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1.
Viruses ; 13(1)2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374445

RESUMO

There are >200 different types of human papilloma virus (HPV) of which >51 infect genital epithelium, with the ~14 of these classed as high-risk being more commonly associated with cervical cancer. During development of the disease, high-risk types have an increased tendency to develop a truncated non-replicative life cycle, whereas low-risk, non-cancer-associated HPV types are either asymptomatic or cause benign lesions completing their full replicative life cycle. HPVs can also be present as non-replicative so-called "latent" infections and they can also show superinfection exclusion, where cells with pre-existing infections with one type cannot be infected with a different HPV type. Thus, the HPV repertoire and replication status present in an individual can form a complex dynamic meta-community which changes with respect to both time and exposure to different HPV types. In light of these considerations, it is not clear how current prophylactic HPV vaccines will affect this system and the potential for iatrogenic outcomes is discussed in light of recent outcome data.


Assuntos
Proteínas do Capsídeo/imunologia , Proteínas Oncogênicas Virais/imunologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Superinfecção/virologia , Latência Viral , Feminino , Humanos , Incidência , Neoplasias/etiologia , Papillomaviridae/classificação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Prevalência , Lesões Intraepiteliais Escamosas Cervicais/etiologia , Lesões Intraepiteliais Escamosas Cervicais/patologia , Vacinação , Latência Viral/imunologia , Replicação Viral
2.
Anticancer Res ; 40(11): 5995-6002, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109537

RESUMO

Steroid contraceptive hormones may promote human papilloma virus (HPV) - DNA integration into the host genome, may bind to specific HPV-DNA sequences within transcriptional regulatory regions, and may modulate cell apoptosis. Most epidemiological studies, reported in this narrative review, have shown that oral contraception is associated with a 1.5-3.3-fold higher relative risk of cervical carcer, but only in users for >5 years and especially in HPV-positive women. The relative risk declines with increasing time since last use and is not different from that of never users after >10 years. Ten-year oral contraceptive use from the age of 20 years is associated with an increase in the cumulative incidence of invasive cervical cancer at the age of 50 years of approximately 1 case per 1,000. Oral contraception has a very small negative impact on the absolute risk of cancer of the uterine cervix.


Assuntos
Anticoncepcionais/efeitos adversos , Estrogênios/efeitos adversos , Progestinas/efeitos adversos , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia , Feminino , Humanos , Papillomaviridae/fisiologia , Fatores de Risco , Neoplasias do Colo do Útero/virologia
3.
Anticancer Res ; 40(11): 6195-6203, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109556

RESUMO

BACKGROUND: Head and neck squamous cell cancer (HNSCC) affects the oral cavity and the pharynx. The aim of the study was to investigate the effects of selective tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, nilotinib and dasatinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus on the expression of apoptosis-related proteins caspase-3, FAS cluster of differentiation (CD)-95 and FAS ligand in human papilloma virus (HPV)-dependent squamous cancer. MATERIALS AND METHODS: Two HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with TKIs or everolimus and protein concentrations of target proteins were analyzed with enzyme-linked immunosorbent assay (ELISA). RESULTS: Caspase-3 was affected by the tested TKIs in HPV-positive SCC, whereas FAS CD95 and FAS ligand were influenced in HPV-negative SCC. DISCUSSION: This is the first study to analyze the influence of TKIs and everolimus on key proteins of apoptosis. Our results provide novel information contributing to a better understanding of the cell biology of HPV-dependent HNSCC and might contribute to the discovery of novel pharmaceutical treatment strategies for HNSCC.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Everolimo/farmacologia , Papillomaviridae/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Papillomaviridae/efeitos dos fármacos , Receptor fas/metabolismo
4.
PLoS One ; 15(9): e0238705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941440

