Search

Objetivo: Fornecer um guia no formato de checklist para auxiliar pesquisadores na condução de revisões integrativas em Odontologia. Métodos: O guia para revisões integrativas em Odontologia foi construído a partir do Preferred Reporting Items for Systematic Reviews and Meta-Analyses (The PRISMA Statement). Resultados: Para o delineamento de revisões integrativas em Odontologia é preciso percorrer etapas distintas: 1. Identificação do tema (elaboração da pergunta de pesquisa); 2. Estabelecimento dos critérios de elegibilidade de estudos; 3. Busca sistematizada em diversas fontes de informação; 4. Coleta de dados; 5. Análise dos dados; 6. Discussão; 7. Apresentação da revisão/síntese do conhecimento. Os erros mais comuns ao realizar uma revisão integrativa estão relacionados à descrição incompleta ou não realização de etapas importantes, tais como: 1. Processo de seleção das evidências; 2. Estratégia de busca reprodutível; 3. Detalhes relacionados à busca, seleção e inclusão de estudos; 4. Aplicação dos critérios de elegibilidade; 5. Processo de extração dos dados (definição clara dos dados a serem extraídos, número de revisores envolvidos); 6. Apresentação do processo de seleção de estudos no formato de fluxograma; 7. Avaliação da qualidade dos estudos; 8. Síntese dos resultados. Conclusão: O guia para revisões integrativas em Odontologia apresenta utilidade na redução de equívocos metodológicos frequentemente observados nesse desenho de estudo, bem como estimula a condução de trabalhos com delineamentos robustos.

The microenvironment of oral cancer is highly dynamic and has been proved to affect tumor progression. Pericytes are blood vessels surrounding cells that have recently gained attention for their roles in vascular and cancer biology. The objective of the present study was to survey the scientific literature for conclusive evidence about whether pericytes are part of blood vessels in oral squamous cell carcinoma (OSCC) and their roles in the tumor microenvironment and clinical outcomes. A systematic electronic search was undertaken in Medline Ovid, PubMed, Web of Science, and Scopus. Eligibility criteria were: publications adopting in vivo models of OSCC that included pericyte detection and assessment by pericyte markers (e.g., α-smooth muscle actin, neuron-glial antigen 2 and platelet-derived growth factor receptor-β). The search yielded seven eligible studies (from 2008 to 2018). The markers most commonly used for pericyte detection were α-smooth muscle actin and neuron-glial antigen 2. The studies reviewed showed the presence of immature vessels exhibiting a reduction of pericyte coverage in OSCC and indicated that anti-cancer therapies could contribute to vessel normalization and pericyte regain. The pericyte population is significantly affected during OSCC development and cancer therapy. While these findings might suggest a role for pericytes in OSCC progression, the limited data available do not allow us to conclude whether they modify the tumor microenvironment and clinical outcome. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-020-01188-2) contains supplementary material, which is available to authorized users.

Objetivo: Conhecer os fatores associados à doença renal crônica (DRC) em pacientes com HIV/AIDS em uso de terapia antirretroviral (TARV) assistidos em um ambulatório em um município de Minas Gerais. Métodos: Estudo retrospectivo, de análise de informações de prontuários dos pacientes em acompanhamento no serviço em um período de 10 anos, considerando os fatores associados para o desenvolvimento de DRC. O trabalho foi submetido e aprovado pela Secretaria Municipal de Saúde do município e ao comitê de Ética em Pesquisa. Resultados: Na amostra analisada, houve correlação significante da nefrotoxicidade com sexo biológico, hipertensão arterial sistêmica, dislipidemia, acompanhamento com nefrologista, hemodiálise e alteração dos elementos anormais de sedimentação. As demais variáveis, Diabetes Mellitus, tabagismo, etilismo, doença cardiovascular, litíase, infecção urinária, hepatite B e C e transplante renal, no presente ensaio, não demonstraram correlação com TARV nefrotóxica como evidenciado na literatura. Conclusão: Fatores já evidenciados de estarem relacionados com DRC, como hipertensão arterial sistêmica, dislipidemia, sexo biológico, alteração dos elementos anormais de sedimentação, acompanhamento com nefrologista e hemodiálise foram associados com TARV nefrotóxica e consequente DRC na amostra estudada.

