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1.
Ann Otol Rhinol Laryngol ; 129(9): 863-871, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32364419

RESUMO

OBJECTIVES: Tobacco and alcohol are the main etiological factors common to laryngeal cancers. However, the Human Papilloma Virus (HPV) constitutes an alternative risk factor according to several studies. In Tunisia, despite the annual increasing incidence of laryngeal squamous cell carcinoma (LSCC), the prevalence and prognostic significance of HPV have never been explored.In this study, we sought to highlight HPV DNA in 70 biopsies of laryngeal cancer, and to analyze the status of HPV infection in association with p53, p16, survivin, and IGF-1R expressions. METHODS: HPV high risk (HPV HR) DNA was detected in tumors by in situ hybridization. However, the expression of p53, p16, survivin and IGF-1R were stained by immunohistochemistry test. The correlations of HPV status with clinicopathological parameters, overall survival, disease-free survival and proteins expressions were statistically evaluated. RESULTS: HPV HR DNA was detected in 39 out of 70 (55.71%) laryngeal tumors. HPV+ patients have a better overall survival (P = .081) and long disease-free-survival (P = .016) with a low rate of recurrence (P = .006) than HPV- patients. No significant correlations were found between HPV HR status and clinicopathological parameters (all P > .005). Moreover, HPV+ tumors were not associated with expression of p53, p16 and survivin. However, HPV HR status correlates with weak to moderate IGF-1R expression (P = .043). CONCLUSION: The substantial detection of HPV HR in LSCC tumors suggest that this virus plays an important part in laryngeal cancer in Tunisia. It is a good prognostic factor. In addition, HPV infection could act to block the pathway of IGF-1R expression.


Assuntos
Neoplasias Laríngeas/virologia , Infecções por Papillomavirus/virologia , Idoso , Idoso de 80 Anos ou mais , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , DNA Viral/análise , Feminino , Humanos , Neoplasias Laríngeas/química , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/mortalidade , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/metabolismo , Prevalência , Prognóstico , Receptor IGF Tipo 1/análise , Receptor IGF Tipo 1/biossíntese , Estudos Retrospectivos , Taxa de Sobrevida , Survivina/análise , Survivina/biossíntese , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/biossíntese , Tunísia
2.
Talanta ; 210: 120638, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987215

RESUMO

The cancer diagnosis with single level of biomarkers suffers from limitation of insufficient accuracy. Hence, developing sensitive, rapid and adaptative analytical strategies for double-level biomarkers are essential for improving the accuracy of clinical cancer diagnosis at early stage. Herein, a DNA biosensor was established based on the catalytic hairpin assembly-mediated Y-junction nicking enzyme assisted signal amplification (CHA-YNEASA) circuits, where the two circuits were concatenated by molecular beacon (MB). In absence of target, both the CHA and YNEASA circuits were effectively hindered because of MB's outstanding ability to control signal background. In presence of target, the initiated CHA circuits made enzyme recognition sequences in close proximity to the assisted sequences to open MB, leading to further trigger the YNEASA circuits. Due to the unique design of dual signal amplification strategies, CHA-YNEASA circuits significantly shorten the reaction time, and improve signal-to-background ratio as well as facilitate the analysis process. It was demonstrated that a high sensitivity with limit of detection (LOD) of 0.9 pM for p53 gene detection was obtained just within 23 min by the proposed DNA biosensor. Moreover, mismatched p53 gene at nucleic acid level was effectively discriminated and strong anti-interference capability was achieved. Noticeably, the DNA biosensor was adaptative for designing a cytosensor at cell level using hairpin DNA, containing MUC1 aptamer and initiation strand of CHA-YNEASA circuits, as switch based on modularity principle. The cytosensor is able to measure MUC1 positive breast cancer cells (MCF-7) with the LOD as low as 100 cells/mL. Excellent specificity for MUC1 negative cells, and good anti-interference capability in 10% fetal bovine serum (FBS) were observed by the cytosensor. Therefore, the proposed DNA biosensor is a sensitive, rapid, adaptative platform for detection of double-level biomarkers, offering novel strategy applied for clinical cancer diagnosis.


Assuntos
Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais , DNA de Neoplasias/química , Técnicas Eletroquímicas , Técnicas de Amplificação de Ácido Nucleico , Proteína Supressora de Tumor p53/análise , Humanos , Células MCF-7 , Proteína Supressora de Tumor p53/genética
3.
J Clin Pathol ; 73(3): 147-153, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31563883