RESUMO

OBJECTIVE: To evaluate the changes of vaginal microbiota during cervical carcinogenesis in women with high-risk human papillomavirus infection. MATERIALS AND METHODS: Vaginal microbiota was analyzed using next-generation sequencing in women with normal, cervical intraepithelial neoplasia (CIN), or cervical cancer. RESULTS: A marked decrease of Lactobacillus crispatus was found in the CIN/cancer groups compared with that in the normal group. The diversity of microorganisms increased in patients with CIN or cervical cancer with HPV infection. Atopobium vaginae (OR 4.33, 95% CI 1.15-16.32), Dialister invisus (OR 4.89, 95% CI 1.20-19.94), Finegoldia magna (OR 6.00, 95% CI 1.08-33.27), Gardnerella vaginalis (OR 7.43, 95% CI 1.78-31.04), Prevotella buccalis (OR 11.00, 95% CI 2.00-60.57), and Prevotella timonensis (OR 6.00, 95% CI 1.46-24.69) were significantly associated with the risk of CIN 2/3 or cervical cancer. CONCLUSION: Women with the CIN and cervical cancer showed a high diversity in vaginal microbiota. Depletion of Lactobacillus crispatus and increased abundance of anaerobic bacteria were detected in women with cervical disease.


Assuntos
Carcinogênese/patologia , Microbiota , Papillomaviridae/fisiologia , Infecções por Papillomavirus/microbiologia , Vagina/microbiologia , Bactérias/classificação , Biodiversidade , Feminino , Humanos , Análise de Componente Principal , Especificidade da Espécie
6.
PLoS One ; 15(8): e0237988, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853216

RESUMO

OBJECTIVE: To evaluate the 9-year incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cumulative adherence to perform a next test in a cohort of women aged 40+ years with no cervical screening cytology within a window of 5 years (underscreened women), after baseline cervical cytology and HPV tests. METHODS: In Catalonia, Spain, co-testing with cytology and HPV test has been recommended in the Public Health system since 2006 for underscreened women. In 2007, 1,594 women with underscreened criteria were identified and followed through medical records form Pathological Department. 9-year cumulative incidence of histologically confirmed CIN2+ and cumulative adherence to perform a next test were estimated using Kaplan-Meier statistics. RESULTS: Follow-up was available for 1,009 women (63.3%) resulting in 23 women with. CIN2+ (2.3%). Of them, 4 women (17%) had both tests negative at baseline (3CIN2 and 1CIN3) with cumulative incidence of CIN2+ of 0.4% (95% CI: 0.1-1.4) at 5-years and 1.3% (95% CI: 0.4-3.7) at 9-years. During the first year, the prevalence among women with both tests positive was 27.0% (95% CI: 13.0-50.6) for CIN2+. Lost to follow-up was higher among women with both tests negative compared to those with both positive tests (38.7% vs 4.2%, p-value <0.001). 40.5% of the women HPV-/cyto- had a re-screening test during the 4 years following the baseline, increasing until 53.5% during the 6 years of follow-up. CONCLUSIONS: HPV detection shows a high longitudinal predictive value at 9-year to identify women at risk to develop CIN2+. The data validate a safe extension of the 3-year screening intervals (current screening interval) to 5-year intervals in underscreened women that had negative HPV result at baseline. It is necessary to establish mechanisms to ensure screening participation and adequate follow-up for these women.


Assuntos
Programas de Rastreamento , Papillomaviridae/isolamento & purificação , Neoplasias do Colo do Útero/virologia , Idoso , Estudos de Coortes , Detecção Precoce de Câncer , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Papillomaviridae/fisiologia , Risco , Fatores de Tempo , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia
7.
Sci Rep ; 10(1): 7863, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398763

RESUMO

Equine penile squamous cell carcinoma (EpSCC) is a relatively common cutaneous neoplasm with a poor prognosis. In this study, we aimed to determine the protein expression and colocalisation of FRA1, c-Myc, Cyclin D1, and MMP7 in normal (NT), tumour (T), hyperplastic epidermis and/or squamous papilloma (Hyp/Pap), poorly-differentiated (PDSCC), or well-differentiated (WDSCC) EpSCC using a tissue array approach. Further objectives were to correlate protein expression to (i) levels of inflammation, using a convolutional neural network (ii) equine papillomavirus 2 (EcPV2) infection, detected using PCR amplification. We found an increase in expression of FRA1 in EpSCC compared to NT samples. c-Myc expression was higher in Hyp/Pap and WDSCC but not PDSCC whereas MMP7 was reduced in WDSCC compared with NT. There was a significant increase in the global intersection coefficient (GIC) of FRA1 with MMP7, c-Myc, and Cyclin D1 in EpSCC. Conversely, GIC for MMP7 with c-Myc was reduced in EpSCC tissue. Inflammation was positively associated with EcPV2 infection in both NT and EpSCC but not Hyp/Pap. Changes in protein expression could be correlated with EcPV2 for Cyclin D1 and c-Myc. Our results evaluate novel biomarkers of EpSCC and a putative correlation between the expression of biomarkers, EcPV2 infection and inflammation.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/genética , Neoplasias Penianas/genética , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/virologia , Ciclina D1/genética , Ciclina D1/metabolismo , Cavalos , Masculino , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Papillomaviridae/fisiologia , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Neoplasias Penianas/diagnóstico , Neoplasias Penianas/virologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Curva ROC , Análise Serial de Tecidos/métodos
8.
BMC Infect Dis ; 20(1): 297, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321435

