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1.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206291

RESUMO

Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete (MUC2) and incomplete (MUC2, MUC5AC, and MUC6) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and MUC6 in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy.


Assuntos
Neoplasias Gástricas/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer , Fator de Transcrição GATA6/análise , Fator de Transcrição GATA6/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Intestinos , Metaplasia/diagnóstico , Metaplasia/genética , Metaplasia/metabolismo , Mucina-5AC/análise , Mucina-5AC/genética , Mucina-2/análise , Mucina-2/genética , Mucina-6/análise , Mucina-6/genética , Mutação , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/genética
2.
Virchows Arch ; 479(2): 305-315, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33682013

RESUMO

Differentiated vulvar intraepithelial neoplasia (dVIN) is a premalignant lesion that is known to progress rapidly to invasive carcinoma. Accurate histological diagnosis is therefore crucial to allow appropriate treatment. To identify reliable diagnostic features, we evaluated the inter-observer agreement in the histological assessment of dVIN, among a bi-national, multi-institutional group of pathologists. Two investigators from Erasmus MC selected 36 hematoxylin-eosin-stained glass slides of dVIN and no-dysplasia, and prepared a list of 15 histological features of dVIN. Nine participating pathologists (i) diagnosed each slide as dVIN or no-dysplasia, (ii) indicated which features they used for the diagnosis, and (iii) rated these features in terms of their diagnostic usefulness. Diagnoses rendered by > 50% participants were taken as the consensus (gold standard). p53-immunohistochemistry (IHC) was performed for all cases, and the expression patterns were correlated with the consensus diagnoses. Kappa (ĸ)-statistics were computed to measure inter-observer agreements, and concordance of the p53-IHC patterns with the consensus diagnoses. For the diagnosis of dVIN, overall agreement was moderate (ĸ = 0.42), and pair-wise agreements ranged from slight (ĸ = 0.10) to substantial (ĸ = 0.73). Based on the levels of agreement and ratings of usefulness, the most helpful diagnostic features were parakeratosis, cobblestone appearance, chromatin abnormality, angulated nuclei, atypia discernable under × 100, and altered cellular alignment. p53-IHC patterns showed substantial concordance (ĸ = 0.67) with the consensus diagnoses. Histological interpretation of dVIN remains challenging with suboptimal inter-observer agreement. We identified the histological features that may facilitate the diagnosis of dVIN. For cases with a histological suspicion of dVIN, consensus-based pathological evaluation may improve the reliability of the diagnosis.


Assuntos
Carcinoma in Situ/patologia , Diferenciação Celular , Neoplasias Vulvares/patologia , Bélgica , Biomarcadores Tumorais/análise , Biópsia , Carcinoma in Situ/química , Inibidor p16 de Quinase Dependente de Ciclina/análise , Feminino , Humanos , Imuno-Histoquímica , Países Baixos , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Proteína Supressora de Tumor p53/análise , Neoplasias Vulvares/química
3.
FASEB J ; 35(3): e21351, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33570788

RESUMO

Autophagy plays an important role in the normal development and function of trophoblast cells and is precisely regulated during pregnancy. Dysregulated autophagy contributes to the abnormal proliferation of trophoblasts, which is closely related to the occurrence of pregnancy-related diseases. Placenta specific 8 (PLAC8, Onzin) is a multifaceted protein proven to promote autophagy and potentiate various tumor progression. Its role in trophoblasts remains elusive. In our present study, PLAC8 expression was detected in tissues of first-trimester placentas (n = 5), term placentas (n = 5), choriocarcinoma (n = 5), and placental site trophoblastic tumor (n = 5). PLAC8 expression was increased in gestational neoplasms compared with normal pregnancies. mCherry-EGFP-LC3B reporter and transmission electron microscopy confirmed PLAC8 promoted the autophagic flux of human trophoblast cells. Both gain-of-function and loss-of-function experiments demonstrated PLAC8-regulated autophagy-related genes, including ATG5, ATG12, and Beclin-1. In addition, our data showed that PLAC8 co-localized with p53 and promoted its degradation, and p53 re-expression partially abrogated the PLAC8-induced autophagy activity. Furthermore, the overexpression of PLAC8 promoted cell viability and proliferation, acting as a protective mechanism of trophoblasts against the cytotoxicity of etoposide (VP-16). Such a phenomenon was effectively abrogated by autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ). In conclusion, PLAC8-induced autophagy to promote the proliferation of trophoblasts. This study provided insights into the mechanism of PLAC8-induced autophagy in trophoblasts, which is significant for a wide range of gestational diseases and may contribute to developing novel treatment strategies for trophoblastic diseases.


