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1.
Braz Dent J ; 30(4): 404-409, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31340232

RESUMO

Crossover studies continue to be published in spite of warnings about their inherent risks in relation to behavioral outcomes. This study took the opportunity of access to secondary data analysis in order to demonstrate the impact of a crossover design on the outcomes of randomized clinical trials aimed at the behavior of children during dental treatment. We evaluated the effect of the sequence of sedative administration, the sedative and the participant's age on the behavior of children undergoing two sequential dental visits. Eighteen uncooperative healthy young children were equally randomly assigned to: (G1) 1.0 mg/kg oral midazolam (first session) and oral placebo (second session); (G2) oral placebo (first) and 1.0 mg/kg oral midazolam (second). One trained observer assessed children's behavior. Data were analyzed by three-way mixed ANOVA. Both midazolam [mean(SD); 71.7%(16.5)] and placebo [48.6%(33.1)] produced more struggling behavior when they were administered in the first session compared to the second one (p=0.001). For the placebo, children aged 2-3 years exhibited more struggling behavior [G1 54.9%(36.2); G2 80.5%(8.3)] than those aged 4-5 years (p=0.04). Also, the reduction of percentage of struggling behavior was higher in G1 for older children (76.2%) and in G2 for younger children (32.9%). There were significant interactions between drug and sequence of administration, and between drug and age. The results of our study confirm the conventional wisdom that crossover study design is inappropriate to evaluate children's behavior/anxiety related-dental treatment under sedation and the results of crossover studies of dental sedation should be treated with extreme caution.

2.
Braz. dent. j ; 30(4): 404-409, July-Aug. 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1011571

RESUMO

Abstract Crossover studies continue to be published in spite of warnings about their inherent risks in relation to behavioral outcomes. This study took the opportunity of access to secondary data analysis in order to demonstrate the impact of a crossover design on the outcomes of randomized clinical trials aimed at the behavior of children during dental treatment. We evaluated the effect of the sequence of sedative administration, the sedative and the participant's age on the behavior of children undergoing two sequential dental visits. Eighteen uncooperative healthy young children were equally randomly assigned to: (G1) 1.0 mg/kg oral midazolam (first session) and oral placebo (second session); (G2) oral placebo (first) and 1.0 mg/kg oral midazolam (second). One trained observer assessed children's behavior. Data were analyzed by three-way mixed ANOVA. Both midazolam [mean(SD); 71.7%(16.5)] and placebo [48.6%(33.1)] produced more struggling behavior when they were administered in the first session compared to the second one (p=0.001). For the placebo, children aged 2-3 years exhibited more struggling behavior [G1 54.9%(36.2); G2 80.5%(8.3)] than those aged 4-5 years (p=0.04). Also, the reduction of percentage of struggling behavior was higher in G1 for older children (76.2%) and in G2 for younger children (32.9%). There were significant interactions between drug and sequence of administration, and between drug and age. The results of our study confirm the conventional wisdom that crossover study design is inappropriate to evaluate children's behavior/anxiety related-dental treatment under sedation and the results of crossover studies of dental sedation should be treated with extreme caution.


Resumo Pouco se sabe sobre o impacto de um delineamento cruzado nos desfechos de ensaios clínicos randomizados voltados ao comportamento de crianças durante tratamento odontológico. Este estudo objetivou avaliar o efeito da sequência de administração do sedativo, da droga em si e da idade dos participantes no comportamento de crianças que receberam duas consultas odontológicas consecutivas. Dezoito crianças saudáveis não colaboradoras, 2-5 anos de idade, foram randomizadas em dois grupos: G1 - 1,0 mg/kg midazolam oral (primeira sessão) e placebo oral (segunda sessão); G2 - placebo (primeira) e 1,0 mg/kg midazolam oral (segunda). Um observador treinado avaliou o comportamento infantil. Os dados foram analisados por ANOVA de três fatores (alfa=0,05). Midazolam [média(DP); 71,7%(16,5)] e placebo [48,6%(33,1)] resultaram em mais comportamento não cooperativo quando administrados na primeira sessão comparado com a segunda (p=0,001). Com o uso do placebo, crianças de 2-3 anos de idade exibiram mais comportamento não cooperativo [G1 54,9%(36,2); G2 80,5%(8,3)] que as de 4-5 anos de idade (p=0,04). Além disso, a porcentagem de redução do comportamento não cooperativo foi maior em crianças mais velhas em G1 (76,2%) e em crianças mais novas em G2 (32,9%). Considerando a avaliação do comportamento infantil sob sedação, a primeira sessão odontológica influenciou a segunda visita. Os resultados deste estudo confirmam a especulação de que o delineamento cruzado é inadequado para avaliar o comportamento odontológico relacionado à ansiedade/comportamento infantil; os resultados dos ensaios cruzados de sedação odontológica devem ser tratados com extrema cautela.

