National Institute of Health Dr. Ricardo Jorge
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Overweight, Obesity, And Cardiovascular Disease In Heterozygous Familial Hypercholesterolaemia: The EAS FH Studies Collaboration Registry
No full textBackground and aims: Overweight and obesity are modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population, but their prevalence in individuals with heterozygous familial hypercholesterolaemia (HeFH) and whether they confer additional risk of ASCVD independent of LDL cholesterol (LDL-C) remains unclear.
Methods: Cross-sectional analysis was conducted in 35 540 patients with HeFH across 50 countries, in the EAS FH Studies Collaboration registry. Prevalence of World Health Organization-defined body mass index categories was investigated in adults (n = 29 265) and children/adolescents (n = 6275); and their association with prevalent ASCVD.
Results: Globally, 52% of adults and 27% of children with HeFH were overweight or obese, with the highest prevalence noted in Northern Africa/Western Asia. A higher overweight/obesity prevalence was found in non-high-income vs. high-income countries. Median age at familial hypercholesterolaemia diagnosis in adults with obesity was 9 years older than in normal weight adults. Obesity was associated with a more atherogenic lipid profile independent of lipid-lowering medication. Prevalence of coronary artery disease increased progressively across body mass index categories in both children and adults. Compared with normal weight, obesity was associated with higher odds of coronary artery disease in children (odds ratio 9.28, 95% confidence interval 1.77-48.77, adjusted for age, sex, lipids, and lipid-lowering medication) and coronary artery disease and stroke in adults (odds ratio 2.35, 95% confidence interval 2.10-2.63 and odds ratio 1.65, 95% confidence interval 1.27-2.14, respectively), but less consistently with peripheral artery disease. Adjusting for diabetes, hypertension and smoking modestly attenuated the associations.
Conclusions: Overweight and obesity are common in patients with HeFH and contribute to ASCVD risk from childhood, independent of LDL-C and lipid-lowering medication. Sustained body weight management is needed to reduce the risk of ASCVD in HeFH.The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron. K.I.D. acknowledges support for a PhD Studentship from the National Institute for Health and Care Research (NIHR) Applied Research Collaboration Northwest London. K.K.R. acknowledges support from the NIHR Applied Research Collaboration Northwest London and Imperial NIHR Biomedical Research Centre. A.J.V.-V. acknowledges support from the Programme “Beatriz Galindo” from the Ministry of Universities, Spain, and University of Seville, Spain. A.L.C. is supported in part by the grant Ricerca Corrente from the Ministry of Health to IRCCS MultiMedica. H.N. acknowledges support from the Ministry of Higher Education (MOHE), National Professorial Council (MPN) and Universiti knologi MARA (UiTM), Malaysia. The Austrian Familiar Hypercholesterolemia Registry, which contributed to the FHSC registry, has been supported by funds form the Austrian Heart Foundation and the Tyrolean Regional Government
Extension of Poultry Meat Shelf Life Using Cynara cardunculus L. Leaf Extracts as a Natural Preservative
No full text(This article belongs to the Special Issue Preservation and Shelf Life Extension of Food Products)Food additives are used to prevent food spoilage and extend its shelf life. However, con cerns regarding the potential health implications associated with some synthetic additives have prompted research efforts aimed at identifying natural alternatives, such as plant extracts. Cynara cardunculus L. (cardoon) is known for its antimicrobial and antioxidant properties. The aim of this study was to evaluate the capability of ethanolic food-grade extracts from cultivated cardoon and globe artichoke leaves to preserve poultry breast meat during refrigerated storage. A total of seven treatment groups were tested: one control group (no extract) and six active groups with 0.5%, 1%, and 2% (w/w) of either cultivated cardoon or globe artichoke leaf extracts. Lipid oxidation, moisture, colour, pH, acidity, and microbial growth were assessed in poultry meat samples over 15 days. Both extracts were effective in extending shelf life, up to 11 days, by delaying lipid oxidation and microbial growth. Cardoon extract (1% w/w) displayed superior antimicrobial efficacy, maintaining microbial counts below 5 Log CFU/g meat until day 15, compared to the control. Culti vated cardoon leaf extract proves promising as a natural antimicrobial and antioxidant, extending the shelf life of poultry meat. This presents an opportunity to maintain the quality of meat products, aligning with consumer preferences for natural ingredients and sustainable practices.CardAPium Project (2023.15813.PEX) financed by Portuguese national funds Fundação para a Ciência e a Tecnologia (FCT) (https://doi.org/10.54499 /2023.15813.PEX).
