fármacos , Papillomavirus Humano 16/patogenicidade , Humanos , Papillomaviridae/efeitos dos fármacos , Papillomaviridae/patogenicidade , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Serina-Treonina Quinases TOR/antagonistas & inibidores
6.
MMWR Morb Mortal Wkly Rep ; 69(37): 1283-1287, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32941412

RESUMO

Human papillomavirus (HPV) causes most cervical cancers and some cancers of the penis, vulva, vagina, oropharynx, and anus. Cervical precancers can be detected through screening. HPV vaccination with the 9-valent HPV vaccine (9vHPV) can prevent approximately 92% of HPV-attributable cancers (1).* Previous studies have shown lower incidence of HPV-associated cancers in non-Hispanic American Indian and Alaska Native (AI/AN) populations compared with other racial subgroups (2); however, these rates might have been underestimated as a result of racial misclassification. Previous studies have shown that cancer registry data corrected for racial misclassification resulted in more accurate cancer incidence estimates for AI/AN populations (3,4). In addition, regional variations in cancer incidence among AI/AN populations suggest that nationally aggregated data might not adequately describe cancer outcomes within these populations (5). These variations might, in part, result from geographic disparities in the use of health services, such as cancer screening or vaccination (6). CDC analyzed data for 2013-2017 from central cancer registries linked with the Indian Health Service (IHS) patient registration database to assess the incidence of HPV-associated cancers and to estimate the number of cancers caused by HPV among AI/AN populations overall and by region. During 2013-2017, an estimated 1,030 HPV-associated cancers were reported in AI/AN populations. Of these cancers, 740 (72%) were determined to be attributable to HPV types targeted by 9vHPV; the majority were cervical cancers in females and oropharyngeal cancers in males. These data can help identify regions where AI/AN populations have disproportionately high rates of HPV-associated cancers and inform targeted regional vaccination and screening programs in AI/AN communities.


Assuntos
/estatística & dados numéricos , Índios Norte-Americanos/estatística & dados numéricos , Neoplasias/etnologia , Neoplasias/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/etnologia , Feminino , Humanos , Incidência , Masculino , Sistema de Registros , Estados Unidos/epidemiologia
7.
Obstet Gynecol ; 136(4): 663-665, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32925610

RESUMO

Multiple studies suggest that health care workers treating human papillomavirus (HPV)-associated conditions may experience occupational exposure to the virus. Case reports describe the development of cancer and other disease in health care professionals at low risk for such conditions except for their work. Despite limited data, vaccination can be a safe and effective method to reduce this uncertain risk. We argue that health care workers, including physicians, nurses, and others, who participate in the treatment of HPV-associated disease should consider vaccination.


Assuntos
Pessoal de Saúde , Exposição Ocupacional , Neoplasias Orofaríngeas , Papillomaviridae , Infecções por Papillomavirus , Atitude do Pessoal de Saúde , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Procedimentos Cirúrgicos em Ginecologia/métodos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Exposição Ocupacional/prevenção & controle , Vírus Oncogênicos , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/prevenção & controle , Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/uso terapêutico , Vacinação/métodos
8.
Adv Exp Med Biol ; 1268: 195-209, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918220

RESUMO

Human papillomaviruses (HPVs) infect squamous epithelia and can induce hyperproliferative lesions. More than 220 different HPV types have been characterized and classified into five different genera. While mucosal high-risk HPVs have a well-established causal role in anogenital carcinogenesis, the biology of cutaneous HPVs is less well understood.From patients with the rare genetic disorder epidermodysplasia verruciformis (EV) and animal models, evidence is accumulating that cutaneous PV of genus ß synergize with ultraviolet (UV) radiation in the development of cutaneous squamous cell carcinoma (cSCC). In 2009, the International Agency for Research on Cancer (IARC) classified the genus ß-HPV types 5 and 8 as "possible carcinogenic" biological agents (group 2B) in EV disease. Epidemiological and biological studies indicate that genus ß-PV infection may also play a role in UV-mediated skin carcinogenesis in non-EV patients. However, they rather act at early stages of carcinogenesis and become dispensable for the maintenance of the malignant phenotype, compatible with a "hit-and-run" mechanism.This chapter will give an overview on genus ß-PV infections and discuss similarities and differences of cutaneous and genus α mucosal high-risk HPV in epithelial carcinogenesis.


