Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics

Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n 5 412) to determine if these alterations could be used to distinguish GCT from other osteoclast-rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast-rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast-rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution.

Introduction to the Special Section Value Development from Middle Childhood to Early Adulthood: New Insights from Longitudinal and Genetically Informed Research

Research into values at an early age has only started recently, although it has expanded quickly and dynamically in the past years. The purpose of this article is twofold: First, it provides an introduction to a special section that aims to help fill the gap in value development research. The special section brings together four new longitudinal and genetically informed studies of value development from the beginning of middle childhood through early adulthood. Second, this article reviews recent research from this special section and beyond, aiming to provide new directions to the field. With new methods for assessing children's values and an increased awareness of the role of values in children's and adolescents' development, the field now seems ripe for an in-depth investigation. Our review of empirical evidence shows that, as is the case with adults, children's values are organized based on compatibilities and conflicts in their underlying motivations. Values show some consistency across situations, as well as stability across time. This longitudinal stability tends to increase with age, although mean changes are also observed. These patterns of change seem to be compatible with Schwartz's (1992) theory of values (e.g., if the importance of openness to change values increases, the importance of conservation values decreases). The contributions of culture, family, peers, significant life events, and individual characteristics to values are discussed, as well as the development of values as guides for behavior.

Reciprocal relations across time between basic values and value-expressive behaviors: A longitudinal study among children

Tracing children’s values and value-expressive behavior over a sixth-month period, we examined stability and change of values and behavior and the reciprocal relations between them. Three hundred and ten sixth-grade students in Italy completed value and value-expressive behavior questionnaires three times in three-month intervals during the scholastic year. We assessed Schwartz's (1992) higher-order values of conservation, openness to change, self-enhancement, and self-transcendence, as well as their respective expressive behaviors. Reciprocal relations over time between values and behaviors were examined using a cross-lagged longitudinal design. Results showed that values and behaviors had reciprocal longitudinal effects on one another, after the stability of the variables was taken into account (i.e., values predicted change in behaviors, but also behaviors predicted change in values). Our findings also revealed that: (1) values were more stable over time than behaviors, and (2) the longitudinal effect of values on behaviors tended to be stronger than the longitudinal effect of behaviors on values. Findings are discussed in light of the recent developmental literature on value change.

Do financial distress and liquidity crises affect value and size premiums?

This study investigates the impact of liquidity crises on the relationship between stock (value and size) premiums and default risk in the US market. It first examines whether financial distress can explain value and size premiums, and then, subsequently, aims to determine whether liquidity crises increase the risk of value and size premium investment strategies. The study employs a time-varying approach and a sample of US stock returns for the period between January 1982 and March 2011, a period which includes the current liquidity crisis, so as to examine the relationship between default risk, liquidity crises and value and size premiums. The findings indicate that the default premium has explanatory power for value and size and premiums, which affect firms with different characteristics. We also find that liquidity crises may actually increase the risks related to size and value premium strategies.

Creating shared value – a nova abordagem estratégica de Responsabilidade social empresarial

Dissertação de Mestrado apresentada ao Instituto Supeior de Contabilidade e Administração do Porto para a obtenção do grau de Mestre em Marketing Digital, sob a orientação da Doutora Sandrina Francisca Teixeira

Constructing Cultural Policies in Romania. A possible model for communicating the national value system

The premise of this paper is that a model for communicating the national value system must start from a strategy aimed at the identification, the cultivation and communication of values that give consistency to the value system. The analysis concentrates on the elements of such strategies and on the implications of applying a value communication program on the identity architecture of the community. The paper will also discuss the role of the national value system in the context of the emerging global culture, where the individual has the power to create his/her own hybrid cultural model.

Effect of peel and seed removal on the nutritional value and antioxidant activity of tomato (Lycopersicon esculentum L.) fruits

The effect of peel and seed removal, two commonly practiced procedures either at home or by the processing industry, on the physicochemical properties, bioactive compounds contents and antioxidant capacity of tomato fruits of four typical Portuguese cultivars (cereja, chucha, rama and redondo) were appraised. Both procedures caused significant nutritional and antioxidant activity losses in fruits of every cultivar. In general, peeling was more detrimental, since it caused a higher decrease in lycopene, bcarotene, ascorbic acid and phenolics contents (averages of 71%, 50%, 14%, and 32%, respectively) and significantly lowered the antioxidant capacity of the fruits (8% and 10%, using DPPH. and b-carotene linoleate model assays, correspondingly). Although seeds removal favored the increase of both color and sweetness, some bioactive compounds (11% of carotenoids and 24% of phenolics) as well as antioxidant capacity (5%) were loss. The studied cultivars were differently influenced by these procedures. The fruits most affected by peeling were those from redondo cultivar (-66% lycopene, -44% b-carotene, -26% ascorbic acid and -38% phenolics). Seeds removal, in turn, was more injurious for cereja tomatoes (-10% lycopene, -38% b-carotene, -25% ascorbic acid and -63% phenolics). Comparatively with the remaining ones, the rama fruits were less affected by the trimming procedures.