RESUMO

BACKGROUND: Most individuals are infected with human papillomavirus (HPV) at least once in their lifetime. Infections with low-risk types can cause genital warts, whereas high-risk types can cause malignant tumors. The aim of this study was to determine the burden of anogenital diseases potentially related to HPV in young women based on German statutory health insurance claims data. METHODS: We conducted a retrospective claims data analysis using the "Institute for Applied Health Research Berlin" (InGef) Research Database, containing claims data from approximately 4 million individuals. In the period from 2012 to 2017 all women born in1989-1992, who were continuously insured between the age of 23-25 years were identified. Using ICD-10-GM codes (verified diagnosis in the outpatient sector or primary or secondary diagnosis in the inpatient sector) the administrative prevalence (95% confidence interval) of genital warts (A63.0), anogenital diseases grade I (K62.8, N87.0, N89.0, N90.0), grade II (N87.1, N89.1, N90.1) and grade III (D01.3, D06.-, D06.0, D07.1, D07.2, N87.2, N89.2, N90.2) was calculated (women with diagnosis divided by all women). RESULTS: From 2012 to 2017, a total of 15,358 (birth cohort 1989), 16,027 (birth cohort 1990), 14,748 (birth cohort 1991) and 14,862 (birth cohort 1992) women at the age of 23-25 were identified. A decrease of the administrative prevalence was observed in genital warts (1.30% (1.12-1.49) birth cohort 1989 vs. 0.94% (0.79-1.10) birth cohort 1992) and anogenital diseases grade III (1.09% (0.93-1.26) birth cohort 1989 vs. 0.71% (0.58-0.86) birth cohort 1992). In anogenital diseases grade III, this trend was especially observed for severe cervical dysplasia (N87.2) (0.91% (0.76-1.07) birth cohort 1989 vs. 0.60% (0.48-0.74) birth cohort 1992). In contrast, anogenital diseases grade I (1.41% (1.23-1.61) birth cohort 1989 vs. 1.31% (1.14-1.51) birth cohort 1992) and grade II (0.61% (0.49-0.75) birth cohort 1989 vs. 0.52% (0.42-0.65) birth cohort 1992) remained stable. CONCLUSIONS: A decrease of the burden of anogenital disease potentially related to HPV was observed in the younger birth cohorts. This was observed especially for genital warts and anogenital diseases grade III. Further research to investigate this trend for the upcoming years in light of varying HPV vaccination coverage for newer birth cohorts is necessary.


Assuntos
Doenças do Ânus/epidemiologia , Doenças dos Genitais Femininos/epidemiologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/epidemiologia , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adulto , Doenças do Ânus/virologia , Neoplasia Intraepitelial Cervical/epidemiologia , Neoplasia Intraepitelial Cervical/virologia , Estudos de Coortes , Condiloma Acuminado/epidemiologia , Condiloma Acuminado/virologia , Feminino , Doenças dos Genitais Femininos/virologia , Alemanha/epidemiologia , Humanos , Infecções por Papillomavirus/complicações , Prevalência , Estudos Retrospectivos , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem
9.
Cancer Cytopathol ; 128(4): 227-228, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32251554
10.
Med Oncol ; 37(5): 37, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32232578