RESUMO

AIMS: Characterising the factors responsible for metastatic triple-negative breast cancer (TNBC) is of significant importance, considering its high mortality rate and scant data. In this study, we evaluated the characteristics, clinical behaviour and role of biomarkers (androgen receptor (AR), oestrogen receptor beta (ERß) and p53) in metastatic TNBC. METHODS: Immunohistochemistry was performed for AR, ERß and p53 on 125 primary TNBCs with known metastasis and correlated with clinicopathological parameters and outcome. AR and p53 mRNA profiling was also carried out on 34 tumours from the same series and correlated with outcomes. RESULTS: In this cohort, grade 3 and pT2 tumours predominated. The most common site for metastasis was the lung and pleura (41, 32.8%), and 15 (12.0%) cases demonstrated metastasis in multiple sites. Among these, 92% of tumours metastasised without preceding local recurrences. Five- and ten-year overall survival (OS) rates were 27% and 7.2%, while 5- and 10- year survival rates after metastasis were 9.6% and 3.2% respectively. AR, ERß and p53 protein expressions were observed in 16%, 96.8% and 58.1% of tumours, respectively. A combinational phenotype of AR-ERß+p53+ tumours was associated with poorer OS (HR 1.543, 95%CI 1.030 to 2.310, p=0.035). Higher AR mRNA levels were significantly associated with favourable OS (p=0.015) and survival after metastasis (p=0.027). CONCLUSIONS: Metastatic TNBC harboured aggressive behaviour and displayed predominantly visceral metastasis with most metastatic events occurring without intervening local recurrences. A combinational phenotype of AR-ERß+p53+ was significantly associated with poorer OS.


Assuntos
Biomarcadores Tumorais/análise , Receptor beta de Estrogênio/análise , Receptores Androgênicos/análise , Neoplasias de Mama Triplo Negativas/química , Proteína Supressora de Tumor p53/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Receptores Androgênicos/genética , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/genética
4.
An Bras Dermatol ; 94(6): 698-703, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31789247

RESUMO

BACKGROUND: A skin field cancerization is a cutaneous area with subclinical changes resultant from chronic sun exposure, with a higher predisposition to development of pre-neoplastic and neoplastic lesions. So far, there are no well-defined objective parameters that can indicate their degree of activity. OBJECTIVES: To describe and compare morphometric aspects and expression of factors related to apoptosis and cell proliferation in actinic keratosis (AK), in both photoexposed and photoprotected epidermis. METHODS: A cross-sectional study of patients with actinic keratosis in the forearms, biopsied at two points: the actinic keratosis and the axillary region. The biopsies of the actinic keratosis, perilesional area, and axilla were evaluated through keratinocyte intraepithelial neoplasia (KIN), and immunohistochemistry of p53, survivin, and Ki67. Nuclear morphometry of basal layer cells was performed through digital image analysis: entropy, area, perimeter, Ra, fractal dimension, circularity, color intensity, and largest diameter. RESULTS: There were 13 patients included and 38 actinic keratosis biopsied. In morphometry, 1039 nuclei were analyzed, of which 228 represented axillary skin, 396 demonstrated actinic keratosis, and 415 represented the perilesional area to the actinic keratosis. There was a significant difference (p<0.05) in all variables tested for the topographies evaluated. A significant correlation was identified between nucellar morphometric elements, KIN, proliferation markers, and apoptosis. Joint patterns of p53, Ki67, and KIN discriminated the topographies sampled. STUDY LIMITATIONS: This was a cross-sectional study with a small number of patients. CONCLUSIONS: There are patterns of proliferation, resistance to apoptosis, and different cellular morphometrics between photoprotected skin and photoexposed skin. The joint expression of p53, Ki67, and KIN can characterize skin field cancerization activity.


Assuntos
Ceratose Actínica/patologia , Lesões Pré-Cancerosas/patologia , Pele/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biópsia , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Estudos Transversais , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Valores de Referência , Neoplasias Cutâneas/patologia , Estatísticas não Paramétricas , Survivina/análise , Proteína Supressora de Tumor p53/análise
5.
Braz Oral Res ; 33: e103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31778473

RESUMO

The immunoexpression of p16, p53, and Bax in oral tongue squamous cell carcinoma (OTSCC) in young and elderly patients is assessed based on clinical and morphological parameters. The sample consists of 60 OTSCC cases: 30 in young (age ≤ 45 years) and 30 in elderly (age ≥ 60 years) patients. Clinical (tumor size, regional node metastasis, distant metastasis, and clinical stage) and morphological (histological grade of malignancy) parameters were evaluated. Immunohistochemical quantitative analysis was performed using anti-p16, anti-p53, and anti-Bax antibodies. None of the evaluated proteins exhibited statistically significant differences between young and elderly patients (p>0.05). There was a significant association of p16 immunoexpression with clinical parameters in elderly patients. There were no associations of p53 and Bax with any of the clinico-morphological parameters. Correlations between p16 and Bax and between p53 and Bax immunoexpression were observed in young patients (r = 0.363; p = 0.048) and in elderly patients (r = 0.433; p = 0.017), respectively. In conclusion, the assessed proteins could not be used to determine differences in the biological behavior of OTSCC between young and elderly patients. Therefore, all proteins activated the pro-apoptotic pathway of OTSCC in both groups.