Assuntos
Autofagia/fisiologia , Proteínas/fisiologia , Trofoblastos/fisiologia , Adulto , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Doença Trofoblástica Gestacional/química , Humanos , Gravidez , Proteínas/análise , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/metabolismo
4.
Comput Biol Chem ; 92: 107457, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33610131

RESUMO

The global incidence of breast invasive carcinoma (BRIC) has risen significantly in recent years, so it is important to identify the novel biomarkers for the early detection and treatment of BRIC. The role of the TP53 gene is well studied in the pathogenesis of BRIC but still, observations are conflicting. Therefore, this study was initiated to have a consolidated overview of TP53 contributions in the BRIC initiation and progression by analyzing its mutatome, expression variations, promoter methylation level, clinical outcome, and drug sensitivity analysis in BRIC using cBioPortal, UALCAN, KM plotter, and CCLE GDSC toolkit database. Mutatome analysis revealed that TP53 was mutated in 30 % BRIC cases and among all the noted mutations, missense and truncation mutation were noticed as the most frequent mutations and thought to be involved in the up-regulation of TP53 expression. TP53 transcription, translation, and promoter methylation levels in BRIC patients of various clinicopathological features were high relative to the normal controls. Kaplan Meier overall survival (OS) analysis revealed a good prognostic value of TP53 overexpression for the survival in BRIC patients. Moreover, TP53 overexpression was found to alter the effectiveness of various drugs used in the chemotherapy of BRIC. Collectively, our findings suggested that TP53 might be a potential diagnostic and prognostic marker for the survival in BRIC patients of various clinicopathological features.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Proteína Supressora de Tumor p53/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Adulto Jovem
5.
Dermatol Ther ; 34(2): e14817, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33497503

RESUMO

Seborrheic keratosis (SK), actinic keratosis (AK), and Bowen's disease (BD) are squamoproliferative disorders of the skin. Histologically, they may mimic each other and therefore, they might be misinterpreted, especially in small samples. The aim of this study is to clarify the expression of p63, p16, and p53 proteins in SK, AK, and BD and evaluate the efficacy of these markers in order to distinguish between the aforementioned lesions. A total of 46 cases were collected (15 SK, 16 AK, and 15 BD) and stained for p63, p16, and p53. The stain intensity and the cell distribution labeling were scored and then analyzed by SPSS software. All cases of BD which became positive for p53 revealed basal keratinocytes sparing. Instead, all or nearly all basal keratinocytes in AK cases were positive for this marker. These were also seen in p16 staining results and they were between AK and BD (P = .024). Our study demonstrates p16 and p53 are useful markers in separating AK and BD according to basal keratinocytes involvement and sparing, respectively.


Assuntos
Doença de Bowen , Inibidor p16 de Quinase Dependente de Ciclina/análise , Ceratose Actínica , Ceratose Seborreica , Neoplasias Cutâneas , Fatores de Transcrição/análise , Proteína Supressora de Tumor p53/análise , Proteínas Supressoras de Tumor/análise , Doença de Bowen/diagnóstico , Humanos , Imuno-Histoquímica , Ceratose Actínica/diagnóstico , Ceratose Seborreica/diagnóstico , Neoplasias Cutâneas/diagnóstico
6.
Virchows Arch ; 478(3): 527-534, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32815035

RESUMO

Hibernoma is a rare benign adipocytic tumor composed of a proliferation of brown and white fat cells varying in their proportions. The tumor may also contain fat cells resembling lipoblasts, which makes it difficult to distinguish it from atypical lipomatous tumor/well differentiated liposarcoma (ALT/WDLS). Although nuclear expressions of murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) are widely used as immunohistochemical surrogate markers for ALT/WDLS, the utility of these proteins in distinguishing between hibernoma and ALT/WDLS still remains to be elucidated. We evaluated immunohistochemical expressions of MDM2 and CDK4 in 10 hibernomas expressing uncoupling protein-1 (UCP-1), a mitochondrial protein transporter consistently expressed in brown fat cells, and lacking MDM2 gene amplification, which was analyzed by fluorescence in situ hybridization (FISH). In contrast to the data previously obtained, nuclear expression of MDM2 was observed in 100% (10/10 cases) of the hibernomas irrespective of the proportion of brown fat cells, whereas no cases were positive for CDK4. The tumors also showed almost concurrent expression of p53 (in 9/10 cases) and ubiquitin-specific-processing protease 7 (USP7) (in 10/10 cases), which deubiquitinates and stabilizes MDM2, potentially resulting in its nuclear expression without MDM2 gene amplification. MDM2 expression may thus be a diagnostic pitfall for hibernoma particularly in differentiating it from ALT/WDLS.


