Effects of fatty acid synthase inhibitors on lymphatic vessels: an in vitro and in vivo study in a melanoma model.

Fatty acid synthase (FASN) is responsible for the endogenous production of fatty acids from acetyl-CoA and malonyl-CoA. Its overexpression is associated with poor prognosis in human cancers including melanomas. Our group has previously shown that the inhibition of FASN with orlistat reduces spontaneous lymphatic metastasis in experimental B16-F10 melanomas, which is a consequence, at least in part, of the reduction of proliferation and induction of apoptosis. Here, we sought to investigate the effects of pharmacological FASN inhibition on lymphatic vessels by using cell culture and mouse models. The effects of FASN inhibitors cerulenin and orlistat on the proliferation, apoptosis, and migration of human lymphatic endothelial cells (HDLEC) were evaluated with in vitro models. The lymphatic outgrowth was evaluated by using a murine ex vivo assay. B16-F10 melanomas and surgical wounds were produced in the ears of C57Bl/6 and Balb-C mice, respectively, and their peripheral lymphatic vessels evaluated by fluorescent microlymphangiography. The secretion of vascular endothelial growth factor C and D (VEGF-C and -D) by melanoma cells was evaluated by ELISA and conditioned media used to study in vitro lymphangiogenesis. Here, we show that cerulenin and orlistat decrease the viability, proliferation, and migration of HDLEC cells. The volume of lymph node metastases from B16-F10 experimental melanomas was reduced by 39% in orlistat-treated animals as well as the expression of VEGF-C in these tissues. In addition, lymphatic vessels from orlistat-treated mice drained more efficiently the injected FITC-dextran. Orlistat and cerulenin reduced VEGF-C secretion and, increase production of VEGF-D by B16-F10 and SK-Mel-25 melanoma cells. Finally, reduced lymphatic cell extensions, were observed following the treatment with conditioned medium from cerulenin- and orlistat-treated B16-F10 cells. Altogether, our results show that FASN inhibitors have anti-metastatic effects by acting on lymphatic endothelium and melanoma cells regardless the increase of lymphatic permeability promoted by orlistat.

Biomechanical behavior of molars restored with direct and indirect restorations in combination with deep margin elevation.

STATEMENT OF PROBLEM: The existing knowledge is insufficient for comprehending the fatigue survival and fracture resistance of molars that have deep approximal direct and indirect restorations, whether with or without deep margin elevation (DME). PURPOSE: The aim of this laboratory and in silico study is to investigate the fatigue survival, fracture strength, failure pattern and tooth deformation of molars restored with DME in combination with a direct or indirect restoration. MATERIAL AND METHODS: This study utilized 45 extracted sound human molars, divided into three groups (n = 15). Standardized 100% inter-cuspal inlay preparations were performed, extending 2 mm below the CEJ and immediate dentin sealing (IDS) was applied. Group 1 (Co_1) was restored with direct composite; Group 2 (Hyb_2) with a 2 mm DME of direct composite and a glass-ceramic lithium disilicate restoration; Group 3 (Cer_3) a glass-ceramic lithium disilicate restoration. All specimens were exposed to a fatigue process involving thermal-cyclic loading (50N for 1.2 × 106 cycles at 1.7 Hz, between 5 and 55 °C), if teeth survived, they were fractured using a load-to-failure test and failure types were analyzed. Finite element analysis (FEA) was conducted to assess tooth deformation and tensile stress in the restorations. Statistical evaluation of fracture strength was conducted using the Kruskal-Wallis test. Fisher's exact test was utilized to analyze the fracture types and repairability. A statistical significance level of α < 0.05 was set for all analyses. RESULTS: All specimens successfully withstood the fatigue testing procedure, and no statistically significant differences in fracture strength were observed among the three groups (P > 0.05). The Fisher's exact test indicated a significant association between the restorative material and fracture type (F2 = 18.315, df = 2, P = 0.004), but also for repairability (F2 = 13.725, df = 2, P = 0.001). Crown-root fractures were significantly more common in the Cer_3 group compared to the Co_1 group (P = 0.001) and the Co_1 group had significantly more repairable fractures (F2 = 13.197, df = 2, P = 0.001). FEA revealed comparable outcomes of deformation among models and higher maximum tensile stress on models with higher frequency of catastrophic failures. CONCLUSIONS: All tested restoration materials exhibited comparable fatigue survival and fracture strength in this laboratory and in silico study. However, it is important to recognize the potential for more severe and irreparable fractures when opting for deeply luted glass-ceramic inlay restorations in clinical practice. In such cases, it would be prudent to consider the alternative option being a direct composite approach, because of its more forgiving fracture types and repairability. CLINICAL IMPLICATIONS: Molars with deep approximal direct and indirect restorations, whether with or without DME, are comparable in their fatigue survival and fracture resistance to withstand intra-oral forces. Deep direct restorations exhibit more repairable fractures compared to deeply luted glass-ceramics.