RESUMO

The relationship between high-risk-human-papillomavirus (HR-HPV) viral loads and residual/recurrence lesion is uncertain. This study aimed to evaluate the clinical value of HR-HPV viral loads to predict the residual/recurrence lesions among women with high-grade squamous lesions or worse (≥ HSIL) after surgery. Finally, 301 women who underwent primary screening of cervical cancer using polymerase-chain-reaction-(PCR)-reverse-dot-blot-(RDB) human papillomavirus (HPV) genotyping and cytology assays were enrolled. They received surgery and took HR-HPV viral loads with a BioPerfectus Multiplex Real-Time PCR assay. Colposcopy biopsies were performed in patients with HPV-16/18(+) and/or TCT ≥ ASCUS with HR-HPV(+). The risk of HR-HPV viral loads and potentials factors for residual/recurrence lesions were analyzed and the optimal cut-off values of HR-HPV viral loads were calculated. The significant differences were found in residual/recurrence lesions among patients with different ages, margin status, cytology and HR-HPV at 6 months (all P < 0.05). Interestingly, HPV viral loads were observed significant differences in the group of residual lesions, not recurrence group. Furthermore, except for HPV-31/33, the viral loads of HP-16/52/58 were significant differences in residual lesions. The cut-off level of HR-HPV viral loads was 5.22 copies/10,000 cells, providing viable triage for the risk of residual lesions. Compared with different follow-up methods, the HR-HPV viral loads ≥ 5.22copies/10,000 cells (HR 3.39, 95% CI 1.57-7.35) had a higher risk for developing residual lesions. HR-HPV viral loads can be a reliable predictor of residual lesions. Furthermore, women with viral loads ≥ 5.22 copies/10,000 cells may have higher risk for residual disease and should be give a more aggressive treatment and follow-up strategy.


Assuntos
Neoplasia Intraepitelial Cervical/virologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia , Carga Viral , Adulto , Idoso , Neoplasia Intraepitelial Cervical/patologia , Neoplasia Intraepitelial Cervical/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasia Residual , Papillomaviridae/classificação , Papillomaviridae/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/cirurgia , Estudos Prospectivos , Risco , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia , Adulto Jovem
11.
Anticancer Res ; 40(4): 2219-2223, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234917

RESUMO

AIM: To investigate the prevalence of cervico-vaginal co-infection with high-risk (HR) HPV types and other sexually transmitted pathogens (STPs) in women with anogenital warts (AGWs). PATIENTS AND METHODS: In this cross-sectional study, cervico-vaginal smears of women with AGWs were examined with real-time polymerase chain reaction for the presence of HR-HPV types and common STPs. Women with recent cervical HPV infection and general population were used for comparisons. RESULTS: A total of 689 women participated in the study. Among the examined groups, higher rates of cervico-vaginal co-infection with HR-HPV types and other STPs collectively were recorded in women with AGWs (p=0.0049 and p<0.004, respectively). Within the AGWs group, cervical co-infection with HR-HPV types was detected more often in women with recurrent disease (p<0.001). CONCLUSION: The higher rates of cervico-vaginal co-infection with HR-HPV types and common STPs in women with AGWs may affect their risk for cervical carcinogenesis and the natural course of their disease.


Assuntos
Doenças do Ânus/epidemiologia , Condiloma Acuminado/epidemiologia , Doenças dos Genitais Femininos/epidemiologia , Infecções por Papillomavirus/epidemiologia , Verrugas/epidemiologia , Adolescente , Adulto , Doenças do Ânus/virologia , Colo do Útero/virologia , Condiloma Acuminado/virologia , Estudos Transversais , Feminino , Doenças dos Genitais Femininos/virologia , Grécia/epidemiologia , Humanos , Pessoa de Meia-Idade , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Prevalência , Esfregaço Vaginal , Verrugas/virologia , Adulto Jovem
12.
J Virol ; 94(10)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132238