Assuntos
Adipócitos/química , Biomarcadores Tumorais/análise , Núcleo Celular/química , Lipoma/química , Proteínas Proto-Oncogênicas c-mdm2/análise , Adipócitos/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Núcleo Celular/patologia , Quinase 4 Dependente de Ciclina/análise , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lipoma/genética , Lipoma/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/análise , Peptidase 7 Específica de Ubiquitina/análise , Proteína Desacopladora 1/análise , Adulto Jovem
7.
Bioelectrochemistry ; 137: 107647, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32971485

RESUMO

In this work, we fabricated a novel sandwich-type electrochemical immunosensor for quantitative and ultra-sensitive determination of tumor suppressor protein p53 by signal amplification strategy. Conductive polymers poly (3, 4-ethylenedioxythiophene): polystyrenesulfonate (PEDOT:PSS) has significantly effect on enhancing charge transfer and markedly increases the sensitivity of electrochemical immunosensing. Gold nanoparticles (AuNPs) as high conductivity nanocarriers were also used to capture monoclonal antibodies (Ab1) due to their large specific surface areas. In addition, pH responsive zeolitic imidazolate framework (ZIF-8) was used to load the redox probe 2, 3-diaminophenazine (DAP) and the secondary antibodies (Ab2) to form a sensitive-type ZIF-8-DAP-Ab2 immunoprobe. After the sandwich-type immunoassay with the free p53 protein, with the release of probe DAP after the electrochemical signal amplificated by PEDOT:PSS and AuNPs, the ultra-sensitive and quantitative determination of p53 protein was realized with working range of 1-120 ng mL-1 and low detection limit of 0.09 ng mL-1. Besides, the fabricated electrochemical immunosensor exhibited good recovery, high sensitivity, reliability, and selectivity.


Assuntos
Técnicas Eletroquímicas/instrumentação , Imunoensaio/instrumentação , Proteína Supressora de Tumor p53/análise , Ouro/química , Humanos , Limite de Detecção , Nanopartículas Metálicas/química , Microscopia de Força Atômica , Polímeros/química , Reprodutibilidade dos Testes
8.
Laryngoscope ; 131(7): 1522-1527, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33369763

RESUMO

OBJECTIVE: This is an ancillary study of a multi-institutional randomized non-inferiority phase III trial of accelerated fractionation (AF) versus standard fractionation (SF) radiation therapy for T1-2N0M0 glottic cancer (JCOG0701). Biopsy specimens of tumors from the patients enrolled in the JCOG0701 are collected and the association between clinical outcomes and histopathologic features such as expression of epithelial cell adhesion molecule (EpCAM), p53, and p16 were investigated. METHODS: Five slices of undyed slides from biopsy specimens were sent to the National Cancer Center Hospital and all the specimens were assessed for the expression of EpCAM, p53, and p16. The primary objective was to investigate the association between 3-year progression-free survival (PFS) and expression of EpCAM, p53, and p16. RESULTS: A total of 88 out of 370 patients were enrolled in this ancillary study. The 3-year PFS for tumors with strong expression of EpCAM was 70.6% (95% CI 43.1%-86.6%), while that of tumors without strong expression of EpCAM was 77.5% (95% CI 65.9%-85.5%) with no remarkable difference between groups (P = .67). Likewise, there was no significant difference in 3-year PFS between tumors regardless of p53 or p16 status. However, in a subgroup analysis for 17 patients with a strong expression of EpCAM, AF showed better 3-year PFS than SF (100% vs 54.5%, P = .07). CONCLUSIONS: From the current study, it could not be concluded that EpCAM, p16, and p53 were prognostic factors for early-stage glottic cancer after primary radiation therapy. AF might be an appropriate fractionation for tumors with a strong expression of EpCAM. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1522-1527, 2021.


