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Study of the association of differential allelic expression with breast cancer clinical features
No full textGenome-wide association studies have identified thousands of low-risk variants associated with BC. Since most associated variants are in non-coding regions of the genome and can be in linkage disequilibrium with many others, it’s difficult to pinpoint the true causal variant and its target gene.
Post-GWAS functional analysis have shown that altering the expression of genes by cis-acting variants is a common mechanism involved in risk for breast cancer (BC). Therefore, we hypothesize that germline cis-regulatory variants may determine/contribute to tumour clinical features. We propose to test the association of allelic expression (AE) ratios with BC tumours clinical features and patient’s survival. Differences in allelic ratios distributions between tumours with different molecular profiles would indicate a different genetic background for cis-regulatory variants between these tumours. To perform this analysis, we used The Cancer Genome Atlas – Breast Cancer (TCGA-BRCA) normal-matched dataset, and with the R programming language, we complemented this data with allelic expression ratios in various SNPs previously calculated, resulting in a dataset of 105 patients with both clinical and AE data.
We identified 63 variants displaying significant effect sizes (|Hedges’s G| ≥ 0.5, 95% interval not crossing 0) for ER statuses, 119 for PR status and 58 for HER2 status, some of them associated with two receptor statuses. Only one variant (rs3764859 in COQ6 and ENTPD5 genes) was found statistically associated with ER status after correction for multiple testing (q-value ≤ 0.1). Additionally, six of the variants were also associated with survival including rs2236225, a variant located at gene MTHFD1 that showed a larger expression difference in both negative ER and PR populations compared to their positive counterparts.
We found evidence that cis-acting variants may determine BC clinical features and disease development, and therefore BC subtypes. However, these findings need to be replicated in an independent dataset to be validated.O cancro da mama feminino representa 11,7% de incidência de cancro a nível mundial, constituindo o cancro mais comum, reclamando 6,9% da mortalidade mundial associada com cancro. Em Portugal, o cancro da mama é a neoplasia mais comum nas mulheres (26,4%) sendo responsável pela maior fração de mortalidade feminina relacionada com cancro (15,5%). A biologia tumoral e quadro clínico fazem o cancro da mama uma doença heterogénea, que pode ser subdividida em diferentes subtipos de tumor da mama com perfis de expressão génica distintos. É também uma doença complexa que engloba fatores de risco ambientais e genéticos na sua etiologia. Estudos de associação do genoma completo (GWAS) já identificaram milhares de variantes de baixo risco associadas com cancro da mama, e inclusive, quatro subtipos específicos de tumores. Contudo, a maioria das variantes associadas estão em regiões não codificantes do genoma, e cada variante identificada pode estar em desequilíbrio de ligação (LD) com outras variantes, o que dificulta localizar verdadeira a variante causal e o seu gene alvo com precisão e confiança.
A importância e valor intrísico deste estudo consiste na identificação de variantes que podem estar associadas a cancro da mama e os seus subtipos. Estas associações acarretam implicações e ramificações importantes para o estudo da patologia em questão, uma vez que podem elucidar mecanismos de atuação da doença bem como a biologia de mesma. Esta melhor compreensão permite prever como e que o carcinoma evolui em populações de subtipos específicos e de que forma esta pode responder a terapia de acordo com as mutações adquiridas.
O cancro da mama, pode apresentar combinações específicas de caraterísticas moleculares e devido a essa peculiaridade, é possível agrupar os tumores em subtipos de cancro da mama que expressam e deixam de expressar uma gama de recetores, originando uma chave de expressão génica tumoral. O subtipo mais comum é identificado como Luminal A e carateriza-se pela maior expressão dos recetores de estrogénio (ER) e progesterona (PR) enquanto a expressão de recetor tipo 2 do fator de crescimento epidérmico humano (HER2) está reduzida. Por ordem de maior para menor incidência, o Luminal A (ER+/PR+/HER2-) é seguido por Luminal B (ER+/PR-/HER2+), Triplo Negativo (ER-/PR-/HER2-) e HER2-enriquecido (HER2+).