3.
J Endod ; 45(6): 716-723, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31060815

RESUMO

INTRODUCTION: There is evidence that acute periapical lesions present a greater potential for cyst formation. Recently, it was found that these lesions have cells with characteristics of pluripotent stem cells, which may influence cyst development. However, a more complete phenotype investigation of stem cells in a specific sample of periapical abscesses is required. The aim of this study was to analyze the immunohistochemical expression of mesenchymal stem cell (MSC) markers in periapical abscesses and to evaluate differences in their expression in relation to acute and chronic periapical lesions. METHODS: Immunohistochemistry was used to access MSC marker expression (CD44, CD73, and CD105) in samples of periapical abscesses (n = 10), granulomas (n = 10), cysts (n = 10), and apical papillae (n = 10). Immunohistochemical expression was evaluated by a quantitative scoring system. The chi-square test was used to assess the association between MSC marker expression and the histopathological diagnosis at a 5% significance level. RESULTS: CD44 and CD73 immunostaining was observed in mesenchymal cells located in the outer portion of the abscess and periapical cyst specimens. CD105 immunoexpression was found predominantly in mesenchymal and vascular endothelial cells of the lesions studied. MSC marker expression was higher in the periapical abscesses, with a significant association between MSCs and the histopathological diagnosis of an abscess (P < .05). CONCLUSIONS: The periapical region is a rich source of MSCs. The greater presence of MSCs in periapical abscesses found in this study could hold an important clue into understanding the pathological pathway of periapical cyst formation.

4.
Oral Oncol ; 93: 52-58, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31109696

RESUMO

The presence of lymphovascular invasion is considered a prognostic determinant for different human neoplasms and is frequently taken into account by surgeons and oncologists to determine patients' treatment. However, the exact frequency of this microscopic event and its prognostic impact for patients affected by adenoid cystic carcinoma (AdCC) remains unclear. Therefore, the aim of this study was to carry out a systematic review and meta-analysis to address the prevalence and the prognostic potential of lymphovascular invasion in head and neck AdCC. A literature search on PubMed, Scopus, ClinicalTrials.gov, Web of Science and ProQuest databases was undertaken in January 2019. The primary outcomes of interest were overall survival (OS) and disease-free survival (DFS). The relative frequency of lymphovascular invasion and its possible association with other clinicopathological parameters were addressed. A total of 22 studies and 2117 patients were included in this study. The frequency of lymphovascular invasion ranged from 5.2% to 72.5%. Lymphovascular invasion was associated with an increased likelihood of lymph node metastasis (OR = 2.58; 95% CI 1.61-4.12; p = 0.0001) and death (OR = 3.09; 95% CI 1.82-5.26; p = 0.0001), solid/higher-grade AdCC were more likely to present lymphovascular invasion (OR = 5.51; 95% CI 1.87-16-21; p = 0.002) and patients with this microscopic finding had a significantly lower OS (HR = 8.30; 95% CI 1.68-40.91; p = 0.009) and DFS (HR = 3.76; 95% CI 1.13-12.53; p = 0.03). In conclusion, lymphovascular invasion seems to be a significant predictor of poor prognosis for head and neck AdCC patients.

5.
Arch Toxicol ; 93(7): 1955-1964, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31020376

RESUMO

Acetaminophen (APAP) is one of the most widely consumed drugs in the world. Studies have shown renal and hepatic damage as the direct result of high oxidative stress induced by APAP. Since the cardiovascular system is sensitive to oxidative stress and literature describes increased cardiovascular dysfunction in APAP consumers, this work aimed to evaluate harmful effects of APAP on the vascular system. Rats were exposed to APAP (400 mg/kg/day in drinking water) for 14 days. Plasma and aortas were collected and stored in - 80 °C and a selection of arteries was prepared for isometric tension recordings, morphological, immunohistochemical and protein expression analysis. The APAP-treated group presented increased transaminases (ALT/AST) and malondialdehyde levels in the plasma compared to controls. Lipid peroxidation, glutathione reductase and superoxide dismutase levels were increased in the plasma and arteries of the APAP group. Nevertheless, glutathione level was reduced as compared to control group. The vasodilation response to acetylcholine and sodium nitroprusside (0.1 nM to 10 µM) was also impaired after APAP treatment; however, the vascular relaxation was restored after treatment with vitamin C (100 µM). Arteries from the APAP group presented reduced wall thickness, collagen deposition, elastic fibers and increased immunoreactivity to nitrotyrosine. eNOS and sGC protein expression remained unchanged and were at similar levels as controls. These findings showed higher oxidative stress and impaired vasodilation in rats exposed to APAP. Furthermore, arteries presented reduced cell layers, collagen, elastin deposition and significantly increased immunoreactivity to nitrotyrosine after APAP treatment.