Assuntos
Biomarcadores Tumorais/análise , Fracionamento da Dose de Radiação , Glote/patologia , Neoplasias Laríngeas/radioterapia , Idoso , Biomarcadores Tumorais/metabolismo , Biópsia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Progressão da Doença , Molécula de Adesão da Célula Epitelial/análise , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Humanos , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Intervalo Livre de Progressão , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/metabolismo
9.
Comput Biol Chem ; 90: 107427, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33360419

RESUMO

Breast cancer therapy with classical chemotherapy is unable to eradicate breast cancer stem cells (BCSCs). Loss of p53 function causes growth and differentiation in cancer stem cells (CSCs); therefore, p53-targeted compounds can be developed for BCSCs-targeted drugs. Previously, hesperidin (HES), a citrus flavonoid, showed anticancer activities and increased efficacy of chemotherapy in several types of cancer in vitro and in vivo. This study was aimed to explore the key protein and molecular mechanism of hesperidin in the inhibition of BCSCs using bioinformatics and in vitro study. Bioinformatics analysis revealed about 75 potential therapeutic target proteins of HES in BCSCs (TH), in which TP53 was the only direct target protein (DTP) with a high degree score. Furthermore, the results of GO enrichment analysis showed that TH was taken part in the biological process of regulation of apoptosis and cell cycle. The KEGG pathway enrichment analysis also showed that TH is involved in several pathways, including cell cycle, p53 signaling pathway. In vitro experiment results showed that HES inhibited cell proliferation, mammosphere, and a colony formation, and migration in on MCF-7 3D cells (mammospheres). HES induced G0/G1 cell cycle arrest and apoptosis in MCF-7 cells 3D. In addition, HES treatment reduced the mRNA level of p21 but increased the mRNA level of cyclin D1 and p53 in the mammosphere. HES inhibits BCSCs in mammospheres. More importantly, this study highlighted p53 as a key protein in inhibition of BCSCs by HES. Future studies on the molecular mechanism are needed to validate the results of this study.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Hesperidina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Mapas de Interação de Proteínas , Proteína Supressora de Tumor p53/análise , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Hesperidina/química , Humanos , Células MCF-7 , Estrutura Molecular , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Sensors (Basel) ; 20(21)2020 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-33171594

RESUMO

The concentration of wild-type tumour suppressor p53wt in cells and blood has a clinical significance for early diagnosis of some types of cancer. We developed a disposable, label-free, field-effect transistor-based immunosensor (BioFET), able to detect p53wt in physiological buffer solutions, over a wide concentration range. Microfabricated, high-purity gold electrodes were used as single-use extended gates (EG), which avoid direct interaction between the transistor gate and the biological solution. Debye screening, which normally hampers target charge effect on the FET gate potential and, consequently, on the registered FET drain-source current, at physiological ionic strength, was overcome by incorporating a biomolecule-permeable polymer layer on the EG electrode surface. Determination of an unknown p53wt concentration was obtained by calibrating the variation of the FET threshold voltage versus the target molecule concentration in buffer solution, with a sensitivity of 1.5 ± 0.2 mV/decade. The BioFET specificity was assessed by control experiments with proteins that may unspecifically bind at the EG surface, while 100pM p53wt concentration was established as limit of detection. This work paves the way for fast and highly sensitive tools for p53wt detection in physiological fluids, which deserve much interest in early cancer diagnosis and prognosis.


Assuntos
Técnicas Biossensoriais , Imunoensaio , Proteína Supressora de Tumor p53/análise , Tampões (Química) , Eletrodos , Ouro , Humanos , Transistores Eletrônicos
11.
Biomed Res Int ; 2020: 5389731, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029515

RESUMO

Introduction: Freezing of ovarian tissue is used for preservation of fertility. The freezing-thawing process is accompanied by oxidative stress and induction of apoptosis. Apoptosis is a complex process that has been studied in animal models. The present study was aimed at investigating the effect of selenium on suppression of apoptosis during vitrification-thawing process of mice ovary via studying expression of apoptosis-related genes, and also, we aimed to design statistical models for the roles of single genes and gene-gene interactions in suppression of apoptosis. Methods: A total of 10 right ovary samples from 10 mice were randomly divided into two groups of selenium treatment (at dose 5 µg/ml sodium selenite, through adding to the media) and control group. Vitrification-thawing process was done according to the existed protocols. Real-time PCR was used for gene expression study. The apoptosis gene profile included P53, Bax, Fas, and Bcl-2. General linear model was applied to study single gene associations and gene-gene interactions. Results: From the studied genes, P53 showed a significant downregulation in the selenium group in comparison to the control group (∆∆CT = 1.96; P = 0.013; relative expression (RE) = 0.28). Bcl-2 showed a significant upregulation in the selenium group in comparison to the control group (∆∆CT = -2.49; P < 0.001; RE = 3.49). No significant result was found for other genes. According to the multiple models, Bcl-2 showed a protective single gene association (beta = -0.33; P = 0.032), and Fas∗Bcl-2 interaction was significantly positive (beta = 0.19; P = 0.036). Conclusion: Addition of selenium to cryomedia of vitrification-thawing process could reduce the apoptosis induced by freezing-thawing stress in mice ovary via downregulation of P53 and upregulation of Bcl-2 at transcription level. Multivariable statistical models should be performed in future researches to study biological systems.