RESUMO

The TEAD family of transcription factors requires associating cofactors to induce gene expression. TEAD1 is known to activate the early promoter of human papillomavirus (HPV), but the precise mechanisms of TEAD1-mediated transactivation of the HPV promoter, including its relevant cofactors, remain unexplored. Here, we reveal that VGLL1, a TEAD-interacting cofactor, contributes to HPV early gene expression. Knockdown of VGLL1 and/or TEAD1 led to a decrease in viral early gene expression in human cervical keratinocytes and cervical cancer cell lines. We identified 11 TEAD1 target sites in the HPV16 long control region (LCR) by in vitro DNA pulldown assays; 8 of these sites contributed to the transcriptional activation of the early promoter in luciferase reporter assays. VGLL1 bound to the HPV16 LCR via its interaction with TEAD1 both in vitro and in vivo Furthermore, introducing HPV16 and HPV18 whole genomes into primary human keratinocytes led to increased levels of VGLL1, due in part to the upregulation of TEADs. These results suggest that multiple VGLL1/TEAD1 complexes are recruited to the LCR to support the efficient transcription of HPV early genes.IMPORTANCE Although a number of transcription factors have been reported to be involved in HPV gene expression, little is known about the cofactors that support HPV transcription. In this study, we demonstrate that the transcriptional cofactor VGLL1 plays a prominent role in HPV early gene expression, dependent on its association with the transcription factor TEAD1. Whereas TEAD1 is ubiquitously expressed in a variety of tissues, VGLL1 displays tissue-specific expression and is implicated in the development and differentiation of epithelial lineage tissues, where HPV gene expression occurs. Our results suggest that VGLL1 may contribute to the epithelial specificity of HPV gene expression, providing new insights into the mechanisms that regulate HPV infection. Further, VGLL1 is also critical for the growth of cervical cancer cells and may represent a novel therapeutic target for HPV-associated cancers.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Papillomaviridae/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Linhagem Celular , Colo do Útero , Epitélio , Feminino , Regulação Viral da Expressão Gênica , Técnicas de Silenciamento de Genes , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/fisiologia , Humanos , Queratinócitos/virologia , Proteínas Musculares/metabolismo , Papillomaviridae/fisiologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Regiões Promotoras Genéticas , Transcrição Genética , Ativação Transcricional , Transcriptoma , Regulação para Cima , Neoplasias do Colo do Útero/virologia
14.
J Virol ; 94(8)2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31996427

RESUMO

Human papillomavirus (HPV) type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Our previous international epidemiological studies revealed that HPV58 carrying an E7 natural variant, T20I/G63S (designated V1), was associated with a higher risk of cervical cancer. We recently showed that V1 possesses a greater ability to immortalize and transform primary cells, as well as degrading pRB more effectively, than the prototype and other common variants. In this study, we performed a series of phenotypic and molecular assays using physiologically relevant in vitro and in vivo models to compare the oncogenicity of V1 with that of the prototype and other common natural variants. Through activation of the AKT and K-Ras/extracellular signal-regulated kinase (ERK) signaling pathways, V1 consistently showed greater oncogenicity than the prototype and other variants, as demonstrated by increased cell proliferation, migration, and invasion, as well as induction of larger tumors in athymic nude mice. This study complements our previous epidemiological and molecular observations pinpointing the higher oncogenicity of V1 than that of the prototype and all other common variants. Since V1 is more commonly found in eastern Asia, our report provides insight into the design of HPV screening assays and selection of components for HPV vaccines in this region.IMPORTANCE Epidemiological studies have revealed that a wild-type variant of HPV58 carrying an E7 variation, T20I/G63S (V1), is associated with a higher risk of cervical cancer. We previously reported that this increased oncogenicity could be the result of the virus's greater ability to degrade pRB, thereby leading to an increased ability to grow in an anchorage-independent manner. In addition to this, this report further showed that this HPV variant induced activation of the AKT and K-Ras/ERK signaling pathways, thereby explaining its genuine oncogenicity in promoting cell proliferation, migration, invasion, and formation of tumors, all to a greater extent than the prototype HPV58 and other common variants.