A maioria dos casos de cancro da mama são esporádicos, contudo cerca de 20%-30% apresentam hereditariedade, dos quais 5-10% apresentam uma forte componente herdada e um risco acrescido. Esta componente herdada tem diferentes graus de risco para o seu portador, que pode chegar a um risco acrescido de 10 a 20 vezes, como no caso dos portadores de mutações patogénicas nos genes BRCA1 e BRCA2, apesar de conjuntamente apresentarem uma frequência apenas de 0.4% em cancro da mama. Num grau intermédio, mutações em genes como CHEK2 e ATM conferem o dobro do risco de cancro da mama, e por último, as componentes hereditárias de baixo risco (inferior a 1.5) são normalmente causadas por polimorfismos de nucleótido único (SNP) como o polimorfismo Pro919Ser no gene BRIP1. A introdução dos estudos de associação do genoma inteiro possibilitou a descoberta de centenas de variantes de baixo risco associadas com cancro da mama, e também associadas especificamente com subtipos moleculares de cancro da mama, que apresentam sobre ou subre expressão de recetores hormonais.
A análise funcional pós-GWAS das variantes associadas a risco demonstrou que a alteração da expressão génica por variantes cis-regulatórias constitui um mecanismo comum envolvido em risco para cancro da mama. Estas variantes regulam a expressão dos genes de um modo específico para cada um dos alelos do gene, estando geralmente associados a regiões regulatórias como promotores ou enhancers. Consequentemente, propusémos a hipótese que as variantes cis-regulatórias na linha germinal podem não só contribuir para risco mas também para determinar as características tumorais e quadro clínico do paciente. Para responder a esta pergunta, testámos a associação dos rácios de expressão alélica (AE) - um valor que mede diretamente o efeito de variantes cis-regulatórias – com caraterísticas clínicas de tumores da mama e sobrevivência dos pacientes. De modo a efetuar esta análise, foi utilizado o conjunto de dados The Cancer Genome Atlas – Breast Cancer (TCGA-BRCA) tecido normal-tumoral adjacente, para o qual possuímos dados de rácios de expressão alélica para vários polimorfismos de nucleótido único localizados em regiões transcritas de genes, assim como informação clínica para 105 indivíduos.
Testámos estatisticamente (recorrendo a linguagem de programação R) a associação entre rácios de expressão alélica (AE) medidos em 8039 SNPs expressos (aeSNPs) num número variável de indivíduos heterozigóticos para estas variantes, e a presença ou ausência dos recetores de estrogénio (ER), progesterona (PR) e sobre-expressão do fator de crescimento epidérmico humano 2 (HER2). Para esta análise aplicou-se o teste t de Student para variantes com rácios de AE que seguiam uma distribuição normal ou Mann-Whitney para variantes cujos rácios de AE apresentavam uma distribuição não normal, de acordo com os resultados do teste de normalidade Shapiro-Wilk. De forma a quantificar o tamanho de efeito (“effect size”) de AE entre tumores com presença ou ausência de receptores, utilizou-se o teste de Hedges’ G. A análise de sobrevivência de acordo com os rácios de AE foi executada nos aeSNPs que apresentavam um tamanho de efeito significativo, usando um teste Two Stage Hazard Rate Comparison (TSHRC).
Identificámos 63 variantes que demonstravam tamanhos de efeito significantes de acordo com a presença/ausência de ER, 119 de PR e 58 sobre-expressão de HER2, e alguns destes, inclusive, associados com mais do que um recetor. Apenas uma variante (rs3764859 localizada nos genes COQ6 e ENTPD5) apresentou-se estatisticamente associada com a presença/ausência do recetor de estrogénio após correção para testes múltiplos (q-value ≤ 0.1). Uma variante em particular - rs2236225, demonstrou uma elevada diferença na distribuição dos rácios de AE nas populações ER e PR negativas quando comparadas com a fração positiva e já foi previamente associada com mau prognóstico em mulheres na pré menopausa. Finalmente, 6 aeSNPs apresentavam valores de sobrevida livre de doença diferentes entre populações com rácios de expressão alélica opostos de acordo com o TSHRC.
