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1.
Artigo em Inglês | MEDLINE | ID: mdl-32257968

RESUMO

E7 protein from cutaneous as well as mucosal HPV types can alter NF-κB activity. Conflicting literature data show a HPV-induced up- or down-regulation of the NF-κB pathway in different cell lines. In a previous study we detected the expression of E7 gene of HPV15 in a subungual tumor of a patient affected by incontinentia pigmenti (IP). IP is a rare X-linked genodermatosis in which the IKKγ gene is altered. From observations in transgenic IKKγ defective mice, it was suggested that IKK-deficient cells may undergo rapid hyper-proliferation and apoptosis/necrosis, leading to increased pro-inflammatory cytokine production in the neighboring IKK-positive cells. The objective of this study was to ascertain if beta HPV 15 can alter apoptosis and NF-κB pathway in normal and IKKγ-deficient keratinocytes. The human immortalized keratinocyte cell line (HaCaT), and human primary keratinocyte (HPK) cells were transduced with a retrovirus expressing E6-E7 proteins of HPV 15 and IKKγ was successful silenced mimicking the HPV15 infection and IP. HPV15 E6-E7 gene expression improved NF-κB activity in human keratinocytes even when IKKγ was silenced by siRNA. In IKKγ silenced keratinocyte cells, TNF-α-induced apoptosis was strongly reduced by the expression of HPV15 E6-E7 genes. Beta HPV15 exerted this anti-apoptotic activity by decreasing pro-apoptotic BAK and cleaved Caspase 3 proteins. In conclusion, we can speculate that presence of persistent infection by beta papillomavirus might influence the biological fate of IP by altering NF-κB activation and apoptosis in IKKγ mutated cells, favoring their survival and possibly the development of tumors in the late stage of disease. Taken together, our data reinforce the importance of host genetic background in the pathogenesis of HPV-associated skin lesions.


Assuntos
NF-kappa B , Infecções por Papillomavirus , Apoptose , Humanos , Queratinócitos , Papillomaviridae
2.
Minerva Ginecol ; 71(6): 442-459, 2019 Dec.
Artigo em Italiano | MEDLINE | ID: mdl-31741364

RESUMO

HPV vaccination has been introduced in clinical practice in recent years and represents the most effective strategy of primary prevention of cervical carcinoma and of female genital preneoplastic conditions. One of the major issues of the subject is represented by vaccination coverage of the target population. Since its introduction, HPV vaccine efficacy has been progressively demonstrated also towards extragenital HPV-correlated conditions and in males too. Moreover, even subjects of older age groups or subjects who already had HPV infections have been demonstrated to received benefits from vaccination, due to improvements of their immunological response. Recently, vaccine efficacy has also been investigated in terms of adjuvant administration after treatments of preneoplastic or benign conditions of the female lower genital tract caused by HPVs; preliminary results indicate an interesting and promising field of application. On this basis, in this article an analysis of the state of the art has been performed, with specific regard to the Italian scenario and with the focus of future perspectives of implementation of the HPV vaccination policy. From the available evidences, the Italian HPV Study Group recommends the extension of systematic HPV vaccination to males too, to adult subjects and also after conservative treatment of genital HPV correlated conditions.


Assuntos
Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinação/métodos , Adolescente , Adulto , Fatores Etários , Feminino , Humanos , Itália , Masculino , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia
3.
Ther Adv Med Oncol ; 11: 1758835919853192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452691

RESUMO

Background: The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT). Methods: Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered. Results: The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature (p = 0.011). In models of Ki-67 reduction, 'luminal B' subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant (p < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival (p = 0.027) and overall survival (p = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades (p < 0.05 for both). Conclusions: We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms.