6.
Trials ; 20(1): 97, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30709370

RESUMO

BACKGROUND: Oral mucositis (OM) is the most frequent and debilitating acute side effect associated with head and neck cancer (HNC) treatment. When present, severe OM negatively impacts the quality of life of patients undergoing HNC treatment. Photobiomodulation is a well-consolidated and effective therapy for the treatment and prevention of severe OM, and is associated with a cost reduction of the cancer treatment. Although an increase in the quality of life and a reduction in the severity of OM are well described, there is no study on cost-effectiveness for this approach considering the quality of life as a primary outcome. In addition, little is known about the photobiomodulation effects on salivary inflammatory mediators. Thus, this study aimed to assess the cost-effectiveness of the photobiomodulation therapy for the prevention and control of severe OM and its influence on the salivary inflammatory mediators. METHODS/DESIGN: This randomized, double-blind clinical trial will include 50 HNC patients undergoing radiotherapy or chemoradiotherapy. The participants will be randomized into two groups: intervention group (photobiomodulation) and control group (preventive oral care protocol). OM (clinical assessment), saliva (assessment of collected samples) and quality of life (Oral Health Impact Profile-14 and Patient-Reported Oral Mucositis Symptoms questionnaires) will be assessed at the 1st, 7th, 14th, 21st and 30th radiotherapy sessions. Oxidative stress and inflammatory cytokine levels will be measured in the saliva samples of all participants. The costs are identified, measured and evaluated considering the radiotherapy time interval. The incremental cost-effectiveness ratio will be estimated. The study will be conducted according to the Brazilian public health system perspective. DISCUSSION: Photobiomodulation is an effective therapy that reduces the cost associated with OM treatment. However, little is known about its cost-effectiveness, mainly when quality of life is the effectiveness measure. Additionally, this therapy is not supported by the Brazilian public health system. Therefore, this study widens the knowledge about the safety of and strengthens evidence for the use of photobiomodulation therapy, providing information for public policy-makers and also for dental care professionals. This study is strongly encouraged due to its clinical relevance and the possibility of incorporating new technology into public health systems. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials-ReBEC, RBR-5h4y4n . Registered on 13 June 2017.


Assuntos
Quimiorradioterapia/efeitos adversos , Irradiação Craniana/efeitos adversos , Neoplasias de Cabeça e Pescoço/radioterapia , Terapia com Luz de Baixa Intensidade/métodos , Lesões por Radiação/prevenção & controle , Glândulas Salivares/efeitos da radiação , Estomatite/prevenção & controle , Biomarcadores/metabolismo , Brasil , Quimiorradioterapia/economia , Análise Custo-Benefício , Irradiação Craniana/economia , Citocinas/metabolismo , Método Duplo-Cego , Neoplasias de Cabeça e Pescoço/economia , Custos de Cuidados de Saúde , Humanos , Mediadores da Inflamação/metabolismo , Terapia com Luz de Baixa Intensidade/efeitos adversos , Terapia com Luz de Baixa Intensidade/economia , Estresse Oxidativo , Lesões por Radiação/economia , Lesões por Radiação/etiologia , Lesões por Radiação/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Saliva/metabolismo , Glândulas Salivares/metabolismo , Índice de Gravidade de Doença , Estomatite/economia , Estomatite/etiologia , Estomatite/metabolismo , Fatores de Tempo , Resultado do Tratamento
7.
Mod Pathol ; 32(6): 799-806, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30643167