Ph.D. scholarship from Fundação para a Ciência e Tecnologia (FCT)—2021.08154.BD (https://doi.org/10.54499/2021.08154.BD). Company NINA, Lda, for kindly supplying the cardoon leaves
Patient and family engagement interventions for enhancing patient safety in the perioperative journey: a scoping review
No full textBackground: Surgical procedures present intricate challenges within healthcare delivery, often associated with higher risks of adverse events compared with non-surgical contexts. Patient and family engagement (PFE) throughout the perioperative journey is a possibility to enhance care quality, safety and patient-centredness. However, literature addressing PFE across the entirety of the perioperative journey remains sparse.
Objective: The current scoping review aims to comprehensively map the existing interventions with PFE approach focused on improving patient safety across various types of surgical procedures throughout the perioperative journey. In addition, the review aims to understand the level and type of PFE approach adopted in this context.
Eligibility criteria: Articles published in indexed peer-reviewed journals from 2003 to 2023, written in English, Portuguese or Spanish, that report on interventions with PFE approach targeting adult surgical patients, their families, caregivers, patient advocates and patient champions. The review includes articles reporting on both inpatient and ambulatory surgical patients.
Methods: Following Joanna Briggs Institute guidelines and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews framework, this review systematically searched PubMed, Web of Science, SCOPUS, CINAHL, and PsycINFO for relevant articles. Eligible interventions were categorised using PFE framework regarding the level of engagement and mapped according to the WHO Global Patient Safety Action Plan 2021-2030.
Results: Out of 765 records initially identified, 32 met the eligibility criteria for data extraction and analysis, of which 40% originated from the USA, followed by the UK (18%) and Canada (12%). 47% of the interventions targeted 'multiple/all types' of procedures, 19% focused on cardiothoracic surgeries and 9% on gynaecological procedures or organ transplant. The majority of the interventions (88%) focused on PFE at the direct care level, predominantly adopting a consultation-based approach. Furthermore, 81% of eligible interventions emphasised patient information and education, 16% addressed codevelopment of policy and 3% of interventions focused on patient advocacy.
Conclusion: The findings show a predominant focus on PFE interventions targeting patient safety at the direct care level, particularly in the provision of patient information and education. However, interventions at organisational and policy-making levels are notably scarce. Further investment is required to promote interventions engaging patients and families at broader organisational and policy-making levels.What is already known on this topic: Prior research has shown that surgical patients are at 2.3 times higher risk of adverse events, highlighting the potential role of patient and family engagement (PFE) approach in improving patient safety and quality in healthcare. Nonetheless, the current body of literature falls short of providing a holistic understanding of PFE across the entire perioperative process, underscoring the necessity for more in-depth exploration.
What this study adds: This study provides a comprehensive mapping of the interventions using PFE approach across various periods of the perioperative journey, highlighting their focus areas, geographical distribution and type of surgical procedure. The findings show that most of the interventions adopted consultation type of PFE approach with fewer using involvement or partnership and shared leadership. In addition, the study reveals a predominance of PFE interventions at the direct care level, particularly in patient information and education, while also identifying a scarcity of interventions targeting organisational and policy-making levels.
How this study might affect research, practice or policy: The study highlights the pressing need for expanded PFE interventions at organisational and policy-making levels, as well as across the entire spectrum of the engagement continuum.The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020
Functional networks of DI3L2 in cancer
No full textThe DIS3-like 3′-5′ exoribonuclease 2 (DIS3L2) triggers decay in an exosome-independent manner and preferentially degrades RNA species possessing a non-templated oligo-uridine 3’-end tail. It is capable of inducing decay over a variety of RNAs, including mRNAs, rRNAs, miRNAs and other non-coding RNAs. It has been shown that DIS3L2 is involved in cancer-related cellular processes. Nevertheless, its function in tumorigenesis remains largely unexplored. Recently, we and others showed that DIS3L2-mediated decay together with uridylation also participate in nonsense-mediated mRNA decay (NMD), thus revealing a new NMD branch. NMD is a surveillance pathway that recognizes and degrades mRNAs harboring premature translation-termination codons, protecting the cell from potentially harmful truncated proteins. However, NMD also regulates the level of normal and fully functional mRNAs, arising as a mechanism of gene expression regulation. Here, we aim to analyze how DIS3L2 and uridylation regulate the human transcriptome, in order to shed light on how this ribonuclease is related to NMD and how its deregulation contributes to tumorigenesis. For this purpose, high-throughput mRNA sequencing has been performed in the SW480 colorectal cancer cell line depleted of DIS3L2 or DIS3L2 plus terminal uridylyl transferases 4 and 7. Gene ontology analysis over the set of genes up-regulated under those two conditions, show enrichment in molecular functions and biological processes related with cancer, and cell events directly implicated in RNA processing and RNA degradation. Preliminary results on the features of the deregulated transcripts also show significant differences between conditions, an important aspect that is guiding us to determine grades of sensitivities in the decay of DIS3L2-subtrates. Currently, we are unveiling the role of DIS3L2 in oncogenesis and analyzing its substrate specificity.N/
Translational switch during integrated stress response: the examples of p53 and UPF1
No full textThe scanning model for eukaryotic mRNA translation initiation states that the small ribosomal subunit, along with initiation factors, binds to the cap structure at the 5’ end of the mRNA and scans the 5’ untranslated region (5’UTR) until an initiation codon is found. However, when cells are exposed to stress stimuli, cap-dependent translation is inhibited, while the synthesis of some proteins is maintained by alternative mechanisms of translation initiation, which are vital for cell survival and stress recovery. Here we show two examples in which a translational switch occurs during integrated stress response (ISR).