Assuntos
Antioxidantes/farmacologia , Proteínas Reguladoras de Apoptose , Expressão Gênica/efeitos dos fármacos , Ovário , Selênio/farmacologia , Animais , Proteínas Reguladoras de Apoptose/análise , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Meios de Cultura/química , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Ovário/efeitos dos fármacos , Ovário/metabolismo , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Vitrificação
12.
Br J Radiol ; 93(1115): 20200661, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877208

RESUMO

OBJECTIVES: To determine the performance of pretreatment structural and arterial spin labelling (ASL) MRI in predicting p53 mutation in patients with high-grade gliomas (HGGs). METHODS: Pre-treatment structural and ASL MRI were performed in 57 patients with histologically confirmed HGGs and information of p53 status. Whole-lesion histogram analysis of cerebral blood flow (CBF) images of the enhancing tumour and the peritumoral oedema in the HGGs were performed. Visually AcceSAble Rembrandt Images features were used as qualitative analysis. The differences of ASL histogram parameters and Visually AcceSAble Rembrandt Images features between HGGs with or without p53 mutation were analyzed with post hoc correction for multiple comparisons. LASSO regression was performed to select the optimal features that could predict p53 mutation, followed by receiver operating characteristic analysis to determine the predictive efficacy. RESULTS: A total of 33 HGGs with p53 mutation and 24 without p53 mutation were included. HGGs with mutant p53 showed lower CBFpercentile5 and CBFuniformity of the enhancing tumour (p < 0.05) and higher prevalence of the qualitative MRI feature of enhancing tumour crossing midline (ETCM) (p < 0.05) as compared with HGGs with wild-type p53. LASSO regression showed that the CBFuniformity of the enhancing tumour and ETCM were predictive features for p53 mutation. CBFuniformity showed an acceptable performance in predicting p53 mutation (area under the curve = 0.721), when combined with the feature of ETCM, its predictive efficacy was significantly improved (area under the curve = 0.814, p = 0.012). CONCLUSION: An integrated pre-treatment structural and ASL MRI can help to predict p53 mutation in HGGs.


Assuntos
Neoplasias Encefálicas/genética , Imagem Ecoplanar/métodos , Genes p53/genética , Glioma/genética , Mutação , Adulto , Área Sob a Curva , Edema Encefálico/diagnóstico por imagem , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Circulação Cerebrovascular , Feminino , Glioma/irrigação sanguínea , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Período Pré-Operatório , Curva ROC , Marcadores de Spin , Proteína Supressora de Tumor p53/análise
13.
Hum Pathol ; 105: 53-66, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32971129

RESUMO

Four molecular subgroups of gastric cancer (GC) have been proposed, ie, Epstein-Barr virus (EBV)-positive, microsatellite instable, chromosomal instable (CIN), and genomically stable GC. Based on the complex relationship between chromosomal instability and TP53 mutational status, we hypothesized that the typical clinicopathological characteristics caused by chromosomal instability are correlated with the p53 expression that is detected by immunohistochemistry. Four hundred sixty-seven whole-tissue sections of patients with therapy-naive GC were stained with anti-p53 antibody. The histoscore and staining pattern were analyzed for each slide. Different algorithms of immunohistochemistry evaluation were formed and correlated with clinicopathological characteristics. The algorithms were validated by assessing the mutational status of TP53 in 111 cases. Four hundred forty-two GCs were p53 positive, and 25 were negative, including 414 GCs with a homogeneous pattern and 53 GCs with a heterogeneous staining pattern. There was no correlation with overall or tumor-specific survival. In comparison with clinicopathological characteristics, the algorithm high versus low showed correlations with microsatellite instability, hepatocyte growth factor receptor (MET), and TP53 mutational status. The algorithm Q1/Q4 versus Q2/Q3 appeared to be correlated with the phenotype as per the Laurén classification, microsatellite instability, EBV status, and p53 expression pattern. The algorithm <90% = 0 and <50% = 3+ versus ≥90% = 0 or ≥50% = 3+ showed correlations with the EBV status, microsatellite instability, grading, and p53 expression pattern. The algorithm homogeneous versus heterogeneous did not correlate with any clinicopathological characteristic. Our results showed that the immunohistochemistry of p53, TP53 mutational status, and CIN subtype were connected. However, different algorithms for p53 immunohistochemical evaluation cannot be used to predict TP53 mutations in CIN GCs in individual cases.