The digital competence of academics in higher education: is the glass half empty or half full?

This paper aims to evaluate and discuss the digital competence of academics at universities, to identify challenges and define recommendations for policy. This study was conducted through collaboration between the Joint Research Centre (JRC) of the European Commission and Metared of the Universia Foundation, surveying 30,407 participants who present the perceptions of their own digital competence levels. These self-reflections took place in universities in seven countries, namely Argentina, Brazil, Colombia, Chile, Peru, Mexico and Portugal, and used the Check-In tool, which consists of 22 questions based on the European Framework for the Digital Competence of Educators-or 'DigCompEdu' framework. A descriptive statistical analysis was performed, followed by a qualitative evaluation. Almost 70% of the academics have an average intermediate level of competence when the data is aggregated, with results varying in each DigCompEdu area according to the specific question asked. There is no significant difference between young and senior academics, as well as between men and women. The results present a discussion of whether the age and gender of educators and their work environment have an impact on their digital competence level, and at the same time highlights the areas in which educators perceive themselves to be most and least competent. It shows how the amount of institutional support that is offered affects the academics' perceptions of their level of digital competence. On the basis of the results, recommendations are presented for higher-education institutions, with the aim of supporting the professional development of their academics.

Viscosity and thermal kinetics of 10 preheated restorative resin composites and effect of ultrasound energy on film thickness.

OBJECTIVE: This study investigated viscosity and thermal kinetics of 10 selected preheated restorative resin composites and the effect of ultrasound energy on film thickness. METHODS: A range of different resin composites was tested: Charisma Diamond, IPS Empress Direct, Enamel Plus HRi, Essentia, Estelite Omega, Filtek Z100, Filtek Z350 XT, Gradia, TPH Spectrum and VisCalor. A flowable resin composite (Opallis Flow) and two resin cements (RelyX Veneer, Variolink Esthetic LC) also were tested. Viscosity (Pa s) was measured at 37 °C and 69 °C (preheating temperature) using a rheometer. Film thickness (µm) was measured before and after application of ultrasound energy. Temperature loss within resin composite following preheating (°C/s) was monitored. Data were statistically analyzed (α = 0.05). RESULTS: Viscosity at 69 °C was lower than at 37 °C for all materials except the flowable resin composite. Preheating reduced viscosity between 47% and 92% for the restorative resin composites, which were generally more viscous than the flowable materials. Film thickness varied largely among materials. All preheated resin composites had films thicker than 50 µm without ultrasound energy. Application of ultrasound reduced film thickness between 21% and 49%. Linear and nonlinear regressions did not identify any relationship between filler loading, viscosity, and/or film thickness. All materials showed quick temperature reduction following preheating, showing maximum temperature loss rates after approximately 10 s. SIGNIFICANCE: Distinct restorative resin composites react differently to preheating, affecting viscosity and film thickness. The overall performance of the preheating technique depends on proper material selection and use of ultrasound energy for reducing film thickness.

Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model.

Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate. In contrast to most normal cells, malignant cells depend on FASN activity for growth and survival. In fact, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Here, we show that the specific inhibition of FASN activity by the antiobesity drug Orlistat or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16-F10. These results prompted us to verify the effect of FASN inhibition on the metastatic process in a model of spontaneous melanoma metastasis, in which B16-F10 cells injected in the peritoneal cavity of C57BL/6 mice metastasize to the mediastinal lymph nodes. We observed that mice treated with Orlistat 48 hr after the inoculation of B16-F10 cells exhibited a 52% reduction in the number of mediastinal lymph node metastases, in comparison with the control animals. These results suggest that FASN activity is essential for B16-F10 melanoma cell proliferation and survival while its inactivation by Orlistat significantly reduces their metastatic spread. The chemical inhibition of FASN activity could have a potential benefit in association with the current chemotherapy for melanoma.

Avaliação do planejamento para prótese parcial removível e da qualidade dos modelos e requisições enviados aos laboratórios / Evaluation of planning for removable partial denture and quality of casts and prescriptions sent to the dental laboratories

Objetivo: Avaliar a qualidade dos modelos de gesso e requisições enviados a laboratórios de prótese dentária para confecção de Prótese Parcial Removível (PPR) e analisar o planejamento das estruturas metálicas a serem confeccionadas. Material e Método: A amostra foi composta por modelos e requisições enviados por cirurgiões-dentistas a quatro laboratórios comerciais da cidade de Goiânia-GO, selecionados a partir de uma lista fornecida pela Vigilância Sanitária do Município. Para coleta de dados foi utilizado um roteiro estruturado. Os modelos foram identificados segundo a Classificação de Kennedy e as Regras de Applegate. Informações adicionais foram agrupadas nas seguintes categorias: condições gerais dos modelos (local de vazamento, material de moldagem, gesso, presença de bolhas nas superfícies de assentamento da PPR), requisição do trabalho ao laboratório (avaliadas segundo a clareza das informações nelas contidas) e planejamento da estrutura metálica (desenho, qualidade dos preparos dentários ? nichos, planos guia, retenções). Resultados: Foram avaliados 121 modelos, dos quais apenas 36 (29,8%) possuíam requisição por escrito e somente 11 (9,1%) possuíam indicação do desenho das estruturas metálicas. Foram verificadas bolhas positivas e/ou negativas em 85 (70%) modelos. Apenas 22(18,2%) apresentavam nichos e 6 (5%) possuíam evidências de preparos de planos guia. 76 (62,8%) apresentavam paralelismo relativo das superfícies dos dentes pilares e em 74 (61,2%) as retenções foram consideradas adequadas. Conclusões: A qualidade dos modelos e requisições encaminhados aos laboratórios para confecção de PPR é precária. Na maioria dos casos, o planejamento da estrutura metálica é delegado ao técnico de prótese dentária e os preparos dentais básicos para PPR não são realizados.

Objective: This paper aims to evaluate the planning of frameworks for Removable Partial Denture and quality of casts and work orders sent to dental laboratories. Material and Methods: The sample consisted of casts and prescriptions sent by dentists to four commercial dental laboratories located in Goiânia-GO selected from a list provided by the city health surveillance. For data collection it was used a structured form. The casts were grouped according to the classification of Kennedy (1925) and the Rules of Applegate (1935). Additional information was grouped into the following categories: cast general condition (place of pouring, impression material, plaster type, presence of blisters on cast surfaces), work orders sent to dental laboratories (evaluated according to explicitness of information contained therein) and framework planning (framework design, quality of dental preparations ? rest seats, guide planes, retention). Results: It were assessed a total of 121 casts, and 36(29.8%) had a prescription of the work to be done and 11(9.1%) of all casts had the design of frameworks to be made. Only 22(18.2%) casts had rest seats prepared. Only 6(5%) had evidence of preparation of guide planes, 76(62.8%) had a relative parallel surfaces between edentulous spaces and 74(61.2%) regions which receive retention clasp arms were considered suitable. Conclusions: The quality of casts and work orders sent to the dental laboratories is precarious. The planning stage for removable partial denture, in most cases, is delegated to the dental lab, where professionals do not even bother to make the basic dental preparations for this kind of rehabilitation.