Assuntos
Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias da Língua/patologia , Proteína Supressora de Tumor p53/análise , Proteína X Associada a bcl-2/análise , Adulto , Fatores Etários , Idoso , Apoptose , Biomarcadores Tumorais/análise , Ciclo Celular , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Carga Tumoral
6.
Turk J Med Sci ; 49(5): 1547-1554, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652035

RESUMO

Background/aim: Nicotinamide N-methyltransferase (NNMT) is an enzyme that is overexpressed in malignancies. NNMT expression has not been previously studied in endometrial cancer (EC). Increased phospho-Akt (pAkt) levels in response to NNMT overexpression have been reported in in vitro studies of different cancer types. We assayed NNMT expression in primary and metastatic high-grade EC and investigated the relationship of NNMT with p53, pAkt, and survival. Materials and methods: NNMT, pAkt, and p53 expressions were assayed in 100 tissue samples of benign endometria, primary EC, and metastatic EC by immunohistochemistry. Results: The NNMT immunoreactivity score was significantly higher in primary high-grade EC than benign endometrial tissue (P = 0.001). NNMT expression in metastatic tissue was significantly higher than in primary cancer (P < 0.001). Metastatic stromal NNMT expression was significantly higher than that of the adjacent tumor and stroma adjacent to the primary tumor. p53 expression in the primary tumor showed a significant positive correlation with omental NNMT and pAkt expression. NNMT expression was also correlated with pAkt expression in metastatic tissue. NNMT overexpression in metastatic tissue was associated with decreased survival (P = 0.039). Conclusion: This study suggests that NNMT may promote cancer progression and that NNMT overexpression is associated with aberrant p53 expression, pAkt, and poor survival. NNMT's role in cancer progression could make it a target of EC therapy.


Assuntos
Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/mortalidade , Nicotinamida N-Metiltransferase/biossíntese , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/química , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Nicotinamida N-Metiltransferase/análise , Proteínas Proto-Oncogênicas c-akt/análise , Estudos Retrospectivos , Taxa de Sobrevida , Proteína Supressora de Tumor p53/análise
7.
Cancer Biomark ; 26(3): 281-289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31594208

RESUMO

BACKGROUND: Urothelial carcinoma of the bladder is a heterogeneous disease for which reliable prognostic molecular biomarkers have not been established. OBJECTIVE: To investigate the prognostic value of tumor-associated trypsin inhibitor (TATI) expression combined with p53 expression in bladder cancer patients who have undergone radical cystectomy. METHODS: Tissue microarrays from 110 patients were analyzed immunohistochemically for TATI and p53 protein expression. Complete clinical-pathological information and follow-up data were collected. Univariable Kaplan-Meier analysis and log-rank test were performed to assess the association between TATI and p53 expression patterns with clinical outcomes. Cox's proportional hazard analysis was performed to identify potential independent risk factors for predicting disease progression and evaluate the prognostic value of combining the expression of TATI and p53 on progression-free survival (PFS) and overall survival (OS). RESULTS: TATI expression was positively correlated with favorable differentiation of bladder cancer, and lower tumor stage. p53 expression was positively related to tumor stage, tumor grade, and lymph-node invasion. Univariate Kaplan-Meier analysis revealed significant differences between TATI-positive vs. TATI-negative and p53-positive vs. p53-negative patients, regarding PFS. Multivariate analysis showed that both TATI and p53 expression were independent factors for predicting disease progression. CONCLUSION: TATI expression patterns could enhance the prognostic value of p53 overexpression on progression.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células de Transição/mortalidade , Inibidor da Tripsina Pancreática de Kazal/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Bexiga Urinária/patologia , Idoso , Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Cistectomia , Progressão da Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida , Análise Serial de Tecidos , Inibidor da Tripsina Pancreática de Kazal/análise , Proteína Supressora de Tumor p53/análise , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
8.
BMC Complement Altern Med ; 19(1): 231, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462222

RESUMO

BACKGROUND: In Korea and China, asiasari radix (AR) is widely used as a traditional anti-inflammatory and analgesic agent. After its skin-regenerating and hair loss-preventing activities were identified, several types of AR extracts were used for aesthetic purposes. Nevertheless, the effect of ARE on various types of skin cancers was not fully studied yet. METHODS: In this study, we tested the effect of an ethanolic AR extract (ARE) on G361 human melanoma and HaCaT human keratinocyte cell lines. After ARE exposure, cell growth and the expression patterns of proteins and genes were monitored. RESULTS: The ARE-mediated cell growth inhibition was greater in G361 cells than in HaCaT cells due to differences in its cell growth regulation effects. Interestingly, ARE treatment induced caspase-3-mediated apoptosis in G361 cells, but not in HaCaT cells. Furthermore, ARE reduced the expression of p53 and p21 proteins in G361 cells, whereas it induced their expression in HaCaT cells. ARE induced cell death in G361 cells through the reactive oxygen species (ROS)-dependent regulation of p53 and p21 in G361 cells. Microarray analysis showed that ARE regulates Mouse double minute 2 homolog (MDM2) and CASP8 and FADD-like apoptosis regulator (CFLAR) gene expression in G361 and HaCaT cells differently. CONCLUSION: The treatment of ARE preferentially induces apoptosis in melanoma cells by the ROS-dependent differential regulation of p53 level. Therefore, ARE can be used as a new medicinal option for melanoma.