4.
J Low Genit Tract Dis ; 23(1): 39-42, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30371554

RESUMO

OBJECTIVE: Many methods are available today for human papillomavirus (HPV) testing; they differ for technology, targets, and information on the genotypes detected. In this study, we evaluated the performance of the Onclarity HPV assay in detection and follow-up of cervical preneoplastic lesions. MATERIALS AND METHODS: One hundred sixty-seven women referred to the European Institute of Oncology, Milan, for treatment of cervical lesions were enrolled. We investigated the utility of Onclarity extended genotyping HPV test in the management of cervical intraepithelial neoplasia (CIN) 2+ preneoplastic lesion. RESULTS: At baseline, the concordance was 92% (150/163) between Onclarity and Hybrid Capture 2 (HC2) and 93% (142/152) between Onclarity and linear array, respectively. At follow-up, the concordance between Onclarity and HC2 was 80%. Seven women relapsed: 6 had persistence of the same genotypes and 1 patient tested negative not only with Onclarity but also with HC2 for the presence of a low-risk genotype in the sample. CONCLUSIONS: This study showed that the evaluation of the HPV genotype persistence may represent a valid option to monitor patients treated for CIN 2+ lesions, because relapses were detected only in patients with persistence of the same genotype detected at baseline.


Assuntos
Neoplasia Intraepitelial Cervical/virologia , Gerenciamento Clínico , Técnicas de Genotipagem/métodos , Técnicas de Diagnóstico Molecular/métodos , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Adulto , Feminino , Genótipo , Humanos , Itália , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Estudos Prospectivos , Recidiva
5.
J Cell Physiol ; 234(6): 7708-7717, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30536609

RESUMO

Data from 423 human epidermal growth factor receptor 2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6-35.4) and clinical benefit was 52.7% (95% CI, 48-57.5). ORR was negatively affected by prior exposure to everolimus/exemestane ( p = 0.002) and favorably influenced by early line-treatment ( p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8-16) and median overall survival was 24 months (95% CI, 17-30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2-, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/efeitos dos fármacos , Resultado do Tratamento
6.
Cancer Biol Ther ; 20(2): 192-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30403909

RESUMO

We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test. Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached. When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06). The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively). In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Taxoides/uso terapêutico , Trastuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxoides/farmacologia , Trastuzumab/farmacologia
7.
Viruses ; 9(12)2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29257060

RESUMO

The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle strategies in order to ensure a chronic persistence in the host, virtually avoiding systemic sequelae and death. This process promotes the periodic shedding of large amounts of infectious particles to maintain a virus reservoir in individual hosts, while allowing virus spreading within the community. To achieve such a successful lifestyle, the human papilloma virus (HPV) needs to escape the host defence systems. The key to understanding how this is achieved is in the virus replication process that provides by itself an evasion mechanism by inhibiting and delaying the host immune response against the viral infection. Numerous studies have demonstrated that HPV exploits both the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) DDR pathways to replicate its genome and maintain a persistent infection by downregulating the innate and cell-mediated immunity. This review outlines how HPV interacts with the ATM- and ATR-dependent DDR machinery during the viral life cycle to create an environment favourable to viral replication, and how the interaction with the signal transducers and activators of transcription (STAT) protein family and the deregulation of the Janus kinase (JAK)-STAT pathways may impact the expression of interferon-inducible genes and the innate immune responses.


Assuntos
Enzimas Reparadoras do DNA/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Papillomaviridae/fisiologia , Replicação Viral , Animais , Humanos
9.
BMC Infect Dis ; 17(1): 126, 2017 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-28166736

RESUMO

BACKGROUND: The Human papillomavirus is the most common sexually transmitted virus worldwide. The objective of this study was to estimate: 1) the prevalence and the incidence of external genital warts (eGW) in a sample of women attending community outpatient clinics and 2) the total number of eGW cases in the Italian female population aged 15-64 years. METHODS: A prospective study was performed for a 12-month period between 2009 and 2010, among a sample of women attending community gynecological outpatient clinics located throughout Italy. Demographic data, for every woman aged 15-64 years, were collected. For women diagnosed with eGW, behavioral and clinical data were recorded. Prevalence of eGW was calculated as the proportion between the number of women with eGW and that of women visiting any of the participating gynecologists; incidence of eGW was calculated as the proportion between the number of women with a new diagnosis of eGW and that of women visiting any of the participating gynecologists. Standardized prevalence by age was used to estimate the number of eGW cases occurring in the Italian female population aged 15-64 years. RESULTS: In 2009-2010, 44 community gynecologists were included in the network. In one-year period, 16,410 women visited any of the participating gynecologists; 63 women were diagnosed with eGW, corresponding to a prevalence of 3.8 cases per 1,000 women per year (95%CI: 2.9-4.9). The incidence of eGW was 3.0 cases per 1,000 women per year (95%CI: 2.2-3.9). Women aged 15-24 years showed both the highest prevalence and incidence. Prevalence and incidence significantly decreased by increasing age group (p <0.001), and were higher in Southern Italy compared to Central-Northern Italy. The estimated number of women with eGW among women aged 15-64 years in Italy, in 2010, was approximately 69,000. CONCLUSIONS: These data show a high prevalence and incidence of eGW among young women in Italy, stress the effectiveness of community clinical networks in investigating STI epidemiology among women from the general population, confirm the relevance of HPV vaccination programs among adolescents, and underscore the need of promoting safe sex, implementing early diagnosis, treatment and prevention of genital warts.