Neste trabalho encontrámos evidências de que as variantes cis-regulatórias podem determinar caraterísticas de cancro da mama e do desenvolvimento da doença, e consequentemente de subtipos moleculares de cancro da mama. Contudo, estas descobertas precisam de ser replicadas de uma forma independente noutro conjunto de dados de forma a serem validadas. Outro tipo de estudos também será necessário para mapear as variantes cis-regulatórias cujos efeitos encontrámos associados com a biologia dos tumores, e revelar qual o seu mecanismo de regulação génica inerente. Este estudo demonstra o potencial de integrar análise de expressão alélica com informação clínica para melhor compreender a etiologia dos diferentes subtipos moleculaers de cancro da mama
Environmental change in SW Portugal during the last 3900 years BP: an ostracoda assessment
No full textOstracod, geochemical, mineralogical, and sedimentological proxies from a sediment core collected off Sagres (southwestern Portugal) were used to reconstruct Holocene environmental and hydrodynamic changes. Reduced variability of geochemical elements between ~4000 and ~1290 calibrated years before present suggests relatively stable conditions, regularly disturbed by higher-energy events. At ~1290 cal yrs BP, a transition from arid to wetter conditions is suggested based on enhanced terrestrial/detrital input after this time. Ostracod assemblages further captured fine-scale hydrodynamic variability, offering greater sensitivity to oceanographic changes. Our results support a broader pattern of middle-to-late Holocene drying conditions in southern Iberia, followed by a shift to wetter conditions during periods of negative North Atlantic Oscillation (NAO) index. Our study provides new data on offshore ostracods from the western Algarve, underscoring their value for high-resolution paleoenvironmental reconstructions.LA/P/0068/202
Sources of discomfort and treatment strategies for trauma patients in the pre-hospital setting: a scoping review
No full textIntroduction: Trauma remains a leading cause of mortality and long-term disability worldwide, often causing significant discomfort during prehospital care. Addressing these discomforts effectively is crucial for improving patient outcomes. This scoping review aimed to identify and categorize the types of discomforts experienced by adult trauma victims in prehospital settings and map the pharmacologic and nonpharmacologic interventions used to mitigate them. Methods: This scoping review followed the Joanna Briggs Institute framework and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. A comprehensive search was performed in databases including MEDLINE, CINAHL, Scopus, Embase, PsycINFO, Joanna Briggs Institute Evidence Synthesis, Cochrane Database, and relevant gray literature sources. Studiesinvolving adult trauma patients(>_18 years) in prehospital care that reported on discomfort and interventions were included without restrictions on publication date. Results: Seventeen studies met the inclusion criteria, covering various international contexts. Acute pain was the most frequently reported discomfort, followed by anxiety, fear, cold-induced discomfort, and discomfort caused by immobilization. Pharmacologic interventions predominantly included opioids, nonsteroidal anti-inflammatory drugs, paracetamol, ketamine, and methoxyflurane, whereas nonpharmacologic interventions comprised acupressure, transcutaneous electrical nerve stimulation, cryotherapy, warming measures, communication strategies, and emotional support. Nonpharmacologic interventions, especially acupressure and communication techniques, showed promising results in reducing pain and anxiety. Discussion: The findings underline the multidimensional nature of discomfort in prehospital trauma care and highlight effective interventions, including pharmacologic and complementary nonpharmacologic strategies. However, significant gaps remain regarding standardized assessment tools for non–pain-related discomforts and combined interventions. This review underscores the necessity for comprehensive management protocols and further research to optimize patient comfort and care outcomes in trauma settings
Metabolism and the impact of protein intake in chronic critically ill adult patients: protocol for a unicentric prospective cohort study (MetaChronic Study)
No full textBackground: Survival of acutely critically ill patients has improved, resulting in a growing population of chronic critically ill (CCI) patients with prolonged organ dysfunction, mechanical ventilation, and high morbidity. While nutritional guidelines during the acute phase of critical illness are well defined, our understanding of metabolism and nutritional needs in CCI patients is limited. Persistent inflammation may influence the metabolic response and nutritional uptake, highlighting the need for prospective studies in this area. Methods: The MetaChronic Study is a single-center, prospective cohort study of metabolism in patients with CCI. Adult ICU patients with invasive mechanical ventilation ≥48 h and ICU stay >7 days are eligible. Patients are followed for up to 42 days after ICU admission, with final outcomes assessed at 90 days. Resting energy expenditure is measured weekly by serial indirect calorimetry. Weekly protein and calorie intake are recorded and inflammation is assessed using serum C-reactive protein and procalcitonin measurements. Patients are categorized according to high or low protein intake (>1.3 g/kg/ day vs. ≤1.3 g/kg/day after the first week). The primary objective is to characterize longitudinal metabolic trajectories. Secondary objectives include subgroup analyses (septic, trauma, neurocritical patients), assessment of the interaction between inflammation and metabolic rate, and exploratory analyses of the association between protein intake and clinical outcomes. Ethics and dissemination: The study has been approved by the institutional ethics committee. Findings will be disseminated through peer-reviewed journals and scientific conferences