Cisplatin plays a central role in cancer chemotherapy, but resistance to this drug remains a major obstacle in treatment. Drawbacks related to cisplatin failure may be associated with cell energy metabolism. This study investigated whether photobiomodulation (PBM) can potentiate the effects of cisplatin on keratinocytes (HaCat) and cancer cells (SCC25 and HN12). Cells were treated with laser (GaAlAs; 660 nm; 60 mW; 0.33 J; 2.14 W cm-2 ; 11.7 J cm-2 and 6 s) and cisplatin (7.8 μg mL-1 ) to evaluate cell viability, Ki-67, VEGF, TGF-β1, EGF expression and ROS production. Observations were validated in the SCC25 cell lineage, where the type of cell death (necrosis/apoptosis) and the amount of ATP were assessed. Cell lineages showed increased sensitivity to cisplatin associated with PBM (Cis-PBM). Ki-67 was augmented in all cell lineages treated with Cis-PBM when compared to cisplatin alone (Cis). Cis or Cis-PBM significantly decreased VEGF expression in cancer cells, while no changes were seen in the expression of TGF-β1 or EGF compared to control. ROS levels were similar in the Cis and Cis-PBM groups. Cells treated with Cis-PBM died by apoptosis, leading to greater consumption of ATP. These observations suggest that PBM may potentiate the effects of cisplatin, leading to increased drug cytotoxicity and enhanced cell death.

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.

Rheumatoid arthritis (RA) is an autoimmune disorder associated with increased periodontal destruction. It is thought that RA increases the risk of periodontal disease; it is not known how it influences the oral microbiota. Our aim was to analyze the impact of RA on subgingival microbiota and its association with periodontal inflammation and RA activity. Forty-two patients with RA were compared to 47 control subjects without RA. Patients were screened for probing depth, clinical attachment level, bleeding on probing and classified as with or without periodontitis. Subgingival plaque was examined by Illumina MiSeq Sequencing of 16S rRNA gene V4 region and inflammatory cytokines were measured in saliva. RA was associated to severe periodontal disease. In addition, the severity of RA, reflected by the number of tender and swollen joints, was significantly correlated with the presence of pathogenic oral bacteria (i.e. Fusobacterium nucleatum and Treponema socransky). Non-periodontitis RA patients compared to healthy controls had increased microbial diversity and bacterial load, higher levels of pathogenic species (Prevotella, Selenomonas, Anaeroglobus geminatus, Parvimonas micra, Aggregatibacter actinomycetemcomitans) and reduction of health-related species (Streptococcus, Rothia aeria, Kingela oralis). Genes involved with bacterial virulence (i.e. lipopolysaccharide biosynthesis, peptidases) were more prevalent in the subgingival metagenome of subjects with RA. In addition, the degree of oral inflammation reflected by IL-2, IL-6, TNF-α, IFN-γ salivary levels was increased in non-periodontitis RA patients in comparison with controls. Our findings support the hypothesis that RA triggers dysbiosis of subgingival microbiota, which may contribute to worsening periodontal status.Author SummaryRheumatoid arthritis (RA) is an autoimmune disease characterized by joints inflammation, swelling, pain and stiffness. Exactly what starts this disease is still unclear. Some recent studies have suggested mucosal surfaces in the body, like those in the gums, could affect the disease process. It has been observed that people with RA have higher risk of periodontitis (a bacterial inflammatory disease of the gums), compared with the general population, and this may be the start of the autoimmune process. Also, periodontitis increases the severity of RA while interventions by treating periodontitis can improve the symptoms of RA. One of the possible mechanisms that link the higher prevalence of periodontitis in RA patients is the dysbiosis of the oral microbiota triggered by the chronic inflammation in RA. Increased levels of molecules of inflammation may affect the oral environment and change the type of bacteria that live there. Here, we examined RA patients and healthy subjects, screening their oral health and inflammatory markers. We collected their saliva and the dental plaque from the space between the teeth and the gum. We found that RA patients exhibited severe periodontitis, increased levels of inflammatory mediators on their saliva and distinct bacterial communities, with higher proportions of bacteria species linked to periodontal disease, even in patients without periodontitis. We also found that the presence of these bacteria species was linked to worse RA conditions. Our study provides new insights to understand the bi-directional mechanisms linking periodontal disease to the development of RA, showing that we need to pay attention to the oral cavity in patients with RA and refer people for dental evaluation. This practice might have a positive impact in the course of RA.