Assuntos
Condiloma Acuminado/epidemiologia , Adolescente , Adulto , Condiloma Acuminado/diagnóstico , Demografia , Feminino , Humanos , Incidência , Itália/epidemiologia , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Adulto Jovem
10.
Int J Gynaecol Obstet ; 136(3): 266-271, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28099686

RESUMO

OBJECTIVE: To evaluate, from a gynecology perspective, the transition from cytology-based HPV screening to primary HPV screening. METHODS: Studies examining switching from cytology-based screening to primary HPV-DNA testing with triaging of patients with positive test results were retrieved and reviewed, with a particular focus on screening in an Italian setting. RESULTS: The increased complexity of patient-management decisions when implementing HPV-based screening was a critical issue discussed in the literature. The change in strategy represents a paradigm shift in moving from a medical perspective of identifying the disease in individual patients, to a public-healthcare perspective of excluding HPV from the healthy population and identifying a small sub-group of individuals at increased risk of HPV. CONCLUSION: With knowledge about HPV screening evolving rapidly, new programs and related algorithms need to be sufficiently flexible to be adjusted according to ongoing research and the validation of new assays. The establishment of a national working group (including epidemiologists, gynecologists, pathologists, and healthcare providers) will be necessary to properly implement and govern this important technical and cultural transition.


Assuntos
Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Colposcopia , Análise Custo-Benefício , Feminino , Testes de DNA para Papilomavírus Humano , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Esfregaço Vaginal
11.
Int J Gynaecol Obstet ; 136(3): 258-265, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28087890

RESUMO

HPV-related diseases affect anogenital and oropharyngeal regions, heavily affecting the psychosexual dimension of both male and female individuals. HPV vaccination programs based on a bivalent or quadrivalent vaccine have opened broad perspectives for primary prevention. A nonavalent HPV vaccine (9vHPV), covering nine genotypes (HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV45, HPV52, and HPV58), might provide further improvement in terms of direct protection. In the present report, efficacy and safety data from 9vHPV vaccine development programs are examined. Efficacy data come from a pivotal trial, which was conducted among women aged 16-26 years randomly assigned to receive either the 9vHPV or the quadrivalent HPV (4vHPV) vaccine. The 9vHPV vaccine was shown to have potential benefits as compared with 4vHPV, increasing the overall estimated rate of prevention to 90% for cervical cancer and up to 80% for precancerous cervical lesions. For all other HPV-related pre-invasive and invasive lesions, 9vHPV showed potentially greater disease reduction, depending on the anatomic region examined. Thus, the 9vHPV vaccine shows clinical potential for the prevention of HPV-related diseases in both sexes. Future adoption of 9vHPV will depend on factors including market price, cost-effectiveness data, use of a two-dose schedule, and safety and efficacy monitoring in real-life programs.


Assuntos
Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/uso terapêutico , Neoplasias do Colo do Útero/prevenção & controle , Feminino , Humanos , Masculino , Papillomaviridae/genética , Vacinas contra Papillomavirus/classificação , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias do Colo do Útero/virologia
12.
Hum Vaccin Immunother ; 13(2): 291-297, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27929754