Assuntos
Adenocarcinoma/genética , Algoritmos , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Imuno-Histoquímica , Mutação , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma/química , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/análise , Feminino , Predisposição Genética para Doença , Alemanha , Humanos , Masculino , Instabilidade de Microssatélites , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Neoplasias Gástricas/química , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/análise
14.
Proc Natl Acad Sci U S A ; 117(38): 23663-23673, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32900967

RESUMO

Cell stress and DNA damage activate the tumor suppressor p53, triggering transcriptional activation of a myriad of target genes. The molecular, morphological, and physiological consequences of this activation remain poorly understood in vivo. We activated a p53 transcriptional program in mice by deletion of Mdm2, a gene that encodes the major p53 inhibitor. By overlaying tissue-specific RNA-sequencing data from pancreas, small intestine, ovary, kidney, and heart with existing p53 chromatin immunoprecipitation (ChIP) sequencing, we identified a large repertoire of tissue-specific p53 genes and a common p53 transcriptional signature of seven genes, which included Mdm2 but not p21 Global p53 activation caused a metaplastic phenotype in the pancreas that was missing in mice with acinar-specific p53 activation, suggesting non-cell-autonomous effects. The p53 cellular response at single-cell resolution in the intestine altered transcriptional cell state, leading to a proximal enterocyte population enriched for genes within oxidative phosphorylation pathways. In addition, a population of active CD8+ T cells was recruited. Combined, this study provides a comprehensive profile of the p53 transcriptional response in vivo, revealing both tissue-specific transcriptomes and a unique signature, which were integrated to induce both cell-autonomous and non-cell-autonomous responses and transcriptional plasticity.


Assuntos
Especificidade de Órgãos/genética , Análise de Célula Única , Transcriptoma/genética , Proteína Supressora de Tumor p53 , Animais , Imunoprecipitação da Cromatina , Feminino , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pâncreas/citologia , Pâncreas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
15.
Anal Chem ; 92(18): 12423-12428, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32786451

RESUMO

Intrinsically disordered proteins (IDPs) constitute an important class of biomolecules with high flexibility. Atomic-resolution studies for these molecules are essentially limited to NMR spectroscopy, which should be performed under physiological pH and temperature to populate relevant conformational ensembles. In this context, however, fundamental problems arise with established triple resonance NMR experiments: high solvent accessibility of IDPs promotes water exchange, which disfavors classical amide 1H-detection, while 13C-detection suffers from significantly reduced sensitivity. A favorable alternative, the conventional detection of nonexchangeable 1Hα, so far resulted in broad signals with insufficient resolution and sensitivity. To overcome this, we introduce here a selective Hα,Cα-correlating pure shift detection scheme, the selective Hα,Cα-HSQC (SHACA-HSQC), using extensive hetero- and homonuclear decoupling applicable to aqueous samples (≥90% H2O) and tested on small molecules and proteins. SHACA-HSQC spectra acquired on IDPs provide uncompromised resolution and sensitivity (up to fivefold increased S/N compared to the standard 1H,13C-HSQC), as shown for resonance distinction and unambiguous assignment on the disordered transactivation domain of the tumor suppressor p53, α-synuclein, and folded ubiquitin. The detection scheme can be implemented in any 1Hα-detected triple resonance experiment and may also form the basis for the detection of isotope-labeled markers in biological studies or compound libraries.


Assuntos
Proteínas Intrinsicamente Desordenadas/análise , Humanos , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Proteína Supressora de Tumor p53/análise , Ubiquitina/análise , alfa-Sinucleína/análise
16.
Pathol Res Pract ; 216(8): 153025, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32703491