Bisphenol A (BPA) is an endocrine disrupting chemical able to promote hormone-responsive tumors. The major route of BPA contamination being oral, the aim of the present study was to investigate BPA effects on oral cells. Here, we evaluated the impact of sub-chronic in vivo exposure to BPA and its in vitro effects on neoplastic and non-neoplastic oral cells. We evaluated the oral mucosa of mice chronically exposed to BPA (200 mg/L). The response of keratinocytes (NOK–SI) and Head and Neck (HN) Squamous Cell Carcinoma (SCC), HN12 and HN13 cell lines to BPA was examined. In vivo, BPA accumulated in oral tissues and caused an increase in epithelial proliferative activity. BPA disrupted the function of keratinocytes by altering pro-survival and proliferative pathways and the secretion of cytokines and growth factors. In tumor cells, BPA induced proliferative, invasive, pro-angiogenic, and epigenetic paths. Our data highlight the harmful effects of BPA on oral mucosa and, tumorigenic and non-tumorigenic cells. Additionally, BPA may be a modifier of oral cancer cell behavior by prompting a functional shift to a more aggressive phenotype.

The chemokine CCL3 is a chemotactic cytokine crucial for inflammatory cell recruitment in homeostatic and pathological conditions. CCL3 might stimulate cancer progression by promoting leukocyte accumulation, angiogenesis and tumour growth. The expression of CCL3 and its receptors CCR1 and CCR5 was demonstrated in oral squamous cell carcinoma (OSCC), but their role was not defined. Here, the functions of CCL3 were assessed using a model of chemically induced tongue carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). Lineages of OSCC were used to analyse the effects of CCL3 in vitro. The 4NQO-induced lesions exhibited increased expression of CCL3, CCR1 and CCR5. CCL3-/- and CCR5-/- mice presented reduced incidence of tongue tumours compared to wild-type (WT) and CCR1-/- mice. Consistently, attenuated cytomorphological atypia and reduced cell proliferation were observed in lesions of CCL3-/- and CCR5-/- mice. OSCC from CCL3-/- mice exhibited lower infiltration of eosinophils and reduced expression of Egf, Fgf1, Tgf-β1, Vegfa, Vegfb, Itga-4, Vtn, Mmp-1a, Mmp-2 and Mmp-9 than WT mice. In vitro, CCL3 induced invasion and production of CCL5, IL-6, MMP -2, -8, -9. Blockage of CCL3 in vitro using α-CCL3 or Evasin-1 (a CCL3-binding protein) impaired tumour cell invasion. In conclusion, CCL3/CCR5 axis has pro-tumourigenic effects in oral carcinogenesis. The induction of inflammatory and angiogenic pathways and eosinophils recruitment appear to be the underlying mechanism explaining these effects. These data reveal potential protective effects of CCL3 blockade in oral cancer.

Objectives: To investigate salivary biomarkers associated with bone remodeling and tissue repair in patients receiving radiotherapy. Study Design: Ethical approval (85229518.9.0000.5149). Patients previously subjected to radiotherapy of the head and neck were prospectively selected. Individuals who did not receive radiotherapy were paired by age and sex and composed the control group. Inclusion and exclusion criteria applied. Nonstimulated saliva was collected and processed for RANK, RANKL, OPG, endothelial growth factor (EGF), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) by enzyme-linked immunosorbent assay (ELISA). Paired t test and Wilcoxon test were used and P values .05). Patients receiving radiotherapy and chemotherapy (n = 16) had lower EGF than controls (P .05). Conclusion: Head and neck radiotherapy lowers the salivary concentrations of tissue repair factors, but not the bone remodeling factors. Support: CNPq, CAPES, FAPEMIG.

The goal of this study was to compare the salivary concentrations of IL-10, TGF-β1 and soluble HLA-G (sHLA-G) in patients with oral squamous cell carcinoma (OSCC) to those in healthy individuals (control group), and to correlate the expression of these mediators in saliva with that in the tumour microenvironment. Neoplastic tissue and saliva samples from patients with OSCC (n=22) were analysed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) respectively. We detected high expression of IL-10 and HLA-G in the tumour microenvironment when compared to healthy oral mucosa samples. Determination of IL-10 salivary concentration enabled us to distinguish patients with OSCC from healthy individuals (P=0.038), which showed correlation with tissue expression of this cytokine. HLA-G salivary release was similar in both groups (P=0.17) and no correlation with tumour expression was observed. TGF-β1 expression was low or absent in tumours, and salivary concentration was similar between groups. Our results suggest that of the three markers analysed, IL-10 is a potential salivary biomarker. Furthermore, the elevated expression of HLA-G and IL-10 in tumour sites could favour the escape of tumour cells from immune defense mechanisms.