Assuntos
Papillomaviridae/patogenicidade , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/virologia , Animais , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/virologia , Epidermodisplasia Verruciforme/etiologia , Epidermodisplasia Verruciforme/virologia , Humanos , Raios Ultravioleta/efeitos adversos
9.
Nat Genet ; 52(8): 800-810, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32747824

RESUMO

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.


Assuntos
Epigenoma/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Transcriptoma/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Adulto , Idoso , Metilação de DNA/genética , Feminino , Humanos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Uganda , Regulação para Cima/genética
10.
Am J Surg Pathol ; 44(9): 1184-1191, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32496434

RESUMO

Tumor cell expression of major histocompatibility complex (MHC) class I is required for antigen presentation and adaptive immune recognition. Absent or diminished MHC class I expression is thought to contribute to immunotherapeutic resistance in some epithelial tumors but has not been previously studied in cervical and vulvar carcinoma. Given that anti-programmed cell death 1 (PD-1) checkpoint inhibition is deployed for programmed cell death ligand 1 (PD-L1)-positive recurrent and metastatic cervical squamous carcinomas, identifying tumors with loss of MHC class I is of clinical interest to optimize the selection of immunotherapeutic candidates. Immunohistochemistry for PD-L1 and MHC class I combined A, B, and C heavy chains (MHC class I) was assessed in 58 human papillomavirus-associated cervical and vulvar lesions, including 27 squamous intraepithelial lesions (SILs) and 31 invasive squamous cell carcinoma (SCC). Although 84% of SCC and 22% of SIL were PD-L1-positive, 35.5% (11/31) of SCC and 18.5% (5/27) of SIL also showed clonal or complete loss of MHC class I. Loss of MHC class I expression was more common in PD-L1-positive (10/26, 38%) versus PD-L1-negative SCC (1/5, 20%). In summary, over one third of human papillomavirus-associated cervical and vulvar SCC show clonal or complete loss of MHC class I expression, including many PD-L1-positive cases. This suggests that the efficacy of checkpoint inhibitors targeting the PD-1/PD-L1 axis may be limited in a subset of cervical and vulvar squamous neoplasms due to an impaired ability to engage with the adaptive immune system related to loss of MHC class I expression.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/virologia , Resistencia a Medicamentos Antineoplásicos , Antígenos de Histocompatibilidade Classe I/imunologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/virologia , Lesões Intraepiteliais Escamosas Cervicais/virologia , Neoplasias do Colo do Útero/virologia , Neoplasias Vulvares/virologia , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Regulação para Baixo , Feminino , Interações Hospedeiro-Patógeno , Humanos , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Lesões Intraepiteliais Escamosas Cervicais/tratamento farmacológico , Lesões Intraepiteliais Escamosas Cervicais/imunologia , Lesões Intraepiteliais Escamosas Cervicais/patologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/imunologia , Neoplasias Vulvares/patologia
11.
PLoS One ; 15(6): e0233499, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484811

RESUMO

INTRODUCTION: The World Health Organization (WHO) recommends that human papillomavirus (HPV) vaccination programs are established to be cost-effective before implementation. WHO recommends HPV vaccination for girls aged 9-13 years to tackle the high burden of cervical cancer. This review examined the existing evidence on the cost-effectiveness of the 9-valent HPV vaccine within a global context. METHODS: The literature search covering a period of January 2000 to 31 July 2019 was conducted in PubMed and Scopus bibliographic databases. A combined checklist (i.e., WHO, Drummond and CHEERS) was used to examine the quality of eligible studies. A total of 12 studies were eligible for this review and most of them were conducted in developed countries. RESULTS: Despite some heterogeneity in approaches to measure cost-effectiveness, ten studies concluded that 9vHPV vaccination was cost-effective and two did not. The addition of adolescent boys into immunisation programs was cost effective when vaccine price and coverage was comparatively low. When vaccination coverage for females was more than 75%, gender neutral HPV vaccination was less cost-effective than vaccination targeting only girls aged 9-18 years. Multi cohort immunization approach was found cost-effective in the age range of 9-14 years. However, the upper age limit at which vaccination was found not cost-effective requires further evaluation. This review identified duration of vaccine protection, time horizon, vaccine price, coverage, healthcare costs, efficacy and discounting rates as the most dominating parameters in determining cost-effectiveness. CONCLUSIONS: These findings have implications in extending HPV immunization programs whether switching to the 9-valent vaccine or the inclusion of adolescent boys' vaccination or extending the age of vaccination. Further, this review also supports extending vaccination programs to low-resource settings where vaccine prices are competitive, donor funding is available, burden of cervical cancer is high and screening options are limited.