Assuntos
Papillomaviridae/classificação , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Animais , Grupo com Ancestrais do Continente Asiático , Proliferação de Células , Modelos Animais de Doenças , Feminino , Variação Genética , Humanos , Camundongos , Camundongos Nus , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Vacinas contra Papillomavirus , Ratos , Neoplasias do Colo do Útero/virologia
15.
Sci Rep ; 10(1): 243, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937831

RESUMO

Oropharyngeal squamous cell carcinoma (OPSCC) incidence is increasing at a nearly epidemic rate, largely driven by the human papillomavirus (HPV). Despite the generally favorable clinical outcomes of patients with HPV driven (HPV+) OPSCC, a significant subset of HPV tumors associated with tobacco exposure have diminished treatment response and worse survival. The tumor immune microenvironment (TIME) has been shown to be a critical driver of treatment response and oncologic outcomes in OPSCC generally and HPV+ OPSCC more specifically. However, the impact of tobacco exposure on the TIME in OPSCC patients remains unclear. We analyzed the relationship between TIME, tobacco exposure and clinical outcomes in OPSCC patients (n = 143) with extensive tobacco exposure (median pack-years = 40). P16 overexpression, a surrogate marker of HPV association, was a strong predictor of relapse-free (RFS) and overall survival (OS) (p < 0.001, p < 0.001 respectively) regardless of tobacco exposure and associated strongly with differential infiltration of the tumor by both CD3 and CD8 lymphocytes measured via immunohistochemistry (p < 001, p < 0.001 respectively). CD3 and CD8 infiltration was a strong predictor of RFS and OS and associated strongly with disease stage (AJCC 8th Edition Staging Manual). Tobacco exposure correlated significantly (p < 0.001) with decreased CD8 infiltration in p16+ OPSCC tumors. Our findings demonstrate that the HPV+ OPSCC clinical outcomes are strongly correlated with the TIME, which is potentially modulated by tobacco exposure. Immunomodulatory strategies targeting this disease in smokers must take into consideration the potential modifying effects of tobacco exposure on treatment effectiveness and clinical outcomes.


Assuntos
Antígenos CD8/metabolismo , Neoplasias Orofaríngeas/induzido quimicamente , Neoplasias Orofaríngeas/metabolismo , Tabaco/efeitos adversos , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/imunologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/fisiologia , Estudos Retrospectivos , Risco , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
16.
Biomed Pharmacother ; 123: 109790, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31896065

RESUMO

Cervical cancer remains one of the leading causes of cancer death worldwide. Immunotherapy is the most promising cancer therapeutics in recent years and has gain positive results in several cancers in the clinic. This study was aimed to investigate the roles and mechanism of IFI16 in cervical cancer immunotherapy. We observed an abnormally high expression of Programmed cell death 1 ligand 1 (PD-L1) and Interferon-inducible 16 (IFI16) in Human papillomavirus (HPV) positive cervical cancer cells compared with HPV negative cervical cancer cells. Moreover, IFI16 promotes cervical cancer development in vitro and in vivo as the oncogenic role of PD-L1. In the subsequent mechanism investigation, we found that IFI16 activated STING-TBK1-mediated immunoregulation, and subsequently activated downstream NF-kB pathway, which interacted with the proximal region of PD-L1 promoter to facilitate PD-L1 expression. In conclusion, we found that IFI16 positively regulate PD-L1 through STING-TBK1-NF-kB pathway, thus promoting cervical cancer progression. The roles of IFI16 in cervical cancer progression deserve further investigation and hold the promise of being developed as a novel immunotherapy target in the future.


Assuntos
Antígeno B7-H1/metabolismo , Progressão da Doença , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Microambiente Tumoral/imunologia , Regulação para Cima , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Animais , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Papillomaviridae/fisiologia , Transdução de Sinais , Neoplasias do Colo do Útero/virologia
17.
Cancer ; 126(4): 737-748, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31721164

RESUMO

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXL2 demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC. METHODS: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC. RESULTS: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC. CONCLUSIONS: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC.


