Interfering with the bromodomain epigenome readers in mucoepidermoid carcinoma of salivary glands

Orientador: Márcio Ajudarte LopesTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de PiracicabaResumo: O carcinoma mucoepidermoide (CME) é a neoplasia maligna mais comum das glândulas salivares. O CME de alto grau possui uma evolução clínica imprevisível e é frequentemente associado a um pior prognóstico. Alguns estudos recentes, associam a progressão do câncer e a resposta inflamatória a uma classe de leitores epigenéticos do tipo bromodomínio. Bromodomínios estão envolvidos na transcrição gênica através de sua interação com resíduos de lisina na cauda das histonas. O BRD4, membro da família BET ("Bromodomain and ExtraTerminal") de bromodomínios, tem sido associado a alguns oncogenes como o c-MYC e outros eventos inflamatórios. Neste estudo, demonstramos que CMEs apresentam uma maior expressão de BRD4 e a interferência farmacológica com estes bromodomínios foi capaz de diminuir a proliferação das células tumorais. Além disso, inibidores da família BET são moduladores eficientes da via do NFkB e potentes inibidores da população de células tronco tumorais. Em estudos prévios, foi demonstrado que CMEs apresentam altos níveis de NFkB que estão associados com sua resistência à radioterapia. Por fim, foi observado que a interferência da interação BRD4 e histona interrompe o ciclo celular e ativa senescência em células tumorais de CME. Em resumo, estes achados identificam bromodomínios como mecanismos epigenéticos que podem estar desregulados em CME e passíveis de interferência farmacológica como nova estratégia para tratamento deste tumorAbstract: Mucoepidermoid carcinomas (MEC) are the most common malignancy of the salivary glands. High-grade MEC is particularly unpredictable and often associated with poor prognosis. Emerging evidence suggests the involvement of bromodomains as a conserved class of epigenome readers in cancer progression and inflammatory response. Bromodomains are directly associated with epigenetic modification of gene transcription through its interaction with the lysine residues of histone tails. The bromodomain family member BRD4 is particularly involved in the control of oncogenes including c-MYC, and in the maintenance of downstream inflammatory events and associated molecules. Here we showed that MECs are endowed with high expression levels of BRD4 and that targeting the acetyl-binding pockets of the bromodomains BET family demonstrated a potent anti-proliferative effect in MEC cells. Additionally, BET inhibitors are efficient modulators of the NFkB signaling pathway and capable of reducing the population of cancer stem cells. Notably, we have previously shown that MEC tumors present high levels of NFkB that are associated with its resistance to radiotherapy. Finally, we observed that targeting disruption of BRD4 histone interaction results in cell cycle arrest and activation of cellular senescence in MEC tumors cells. Altogether, our finding indicates that bromodomains constitute a new epigenetic mechanism found deregulated in MEC and that the use of BET inhibitors constitutes a feasible therapeutic strategy for managing MECDoutoradoEstomatologiaDoutora em Estomatopatologia152660/2015-1CNPQCAPE

Tongue metastasis of cutaneous melanoma : report of two cases and literature review

Malignant metastases to the oral cavity are rare and metastatic melanomas of the tongue are considered exceptionally uncommon, with less than 10 cases published in the English literature so far. Two female patients in the 7th decade of life presented to our dental service with nodules in the tongue. Both patients had multiple metastases at the time of oral diagnosis and primary melanoma originated on the skin. An intra-oral incisional biopsy was performed under local anesthesia and the histopathologic analysis was characterized by the proliferation of atypical epithelioid cells displaying a poorly delimited cytoplasm and hyperchromatic nucleus which contained eosinophilic macronucleoli. Immunohistochemistry was performed in both cases to confirm the clinical hypothesis of metastatic melanoma. After the diagnosis of oral metastatic melanoma, the patients were maintained under palliative care and close medical follow-up. Both patients died four and a half months and 20 months after the diagnosis of tongue metastasis. Although rare, metastatic melanoma should be included in the differential diagnosis of tongue lesions detected in patients with a previous medical history of cutaneous melanoma

Calcified carotid artery atheromas on panoramic radiographs of head and neck cancer patients before and after radiotherapy