RESUMO

Adenomatoid odontogenic tumor is a benign encapsulated epithelial odontogenic tumor that shows an indolent clinical behavior. We have reported in a few adenomatoid odontogenic tumors mutations in KRAS, which is a proto-oncogene frequently mutated in cancer such as lung, pancreas, and colorectal adenocarcinomas. We aimed to assess KRAS mutations in the hotspot codons 12, 13, and 61 in a large cohort of adenomatoid odontogenic tumors and to test the association of these mutations with clinical (age, site, tumor size, follicular/extrafollicular subtypes) and histopathological parameters. Thirty eight central cases were studied. KRAS codon 12 mutations were assessed by TaqMan allele-specific qPCR (p.G12V/R) and/or Sanger sequencing, and codon 13 and 61 mutations were screened by Sanger. Histological tumor capsule thickness was evaluated by morphometric analysis. Additionally, the phosphorylated form of the MAPK downstream effector ERK1/2 was investigated. Statistical analysis was carried out to test the association of KRAS mutations with clinicopathological parameters. KRAS c.35 G >T mutation, leading to p.G12V, was detected in 15 cases. A novel mutation in adenomatoid odontogenic tumor, c.34 G >C, leading to p.G12R, was detected in 12 cases and the other 11 were wild-type. Codon 12 mutations were not associated with the clinicopathological parameters tested. RAS mutations are known to activate the MAPK pathway, and we show that adenomatoid odontogenic tumors express phosphorylated ERK1/2. In conclusion, a high proportion of adenomatoid odontogenic tumors (27/38, 71%) have KRAS codon 12 mutations, which occur independently of the clinicopathological features evaluated. Collectively, these findings indicate that KRAS mutations and MAPK pathway activation are the common features of this tumor and some cancer types. Although it is unclear why different codon 12 alleles occur in different disease contexts and the complex interactions between tumor genotype and phenotype need clarification, on the basis of our results the presence of KRAS p.G12V/R favors the adenomatoid odontogenic tumor diagnosis in challenging oral neoplasm cases.

8.
Oral Oncol ; 88: 95-101, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30616805

RESUMO

OBJECTIVES: The objective of the present study was to investigate the expression of immune checkpoints (PD-L1, PD-L2, PD-1 and CTLA-4), immune inhibitory molecule HLA-G, markers of tumor-infiltrating lymphocytes (TIL) and dendritic cells (DC), as well as its association with clinicopathological features of adenoid cystic carcinomas (ACC) of the salivary glands. MATERIALS AND METHODS: Thirty-six samples from patients with ACC were analyzed immunohistochemically for the expression of PD-L1, PD-L2, PD-1, CTLA-4, HLA-G, CD8, GrB, CD1a and CD83. Positivity of HLA-G, PD-L1 and PD-L2 expression was defined by cut-offs values. CD8+ TIL was measured semiquantitatively and also using cut-off values obtained by the ROC curve considering recurrence of the lesion. RESULTS: ACC showed low CD8+, GrB+  TIL, CD1a and CD83 populations, as well as scarce positivity for CTLA-4 and PD-1. In contrast, PD-L2 and HLA-G expression was increased, while no PD-L1 expression was detected. Interestingly, cases with lower CD8+ TIL density presented greater recurrence rates. CONCLUSION: Our findings suggest that the ACC microenvironment exhibits low immunogenicity, represented by low TIL and DC density. Moreover, there seems to be activation of the immune inhibitory proteins/PD-L2 and HLA-G, a scenario that may favor tumor escape from the immune system and partially explain the poor prognosis of ACC.

9.
Phytother Res ; 33(4): 881-890, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30672024

RESUMO

We explored the effects of a mucoadhesive formulation containing curcuminoid (MFC) from Curcuma longa L. extract on oral mucositis (OM) induced by 5-fluorouracil (5-FU) in hamsters. Seventy-two golden Syrian hamsters were randomly allocated into four groups: control, placebo, chamomilla, and MFC. Animals received an intraperitoneal injection of 5-FU at Days 0 and 2. On Days 3 and 4, the buccal mucosa was scratched. Therapy was initiated on Day 5. Animals received two applications of the substances per day according to the experimental group. Six animals were euthanized on Days 8, 10, and 14. Clinical analysis were performed using photography and histopathological sections of 3 µm were stained by hematoxylin-eosin for semiquantitative analysis of re-epithelization and inflammation. Immunohistochemistry was used for angiogenesis (CD31) and transforming growth factor beta 1 (TGF-ß1) analysis. On Day 5, all groups exhibited OM. Clinical and histopathological findings revealed that on Day 8, both MFC and chamomilla groups exhibited better wound healing. In addition, the MFC group demonstrated lower angiogenesis and TGF-ß1 levels on Day 8 compared with placebo and control groups. Collectively, these findings suggest that MFC has a therapeutic effect on OM, accelerating wound healing through re-epithelization and anti-inflammatory action as modulation of angiogenesis and TGF-ß1 expression.