Assuntos
Aminoácido Oxirredutases/genética , Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Processamento Alternativo , Aminoácido Oxirredutases/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Progressão da Doença , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Papillomaviridae/fisiologia , Interferência de RNA , Transdução de Sinais/genética
18.
Int J Radiat Oncol Biol Phys ; 106(4): 725-732, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785337

RESUMO

PURPOSE: This trial tested the safety and efficacy of a novel, deintensified radiation therapy (RT) approach after initial surgical resection for patients with human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS AND MATERIALS: This single-arm phase 2 prospective clinical trial enrolled 60 patients with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection at a single institution between May 2014 and September 2017. Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high-volume head and neck cancer center with expertise in TORS. Patients received postoperative RT to at-risk areas in the involved neck (60-66 Gy) and uninvolved neck (54 Gy). The resected primary site was treated as an active avoidance structure in the treatment planning of postoperative RT. Concurrent chemotherapy was administered for patients with extranodal extension. RESULTS: Median follow-up of the 60 patients enrolled was 2.4 years (range, 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and 2 patients (3.3%) developed distant metastases. Measured 2-year local recurrence-free survival was 97.9% (95% confidence interval, 86.1%-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy (standard deviation, 10.3 Gy). Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up. CONCLUSIONS: Deintensified postoperative RT that avoids the resected primary tumor site and targets only the at-risk neck after TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/virologia , Neoplasias Orofaríngeas/cirurgia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/fisiologia , Procedimentos Cirúrgicos Robóticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/patologia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Resultado do Tratamento
19.
Clin Immunol ; 210: 108269, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683054

RESUMO

Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.


Assuntos
Mutação com Ganho de Função/genética , Síndromes de Imunodeficiência/diagnóstico , Leucócitos Mononucleares/imunologia , Meningites Bacterianas/diagnóstico , Inibidor de NF-kappaB alfa/genética , Neisseria meningitidis/fisiologia , Papillomaviridae/fisiologia , Infecções por Pseudomonas/diagnóstico , Pseudomonas aeruginosa/fisiologia , Viroses/imunologia , Adulto , Artrite Juvenil , Azitromicina/uso terapêutico , Bronquiectasia , Proliferação de Células , Células Cultivadas , Criança , Displasia Ectodérmica , Gentamicinas/uso terapêutico , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Meningites Bacterianas/tratamento farmacológico , Linhagem , Infecções por Pseudomonas/tratamento farmacológico , Viroses/diagnóstico , Verrugas , Adulto Jovem
20.
Arch Pathol Lab Med ; 144(3): 344-349, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31483999

RESUMO

CONTEXT.­: Detection of high-risk human papillomavirus (HR-HPV) in squamous cell carcinoma is important for classification and prognostication. In situ hybridization (ISH) is a commonly used HR-HPV-specific test that targets viral RNA or DNA. The College of American Pathologists (CAP) provides proficiency testing for laboratories performing HR-HPV ISH. OBJECTIVE.­: To compare the analytical performance of RNA- and DNA-based ISH methods on CAP HR-HPV proficiency tests. DESIGN.­: Data from the 2016-2018 CAP HPV ISH proficiency testing surveys were reviewed. These surveys consist of well-characterized samples with known status for HR-HPV, including 1 to 2 copies, 50 to 100 copies, 300 to 500 copies, and no copies of HR-HPV per cell. RESULTS.­: Ninety-five participants submitted 1268 survey results from 20 cores. Overall, RNA ISH had a significantly higher percentage of correct responses than DNA ISH: 97.4% (450 of 462) versus 80.6% (650 of 806) (P < .001). This disparity appears to be the consequence of a superior sensitivity of RNA ISH compared to DNA ISH for samples with 1 to 2 and with 50 to 100 copies of HR-HPV per cell: 95.2% (120 of 126) versus 53.8% (129 of 240), P < .001, respectively, and 100% (89 of 89) versus 76.3% (119 of 156), P < .001, respectively. CONCLUSIONS.­: An assessment of CAP HR-HPV proficiency test performance indicates that RNA ISH shows significantly higher accuracy than DNA ISH owing to higher analytical sensitivity of RNA ISH in tumors with low (1-2 copies per cell) to intermediate (50-100 copies per cell) HR-HPV viral copy numbers. These data support the use of RNA over DNA ISH in clinical laboratories that perform HR-HPV testing as part of their testing algorithms.


Assuntos
DNA Viral/genética , Hibridização In Situ/métodos , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Patologistas/normas , RNA Viral/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Modelos Logísticos , Técnicas de Diagnóstico Molecular/métodos , Análise Multivariada , Papillomaviridae/fisiologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Patologistas/estatística & dados numéricos , Sensibilidade e Especificidade , Inquéritos e Questionários/estatística & dados numéricos
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