Assuntos
Papillomaviridae/imunologia , Vacinas contra Papillomavirus/economia , Adolescente , Criança , Estudos de Coortes , Análise Custo-Benefício/métodos , Feminino , Custos de Cuidados de Saúde , Humanos , Imunização/economia , Programas de Imunização/economia , Masculino , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Anos de Vida Ajustados por Qualidade de Vida , Vacinação/economia , Cobertura Vacinal/economia
12.
Arch Oral Biol ; 116: 104746, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32464412

RESUMO

OBJECTIVE: The aim of this study was to evaluate the application of in situ hybridization using E6/E7 mRNA probes to identify the frequency of high-risk HPV transcriptionally active and the use of HPV status as a prognostic biomarker in oral cavity squamous cell carcinoma (OCSCC). METHODS: Ninety-nine OCSCC samples were evaluated from Hospital Santa Rita de Cassia, Hospital Universitário Cassiano Antônio de Moraes and University Hospitals Coventry and Warwickshire NHS Trust. After tissue microarray construction, the slides were submitted to an in situ hybridization detection method for HPV E6/E7 mRNA. HPV status was designated a binary classification. Multiple logistic regression examined the association of HPV with clinical features and other risk factors, using SPSS® software. For all hypothesis tests, a significance level of p ≤ 0.05 was considered. RESULTS: HPV frequency in oral squamous cell carcinoma was 8%. There was no association between HPV and clinical variables and between the main prognostic features and known risk factors. There was no difference in the prevalence of HPV for oral cavity squamous cell carcinoma by geography (Brazil vs UK). CONCLUSIONS: A low frequency of E6/E7 mRNA by RNA in situ hybridization was found in oral cavity squamous cell carcinoma, which supports the evidence that HPV-driven cancer of the oral cavity is uncommon.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Papillomaviridae , Infecções por Papillomavirus , RNA Mensageiro , Brasil , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Hibridização In Situ , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/diagnóstico , RNA Viral
13.
PLoS One ; 15(5): e0232107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379782

RESUMO

OBJECTIVE: To explore the relationship between the viral load reflected by the Ct value of Cobas 4800 HPV test and cervical lesions, and the effectiveness of the viral load for secondary triage of HPV-positive women. METHODS: The Chinese Multi-Center Screening Trial (CHIMUST) evaluated both self-collected samples and physician-collected samples from women, aged 30 to 59, who were screened for cervical cancer in 6 regions across China. Using physician collected samples, the relationship between the HPV-Ct values of different subtypes and the cervical lesions was analyzed. Then the combined use of the HPV-Ct values with the HPV subtypes was evaluated as a secondary screening algorithm for the women who were HPV positive. RESULTS: The Ct values of HPV16 and 12 other HPV subtypes(12-type pool), tested with Cobas decreased with the progression of cervical lesion (HPV16: r = -0.429, P<0.001; 12 other HR-HPV subtypes: r = -0.099, P<0.01). The HPV18-Ct value was not correlated with cervical lesion(P>0.05). Compared with HPV16/18 and cytology (HPV16/18 positive and 12-type pool plus cytology ≥ ASC-US), the sequential secondary screening using HPV16/18 and the viral load of 12-type pool (cut-point HPV-Ct≤31) had equal sensitivities for CIN2+ and CIN3+ (83.1%vs.80.3%,100%vs.92.6%,P>0.05), with slightly lower specificities (96.2%vs.94.4%,96.5%vs.93.9%,P<0.001) and higher colposcopy referral rate (4.90%vs.6.59%, P<0.05), but required no cytology. CONCLUSION: Type-specific HPV viral load is closely related to cervical lesions severity. It is feasible and efficient to use HPV16/18 and the viral load of 12 other HPV subtypes (with cut-point HPV-Ct≤31) as the secondary screening for HPV positive women. This algorithm may be useful in low resource regions.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias do Colo do Útero/diagnóstico , Carga Viral/métodos , Adulto , Grupo com Ancestrais do Continente Asiático , Neoplasia Intraepitelial Cervical/virologia , Colo do Útero/patologia , China/epidemiologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/virologia , Sensibilidade e Especificidade , Sorogrupo , Manejo de Espécimes/métodos , Triagem , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
14.
Biomol Concepts ; 11(1): 116-124, 2020 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-32417757