Assuntos
Fluoruracila/toxicidade , Extratos Vegetais/uso terapêutico , Estomatite/tratamento farmacológico , Animais , Cricetinae , Curcuma , Composição de Medicamentos , Masculino , Mesocricetus , Estomatite/induzido quimicamente , Cicatrização/efeitos dos fármacos
10.
Arch Oral Biol ; 98: 99-107, 2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30468994

RESUMO

OBJECTIVES: Programmed death ligand-1 (PD-L1) and human leukocyte antigen-G (HLA-G) are considered immune checkpoint molecules that inhibit T-cell effectiveness, contributing to tumor immune escape. This study investigated PD-L1, HLA-G, CD8, and granzyme B (GrB) expression at different stages of lip carcinogenesis. DESIGN AND RESULTS: Forty cases of lip squamous cell carcinoma (LSCC), 55 actinic cheilitis (AC), and 10 healthy lip mucosa (HLM) were submitted to immunohistochemistry. Semiquantitative (PD-L1, HLA-G), and quantitative (CD8, GrB) analysis were performed. PD-L1 and HLA-G expression in neoplastic cells/keratinocytes and stroma/connective tissue was significantly higher in LSCC and AC, compared to HLM (p<0.05). PD-L1 was not associated with clinicopathological features of the lesions. HLA-G expression by malignant cells was significantly higher in LSCCs with distant metastasis (p = 0.041).CD8+ and GrB+ cell numbers progressively increased from HLMs to LSCC, with AC exhibiting intermediate numbers (p<0.01). Most LSCCs showed coexistence of PD-L1+ and CD8+ cells (72.5%). PD-L1 was directly correlated to CD8+ and GrB+ lymphocytic infiltration in LSCCs (p<0.05). Low cytotoxic immune response was associated with lymph node metastasis in LSCC (p<0.05). CONCLUSIONS: PD-L1 and HLA-G-mediated immune evasion mechanisms are likely to occur from early pre-malignant to advanced malignant stages of lip carcinogenesis, which might provide a rationale for therapeutic blockade of these pathways. PD-L1 expression in LSCCs was correlated with the cytotoxic markers, suggesting that PD-L1 may appear as an escape mechanism in response to an active antitumor response.

11.
Virchows Arch ; 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30483955

RESUMO

The aim of the present study was to investigate the profile of tumor-infiltrating lymphocytes (TIL) in osteosarcomas of the jaws (OSJ). A total of 21 OSJ samples were analyzed in a retrospective and cross-sectional multicenter study. Immunohistochemistry was performed to determine the recognition of TIL such as CD4+, CD8+, granzyme B+ (GrB), programmed cell death protein+ (PD-1), and cytotoxic T lymphocyte-associated antigen 4+ (CTLA-4) in intratumoral and peripheral (stromal) regions. Positivity was determined based on the percentage and density of TIL+ per square millimeter [1 = absent (< 25 cells/mm2), 2 = low (25 to 130 cells/mm2), and 3 = high (> 130 cells/mm2)]. The association of TIL density with clinicopathologic data was determined by the Mann-Whitney test (p < 0.05). OSJ were positive for CD8+ cells in 45% (n = 9) of cases, for CD4+ cells in 30% (n = 6) of cases, and for CTLA-4+ in 4.8% (n = 1) of cases, with a score of 2 (low TIL) in all cases. All cases were negative for GrB and PD-1 (score 1). No association was observed between immune infiltrate and clinicopathologic findings. OSJ showed a microenvironment with low TIL, including failure of effectiveness of the antitumor immune response (absence of GrB+ cells), and few cells exhibited immunotherapeutic targets, such as CTLA-4 and PD-1.

12.
Head Neck Pathol ; 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30019325

RESUMO

T-cell/histiocyte-rich large B-cell lymphoma (THRBCL) is an uncommon subtype of non-Hodgkin's lymphoma. It is a predominant nodal neoplasm; however, extranodal sites, such as the spleen, liver and bone marrow, can be involved at diagnosis. However, only one case of primary THRLBCL in the jaws have been reported. We herein describe a 29-year-old female patient who presented with a swelling of the right mandible that had grown rapidly over the previous 2 months. Periapical and panoramic radiographs showed a multilocular osteolytic lesion located in the mandibular periapical region of the canine and premolar teeth and molar region. Preoperative examination and incisional biopsy were performed. Immunohistochemistry was applied to confirm the diagnosis of THRBCL in the jaw. The treatment consisted of CHOP therapy and radiotherapy. After complete tumor remission following initial treatment, additional sites of the disease appeared in the lung, abdomen and long bones. The patient died within 2 months. THRLBCL is an uncommon and aggressive malignant neoplasm that can involve the jaws, mimicking a periapical disease.