The aims of this study were to verify if head and neck radiotherapy (RT) is able to induce calcified carotid artery atheroma (CCAA) in a large head and neck cancer (HNC) population and also to compare the socio-demographic and clinical findings of patients with and without CCAA detected on panoramic radiographs. Panoramic radiographs taken before and after head and neck radiotherapy (RT) of 180 HNC patients were selected and analyzed in order to identify the presence of CCAA. In addition, CCAA presence or absence on panoramic radiographs were compared and correlated with clinicopathological findings. A high overall prevalence of CCAA was found on panoramic radiographs (63 out of 180 = 35%) of HNC patients. No significant difference of CCAA before and after RT was observed. There were also no differences between groups (with and without CCAA) regarding age, gender, tobacco and alcohol use, arterial hypertension, diabetes mellitus, acute myocardial infarction, hypercholesterolemia, tumor location, clinical stage of disease and RT dose. However, there was a greater prevalence of strokes in patients with CCAA (p<0.05). Although CCAA were frequently found in panoramic radiographs of patients with HNC, RT seems not to alter the prevalence of these calcifications

Fatores prognósticos associados ao SAPS 3 e APACHE II em pacientes idosos admitidos em unidade de terapia intensiva

Study design: a descriptive, prospective cohort study. Objectives: identify the risk factors associated with SAPS 3 and APACHE II score to improve mortality prediction in elderly admitted in the intensive care unit (ICU). Methodology: a cohort study with 174 elderly patients admitted in ICU from July 2016 to June 2017. The primary independent variables analyzed were: presence of stress hyperglycemia, the need for invasive mechanical ventilation (IMV), acute renal failure, level of consciousness and use of vasopressors. The outcomes studied were death and hospital discharge. Results: ICU and hospital mortality were 17.8% and 29.8%, respectively. The multivariate analysis of factors associated with hospital death not contemplated in the obtaining of SAPS 3 demonstrated that IMV, Chronic Obstructive Pulmonary Disease (COPD) and Mean Arterial Pressure (MAP) &lt;70 mmHg improved the prediction of mortality. The Hosmer-Lemeshow test (p=0.472) and area under ROC curve=0.80 (CI95%:0.731-0.872) confirmed, respectively, an appropriate calibration and acceptable-to-excellent discriminatory power for this model. IMV and COPD were also factors associated with the APACHE II score in prediction of mortality with appropriated calibration (p=0.471) and acceptable-to-excellent discriminatory power (area under ROC curve=0.80 [CI95%:0.730-0.868]). Conclusion: IMV, COPD, and MAP &lt;70 mmHg were associated with SAPS3 and APACHE II to predict mortality in elderly admitted to ICU.Modelo de estudo: estudo descritivo, coorte prospectiva. Objetivos: identificar os fatores de risco associados ao escore SAPS 3 e APACHE II para melhorar a predição de mortalidade em idosos internados em unidade de terapia intensiva (UTI). Metodologia:&nbsp;estudo de coorte com 174 idosos internados em UTI no período de julho de 2016 a junho de 2017. As principais variáveis ​​independentes analisadas foram: presença de hiperglicemia de estresse, necessidade de ventilação mecânica invasiva (VMI), insuficiência renal aguda, nível de consciência e uso de vasopressores. Os desfechos estudados foram morte e alta hospitalar. Resultados: A mortalidade na UTI e hospitalar foi de 17,8% e 29,8%, respectivamente. A análise multivariada de fatores associados à morte hospitalar não contemplada na obtenção do SAPS 3 demonstrou que a VMI, Doença Pulmonar Obstrutiva Crônica (DPOC) e Pressão Arterial Média (PAM) &lt;70 mmHg melhoraram a predição de mortalidade. O teste de Hosmer-Lemeshow (p = 0,472) e a área sob curva ROC = 0,80 (IC95%: 0,731-0,872) confirmaram, respectivamente, calibração adequada e poder discriminatório aceitável a excelente para este modelo. VMI e DPOC também foram fatores associados ao escore APACHE II na predição de mortalidade com calibração adequada (p = 0,471) e poder discriminatório aceitável-a-excelente (área sob curva ROC = 0,80 [IC95%: 0,730-0,868]). Conclusão: VMI, DPOC e PAM &lt;70 mmHg foram associados ao SAPS3 e ao APACHE II para predizer mortalidade em idosos internados em UTI.&nbsp

Evaluation of the prevalence of carotid artery atheromas in panoramic radiographs of head and neck cancer patients treated with radiotherap