In the first case, tumor suppressor p53, we show that the ISR leads to the specific induction of a shorter p53 isoform (Δ160p53 isoform). This induction is dependent on translation elongation but does not require the eIF4E-eIF4G interaction. Studies using bicistronic constructs with wild-type Δ160p53 or reporter genes confirmed the presence of an Internal Ribosome Entry Site (IRES) in p53 mRNA, being eIF2α phosphorylation a key event leading to cap-independent expression of Δ160p53 during ISR. Interestingly, cancer-specific mutations in p53 also enhance cap-independent translation of Δ160p53 via Δ160p53IRES. Our data support a model in which an IRES structure in the coding region of p53, and the cancer-specific mutations that affect this structure, control p53 oncogenic functions by regulating Δ160p53 protein expression. A better understanding of Δ160p53IRES structure and function may be advantageous for a more efficient therapeutic targeting of p53.
Human up-frameshift 1 (UPF1) is a key-protein involved in nonsense-mediated mRNA decay, telomere replication and homeostasis, and cell cycle progression. These crucial UPF1 functions suggest its tight gene expression regulation. Indeed, our results show that UPF1 5’UTR is able to mediate cap-independent translation in a bicistronic luciferase vector expressed in cervical and colorectal cancer cell lines. Such activity is maintained under endoplasmic reticulum stress. Interestingly, we found that the UPF1 5’UTR IRES function is inhibited when the first 100 nucleotides, or the last 125, are absent or altered. Understanding these IRESs mechanism of function and their biological relevance might provide tools for developing new therapies for human diseases such as cancer.This work was supported by grants PTDC/MED-ONC/32048/2017 and PTDC/BIM-ONC/4890/2014 from the Fundação para a Ciência e a Tecnologia (FCT), by Grants-in-Aid
16K21111 and 18K07229 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, by Takeda Foundation and Astellas Grant, by Instituto
Nacional de Saúde Doutor Ricardo Jorge, and by UIDB/04046/2020 and UIDP/04046/2020 Centre grants from FCT, Portugal (to BioISI).info:eu-repo/semantics/publishedVersio
Translation of the human ABCE1 transcript is regulated by upstream open reading frames
No full textShort upstream open reading frames (uORFs) are cis-acting elements located within the 5'-leader sequence of transcripts and are defined by an initiation codon in-frame with a termination codon located upstream or downstream of its main ORF (mORF) initiation codon. Recent genome-wide ribosome profiling (Ribo-seq) studies have confirmed the widespread presence of uORFs and have shown that many uORFs can initiate with non-AUG codons. uORFs can impact gene expression of the downstream mORF by triggering mRNA decay or by regulating translation.