Assuntos
Apoptose/efeitos dos fármacos , Asarum/química , Melanoma/metabolismo , Extratos Vegetais/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular , Etanol , Humanos , Raízes de Plantas/química , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/análise
9.
Am J Surg Pathol ; 43(12): 1674-1681, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31393268

RESUMO

Supratentorial extraventricular ependymomas (STEEs) are relatively rare ependymomas, and their pathologic and genetic characteristics are still poorly understood. The aim of this study was to determine the histologic, immunohistochemical, and RELA fusion features, as well as to clarify in more detail the clinical courses of STEEs. Data from a total of 43 patients with STEEs was analyzed retrospectively. The status of RELA fusion was evaluated using fluorescence in situ hybridization. The expression levels of L1CAM, p65, cyclin D1, and p53 were assessed using immunohistochemistry. Progression-free survival and overall survival were calculated via Kaplan-Meier estimation using the log-rank test. Among all 43 STEEs, 65.1% (28/43) are positive for RELA fusion. Interestingly, almost half of the patients with RELA fusion-positive ependymomas are adults (13/28), and 89.3% (25/28) cases are anaplastic ependymomas, which suggests that RELA fusion testing is necessary in adults with STEEs. We investigated the immunohistochemical status of p65, L1CAM and CCND1 protein expression for their ability to predict RELA fusion status. RELA fusion-positive STEEs are frequently associated with expression of p65 (85.2%), L1CAM (85.2%), and CCND1 (81.5%). The accuracy of predicting RELA fusion status was much higher when the expression of p65 and L1CAM was combined, that is, when both were immunopositive. The status of RELA fusion, p53 overexpression, and extent of tumor resection are significantly associated with prognosis.


Assuntos
Biomarcadores Tumorais/genética , Ependimoma/genética , Fusão Gênica , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Supratentoriais/genética , Fator de Transcrição RelA/genética , Adolescente , Adulto , Biomarcadores Tumorais/análise , Biópsia , Criança , Pré-Escolar , Ciclina D1/análise , Progressão da Doença , Ependimoma/química , Ependimoma/patologia , Ependimoma/cirurgia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Molécula L1 de Adesão de Célula Nervosa/análise , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Supratentoriais/química , Neoplasias Supratentoriais/patologia , Neoplasias Supratentoriais/cirurgia , Fatores de Tempo , Fator de Transcrição RelA/análise , Proteína Supressora de Tumor p53/análise , Adulto Jovem
10.
Am J Surg Pathol ; 43(12): 1591-1599, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31335355

RESUMO

The PROMISE diagnostic algorithm, which uses p53, mismatch repair (MMR) protein immunohistochemistry, and DNA polymerase ε (POLE) exonuclease domain mutation testing, is a reliable surrogate of the molecular group in endometrial carcinoma. Its prognostic value has been validated in endometrial carcinoma and ovarian endometrioid carcinoma. Moreover, a similar prognostic grouping has been recently documented in endometrial clear cell carcinoma. Thus, we aimed to explore the role of these markers in ovarian clear cell carcinoma, another endometriosis-associated malignancy. A total of 90 cases were identified and confirmed after secondary review. Immunohistochemistry for p53, MLH1, MSH2, MSH6, and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. POLE mutational analysis was performed in 47 cases. Results were correlated with clinicopathologic variables including disease-free survival (DFS), overall survival, and disease-specific survival (DSS). Endometriosis was found in 67 (74%) cases. Six (7%) tumors were p53 abnormal, 82 (91%) were p53 normal, and 2 (2%) tumors had MMR deficiency (1 MSH6 loss and 1 MSH2/6 loss; both were p53 normal). Several POLE variants of unknown significance were detected, but no pathogenic mutations. The mean follow-up period was 43 months (median: 34, range: 1 to 189). Abnormal p53 status was associated with advanced Federation of Gynecology and Obstetrics stage, lymph node metastases, DFS and DSS (P<0.05, Fisher exact test). In univariate analysis, abnormal p53 and positive lymph node status had worse DFS, whereas bilaterality, surface involvement, and advanced stage were associated with worse DFS, overall survival and DSS (P<0.05, Cox regression). On multivariate analysis, only stage retained statistical association with survival. Using a molecular-based approach designed for endometrial carcinoma, most ovarian clear cell carcinomas fall into the copy-number-low molecular subgroup. However, a small but important subset has an abnormal p53 expression (copy-number-high group). This subset is associated with adverse features including extrapelvic disease, nodal metastases, and recurrence similar to endometrial and ovarian endometrioid cancer. Thus, testing for this marker has potential prognostic significance. The role of other markers in the PROMISE algorithm remains to be elucidated, as we found a low frequency of MMR abnormalities and no pathogenic POLE mutations in our series.