13.
Int J Paediatr Dent ; 2018 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-29984460

RESUMO

BACKGROUND: There is a paucity of evidence about cognitive behaviour therapy in the management of dentally anxious children. AIM: To systematically review evidence of the effectiveness of cognitive behaviour therapy for children with dental anxiety or dental phobia. DESIGN: Clinical trial registries, grey literature, and electronic databases, including The Cochrane Library, EMBASE, PubMed, Scopus, Web of Science, LILACS/BBO, and PsycINFO, were searched (April 2018). The reference lists of relevant studies were hand-searched. Randomised controlled trials that evaluated the effects of cognitive behaviour therapy on dental anxiety or on acceptance of dental treatment in dental patients up to 18 years were included. Two trained and calibrated reviewers performed the study selection and risk of bias assessment. The quality of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Six studies with a total of 269 patients, aged 41 months to 18 years, were included. Cognitive behaviour therapy decreased level of anxiety compared to control groups and improved cooperation/behaviour, although the quality of the evidence was low. CONCLUSIONS: Cognitive behaviour therapy produces better anxiety reduction than diverse behavioural management techniques but the evidence was of low quality and further studies in children are needed.

14.
Pathol Res Pract ; 214(8): 1185-1191, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29970306

RESUMO

The biological process of epithelial-to-mesenchymal transition (EMT) has been studied in oral squamous cell carcinoma (OSCC) metastasis, but it is rarely evaluated at several stages of oral carcinogenesis. This study aimed to analyze the presence of SNAIL and E-cadherin proteins, markers of EMT, in the development and progression of OSCC, evaluating excised specimens of potentially malignant lesions (oral leukoplakia with and without dysplasia-OL and OLD, respectively), tumor tissues (OSCC), metastatic lymph nodes (LN), and normal oral mucosa (NOM) by immunohistochemistry, considering subcellular localization. Additionally, SNAIL and E-cadherin transcripts were evaluated in vitro by qPCR, using SCC-9 cell line in comparison to human keratinocytes (HPEC). There was a significant increase in nuclear expression of SNAIL from NOM to OLD followed by a noticeable decrease in nuclear expression accompanied by increased cytoplasmic expression in OSCC (p<0.05). The E-cadherin cytoplasmic expression was remarkable and statistically significant higher in OSCC and LN, both compared to NOM (p< 0.0001), OL (p<0.01) and OLD (p< 0.0001 and p<0.001, respectively). In vitro, E-cadherin and SNAIL transcripts were lower in SCC-9 compared to HPEC cells, although only the decrease of E-cadherin was statistically significant (p<0.05). Regarding the association of E-cadherin and SNAIL expression with the clinical findings, the analysis revealed an association between the cytoplasmic expression of SNAIL and the invasion pattern (p=0.05) in OSCC. The increased nuclear SNAIL expression may be characteristic of OLD, and the presence of E-cadherin in cell cytoplasm a marker of transformation to malignancy of potentially malignant oral leukoplakias into OSCC.


Assuntos
Caderinas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Bucais/patologia , Fatores de Transcrição da Família Snail/metabolismo , Adulto , Idoso , Antígenos CD , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço
15.
J Oral Pathol Med ; 47(9): 856-863, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29964301

RESUMO

BACKGROUND: Tumor-associated neutrophils (TAN), matrix metalloproteinase-9 (MMP-9), interleukin-17 (IL-17), and angiogenesis have been proposed as prognostic biomarkers of malignant tumors. The purpose of this study was to investigate these inflammatory markers as prognostic factors for oral squamous cell carcinoma (OSCC). METHODS: Specimens of OSCC (n = 30), healthy oral mucosa (negative control, n = 10), oral leukoplakia (n = 10), and apical granuloma with abscess (positive inflammatory controls, n = 10) were immunostained for CD66b (neutrophils), MMP-9, IL-17, and CD105 (neoformed microvessels). Semiquantitative (IL-17) and quantitative (CD66b, IL-17, MMP-9, and CD105) analyses were performed. Clinical information (TNM stage, metastasis, recurrence, and survival) and tumor histological grade were also obtained. RESULTS: Positivity for TAN, MMP-9, IL-17, and CD105 was higher in OSCC than in the negative control (P < 0.05) and oral leukoplakia, but similar to the positive inflammatory control. Coincident high counts of inflammatory markers (CD66b, MMP-9, IL-17, and CD105) were associated with lymph node metastasis of OSCC. Associations between high numbers of neoformed microvessels and advanced clinical stage and a higher degree of malignancy were also demonstrated. CONCLUSIONS: Combined positivity for TAN, MMP-9, IL-17, and CD105 appears to be associated with the metastasis-prone phenotype of OSCC.