RESUMO

HPV16 persistent infection is a well-known condition that precedes human cancer development. High risk HPV E5 proteins cooperate with E6/E7 oncogenes to promote hyper-proliferation of infected cells leading to possible cancer progression. Thus, presence of E5 viral transcripts could be a key marker of active infection and, in turn, a target of immunotherapy. Purpose of the study is to detect E5 transcripts in clinical samples and to explore the activity of novel anti-HPV16 E5 DNA vaccines. HPV transcripts were detected by PCR with specific primers encompassing the splice-donor sites of E5 transcript. For E5-based immunotherapies, 2 E5-based versions of DNA vaccines carrying whole E5 gene or a synthetic multiepitope gene were improved by fusion to sequence of PVX coat protein. These vaccines were challenged with a new luminescent animal model based on C3-Luc cell line. E5 transcripts were detected in clinical samples of women with HPV positive low-grade SIL, demonstrating the validity of our test. In C3 pre-clinical mouse model, vaccine candidates were able to induce a strong cellular immunity as indicated by ELISPOT assays. In addition, E5-CP vaccines elicited strong anti-tumor effects as showed by decreased tumor growth monitored by animal imaging. The tumor growth inhibition was comparable to those obtained with anti-E7 DNA vaccines. In conclusion, detection of E5 transcripts in clinical samples indicates that E5 is a possible target of immunotherapy. Data from pre-clinical model demonstrate that E5 genetic immunization is feasible, efficacious and could be utilized in clinical trials.


Assuntos
Imunoterapia/métodos , Proteínas Oncogênicas Virais/biossíntese , Infecções por Papillomavirus/complicações , Vacinas contra Papillomavirus/administração & dosagem , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Vacinas de DNA/administração & dosagem , Animais , ELISPOT , Feminino , Humanos , Imunidade Celular , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas Virais/análise , Resultado do Tratamento
13.
Int J Endocrinol ; 2016: 8671762, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27725832

RESUMO

Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold). Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis.

14.
Oncoimmunology ; 5(6): e1160187, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27471633

RESUMO

Hippo is a tumor-suppressor pathway that negatively regulates the oncoproteins TAZ and YAP. Moreover, Hippo affects the biology of a variety of non-neoplastic cells in the tumor microenvironment, even including immune cells. We herein assessed the predictive role of TAZ and YAP, assessed by immunohistochemistry, in 50 cervical cancer patients prevalently treated with neoadjuvant chemotherapy. Tumors were classified as positive or negative according to the percentage of tumor-expressing cells and cellular localization. TAZ/YAP were also evaluated in non-neoplastic cells, namely endothelial cells, non-lymphocytic stromal cells and tumor-infiltrating lymphocytes (TILs). TAZ expression in cancer cells (TAZ(pos)) was associated with a reduced pathological complete response (pCR) rate (p = 0.041). Conversely, the expression of TAZ and YAP in TILs (TAZ(TIL+) and YAP(TIL+)) seemed to be associated with increased pCRs (p = 0.083 and p = 0.018, respectively). When testing the predictive significance of the concomitant expression of TAZ in cancer cells and its absence in TILs (TAZ(pos)/TAZ(TIL-)), patients with TAZ(pos)/TAZ(TIL-) showed lower pCR rate (p = 0.001), as confirmed in multivariate analysis (TAZ(pos)/TAZ(TIL-): OR 8.67, 95% CI: 2.31-32.52, p = 0.001). Sensitivity analysis carried out in the 41 patients treated with neoadjuvant chemotherapy yielded comparable results (TAZ(pos)/TAZ(TIL-): OR 11.0, 95% CI: 2.42-49.91, p = 0.002). Internal validation carried out with two different procedures confirmed the robustness of this model. Overall, we found evidence on the association between TAZ expression in cervical cancer cells and reduced pCR rate. Conversely, the expression of the Hippo transducers in TILs may predict increased treatment efficacy, possibly mirroring the activation of a non-canonical Hippo/MST pathway necessary for T-cells activation and survival.