Assuntos
Biomarcadores Tumorais , Carcinoma/diagnóstico , Reparo de Erro de Pareamento de DNA , DNA Polimerase II/genética , Técnicas de Apoio para a Decisão , Mutação , Neoplasias Ovarianas/diagnóstico , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteína Supressora de Tumor p53/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma/enzimologia , Carcinoma/genética , Carcinoma/patologia , Análise Mutacional de DNA , Proteínas de Ligação a DNA/análise , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/análise , Estadiamento de Neoplasias , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco
11.
Medicine (Baltimore) ; 98(25): e16135, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232967

RESUMO

BACKGROUND: TP53 gene polymorphism could increase risks of several kinds of cancer. But it remained controversial whether TP53 gene codon72 polymorphism was associated with the susceptibility to prostate cancer. Thus, we conducted a meta-analysis that evaluated the association between TP53 gene codon72 polymorphism and prostate cancer risk. METHOD: A comprehensive research was performed from PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI) up to December 31, 2018. A random effect model was used to evaluate the effect of the outcome. The statistical analyses were performed with Review Manager 5.3.0 and Stata 14.0. The sensitivity analysis and publication bias tests were also performed to confirm the reliability of this meta-analysis. RESULTS: 22 studies included 3146 cases and 4010 controls were involved in this meta-analysis. Overall, no association was observed between TP53 gene codon72 polymorphism and prostate cancer risk (Arg vs Pro: odds ratio [OR] = 1.12, 95% confidence interval [CI] = 0.98-1.30; ArgArg vs ProPro: OR = 1.26, 95% CI = 0.90-1.75; ProPro vs ArgArg+ ArgPro: OR = 1.17, 95% CI = 0.86-1.57; ArgPro+ ProPro vs ArgArg: OR = 1.21, 95% CI = 0.97-1.51). Subgroup analyses, based on ethnicity, source of control and Hardy-Weinberg equilibrium (HWE) status, showed consistent results. CONCLUSION: The meta-analysis we performed showed that there was no association of TP53 gene codon72 polymorphism with prostate cancer risk.


Assuntos
Neoplasias da Próstata/diagnóstico , Medição de Risco/normas , Proteína Supressora de Tumor p53/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Reprodutibilidade dos Testes , Medição de Risco/métodos , Proteína Supressora de Tumor p53/análise
12.
Mikrochim Acta ; 186(7): 424, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31187253

RESUMO

Phosphorylated p53 proteins are biomarkers with clinical utility for early diagnosis of cancer, but difficult to quantify. An inductively coupled plasma mass spectrometry (ICP-MS) based immunoassay is described here that uses uniform lanthanide nanoparticles (NPs) as elemental tags for the simultaneous determination of two phosphorylated p53 proteins. Apoferritin templated europium (Eu) phosphate (AFEP) NPs and apoferritin templated lutetium (Lu) phosphate (AFLP) NPs with 8 nm in diameter were used to label two phosphorylated p53 proteins at serine 15 and serine 392 sites (p-p5315 and p-p53392), respectively. The assay has a sandwich format, and p-p5315 and p-p53392 were first captured and then recognized by AFEP and AFLP NPs labelled antibodies, respectively. The Eu and Lu were then released from the immune complexes under acidic condition for ICP-MS measurement. The limits of detection for p-p5315 and p-p53392 are 200 and 20 pg·mL-1, with linear ranges of 0.5-20 and 0.05-20 ng·mL-1, respectively. The method was further applied to study the response of p-p5315 and p-p53392 in SCC-7 cells exposed to the natural carcinogen arsenite. A significant up-regulation of p-p5315 and p-p53392 can be observed when cells were exposed to arsenite at 5 µmol·L-1 level for 24 h. Graphical abstract Schematic presentation of the ICP-MS immunoassay using apoferritin templated europium (III) and lutetium (III) phosphate nanoparticles as labels for the simultaneous determination of two phosphorylated p53 proteins. Europium (Eu) phosphate nanoparticles (blue) and lutetium (Lu) phosphate nanoparticles (pink) were synthesized in the size-restricted cavity of apoferritin. They were further coupled with antibodies to prepare Eu and Lu labelled probes for p-p5315 (blue) and p-p53392 (pink), respectively. After formation of a a sandwich, the labelled Eu and Lu were dissociated in acid and then introduced to ICP-MS for the simultaneous determination of two phosphorylated p53 proteins p-p5315 (blue) and p-p53392 (pink).


Assuntos
Anticorpos Imobilizados/imunologia , Biomarcadores Tumorais/análise , Imunoensaio/métodos , Nanopartículas Metálicas/química , Fosfatos/química , Proteína Supressora de Tumor p53/análise , Apoferritinas/química , Biomarcadores Tumorais/química , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Európio/química , Humanos , Limite de Detecção , Lutécio/química , Espectrometria de Massas/métodos , Fosforilação , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/imunologia
13.
Analyst ; 144(13): 3959-3966, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31134974