RESUMO

Aberrant p53 immunohistochemical expression is used to identify the copy-number-high/TP53-mutant subgroup of endometrial cancer (EC). We aimed to determine the diagnostic accuracy of p53 immunohistochemistry as surrogate for TP53 sequencing through a systematic review and meta-analysis. Electronic databases were searched from their inception to June 2019. All studies assessing p53 expression and TP53 mutations in EC were included. Diagnostic accuracy was assessed based on area under the curve (AUC). Immunohistochemical criteria used to define aberrant p53 expression were "overexpression" and "overexpression or complete absence". Subgroup analysis was based on the sequencing technique adopted (Polymerase Chain Reaction + sequencing, or next generation sequencing, NGS). Thirteen observational studies with 727 endometrial cancers were included. Both "overexpression" and "overexpression or complete absence" showed high diagnostic accuracy (AUC = 0.9088 and 0.9030, respectively). The subgroup with "overexpression" and NGS showed the best results, with very high diagnostic accuracy (AUC = 0.9927). In conclusion, immunohistochemistry for p53 is a highly accurate surrogate of TP53 sequencing. Overexpression of p53 in ≥70-80% showed the best accuracy in predicting TP53 mutations. Further studies in this field should adopt optimized immunohistochemical procedures and take into account less common p53 patterns (e.g. cytoplasmic expression).


Assuntos
Biomarcadores Tumorais/análise , Neoplasias do Endométrio/diagnóstico , Proteína Supressora de Tumor p53/análise , Feminino , Humanos , Imuno-Histoquímica/métodos , Análise de Sequência/métodos , Proteína Supressora de Tumor p53/metabolismo
17.
Br J Cancer ; 123(8): 1253-1261, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32690867

RESUMO

BACKGROUND: Radiogenomics is an emerging field that integrates "Radiomics" and "Genomics". In the current study, we aimed to predict the genetic information of pancreatic tumours in a simple, inexpensive, and non-invasive manner, using cancer imaging analysis and radiogenomics. We focused on p53 mutations, which are highly implicated in pancreatic ductal adenocarcinoma (PDAC), and PD-L1, a biomarker for immune checkpoint inhibitor-based therapies. METHODS: Overall, 107 patients diagnosed with PDAC were retrospectively examined. The relationship between p53 mutations as well as PD-L1 abnormal expression and clinicopathological factors was investigated using immunohistochemistry. Imaging features (IFs) were extracted from CT scans and were used to create prediction models of p53 and PD-L1 status. RESULTS: We found that p53 and PD-L1 are significant independent prognostic factors (P = 0.008, 0.013, respectively). The area under the curve for p53 and PD-L1 predictive models was 0.795 and 0.683, respectively. Radiogenomics-predicted p53 mutations were significantly associated with poor prognosis (P = 0.015), whereas the predicted abnormal expression of PD-L1 was not significant (P = 0.096). CONCLUSIONS: Radiogenomics could predict p53 mutations and in turn the prognosis of PDAC patients. Hence, prediction of genetic information using radiogenomic analysis may aid in the development of precision medicine.


Assuntos
Antígeno B7-H1/análise , Genômica por Imageamento , Aprendizado de Máquina , Neoplasias Pancreáticas/química , Proteína Supressora de Tumor p53/análise , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Proteína Supressora de Tumor p53/genética
18.
Medicina (Kaunas) ; 56(7)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32668573

RESUMO

Background and objectives: The present study aims to elucidate the clinicopathologic significance of Epstein-Barr virus (EBV) infection in gastric carcinomas (GCs) through a meta-analysis. Materials and Methods: Sixty-one eligible studies were included in the present meta-analysis. The included patients, with and without EBV infection, were 2063 and 17,684, respectively. We investigated the clinicopathologic characteristics and various biomarkers, including programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs). Results: The estimated EBV-infected rate of GCs was 0.113 (95% confidence interval (CI): 0.088-0.143). The EBV infection rates in GC cells were 0.138 (95% CI: 0.096-0.194), 0.103 (95% CI: 0.077-0.137), 0.080 (95% CI: 0.061-0.106), and 0.042 (95% CI: 0.016-0.106) in the population of Asia, America, Europe, and Africa, respectively. There was a significant difference between EBV-infected and noninfected GCs in the male: female ratio, but not other clinicopathological characteristics. EBV infection rates were higher in GC with lymphoid stroma (0.573, 95% CI: 0.428-0.706) than other histologic types of GCs. There were significant differences in high AT-rich interactive domain-containing protein 1A (ARID1A) and PD-L1 expressions, and high CD8+ TILs between EBV-infected and noninfected GCs. Conclusions: Our results showed that EBV infection of GCs was frequently found in male patients and GCs with lymphoid stroma. EBV infection was significantly correlated with ARID1A and PD-L1 expressions and CD8+ TILs in GCs.