Introduction Bone remodeling is a tightly regulated process influenced by chemokines. ACKR2 is a decoy receptor for CC chemokines functioning as regulator of inflammatory response. In this study we investigated whether the absence of ACKR2 would affect bone phenotype and remodeling induced by mechanical loading. Methods An orthodontic appliance was placed between incisors and first molar of ACKR2 deficient (ACKR2 −/− ) and C57BL6/J (wild-type/WT) mice. Microtomography, histology and qPCR were performed to evaluate bone parameters, orthodontic tooth movement (OTM), bone cells counts and the expression of ACKR2, bone remodeling markers, CC chemokines and chemokines receptors. Bone marrow cells (BMC) from WT and ACKR2 −/− mice were differentiated in osteoclasts and osteoblasts for analysis of activity and expression of specific markers. Results Mechanical stimulus induced ACKR2 production in periodontium. The expression of ACKR2 in vitro was mostly detected in mature osteoclasts and early-differentiated osteoblasts. Although ACKR2 −/− mice exhibited regular phenotype in maxillary bone, the amount of OTM, osteoclasts counts and the expression of pro-resorptive markers were increased in this group. In contrast, the number of osteoblasts and related markers were decreased. OTM resulted in augmented expression of CC chemokines and receptors CCR5 and CCR1 in periodontium, which was higher in ACKR2 −/− than WT mice. In vitro experiments demonstrated an augmented formation of osteoclasts and diminished differentiation of osteoblasts in ACKR2 −/− mice. Conclusions These data suggests that ACKR2 functions as a regulator of mechanically-induced bone remodeling by affecting the differentiation and activity of bone cells and the availability of CC chemokines at periodontal microenvironment. Therapeutic strategies based on increase of ACKR2 might be useful to hinder bone loss in inflammatory conditions.

J Oral Pathol Med (2012) 41: 21–26 Background: Midkine (MK), a 13-kDa heparin-binding growth factor, is overexpressed in various human cancers. However, its role in the development and progression of oral cavity squamous cell carcinoma (OCSCC) is still unclear. Thus, the aim of this study was to evaluate the expression of MK in samples of OCSCC, leukoplakia, and healthy oral mucosa (control). Methods: Surgically excised specimens from patients with primary OCSCC (n = 28) were immunostained for MK, Ki-67, PCNA, p53, bcl-2, Bax, and CD31. Besides this, MK expression was also investigated in leukoplakia and normal oral mucosa. The relationship of MK+ cells with clinical parameters (tumor location, tumor size, lymph node metastasis, and survival) and microscopic parameters (WHO histological grading, intensity of inflammation, proliferation index, apoptosis, and angiogenesis) was also evaluated. Results: The results showed that MK expression was increased in OCSCC in relation to leukoplakia and normal mucosa. Furthermore, MK expression was increased in late-stage tumors (T3/T4) compared with early-stage lesions (T1/T2). MK-positive lesions also showed increased expression of the anti-apoptotic protein bcl-2. Conclusion: OCSCC, particularly late-stage tumors, exhibits increased MK expression, which may be involved in tumor progression via upregulation of anti-apoptotic genes, as shown by the augmented bcl-2 positivity in MK-positive tumors.

Chemokines are small chemotactic proteins that coordinate circulation of immune/inflammatory cells throughout body compartments. Because of this property chemokines and their cell surface receptors are implicated in several physiological and pathological conditions, including cancer. These molecules are expressed by neoplastic or stromal cells and have effects at tumor primary site (e.g. stimulating angiogenesis and tumor cells motility) and lymph nodes (creating a gradient to direct migration of neoplastic cells). In this article we review the current knowledge about the function(s) of chemokines and receptors in squamous cell carcinoma from the oral cavity and head and neck region. Accumulating evidence suggests some chemokine(s) and receptor(s) as potential targets in adjuvant therapies for these malignancies.