RESUMO

MDM2 can mediate the degradation of tumor suppressor p53 through an autoregulatory feedback loop, in which MDM2 abolishes wild-type p53 function and accelerates malignant transformation. However, the incorporation of MDM2 antagonist Nutlin-3 could reactivate the transcriptional activity of p53, up-regulate caspase-3, and induce apoptosis. In this work, the simultaneous and label-free monitoring of p53-MDM2 complex and caspase-3 levels in cancer cells before and after Nutlin-3 treatment was conducted using dual-channel surface plasmon resonance (SPR). The p53-MDM2 complex was captured in one fluidic channel covered with consensus double-stranded (ds)-DNA, while the other channel was pre-immobilized with caspase-3-specific biotinylated DEVD-containing peptides. To amplify the SPR signals, the attachment of streptavidin (SA)-conjugated anti-MDM2 antibody in both channels was achieved. The signal diversity before and after Nutlin-3 treatment is indicative of the difference in the levels of the intracellular p53-MDM2 complex and caspase-3. The limit of detection for p53-MDM2 and caspase-3 down to 4.54 pM and 0.03 ng mL-1, respectively, was attained. Upon treatment with Nutlin-3, MCF-7 cancer cells with wild-type p53 showed decreased expression of the p53-MDM2 complex and an increased caspase-3 level, while MDA-MB-231 cancer cells with mutant p53 exhibited an elevated caspase-3 level and unchanged p53-MDM2 complex expression. The apoptosis of MCF-7 and MDA-MB-231 cancer cells upon Nutlin-3 treatment follows a p53-dependent and a p53-independent pathway, respectively. The proposed method is sensitive, selective and label-free, holding great promise for assaying intracellular p53-MDM2 complex and caspase-3 levels and differentiating Nutlin-3-mediated p53-dependent or p53-independent apoptotic pathways.


Assuntos
Caspase 3/análise , Imidazóis/farmacologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/análise , Ressonância de Plasmônio de Superfície/métodos , Proteína Supressora de Tumor p53/análise , Apoptose/efeitos dos fármacos , Biotina/química , Caspase 3/química , Caspase 3/metabolismo , Linhagem Celular Tumoral , DNA/química , Relação Dose-Resposta a Droga , Humanos , Limite de Detecção , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptavidina/química , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo
14.
Int Braz J Urol ; 45(4): 671-678, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31136111

RESUMO

INTRODUCTION: Penile cancer (PC) occurs less frequently in Europe and in the United States than in South America and parts of Africa. Lymph node (LN) involvement is the most important prognostic factor, and inguinal LN (ILN) dissection can be curative; however, ILN dissection has high morbidity. A nomogram was previously developed based on clinicopathological features of PC to predict ILN metastases. Our objective was to conduct an external validation of the previously developed nomogram based on our population. MATERIALS AND METHODS: We included men with cN0 ILNs who underwent ILN dissection for penile carcinoma between 2000 and 2014. We performed external validation of the nomogram considering three different external validation methods: k-fold, leave-oneout, and bootstrap. We also analyzed prognostic variables. Performance was quantified in terms of calibration and discrimination (receiver operator characteristic curve). A logistic regression model for positive ILNs was developed based on clinicopathological features of PC. RESULTS: We analyzed 65 men who underwent ILN dissection (cN0). The mean age was 56.8 years. Of 65 men, 24 (36.9%) presented with positive LNs. A median 21 ILNs were removed. Considering the three different methods used, we concluded that the previously developed nomogram was not suitable for our sample. CONCLUSIONS: In our study, the previously developed nomogram that was applied to our population had low accuracy and low precision for correctly identifying patients with PC who have positive ILNs.


Assuntos
Carcinoma/patologia , Canal Inguinal/patologia , Linfonodos/patologia , Metástase Linfática/diagnóstico , Nomogramas , Neoplasias Penianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Modelos Logísticos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Curva ROC , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Estatísticas não Paramétricas , Proteína Supressora de Tumor p53/análise
15.
Sao Paulo Med J ; 137(1): 33-38, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31116268

RESUMO

BACKGROUND: There are cases of colorectal tumors that, although small, show more aggressive evolution than large tumors. This motivated us to study whether there are any proteins capable of alerting about these changes. The aim here was to correlate the immunoexpression of the TS, p53, COX2, EGFR, MSH6 and MLH1 biomarkers in tumors in patients with colorectal adenocarcinoma, with the degree of cell differentiation, tumor staging and clinical-pathological prognostic factors. DESIGN AND SETTING: Retrospective observational study at a public tertiary-level hospital. METHODS: We analyzed tissue-microarray paraffin blocks of tumor tissues that had been resected from 107 patients. We used Fisher's exact test to study associations between tumor differentiation/staging and the immunoexpression of biomarkers. We also used Kaplan-Meier estimation, the log-rank test and the adjusted Cox regression model to investigate the patients' overall survival (in months) according to biomarkers and disease-free interval. RESULTS: The degree of tumor differentiation and tumor staging were not associated with the biomarkers, except in cases of patients in stages III or IV, in which there was a correlation with MLH1 expression (P=0.021). Patient survival and disease-free interval were not associated with the biomarkers. CONCLUSION: There were no associations between the degree of tumor differentiation, staging, length of survival or disease-free interval and the immunoexpression of the TS, p53, COX2, EGFR or MSH6 tumor markers. In advanced cases of colorectal adenocarcinoma (stages III and IV), there was a higher percentage of MLH1-negative results.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclo-Oxigenase 2/análise , Proteínas de Ligação a DNA/análise , Receptores ErbB/análise , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/análise , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Valores de Referência , Estudos Retrospectivos , Timidilato Sintase/análise , Análise Serial de Tecidos , Proteína Supressora de Tumor p53/análise , Adulto Jovem
16.
Am J Surg Pathol ; 43(8): 1083-1091, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31107721