RESUMO

The single nucleotide polymorphism (SNP) of the promoter region of MMP-1 (at 1607 bp) and MMP-3 (at 1171 bp) create Ets binding sites. Correlations between these SNPs and sensitivity to several biological processes such as metastasis and recurrence of cancer have been reported in several studies. In this case-control study, we looked for these SNPs in women infected with or not with high-risk human papillomaviruses (HR-HPV). The frequency, distribution and correlation of these SNPs with the presence or absence of HR-HPV infection were evaluated. Genotypes 1G1G, 1G2G and 2G2G for MMP1 and genotypes 5A5A, 5A6A, 6A6A for MMP3 were found in our study population. In general, we noted that the 1G (40.8%) and 2G (64.8%) alleles were more frequent in non-infected women and infected women, respectively, and more specifically this difference was significant in women from Côte d'Ivoire. These results, although yet to be reaffirmed with assays for quantifying the mRNA of these genes, suggest that the SNP of the MMP-1 promoter could promote infection with HR-HPV.


Assuntos
Metaloproteinase 1 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Papillomaviridae , Infecções por Papillomavirus/genética , Neoplasias do Colo do Útero/genética , Adolescente , Adulto , Idoso , Alelos , Burkina Faso , Estudos de Casos e Controles , Costa do Marfim , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/enzimologia , Infecções por Papillomavirus/etiologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/virologia
15.
Biomol Concepts ; 11(1): 125-136, 2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32417758

RESUMO

Objective this study was conducted to determine the distribution of high-risk human papillomavirus (HR-HPV) genotypes in women in the general population of three regions of Burkina Faso. Method This multicenter, descriptive cross-sectional study involved 1321 sexually active women in five cities in three regions of Burkina Faso: Central, Central-Eastern and Hauts-Bassins regions. After collection of endocervical specimens, pre-cervical lesions were screened by visual inspection with acetic acid and lugol (VIA / VILI). HR-HPV genotypes were characterized by multiplex real-time PCR after extraction of viral DNA. Results The mean age of women was 31.98 ± 10.09 years. The HR-HPV infection in the three regions ranged from 26.16% to 43.26% with 35.42% as overall prevalence in women. The most common HR-HPV genotypes in descending order were: HPV 56, 52, 66, 59, 39, 51, 18, 35. The prevalence of bivalent vaccine genotypes (HPV16 / 18) was 7.83% against 63.78% of genotypes not covered by HPV vaccine; 36.32% (170/468) of women had multiple concomitant HR-HPV infections. Conclusion this study showed significant regional variation and high prevalence of HR-HPV infection in women. The predominant genotypes differ from those covered by available vaccines in Burkina Faso. These results will help guide our health policies towards better prevention of cervical cancer. The diversity of oncogenic genotypes is sparking a large-scale study in the West African sub-region, particularly in cases of cancer and the introduction of the nonavalent vaccine which includes HPV 52 found among the predominant genotypes in this study.