Valorisation of gilthead seabream by-products through recovery of antimicrobial proteins for active biopolymer formulations
No full textIn the seafish sector, industrial processing and by-catch currently lead to the waste of over 36 % of global fish production by weight. This is largely due to insufficient revalorization of by-products and the underdevelopment of sustainable practices to manage these discarded volumes, which are often disposed of or released into the environment, contributing to pollution. In this study, antimicrobial proteins were extracted from fish by-products for incorporation into biopolymer formulations. Specifically, the focus was on lysozyme, which was targeted using a molecular-proteomic approach. Protein extractions were conducted at various pH levels from Gilthead seabream (Sparus aurata) tissues (skin with scales and mucus, liver, and intestine) normally discarded during processing, to assess recovery of proteins from the selected tissues. The extracted proteins were separated using mild ion-exchange chromatography, followed by quantification and qualitative analysis via SDS-PAGE. The expression levels of lysozyme types-g and-c were quantified through Real-Time qPCR. The antimicrobial activity of the extracted proteins was assessed against Gram-positive (Listeria monocytogenes) and Gram-negative (Escherichia coli) bacteria using a Minimal Inhibitory Concentration (MIC) assay. The proteins were subsequently incorporated into biodegradable film-forming solutions based on hydroxypropyl methylcellulose/chitosan and hydroxypropyl methylcellulose/guar gum mixtures. These films were further tested against the same human pathogens. The results demonstrate the feasibility of extracting proteins from fish by-products using a non-targeted buffer pH extraction approach, which, even without further chromatographic purification, exhibited promising intrinsic antimicrobial activity for potential applications in the food industry.UID/04326/2025, UID/PRR/04326/2025, EMBRC.PT. ALG-01-0145-FEDER-02212
Metal ecotoxicity in sea anemones: accumulation, effects, and knowledge gaps
No full textMetals are a major class of legacy pollutants that end up in marine ecosystems, posing a significant threat to marine biota, including sea anemones. The current review critically synthesises studies published over the last 50 years on the uptake, tissue distribution, and biological effects of 20 metals across 18 sea anemone species in both field and laboratory settings, including interactions with climate change stressors (salinity and pH). Field studies have focused on bioaccumulation and report the high capacity of sea anemones to accumulate metals, mainly iron and barium, primarily in the pedal disk. Laboratory exposure studies reveal a dose- and timedependent accumulation and highlight that symbionts take up and store essential metals (Cu, Fe, and Mn) due to their key biological roles. Available data point to Exaiptasia pallida as a promising model for metal ecotoxicology. Across studies, metals elicit alterations at molecular to behavioural/morphological levels, including transcriptome reprogramming, oxidative stress, and detoxification failures, as well as genotoxicity, cellular injury, immune dysfunction, metabolic and morphological disruption, reproductive impairment, and bleaching, which are generally amplified by climate change stressors. Ultimately, this review identifies key knowledge gaps and outlines future research directions on metal ecotoxicity in sea anemones. Collectively, these insights position sea anemones as informative sentinels of metal contamination in marine ecosystems.UID/00350/2025; PRT/BD/154998/2023; ALGARVE-FEDER-00764000-TOX-IN-COLD1646
Anthropogenic particles ingestion by fish larvae in important nursery areas of Iberia (South Europe)
No full textMicroplastics (MPs) are now widespread in the marine environment, and their levels are expected to rise as larger plastic debris continues to break down and new plastic waste enters the ocean. Microplastics ingestion has been documented in fish larvae, which are already particularly vulnerable to predation, environmental stressors, and starvation. This study examines for the first time MPs ingestion by wild fish larvae in Southern Iberia, focusing on two key nursery ecosystems of Portugal: the Ria Formosa coastal lagoon and the Guadiana River estuary. Fish larvae collected monthly from surface water, between April 2023 and March 2024, exhibited encounter rates (ER - Total number of ingested particles/ Total number of organisms analysed *100) of 12.99% in Ria Formosa and 11.54% in the Guadiana estuary. No significant differences were observed in ER among taxa and locations. The ingested particles ranged in size from 20 μm to 2 mm and were predominantly made of rayon, transparent and in the form of fibres. No correlation was found between the size of the larvae and that of the ingested particles. Although larval size had a positive effect on MP ingestion, this effect was not significant. There were no differences in polymer type ingestion among taxa. Our results underline the role of nursery areas as exposure spots and the underestimated pressure of the textile industry on marine ecosystems. Further research is needed to assess the potential consequences of this exposure for larval survival, recruitment success, and the health of adult fish populations.This study received Portuguese national funds from FCT - Foundation for Science and Technology through contracts UID/04326/2025 (DOI https://doi.org/10.54499/UID/04326/2025), UID/PRR/04326/2025 (DOI https://doi.org/10.54499/UID/PRR/04326/2025) and LA/P/ 0101/2020 (DOI:10.54499/LA/P/0101/2020), and from the opera