Assuntos
Biomarcadores/análise , Infecções por Vírus Epstein-Barr/complicações , Neoplasias Gástricas/fisiopatologia , Antígeno B7-H1/análise , Proteínas de Ligação a DNA/análise , Infecções por Vírus Epstein-Barr/fisiopatologia , Herpesvirus Humano 4 , Humanos , Instabilidade de Microssatélites , Fragmentos de Peptídeos/análise , Receptor ErbB-2/análise , Neoplasias Gástricas/classificação , Fatores de Transcrição/análise , Proteína Supressora de Tumor p53/análise
19.
Mater Sci Eng C Mater Biol Appl ; 115: 111120, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32600719

RESUMO

This paper reports on biosensors made with a matrix of polylactic acid (PLA) fibers, which are suitable for immobilization of the anti-p53 active layer for detection of p53 biomarker. The PLA fibers were produced with solution blow spinning, a method that is advantageous for its simplicity and possibility to tune the fiber properties. For the biosensors, the optimized time to deposit the fibers was 60 s, with which detection of p53 could be achieved with the limit of detection of 11 pg/mL using electrical impedance spectroscopy. This sensitivity is also sufficient to detect the p53 biomarker in patient samples, which was confirmed by distinguishing samples from cell lines with distinct p53 concentrations in a plot where the impedance spectra were visualized with the interactive document mapping (IDMAP) technique. The high sensitivity and selectivity of the biosensors may be attributed to the specific interaction between the active layer and p53 modeled with a Langmuir-Freundlich and Freundlich isotherms and inferred from the analysis of the vibrational bands at 1550, 1650 and 1757 cm-1 using polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). The successful immobilization of the active layer is evidence that the approach based on solution blown spun fibers may be replicated to other types of biosensors.


Assuntos
Anticorpos/metabolismo , Técnicas Biossensoriais/instrumentação , Proteína Supressora de Tumor p53/análise , Anticorpos/química , Linhagem Celular , Espectroscopia Dielétrica , Humanos , Limite de Detecção , Células MCF-7 , Poliésteres/química
20.
JAMA Netw Open ; 3(7): e207566, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609349

RESUMO

Importance: The low 5-year survival rate of women with high-grade serous epithelial ovarian cancer (HGS-EOC) is related to its late diagnosis; thus, improvement in diagnosis constitutes a crucial step to increase the curability of this disease. Objective: To determine whether the presence of the clonal pathogenic TP53 variant detected in matched primary tumor biopsies can be identified in DNA purified from Papanicolaou test samples collected from women with HGS-EOC years before the diagnosis. Design, Setting, and Participants: This cohort study was conducted among a single-center cohort of women with histologically confirmed diagnosis of HGS-EOC recruited at San Gerardo Hospital, Monza, Italy, from October 15, 2015, to January 4, 2019. Serial dilutions of DNA derived from tumor samples and DNA extracted from healthy women's Papanicolaou test samples were analyzed to define the sensitivity and specificity of droplet digital polymerase chain reaction assays designed to detect the TP53 variants identified in tumors. All available brush-based Papanicolaou test slides performed up to 6 years before diagnosis were investigated at the Mario Negri Institute, Milano, Italy. Data were analyzed from October 2018 to December 2019. Main Outcomes and Measures: The presence of tumor pathogenic TP53 variants was assessed by the droplet digital polymerase chain reaction approach in DNA purified from Papanicolaou test samples obtained from the same patients before diagnosis during cervical cancer screenings. Results: Among 17 included patients (median [interquartile range] age at diagnosis, 60 [53-69] years), Papanicolaou tests withdrawn before diagnosis presented tumor-matched TP53 variants in 11 patients (64%). In 2 patients for whom longitudinal Papanicolaou tests were available, including 1 patient with Papanicolaou tests from 25 and 49 months before diagnosis and 1 patient with Papanicolaou tests from 27 and 68 months before diagnosis, the TP53 clonal variant was detected at all time points. Conclusions and Relevance: These findings suggest that noninvasive early molecular diagnosis of HGS-EOC is potentially achievable through detection of TP53 clonal variants in the DNA purified from Papanicolaou tests performed during cervical cancer screening.


Assuntos
Carcinoma Epitelial do Ovário , Células Clonais/patologia , Cistadenocarcinoma Seroso , Detecção Precoce de Câncer/métodos , Neoplasias Ovarianas , Teste de Papanicolaou , Proteína Supressora de Tumor p53/análise , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Teste de Papanicolaou/métodos , Teste de Papanicolaou/estatística & dados numéricos , Sensibilidade e Especificidade , Fatores de Tempo
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