Assuntos
Carcinogênese/genética , Oncogenes/genética , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia , Adolescente , Adulto , Idoso , Burkina Faso , Estudos Transversais , DNA Viral/genética , Demografia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Prevalência , Fatores de Risco , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle
16.
PLoS One ; 15(5): e0232474, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374757

RESUMO

BACKGROUND: In Brazil, penile cancer (PC) is not uncommon. The highest incidence of PC is in the North and Northeast of the country. In addition to phimosis, the Human Papillomavirus (HPV) and Epstein-Baar Virus (EBV) infections are also related as risk factors for PC. The overexpression of p16INK4a is a surrogate sensitive marker of HPV infection in PC. OBJECTIVES: To correlate p16INK4a overexpression and HPV infection status with EBV infection in a series of PC patients from the Amazon region. METHODS: Tumor tissues from 47 PC cases were analyzed for the presence of HPV and EBV DNA by PCR. All PC patients were diagnosed between 2013 and 2018 at a public reference cancer center hospital in Manaus, Amazonas-Brazil. HPV was genotyped using E7 HPV16/HPV18 type-specific real-time PCR and the PapilloCheck® HPV-Screening assay. p16INK4a expression was evaluated by immunohistochemistry using the automated Ventana® BenchMark Ultra. RESULTS: The mean age of patients at the time of diagnosis was 57.4 years ±SD 17.8 ranging from 20 to 90 years old. Most of the patients (64%) came from rural areas of the Amazonas State. Thirty patients had phimosis (64%). Among the patients with phimosis, 43% (13/30) underwent circumcision, three during childhood and 10 in adulthood. 60% of the patients were smokers or ex-smokers. HPV infection was observed in 45% (21/47) of cases. HPV16 was detected in 13 patients (61%). Other HPV types detected were HPV 6, 11, 42, 51, 53, 68 and 44/55. EBV infection was observed in 30% (14/47) of the patients with PC. Co-infection with HPV and EBV was observed in 28% (6/21) cases. p16INK4a was only investigated in 26 samples. The p16INK4a overexpression was observed exclusively in HPV 16 positive cases and four HPV negative cases. In the survival analysis, the follow-up time was 35.4 months/patient. The mortality rate during the follow up time was 38%. CONCLUSIONS: p16INK4a positivity presented a high correlation to HPV 16 DNA detection, reinforcing its use as a surrogate marker for HPV-driven cancers. Infection with EBV was quite frequent and its role in epithelial penile oncogenesis needs to be demonstrated.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Infecções por Vírus Epstein-Barr/complicações , Papillomaviridae , Infecções por Papillomavirus/complicações , Neoplasias Penianas/etiologia , Neoplasias Penianas/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , DNA Viral/genética , DNA Viral/isolamento & purificação , Infecções por Vírus Epstein-Barr/virologia , Marcadores Genéticos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/patogenicidade , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/patogenicidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Neoplasias Penianas/epidemiologia , Fatores de Risco , Regulação para Cima , Adulto Jovem
17.
Biomol Concepts ; 11(1): 97-101, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32304293

RESUMO

Human papillomavirus (HPV) infection is the most common sexually transmitted infection worldwide. Persistence infection can lead to the development of cervical cancer potentially due to some genetic factors such as polymorphisms in regulatory and coding regions of cytokine genes. The purpose of this study was to determine whether there is a relationship between TNF-308 G/A or IL18 polymorphisms and high-risk HPV infection among sexually active women from Burkina Faso. Ninety-one HPV infected and two hundred and nine HPV negative women (the latter used as healthy controls) were screened. TNFA-308 G/A and IL18-607 C/A polymorphisms were detected using the TaqMan allelic discrimination. HPV 52 (21.19%), HPV 39 (11.86%) and HPV 33 (11.02%) were the most common HPV genotypes. The TNFA-308A and IL18-607 C alleles were predominant in all women in the study. None of the TNFA and IL18 alleles were associated with HPV infection. The results suggest that there is no relationship between TNF-308 G/A or IL18-607C/A polymorphisms and HPV infection among women in the study.


Assuntos
Predisposição Genética para Doença , Interleucina-18/genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Burkina Faso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Papillomaviridae/patogenicidade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
18.
Exp Mol Pathol ; 114: 104435, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32240617