Introduction Mechanical stress can induce molecular changes in gingival crevicular fluid (GCF) and the periodontal ligament (PDL). It is still not clear whether changes in the PDL and GCF are linked. In this study, we aimed to analyze the expression of cytokines in GCF and PDL after mechanical stress. Methods Twenty-three healthy patients were included. The experimental group consisted of premolars subjected to a force of 0.980 N for 1, 3, 7, 14, 21, or 28 days. The contralateral teeth were the controls. GCF and PDL samples were collected at the same time points for analysis of cytokines using the cytometric bead array. Results Interleukin (IL)-6 (IL-6) production was significantly elevated in the PDL on day 1 after force application. Significantly strong positive correlations between GCF and PDL in experimental group were seen on days 3 (interferon-gamma), 7 (IL-10), 14 (IL-17A), and 28 (IL-17A, tumor necrosis factor-alpha), and significantly strong negative correlation were seen on days 14 (interferon-gamma) and 21 (IL-2, IL-10). Conclusions Different patterns of IL-6 expression were seen in the PDL and GCF after mechanical stress. Despite occasional correlations between GCF and PDL, the molecular contributions of the PDL to the GCF changes could not be clearly defined by our model.

Tumor-associated tissue eosinophilia (TATE) has been correlated with prognosis in oral squamous cell carcinoma (OSCC). This study aimed to investigate whether eosinophils depletion affects experimental oral carcinogenesis.BALB/c (wild type - WT) and eosinophil-deficient (Δdb/GATA-1) mice were treated with the carcinogen 4-nitroquinoline-1-oxide (4NQO) in drinking water for 28 weeks. Tongues were collected for histopathological and immunohistochemical analysis, as well as for the evaluation of cytokines/chemokines by ELISA. The tongue SCC induced by 4NQO was associated with a rise in eosinophil numbers. WT-treated group showed a significantly increased incidence of SCC, with higher cytological atypia, in comparison with Δdb/GATA-1 mice. Consistently, the proliferative index was higher in WT compared to the Δdb/GATA-1-treated group. No significant changes in the concentration of CCL3, CCL11 and TNF-α were detected for both groups after 4NQO treatment.These results suggest that eosinophils might be responsible for the deleterious outcome of experimental tongue carcinogenesis, given that their ablation protects mice from OSCC.

A quimiocina CCL3 possui uma diversidade de papéis que podem contribuir para o pior prognóstico do Carcinoma de células escamosas de boca (CCEB); Métodos: Camundongos machos C57BL/6 (WT) e deficientes de CCL3 (CCL3-/-) foram tratados com o 4NQO durante 20 ou 28 semanas. As línguas foram coletadas para análise macroscópica, histopatológica e imunohistoquímica. Os níveis de citocinas também foram avaliados por ELISA. Resultados: Nossos resultados mostraram uma incidência significativamente maior de CCEB nas línguas dos animais WT em comparação com os animais CCL3-/-. Consistente com estes achados, a análise microscópica demonstrou uma proeminente displasia epitelial no grupo WT. A imunoexpressão de PCNA e Ki67 revelou um significativo aumento no índice de proliferação celular nos animais WT, comparados ao grupo CCL3-/-. A concentração de CCL3, TNF-, CCL5 e CCL11 foi significativamente aumentada após o tratamento com 4NQO, entretanto, os animais CCL3-/- mostraram níveis mais baixos de TNF- quando comparados ao grupo WT. Conclusão: Estes dados sugerem que a deleção de CCL3 tem um efeito protetor na carcinogênese oral, o qual pode estar associado com mudanças locais na produção de TNF-. The chemokine CCL3 displays a diversity of roles that may contribute to worse prognosis in oral carcinogenesis. The aim of this study was to evaluate the role of CCL3 in 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis. C57BL/6 (wild type - WT) and CCL3 deficient (CCL3-/-) male mice were treated with 4NQO in drinking water at concentration of 50 ìg/ml during 20 or 28 weeks Their tongues were collected for macroscopic, histopathological and immunohistochemical analysis. Also, the cytokine levels in tongue lesions were evaluated by ELISA. Our results showed a significantly higher incidence of tumors in tongue of WT- in comparison with CCL3-/-- treated mice. Consistently, microscopic analysis demonstrated a pronounced cytological atypia in the WT-treated group. The immunoexpression of PCNA and Ki67 revealed a significant increase of the proliferative index in WT compared with CCL3-/--treated group. The concentration of CCL3, TNF-á, CCL5 and CCL11 was significantly enhanced after 4NQO treatment, but CCL3-/--treated mice showed lower TNF-á level when compared with WT. In conclusion, these data suggest a protective effect of CCL3deletion in oral tongue carcinogenesis which may be associated with local changes in TNF-á production.