tional programmes CRESC Algarve 2020 and COMPETE 2020 through contract EMBRC.PT ALG-01-0145-FEDER-022121. Joana Cruz and Vˆania Baptista were sustained by FCT Scientific Employment Stimulus through the projects 2022.08538.CEECIND (DOI:10.54499/2022 .08538.CEECIND/CP1729/CT0005) and 2021.00956.CEECIND (DOI:10.54499/2021.00956.CEECIND/CP1678/CT0001), respectively. This work was carried out as part of the IMBRSea studies with the support of the Erasmus+programme of the European Union.info:eu-repo/semantics/publishedVersio
Early evidence of earthquake management through mobility and social network adjustments at Vale Boi (SW Iberia)
No full textTectonic processes profoundly influenced the dispersal, evolution, and archaeological record of our Paleolithic ancestors. However, in-depth reconstructions of human resilience against seismic events come mostly from contexts dating to the last 13,000 years. Here, we present geophysical, geological, geochronological, and archaeological data from the openair site of Vale Boy in southwestern Iberia, revealing how foragers mitigated earthquake impacts between ~30,000 and 24,000 years ago. At Vale Boi, faulting formed sedimentary traps that were recurrently exploited by hunter-gatherers and periodically buried by rockfalls, likely triggered by ≥5.7 Mw earthquakes. Despite seismic destruction, hunter-gatherers repeatedly returned to the site, drawn by its strategic access to key resources. They mitigated seismic risks by increasing their mobility and even abandoning Vale Boi, as seen during the Gravettian and at the early/late Proto-Solutrean transition. When seismic and climatic stressors co-occurred (Heinrich Event 2), they did not abandon the site. Instead, they adopted strategies to limit their exposure to rockfall hazard while securing access to increasingly vital coastal and estuarine resources. Until the early Proto-Solutrean, tightly knit social networks supported the survival of Vale Boi foragers during periods of high stress, such as the aftermath of seismic rockfalls. During the late Proto-Solutrean, an expansion of super-regional connections might have functioned as a proactive buffer against future tectonic shocks. Our findings demonstrate that forager resilience to seismic events relied on flexible adjustments in mobility and social connectivity. Despite limitations deriving from its single-site focus, this study underscores the value of deep archaeological sequences for disentangling human responses to intertwined geological and ecological pressures.2002.08622.CEECIND; DL57/2016/CP1361/CT0026; ALG-01-0145-FEDER-2783
Relatório científico II
No full textO segundo volume do relatório científico do projeto Gulbenkian Carbono Azul – Relatório Científico II: Os 10 principais ecossistemas de carbono azul em Portugal continental – complementa e dá suporte ao primeiro volume, Relatório Científico I: Avaliação dos ecossistemas de carbono azul em Portugal continental, ao apresentar informação detalhada, sob a forma de fichas técnicas, para cada um dos ecossistemas de carbono azul estudados. As fichas técnicas incluem a localização geográfica, os tipos de habitats e a área que ocupam, os estatutos de proteção em que estão incluídos, as estimativas de stocks e de taxas de sequestro de carbono, a qualidade ambiental, as ameaças a que estão expostos e as intervenções de conservação implementadas no passado, em curso ou outras aqui propostas para o futuro. Cada ficha culmina com o levantamento das partes interessadas locais para que sejam desencadeados processos de conservação e restauro dos sistemas em análise.info:eu-repo/semantics/publishedVersio
E Agora, José? de José Cardoso Pires e a memória antifascista
No full textE Agora, José? (1977) é o primeiro livro que José Cardoso Pires publica depois da Revolução Portuguesa (1974-1976), reunindo ensaios, textos testemunhais e de intervenção pública, anteriores, coevos ou posteriores a esse marco maior da história portuguesa contemporânea. O dever de memória leva o escritor a recapitular os efeitos castradores da ditadura sobre o campo cultural e a evidenciar a resposta contra-hegemónica antifascista em que se destacou o Neo-realismo. Subsequentemente identifica o substrato antifascista da floração revolucionária,
analisando as suas conquistas, impasses e derrotas no Portugal democrático nascido a 25 de Abril de 1974. Assim se conjugam a auto-representação do escritor que se olha ao espelho depois dos 50 anos e a assunção de um tempo colectivo em que o júbilo emancipatório de Abril sofreu já um golpe contra-revolucionário e os vencedores daquele processo histórico forjam um consenso para obliterar a memória da resistênciainfo:eu-repo/semantics/publishedVersio