RESUMO

In oropharyngeal squamous cell carcinoma (OPSCC), the expression pattern of toll-like receptors (TLRs), in comparison between human papillomavirus (HPV)-positive and -negative tumors differs. TLRs control innate immune responses by activating, among others, the nuclear factor-κΒ (NF-κΒ) signaling pathway. Elevated NF-κΒ activity is detectable in several cancers and regulates cancer development and progression. We studied TLR5 expression in 143 unselected consecutive OPSCC tumors, and its relation to HPV-DNA and p16 status, clinicopathological parameters, and patient outcome, and studied TLR5 stimulation and consecutive NF-κB cascade activation in vitro in two human OPSCC cell lines and immortalized human keratinocytes (HaCat). Clinicopathological data came from hospital registries, and TLR5 immunoexpression was evaluated by immunohistochemistry. Flagellin served to stimulate TLR5 in cultured cells, followed by analysis of the activity of the NF-κB signaling cascade with In-Cell Western for IκΒ and p-IκΒ. High TLR5 expression was associated with poor disease-specific survival in HPV-positive OPSCC, which typically shows low TLR5 immunoexpression. High TLR5 immunoexpression was more common in HPV-negative OPSCC, known for its less-favorable prognosis. In vitro, we detected NF-κΒ cascade activation in the HPV-positive OPSCC cell line and in HaCat cells, but not in the HPV-negative OPSCC cell line. Our results suggest that elevated TLR5 immunoexpression may be related to reduced NF-κΒ activity in HPV-negative OPSCC. The possible prognosis-worsening mechanisms among these high-risk OPSCC patients however, require further evaluation.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Orofaríngeas/genética , Receptor 5 Toll-Like/genética , Fator de Transcrição RelA/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Prognóstico
19.
Anticancer Res ; 40(4): 2117-2123, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234904

RESUMO

BACKGROUND/AIM: The incidence of human papilloma virus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has been increasing in the last decades. Analysis of oral brushing or rinsing samples for screening or stratification could potentially improve screening and prevention. PATIENTS AND METHODS: Oral brushes and mouthwashes were taken from 20 patients with HPV-associated HNSCC before definite therapy. HPV genotyping was performed for the detection of 14 high-risk HPV subtypes and correlated to DNA isolated from tumor tissue. RESULTS: Ten of 20 patients were tested HPV positive by using either method. There was a significant correlation between macroscopic visibility of tumor and positive HPV detection (p<0.001) and HPV detection and tumor size (p<0.001). HPV was detected in all macroscopically visible tumors. Half of the HPV cases who had macroscopically invisible tumors were missed by both methods. CONCLUSION: Both techniques are limited in the detection of macroscopically non-visible and small tumors. Therefore, the application of these techniques for screening or diagnosis of HNSCC is not recommended.


Assuntos
Neoplasias Orofaríngeas/genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Idoso , DNA Viral/genética , DNA Viral/isolamento & purificação , Feminino , Genótipo , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 16/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Antissépticos Bucais/análise , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
20.
Int J Med Sci ; 17(2): 191-206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32038103

RESUMO

Epigenetic alteration of host DNA is a common occurrence in both low- and high-risk human papillomavirus (HPV) infection. Although changes in promoter methylation have been widely studied in HPV-associated cancers, they have not been the subject of much investigation in HPV-induced warts, which are a temporary manifestation of HPV infection. The present study sought to examine the differences in promoter methylation between warts and normal skin. To achieve this, DNA was extracted from 24 paired wart and normal skin samples and inputted into the Infinium MethylationEPIC BeadChip microarray. Differential methylation analysis revealed a clear pattern of hyper- and hypomethylation in warts compared to normal skin, and the most differentially methylated promoters were found within the EIF3EP2, CYSLTR1, C10orf99, KRT6B, LAMA4, and H3F3B genes as well as the C9orf30 pseudogene. Moreover, pathway analysis showed that the H3F3A, CDKN1A, and MAPK13 genes were the most common regulators among the most differentially methylated promoters. Since the tissue samples were excised from active warts, however, this differential methylation could either be a cellular response to HPV infection or an HPV-driven process to establish the wart and/or promote disease progression. Conclusively, it is apparent that HPV infection alters the methylation status of certain genes to possibly initiate the formation of a wart and maintain its presence.


Assuntos
Epigênese Genética/genética , Epigenoma/genética , Regiões Promotoras Genéticas/genética , Verrugas/genética , Peptídeos Catiônicos Antimicrobianos/genética , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Histonas/genética , Humanos , Queratina-6/genética , Laminina/genética , Masculino , Proteína Quinase 13 Ativada por Mitógeno/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Receptores de Leucotrienos/genética , Sequenciamento Completo do Genoma
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