16.
Eur J Cancer ; 58: 52-61, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26963794

RESUMO

The ErbB tyrosine kinase receptors play a key role in regulating many cellular functions and human papillomaviruses (HPVs) may interact with transductional pathway of different growth factor receptors. Here, these interactions were analysed in W12 cell line carrying HPV 16 genome and in clinical samples. W12 cells, in which HPV16 becomes integrated during passages, were utilised to detect viral and ErbB family expression at early (W12E) and late passages (W12G). Interestingly, a strong reduction of ErbB-3 expression was observed in W12G. Loss of the E2 and E5 viral genes occurs in W12G and this may affect ErbB-3 receptor expression. E2 and E5 rescue experiments demonstrated that only E2 gene was able to restore ErbB-3 expression. E2 is a transcriptional factor but the expression levels of ErbB3 were unaffected and ErbB-3 promoter did not show any consensus sequence for E2, thus E2 may interact in another way with ErbB3. Indeed, HPV 16 E2 can modulate ErbB-3 by interacting with the ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp-1) that is involved in the regulation of this receptor, via ubiquitination and degradation. E2 co-immunoprecipitated in a complex with Nrdp-1 leading to hypothesise an involvement of this interaction in ErbB-3 regulation. In addition, 90% of the clinical samples with integrated virus and E2 loss showed no or low ErbB-3 positivity, confirming in vitro results. In conclusion, the new discovered interaction of HPV-16 E2 with Nrdp-1 may affect ErbB-3 expression.


Assuntos
Neoplasia Intraepitelial Cervical/enzimologia , Proteínas de Ligação a DNA/metabolismo , Papillomavirus Humano 16/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/enzimologia , Receptor ErbB-3/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias do Colo do Útero/enzimologia , Adulto , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Viral , Neoplasia Intraepitelial Cervical/genética , Neoplasia Intraepitelial Cervical/patologia , Neoplasia Intraepitelial Cervical/virologia , Proteínas de Ligação a DNA/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Genoma Viral , Interações Hospedeiro-Patógeno , Papillomavirus Humano 16/genética , Humanos , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Ligação Proteica , Proteólise , Receptor ErbB-3/genética , Fatores de Tempo , Transfecção , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Integração Viral , Adulto Jovem
17.
PLoS One ; 11(3): e0149872, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26930412

RESUMO

Cervical cancer cells commonly harbour a defective G1/S checkpoint owing to the interaction of viral oncoproteins with p53 and retinoblastoma protein. The activation of the G2/M checkpoint may thus become essential for protecting cancer cells from genotoxic insults, such as chemotherapy. In 52 cervical cancer patients treated with neoadjuvant chemotherapy, we investigated whether the levels of phosphorylated Wee1 (pWee1), a key G2/M checkpoint kinase, and γ-H2AX, a marker of DNA double-strand breaks, discriminated between patients with a pathological complete response (pCR) and those with residual disease. We also tested the association between pWee1 and phosphorylated Chk1 (pChk1), a kinase acting upstream Wee1 in the G2/M checkpoint pathway. pWee1, γ-H2AX and pChk1 were retrospectively assessed in diagnostic biopsies by immunohistochemistry. The degrees of pWee1 and pChk1 expression were defined using three different classification methods, i.e., staining intensity, Allred score, and a multiplicative score. γ-H2AX was analyzed both as continuous and categorical variable. Irrespective of the classification used, elevated levels of pWee1 and γ-H2AX were significantly associated with a lower rate of pCR. In univariate and multivariate analyses, pWee1 and γ-H2AX were both associated with reduced pCR. Internal validation conducted through a re-sampling without replacement procedure confirmed the robustness of the multivariate model. Finally, we found a significant association between pWee1 and pChk1. The message conveyed by the present analysis is that biomarkers of DNA damage and repair may predict the efficacy of neoadjuvant chemotherapy in cervical cancer. Further studies are warranted to prospectively validate these encouraging findings.


Assuntos
Proteínas de Ciclo Celular/análise , Colo do Útero/patologia , Dano ao DNA , Reparo do DNA , Histonas/análise , Proteínas Nucleares/análise , Proteínas Tirosina Quinases/análise , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Biomarcadores/análise , Colo do Útero/metabolismo , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Terapia Neoadjuvante , Fosforilação , Resultado do Tratamento , Neoplasias do Colo do Útero/genética
18.
J Cancer ; 7(1): 107-14, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26722366

RESUMO

Persistent positivity of HPV-DNA testing is considered a prognostic index of recurrent disease in patients treated for CIN2+. HPV detection, and particularly genotyping, has an adequate high rate of sensitivity and specificity (along with an optimal reproducibility), for accurately predicting treatment failure, allowing for an intensified monitoring activity. Conversely, women with a negative HPV-test 6 months after therapy have a very low risk for residual/recurrent disease, which leads to a more individualized follow-up schedule, allowing for a gradual return to the normal screening scheme. HPV testing should be routinely included (with or without cytology) in post-treatment follow-up of CIN2+ patients for early detection of recurrence and cancer progression. HPV genotyping methods, as a biological indicator of persistent disease, could be more suitable for a predictive role and risk stratification (particularly in the case of HPV 16/18 persistence) than pooled HPV-based testing. However, it is necessary to be aware of the performance of the system, adhering to strict standardization of the process and quality assurance criteria.