RESUMO

Telomere alterations represent one of the major molecular changes in the development of human cancer. We have previously reported that telomere lengths in most serous tubal intraepithelial carcinomas (STIC) are shorter than they are in ovarian high-grade serous carcinomas (HGSC) or in normal-appearing fallopian tube epithelium from the same patients. However, it remains critical to determine if similar telomere alterations occur in TP53-mutated but histologically unremarkable "p53 signature" lesions, as well as incidental STICs without concurrent HGSC. In this study, we quantitatively measured telomere lengths by performing telomere-specific fluorescence in situ hybridization in conjunction with p53 immunolabeling in 15 p53 signatures and 30 incidental STICs without concurrent HGSC. We compared these new results with our previous data in paired STICs and concurrent HGSCs. We found that most p53 signatures (80%) and incidental STICs without HGSC (77%) exhibited significant telomere shortening compared with adjacent normal-appearing fallopian tube epithelium (P<0.01). Interestingly, however, p53 signatures and incidental STICs without HGSC displayed longer telomeres and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC (P<0.001). These findings indicate that telomere shortening occurs in p53 signatures, the earliest precancer lesion. Moreover, incidental STICs without concurrent HGSC are indeed similar to p53 signatures as they have less telomere shortening and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma in Situ/genética , Neoplasias das Tubas Uterinas/genética , Neoplasias Císticas, Mucinosas e Serosas/genética , Encurtamento do Telômero , Telômero/genética , Transcriptoma , Proteína Supressora de Tumor p53/genética , Biomarcadores Tumorais/análise , Carcinoma in Situ/química , Carcinoma in Situ/patologia , Carcinoma in Situ/cirurgia , Neoplasias das Tubas Uterinas/química , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Císticas, Mucinosas e Serosas/química , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/cirurgia , Proteína Supressora de Tumor p53/análise
17.
Mod Pathol ; 32(8): 1095-1105, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30932019

RESUMO

The switch from in situ to invasive tumor growth represents a crucial stage in the evolution of lung adenocarcinoma. However, the biological understanding of this shift is limited, and 'Noguchi Type C' tumors, being early lung adenocarcinomas with mixed in situ and invasive growth, represent those that are highly valuable in advancing our understanding of this process. All Noguchi Type C adenocarcinomas (n = 110) from the LATTICE-A cohort were reviewed and two patterns of in situ tumor growth were identified: those deemed likely to represent a true shift from precursor in situ to invasive disease ('Noguchi C1') and those in which the lepidic component appeared to represent outgrowth of the invasive tumor along existing airspaces ('Noguchi C2'). Overall Ki67 fraction was greater in C2 tumors and only C1 tumors showed significant increasing Ki67 from in situ to invasive disease. P53 positivity was acquired from in situ to invasive disease in C1 tumors but both components were positive in C2 tumors. Likewise, vimentin expression was increased from in situ to invasive tumor in C1 tumors only. Targeted next generation sequencing of 18 C1 tumors identified four mutations private to the invasive regions, including two in TP53, while 6 C2 tumors showed no private mutations. In the full LATTICe-A cohort, Ki67 fraction classified as either less than or greater than 10% within the in situ component of lung adenocarcinoma was identified as a strong predictor of patient outcome. This supports the proposition that tumors of all stages that have 'high grade' in situ components represent those with aggressive lepidic growth of the invasive clone. Overall these data support that the combined growth of Noguchi C tumors can represent two differing biological states and that 'Noguchi C1' tumors represent the genuine biological shift from in situ to invasive disease.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinoma in Situ/patologia , Proliferação de Células , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/química , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma in Situ/química , Carcinoma in Situ/genética , Carcinoma in Situ/cirurgia , Feminino , Humanos , Antígeno Ki-67/análise , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/genética , Vimentina/análise
18.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925722