Models and tools for value systems analysis in collaborative environments

Dissertation to obtain the degree of Doctor in Electrical and Computer Engineering, specialization of Collaborative Networks

A technology diffusion perspective of Enterprise Resource Planning across European Small and Medium Enterprises: from determinants to Use to Value

Tese apresentada como requisito parcial para obtenção do grau de Doutor em Gestão de Informação

How to increase value for customers of style in a box: The first Portuguese online platform for renting luxury dresses

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics

Drivers and barriers to value creation in mobile service delivery

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics

Differences in ERP use and value across Iberian Manufacturing and Services SMEs

Enterprise Resource Planning (ERP) system literature reports very little research on post-adoption stages, that is, actual usage and value. Even fewer studies focus on the specificities of an industry analysis. Based on the Technology-Organizational-Environment (TOE) framework and the Resource-Based View (RBV) theory, we develop a research model to measure and examine determinants of ERP use and value and their impact in the Iberian region (Portugal and Spain) across Manufacturing and Services industries in Small and Medium Enterprises (SMEs). The empirical test was conducted through structural equation modelling, using data from 261 firms in the peninsula in the Manufacturing and Service industries. Results show that amongst ERP use determinants, Training is the most important determinant for Service firms and Compatibility for Manufacturing firms. Firm size, Analytics, and Collaboration contribute to ERP Value in both industries, with Analytics being more important for the Service industry. The paper provides insight into which determinants contribute to ERP use and ERP value in Iberian Manufacturing and Services SMEs, offering managerial and academic implications.

Thomsen-Friedenreich antigens in bladder cancer: evaluation of their prognostic value