Orientador: Marcio Ajudarte LopesDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de PiracicabaResumo: Estudos sugerem que o tratamento radioterápico em região de cabeça e pescoço possa ser considerado um importante fator desencadeador da formação de calcificações em carótida. No entanto, evidências científicas para tal comprovação são limitadas. Portanto, os objetivos deste estudo foram identificar através de radiografias panorâmicas a prevalência de ateromas calcificados da carótida numa população com câncer de cabeça e pescoço antes e depois de serem submetidos à radioterapia e correlacionar com os aspectos sócio-demográficos e comorbidades destes pacientes. Foram selecionados, de forma retrospectiva, 180 pacientes tratados por radioterapia que tinham radiografias panorâmicas realizadas antes e após o término deste tratamento. Os dados clínicos foram coletados dos prontuários médicos. A análise das radiografias panorâmicas mostrou que 35% dos pacientes apresentaram ateromas calcificados da carótida. Não foi encontrada diferença significativa na prevalência de ateromas antes e após a radioterapia. Com relação aos achados clínicos, houve maior prevalência de acidentes vasculares cerebrais em pacientes com ateromas quando comparados aos pacientes que não apresentaram ateromas (p<0,05). Não foram observadas outras diferenças significativas com relação à idade, gênero, hipertensão arterial, diabetes mellitus, infarto agudo do miocárdio, localização do tumor e dose de radiação recebida. Sendo assim, podemos concluir que apesar da radioterapia não ter modificado a prevalência de ateromas calcificados da carótida nesta população estudada, esta alteração é frequentemente encontrada em pacientes com câncer de cabeça e pescoço. Portanto, é importante que os cirurgiões-dentistas fiquem atentos quanto à presença de ateromas em radiografias panorâmicas de pacientes com câncer de cabeça e pescoçoAbstract: Studies suggest that radiotherapy to the head and neck may be an important triggering factor for calcified carotid artery atheromas. However, scientific evidences to prove this matter are limited. Therefore, this essay aimed to identify the prevalence of calcified carotid artery atheromas observed by panoramic radiograph in a head and neck cancer population before and after radiotherapy and to correlate them with the sociodemographic features and comorbidities of these patients. For this research, 180 patients submitted to radiotherapy that had panoramic radiographs before and after this treatment, were selected retrospectively. Clinical data from these patients were collected from their medical records. The panoramic radiographs were examined and 35% of the patients demonstrated calcified carotid artery atheromas. There was no significant difference in the prevalence of atheromas before and after radiotherapy. According to clinical data, there was a greater prevalence of strokes in patients with calcified carotid artery atheromas when compared to patients who did not have atheromas (p<0.05). Differences related to age, gender, arterial hypertension, diabetes mellitus, acute myocardial infarctation, tumor location and radiotherapy dose were not observed. Thus, we can conclude that although radiotherapy did not alter the prevalence of calcified carotid artery atheromas in the studied population, this alteration is commonly found in head and neck cancer patients. Therefore, it is important that dentists be aware to the presence of calcified carotid artery atheromas in panoramic radiographs of head and neck cancer patientsMestradoEstomatopatologiaMestra em Estomatopatologi

Med Oral Patol Oral Cir Bucal-AHEAD OF PRINT -ARTICLE IN PRESS CCAA on panoramic radiographs Calcified carotid artery atheromas on panoramic radiographs of head and neck cancer patients before and after radiotherapy

Abstract Background: The aims of this study were to verify if head and neck radiotherapy (RT) is able to induce calcified carotid artery atheroma (CCAA) in a large head and neck cancer (HNC) population and also to compare the sociodemographic and clinical findings of patients with and without CCAA detected on panoramic radiographs. Material and Methods: Panoramic radiographs taken before and after head and neck radiotherapy (RT) of 180 HNC patients were selected and analyzed in order to identify the presence of CCAA. In addition, CCAA presence or absence on panoramic radiographs were compared and correlated with clinicopathological findings. Results: A high overall prevalence of CCAA was found on panoramic radiographs (63 out of 180 = 35%) of HNC patients. No significant difference of CCAA before and after RT was observed. There were also no differences between groups (with and without CCAA) regarding age, gender, tobacco and alcohol use, arterial hypertension, diabetes mellitus, acute myocardial infarction, hypercholesterolemia, tumor location, clinical stage of disease and RT dose. However, there was a greater prevalence of strokes in patients with CCAA (p&lt;0.05). Conclusions: Although CCAA were frequently found in panoramic radiographs of patients with HNC, RT seems not to alter the prevalence of these calcifications