RESUMO

Temozolomide (TMZ) is an alkylating agent used in the treatment of high-grade malignant glioma, notably glioblastoma multiforme, the most aggressive form of brain cancer. The drug induces a dozen DNA methylation adducts, including O6-methylguanine (O6MeG), which is the most toxic primary DNA lesion as it causes the formation of DNA double-strand breaks (DSBs) that trigger apoptosis. In p53 wild-type cells, TMZ activates p-p53ser15 and p-p53ser46, which have opposing dual functions regulating survival and death, respectively. Since the use of TMZ in a therapeutic setting is limited because of its side effects, the question arises as to the existence of threshold doses that activate the death pathway and start apoptosis. To determine whether there is a threshold for the TMZ-induced DNA damage response and exploring the factors regulating the switch between p53 dependent survival and death, the glioblastoma lines LN-229 (deficient in MGMT) and LN-229MGMT (stably transfected with MGMT) were exposed to different doses of TMZ. p53 protein expression and phosphorylation levels of p-p53ser15 and p-p53ser46 were determined by Western blotting. Also, apoptosis, senescence and autophagy levels were checked after different doses of TMZ. The results show that pro-survival p-p53ser15 and pro-death p-p53ser46 were induced by O6MeG in a specific dose- and time-dependent manner. p-p53ser15 was an early response while p-p53ser46 was activated at later times following treatment. Unexpectedly, the dose-response curves for total p53, p-p53ser15 and p-p53ser46 were linear, without an obvious threshold. O6MeG induces apoptosis late after treatment as a linear function of TMZ dose. This was observed for both p53 proficient LN-229 and p53 lacking LN-308 cells. A linear dose-response after TMZ was also observed for senescence and autophagy as well as γH2AX, an indicator of DSBs that are considered to be the downstream trigger of apoptosis, senescence and autophagy. LN-229MGMT cells were highly resistant to all measured endpoints because of repair of the critical primary lesion. Although LN-308 were less responsive than LN-229 to TMZ, they displayed the same TMZ-induced DSB level. The observed linear dose-responses are not compatible with the view that low DNA damage level evokes survival while high damage level activates death functions. The data bear important therapeutic implications as they indicate that even low doses of TMZ may elicit a cytotoxic response. However, since O6MeG triggers apoptosis, senescence and autophagy in the same dose range, it is likely that the accumulation of senescent cells in the population counteracts the killing effect of the anticancer drug.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Temozolomida/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Fosforilação/efeitos dos fármacos , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/metabolismo
19.
Curr Gastroenterol Rep ; 21(4): 14, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30868278

RESUMO

PURPOSE OF REVIEW: Despite gastrointestinal societal recommendations for endoscopic screening and surveillance of Barrett's esophagus, the rates of esophageal adenocarcinoma continue to rise. Furthermore, this current practice is costly to patients and the medical system without clear evidence of reduction in cancer mortality. The use of biomarkers to guide screening, surveillance, and treatment strategies might alleviate some of these issues. RECENT FINDINGS: Incredible advances in biomarker identification, biomarker assays, and minimally-invasive modalities to acquire biomarkers have shown promising results. We will highlight recently published, key studies demonstrating where we are with using biomarkers for screening and surveillance in clinical practice, and what is on the horizon regarding novel non-invasive and minimally invasive methods to acquire biomarkers. Proof-of principle studies using in silico models demonstrate that biomarker-guided screening, surveillance, and therapeutic intervention strategies can be cost-effective and can reduce cancer deaths in patients with Barrett's esophagus.


Assuntos
Adenocarcinoma/diagnóstico , Esôfago de Barrett/diagnóstico , Biomarcadores Tumorais/análise , Detecção Precoce de Câncer/métodos , Neoplasias Esofágicas/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , DNA de Neoplasias/análise , Esofagoscopia/métodos , Humanos , Proteína Supressora de Tumor p53/análise
20.
Dig Dis Sci ; 64(5): 1089-1097, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30911864

RESUMO

Risk stratification of patients with Barrett's esophagus (BE) presently relies on the histopathologic grade of dysplasia found in esophageal biopsies, which is limited by sampling error and inter-pathologist variability. p53 immunostaining of BE biopsies has shown promise as an adjunct tool but is not recommended by American gastroenterology societies, who cite insufficient evidence of its prognostic value. We have conducted a systematic review and meta-analyses to clarify this value. We searched for studies that: (1) used immunohistochemistry to assess p53 expression in esophageal biopsies of BE patients and (2) reported subsequent neoplastic progression. We performed separate meta-analyses of case-control studies and cohort studies. We identified 14 relevant reports describing 8 case-control studies comprising 1435 patients and 7 cohort studies comprising 582 patients. In the case-control study meta-analysis of the risk of neoplasia with aberrant p53 expression, the fixed- and random-effect estimates of average effect size with aberrant p53 expression were OR 3.84, p < .001 (95% CI 2.79-5.27) and OR 5.95, p < .001 (95% CI 2.68-13.22), respectively. In the cohort study meta-analysis, the fixed- and random-effect estimates of average effect size were RR = 17.31, p < .001 (95% CI 9.35-32.08) and RR = 14.25, p < .001 (95% CI 6.76-30.02), respectively. Separate meta-analyses of case-control and cohort studies of BE patients who had baseline biopsies with p53 immunostaining revealed consistent, strong, and significant associations between aberrant p53 immunostaining and progression to high-grade dysplasia or esophageal adenocarcinoma. These findings support the use of p53 immunostaining as an adjunct to routine clinical diagnosis for dysplasia in BE patients.


Assuntos
Adenocarcinoma/metabolismo , Esôfago de Barrett/metabolismo , Biomarcadores Tumorais/biossíntese , Neoplasias Esofágicas/metabolismo , Coloração e Rotulagem/métodos , Proteína Supressora de Tumor p53/biossíntese , Adenocarcinoma/diagnóstico , Esôfago de Barrett/diagnóstico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/imunologia , Estudos de Casos e Controles , Progressão da Doença , Neoplasias Esofágicas/diagnóstico , Humanos , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/imunologia
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