16.
Chem Biol Interact ; 291: 228-236, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29906455

RESUMO

Preclinical repeated-dose toxicity and efficiency studies developed by our group suggest the potential of FITOPROT in treating mucositis. This serious limiting side effect is observed at a rate of 40-100% in patients under antineoplastic therapy and despite different palliative measures and therapeutic agents have been investigated, still no therapy was completely successful. Therefore, this study aimed to establish the safety and recommended phase II dose of FITOPROT for the prevention and treatment of chemoradiotherapy-induced oral mucositis (OM) in patients with head and neck cancer. Twenty healthy adult participants were randomized into two groups that received pre-established concentrations of the collutory: group 1 (FITOPROT A - mucoadhesive formulation containing 10 mg/mL of curcuminoids extract plus 20% v/v of Bidens pilosa L. extract) and group 2 (FITOPROT B - mucoadhesive formulation containing 20 mg/mL of curcuminoids extract, plus 40% v/v of Bidens pilosa L. extract). Participants rinsed their mouths with FITOPROT, three times daily, for ten consecutive days. No participant experienced toxicity or unacceptable discomfort and/or adverse reactions (CTCAE v5.0), with laboratory and clinical parameters under normal conditions. Side effects observed were low intensity and temporary mucosa/dental surface pigmentation (n = 7) and tooth sensitivity (n = 4), which disappeared after formulation use ceased. No significant cellular genotoxic effects were observed (p > 0.05), and micronuclei frequencies were not changed (p > 0.05). Biochemical assays reveled no altered levels of myeloperoxidase (p = 0.2268), malondialdehyde (p = 0.1188) nor nitric oxide (p = 0.5709) concentration, and no significant difference were found in the levels of pro-inflammatory cytokines (p > 0.05). Thus, FITOPROT demonstrated to be safe and tolerable in both tested doses and is suitable for evaluation in a phase II trial as treatment against OM.


Assuntos
Adesivos/uso terapêutico , Asteraceae/química , Bidens/química , Curcumina/uso terapêutico , Extratos Vegetais/uso terapêutico , Estomatite/tratamento farmacológico , Estomatite/prevenção & controle , Adesivos/farmacologia , Adulto , Curcumina/farmacologia , Citocinas/metabolismo , Demografia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mutagênicos/toxicidade , Extratos Vegetais/farmacologia , Saliva/metabolismo , Estomatite/patologia , Adulto Jovem
17.
J Oral Pathol Med ; 47(8): 788-795, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29935090

RESUMO

BACKGROUND: Actinic cheilitis (AC) is a potentially malignant disorder that can progress to squamous cell carcinoma (SCC), but this process is not fully understood. This study evaluated the immunoexpression of glucocorticoid receptor alpha (GRα) isoform and apoptotic proteins (Bcl-2 and Bax) in AC and lower lip SCC (LLSCC). METHODS: Twenty-two AC and 44 LLSCCs (22 with regional nodal metastasis and 22 without metastasis) were selected. The percentages of nuclear (GRα) and cytoplasmic (GRα, Bcl-2, and Bax) staining in epithelial cells were assessed and correlated with clinical (tumor size/extent and clinical stage) and histopathological parameters (risk of malignant transformation for AC and histopathological grade of malignancy for LLSCCs). RESULTS: Expression of GRα was observed in all cases studied, with relatively high median percentages of positive staining. When compared to AC, LLSCCs exhibited lower nuclear expression and higher cytoplasmic expression of GRα (P < 0.05). Regarding clinicopathological parameters, significant differences were only found for cytoplasmic expression of GRα according to the histopathological grade of LLSCCs (P = 0.036). Higher expression of Bax compared to Bcl-2 was observed in AC and LLSCCs (P < 0.05). In LLSCCs, there was a positive correlation between nuclear and cytoplasmic expressions of GRα (P = 0.006). CONCLUSION: Reduced nuclear translocation and increased cytoplasmic expression of GRα may be important events in lip carcinogenesis but are not involved in the progression of LLSCC. The role of GRα in lip cancer development does not seem to be primarily related to modulations in the expression of Bcl-2 or Bax.

18.
Oral Dis ; 24(8): 1492-1502, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29949225

RESUMO

OBJECTIVES: To investigate the frequency of oral paracoccidioidomycosis from representative geographical regions of Brazil and to compare the data with a literature review. MATERIALS AND METHODS: A retrospective study was conducted on 108,304 biopsies obtained from 1953 to 2016 at six Brazilian oral and maxillofacial pathology services. Demographic data and clinical and histopathological diagnosis of oral paracoccidioidomycosis were evaluated. A literature review of oral paracoccidioidomycosis studies published in three electronic databases was carried out. Data were analysed descriptively. RESULTS: A total of 320 cases of oral paracoccidioidomycosis were surveyed (0.3% of the oral lesions at the centres studied). The lesions were more frequent among male patients. The gingiva/alveolar ridge was the most affected site. Mean age of affected individuals was 51.3 years (±11.7). The literature review showed a higher incidence of oral paracoccidioidomycosis in the south-east and south regions of Brazil. Male individuals and individuals between 50 and 59 years were most affected. CONCLUSIONS: Oral paracoccidioidomycosis is an uncommon lesion observed in oral biopsy samples. The differences in the relative frequency of oral paracoccidioidomycosis are related to geographical variations. Men between 50 and 59 years are more affected. This study provides helpful information for clinicians in the diagnosis of oral paracoccidioidomycosis.