19.
Crit Rev Oncol Hematol ; 97: 157-67, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26346895

RESUMO

BACKGROUND: The story of Human Papillomavirus vaccination demands reflection not only for its public health impact on the prophylactic management of HPV disease, but also for its relevant economic and social outcomes. Greater than ever data confirm the efficacy and support the urge for effective vaccination plans for both genders before sexual debut. METHODS: A review of previous experience in gender-restricted vaccination programs has demonstrated a lower effectiveness. Limiting vaccination to women might increase the psychological burden on women by confirming a perceived inequality between genders; and even if all women were immunized, the HPV chain of transmission would still be maintained through men. RESULTS: The cost-effectiveness of including boys into HPV vaccination programs should be re-assessed in view of the progressive drop of the economic burden of HPV-related diseases in men and women due to universal vaccination. The cost of the remarkable increase in anal and oropharyngeal HPV driven cancers in both sexes has been grossly underestimated or ignored. CONCLUSIONS: Steps must be taken by relevant bodies to achieve the target of universal vaccination. The analysis of HPV vaccination's clinical effectiveness vs. economic efficacy are supportive of the economic sustainability of vaccination programs both in women and men. In Europe, these achievements demand urgent attention to the social equity for both genders in healthcare. There is sufficient ethical, scientific, strategic and economic evidence to urge the European Community to develop and implement a coordinated and comprehensive strategy aimed at both genders and geographically balanced, to eradicate cervical cancer and other diseases caused by HPV in Europe. Policymakers must take into consideration effective vaccination programs in the prevention of cancers.


Assuntos
Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/economia , Saúde Pública , Vacinação/economia , Análise Custo-Benefício , Europa (Continente) , Feminino , Humanos , Masculino , Saúde Pública/economia , Saúde Pública/métodos , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia
20.
Cancer Immunol Immunother ; 64(10): 1329-38, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26138695

RESUMO

Under the optimistic assumption of high-prophylactic HPV vaccine coverage, a significant reduction of cancer incidence can only be expected after decades. Thus, immune therapeutic strategies are needed for persistently infected individuals who do not benefit from the prophylactic vaccines. However, the therapeutic strategies inducing immunity to the E6 and/or E7 oncoprotein of HPV16 are more effective for curing HPV-expressing tumours in animal models than for treating human cancers. New strategies/technologies have been developed to improve these therapeutic vaccines. Our studies focussed on preparing therapeutic vaccines with low-cost technologies by DNA preparation fused to either plant-virus or plant-toxin genes, such as saporin, and by plant-produced antigens. In particular, plant-derived antigens possess an intrinsic adjuvant activity that makes these preparations especially attractive for future development. Additionally, discrepancy in vaccine effectiveness between animals and humans may be due to non-orthotopic localization of animal models. Orthotopic transplantation leads to tumours giving a more accurate representation of the parent tumour. Since HPV can cause cancer in two main localizations, anogenital and oropharynx area, we developed two orthotopic tumour mouse models in these two sites. Both models are bioluminescent in order to follow up the tumour growth by imaging and are induced by cell injection without the need to intervene surgically. These models were utilized for immunotherapies with genetic or plant-derived therapeutic vaccines. In particular, the head/neck orthotopic model appears to be very promising for studies combining chemo-radio-immune therapy that seems to be very effective in patients.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Papillomavirus Humano 16/fisiologia , Imunoterapia/métodos , Infecções por Papillomavirus/terapia , Neoplasias do Sistema Respiratório/terapia , Neoplasias do Colo do Útero/terapia , Vacinas de DNA/imunologia , Animais , Antígenos de Plantas/imunologia , Modelos Animais de Doenças , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Infecções por Papillomavirus/imunologia , Plantas/imunologia , Neoplasias do Sistema Respiratório/imunologia , Neoplasias do Colo do Útero/imunologia
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