RESUMO: Introdução. O cancro de bexiga é uma patologia comum que representa o 6° e o 5° cancro mais incidente em Portugal e na Itália, respetivamente. Em mais de metade dos casos ocorre reincidência durante o primeiro ano, requerendo acompanhamento clínico ao longo da vida. A instilação intravesical de Bacillus Calmette-Guérin (BCG) (uma estirpe atenuada do Mycobacterium bovis) representa uma imunoterapia eficaz no combate ao cancro de bexiga, no entanto, muitos aspetos da interação de BCG com as células tumorais bem como com as células do sistema imunitário permanecem por desvendar. As células tumorais de bexiga expressam frequentemente as formas sialiladas dos antigénios de Thomsen-Friedenreich (TF), i.e., sialil-T (sT) e sialil-Tn (sTn). Contudo ainda se desconhece o significado da sua expressão na malignidade tumoral e se afeta a eficácia da terapêutica BCG. Objetivo do estudo. Investigar o papel dos antigénios sT e sTn no fenótipo maligno de células de cancro de bexiga bem como na resposta mediada pelo sistema imunitário à terapia com BCG. Metodologia. Para tal, foram utilizadas as linhas celulares de cancro da bexiga HT1376 e MCR, geneticamente modificadas por transdução com vetores codificantes para as sialiltransferases ST3GAL1 ou ST6GALNAC1, de forma a expressar homogeneamente os antigénios sT ou sTn respetivamente. Estes modelos celulares foram estudados após confronto com BCG. O nível de BCG internalizado foi avaliado por citometria de fluxo. O perfil global de expressão genética dos modelos celulares antes e após incubação com BCG foi analisado pela tecnologia de microarray. O perfil de citocinas secretadas pelos modelos celulares após incubação com BCG, bem como de macrófagos estimulados pelo secretoma de células de cancro de bexiga que por sua vez foram estimuladas previamente por BCG, foi estudado pelo sistema multiplex de “imuno-esferas”. Resultados. A análise do transcritoma dos modelos celulares revelou que grupos de genes envolvidos em funções específicas foram modulados em paralelo nos dois modelos celulares, após transdução, independentemente da sialiltransferase expressa. Ou seja, em células que expressavam a sialiltransferase ST3GAL1 ou ST6GALNAC1, os genes envolvidos na regulação da segregação cromossómica e na reparação do DNA foram consistentemente regulados negativamente. Genes descritos na literatura como marcadores para o cancro de bexiga foram também modulados. A incubação com BCG resultou numa tendência ao aumento da expressão de genes relevantes na preservação e estabilidade genómica e menor malignidade, no entanto, apenas em células que expressavam sT ou sTn. Entre as dez citocinas testadas, apenas a IL-6 e IL-8 foram expressas pelas linhas celulares de cancro da bexiga, com indução destas após estimulação com BCG, e principalmente em células que expressavam ST3GAL1 ou ST6GALNAC1. Em macrófagos, citocinas inflamatórias, tais como IL-1β, IL-6 e TNFα, e a citocina anti-inflamatória IL-10, foram induzidas apenas pelo secretoma de células de cancro da bexiga confrontadas com BCG, com maior relevância quando estas expressavam ST3GAL1 ou ST6GALNAC1, prevendo a estimulação de macrófagos semelhantes aos de tipo M1 e uma melhor resposta à terapia com BCG. Conclusões. O efeito geral da expressão destas sialiltransferases e dos produtos enzimáticos sT ou sTn nas células de cancro de bexiga conduz a um fenótipo de maior malignidade. Contudo, a maior avidez de estas na produção de citocinas inflamatórias após confronto com BCG, bem como a maior capacidade de estimulação de macrófagos, predirá uma resposta à terapia com BCG mais eficaz em tumores que expressem os antigénios de TF sialilados. Tais conclusões são totalmente concordantes com os nossos mais recentes dados clínicos obtidos em colaboração, que mostram que em doentes com cancro de bexiga que expressam sTn respondem melhor a terapia BCG. ----------ABSTRACT: Background. Bladder cancer is a common malignancy representing the 6th and the 5th most incident cancer in Portugal and in Italy, respectively. More than half of the cases relapse within one year, requiring though a lifelong follow-up. Intravesical instillation of Bacillus Calmette-Guérin (BCG) (an attenuated strain of Mycobacterium bovis) represents an effective immunotherapy of bladder cancer, although many aspects of the interaction of BCG with cancer cells and host immune cells remain obscure. Bladder cancer cells often express the sialylated forms of the Thomsen-Friedenreich (TF), i.e., sialil-T (sT) e sialil-Tn (sTn). However, it’s still unknown the sense of such expression in tumour malignancy and in the BCG therapy efficacy. Aim of the study. To investigate the role of the sT and sTn antigens on the malignant phenotype of bladder cancer cells and the immune mediated response to BCG therapy. Experimental. We have utilized populations of the bladder cancer cell lines HT1376 and MCR, genetically modified by transduction with the sialyltransferases ST3GAL1 or ST6GALNAC1 to express homogeneously sT or sTn antigens. The level of BCG internalized was assessed by flow cytometry. The whole gene expression profile of BCG-challenged or unchallenged bladder cancer cell lines was studied by microarray technology. The profile of cytokines secreted by BCG-challenged bladder cancer cells and that of macrophages challenged by the secretome of BCG-challenged bladder cancer cells was studied by multiplex immune-beads assay. Results. Transcriptome analysis of the sialyltransferase-transduced cells revealed that groups of genes involved in specific functions were regulated in parallel in the two cell lines, regardless the sialyltransferase expressed. Namely, in sialyltransferase-expressing cells, genes involved in the proper chromosomal segregation and in the DNA repair were consistently down-regulated, while genes reported in literature as markers for bladder cancer were modulated. BCG-challenging induced a tendency to up-regulation of the genes preserving genomic stability and reducing malignancy, but only in cells expressing either sT or sTn. Among the ten cytokines tested, only IL-6 and IL-8 were expressed by bladder cancer cell lines and up-regulated by BCG-challenging, mainly in sialyltransferases-expressing cells. In macrophages, inflammatory cytokines, such as IL-1β, IL-6 and TNFα, and the antinflammatory IL-10 were induced only by the secretome of BCG-challenged bladder cancer cells, particularly when expressing either sialyltransferase, predicting the stimulation of M1-like macrophages and a better response to BCG therapy. Conclusions. The general effect of the expression of the two sialyltransferases and their products in the bladder cancer cells is toward a more malignant phenotype. However, the stronger ability of sialyltransferase expressing cells to produce inflammatory cytokines upon BCG-challenging and to stimulate macrophages predicts a more effective response to BCG in tumours expressing the sialylated TF antigens. This is fully consistent with our recent clinical data obtained in collaboration, showing that patients with bladder cancer expressing sTn respond better to BCG therapy.

Fair value measurement: Is the debate around level II and level III assets and liabilities relevant

Double Degree. A Work Project presented as part of the requirements for the Award of a Masters Degree in Finance from the NOVA- School of Business and Economics and a Masters Degree in Business Engineering from Louvain school of Management