19.
Cytokine ; 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29550065

RESUMO

BACKGROUND: Chemokines and chemokine receptors are critical in oral tumourigenesis. The atypical chemokine receptor ACKR2 is a scavenger of CC chemokines controlling the availability of these molecules at tumour sites, but the role of ACKR2 in the context of oral carcinogenesis is unexplored. METHODS: In this study, wild-type (WT) and ACKR2 deficient mice (ACKR2-/-) were treated with chemical carcinogen 4-nitroquinoline-1-oxide (4NQO) for induction of oral carcinogenesis. Tongues were collected for macro and microscopic analysis and to evaluate the expression of ACKRs, CC chemokines and its receptors, inflammatory cytokines, angiogenic factors, adhesion molecules and extracellular matrix components. RESULTS: An increased expression of ACKR2 in squamous cell carcinoma (SCC) lesions of 4NQO-treated WT mice was observed. No significant differences were seen in the ACKR1, ACKR3 and ACKR4 mRNA expression comparing SCC lesions from WT and ACKR2-/- treated mice. Significantly higher expression of CCL2, IL-6 and IL-17 was detected in ACKR2-/- treated mice. In contrast, the expression of other CC-chemokines, and receptors, angiogenic factors, adhesion molecules and extracellular matrix components were similarly increased in SCC lesions of both groups. Clinical and histopathological analysis revealed no differences in inflammatory cell recruitment and in the SCC incidence comparing WT and ACKR2-/- treated mice. CONCLUSION: The results suggest that ACKR2 expression regulates inflammation in tumour-microenvironment but the absence of ACKR2 does not impact chemically-induced oral carcinogenesis.

20.
Life Sci ; 193: 300-308, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-28962868

RESUMO

AIMS: This study evaluated the mechanisms involved in the chemopreventive effects of a mucoadhesive formulation (FITOPROT), containing curcuminoids from Curcuma longa L. (Zingiberaceae) and Bidens pilosa L. (Asteraceae) extract, against 5-FU-induced cellular toxicity using an in vitro oral mucositis model. MAIN METHODS: Effects of FITOPROT on 5-FU-induced cytotoxicity in HaCaT and SSC-4 cells were evaluated by MTT assay. For mechanistic analyses, HaCaT cells were first pretreated with FITOPROT (0.005%) for 24h followed by treatment with FITOPROT and simultaneously exposed to 5-FU (10µg/mL) for additional 24h. KEY FINDINGS: FITOPROT was able to protect HaCaT cells from 5-FU-triggered cell damage. Moreover, the FITOPROT+5-FU association showed higher cytotoxic effects on SSC-4 cancer cells. Flow cytometry and/or fluorescence microscopy analysis showed FITOPROT was able to significantly reduce ROS generation and prevent mitochondrial changes in HaCaT cells. In addition, it avoided the release of cytochrome c from mitochondria to the cytoplasm in cells exposed to 5-FU, and restored their proliferative activity via Ki-67 expression. Furthermore, FITOPROT regulated 5-FU-induced oxidative stress via Nrf2 involvement. HaCaT cells pretreated/treated with FITOPROT also showed normal expression of TNF-R1 and NF-κB inflammatory proteins and decreased levels of pro-inflammatory cytokines (TNF, IL-1ß, IL-6 and IL-8). Moreover, a high-resolution liquid chromatography-mass spectrometry analysis showed the presence of flavonoids rutin, glucoronylated quercetin and dimethylquercetin rutenoside in FITOPROT. SIGNIFICANCE: It was showed that FITOPROT, an antioxidant phytochemicals-rich mucoadhesive formulation, exerts chemopreventive effects against 5-FU-triggered toxicity through antioxidant and anti-inflammatory mechanisms and restoration of proliferative capacity in HaCaT cells.


Assuntos
Ligases/metabolismo , Ligases/farmacologia , Estomatite/prevenção & controle , Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcuma/metabolismo , Curcuma/fisiologia , Citocinas/metabolismo , Flavonoides/farmacologia , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Humanos , Interleucina-1beta/farmacologia , Interleucina-6/farmacologia , Queratinócitos/metabolismo , Ligases/uso terapêutico , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Estomatite/tratamento farmacológico , Estomatite/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
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