Based on 5’-leader sequence ribosome occupancy profiles from Ribo-seq analysis in HCT116 cells, we studied the role of 6 non-AUG and 5 AUG uORFs present in the human ABCE1 mRNA. Using a set of reporter genes expressed in HCT116 cells and luminometry assays, we have observed that there are three AUG uORFs acting in a fail-safe manner to inhibit translation from the main AUG, being this repression immune to eIF2 phosphorylation. Functional aspects and implications of this regulatory mechanism to cell physiology will be discussed.Work partially funded by UID/MULTI/04046/2013 centre grant from FCT, Portugal (to BioISI), and by National Institute of Health Dr. Ricardo Jorge. J.F.P.S., is recipient of a fellowship from BioSys PhD programme (Ref SFRH/BD/106081/2015) from FCT (Portugal)info:eu-repo/semantics/publishedVersio
RNA structure-function analysis of regulatory regions of p53 mRNA
No full textAt least half of all tumors exhibit mutations in the tumor suppressor p53 gene. Indeed, the fact that p53 is frequently mutated in cancer led to its identification as an oncogene, when first described in 1979. Later, it was classified as a tumor suppressor, due to the clarification of its wild-type role in maintaining genome integrity and preventing malignant transformation. The p53 gene can encode for many p53 isoforms, by alternative splicing, alternative promoters and internal translation initiation mechanisms. While full-length p53 (FL-p53) protein works as a tumor suppressor by regulating many biological processes such as cell cycle, apoptosis, senescence and DNA repair, shorter p53 protein isoforms seem to play different roles in the cell. Recently, we have shown that the most common p53 mutations induce the expression of shorter p53 isoforms. Furthermore, we found that shorter p53 isoforms are implicated in cancer progression as they promote enhanced cell survival, proliferation, adhesion and formation of invasive cell structures. Here, with a bicistronic system containing two reporter genes (Renilla luciferase and firefly luciferase), we show that expression of shorter p53 isoforms is mediated by a non-canonical translation initiation mechanism regulated by an Internal Ribosome Entry Site (IRES) in the p53 mRNA. By investigating the effect of common p53 missense mutations on the function of this new IRES, through bioluminescence assays and Western blot analysis, we show that some p53 cancer mutations have a preponderant role in IRES-mediated translation induction of shorter p53 isoforms. With the obtained results we identified a new mechanism by which p53 cancer mutations promote tumorigenesis, which may lead to new understandings of the onset and progression of some types of tumors as well as to the development of new cancer therapies.This work is supported by grants PTDC/MED-ONC/32048/2017 and PTDC/BIMONC/4890/2014 from the Fundação para a Ciência e a Tecnologia, by Grants-in-Aid
16K21111 and 18K07229 from the Ministry of Education, Culture, Sports, Science
and Technology (MEXT) of Japan, by Takeda Foundation and Astellas Grant.info:eu-repo/semantics/publishedVersio
O papel das ribonucleases SMG6 e PM/SCL100 em mecanismos de degradação do RNA mensageiro
No full textDissertação de mestrado em Biologia Molecular e Celular, apresentada à Universidade de Aveiro, 2016Orientação científica de Doutora Luísa Romão Loison, Investigadora principal do Grupo de Metabolismo do mRNA do Departamento de Genética Humana do Instituto Nacional de Saúde Doutor Ricardo Jorge, em Lisboa, e de Doutor Luís Souto Miranda, Professor auxiliar do Departamento de Biologia da Universidade de AveiroEukaryotic gene expression comprises a series of interconnected steps, from transcription to protein synthesis, in which messenger RNAs (mRNAs) are the key intermediates. While the multitude of events that take place throughout the whole process allows for the production of proteins to be controlled at many levels, ensuring maximum efficiency and fidelity, it also makes gene expression susceptible to errors. Eukaryotic cells have developed intricate mRNA quality control mechanisms that recognise and degrade aberrant transcripts. Two examples of these mechanisms are the nonsense-mediated mRNA decay (NMD), which targets mRNAs with premature translation termination codons (PTCs), and the nonstop mRNA decay (NSD), which eliminates mRNAs lacking any in-frame translation termination codons. SMG6 and PM/Scl100 are both ribonucleases which have been implicated in mRNA degradation pathways. One of the mechanisms proposed for mammalian NMD involves an endonucleolytic cleavage of transcripts in the vicinity of the PTC catalyzed by SMG6. On the other hand, the human exosome, which includes the catalytic subunit PM/Scl100, has been associated not only with mRNA surveillance mechanisms, but also with normal mRNA turnover. However, questions relative to the specificity or indispensability of these enzymes in the pathways in which they participate have not yet been answered. The present work aimed to explore the role of SMG6 and PM/Scl100 ribonucleases in the degradation of normal or NSD- and NMD-sensitive mRNAs. The results obtained point to the involvement of SMG6, not only in NMD, but also in NSD and normal mRNA turnover. Moreover, they suggest that SMG6 plays an indirect role on the degradation of NMD targets. PM/Scl100 also appears to intervene in NMD, NSD and normal mRNA turnover; however, the results herein presented suggest that the main contribution to NMD-eliciting transcripts 3’→5’ degradation may be offered by other exoribonucleases.A expressão génica em eucariotas envolve uma série de etapas interligadas,
desde a transcrição do material genético até à síntese da proteína
correspondente, nas quais os RNAs mensageiros (mRNAs) são os
intermediários cruciais. Embora a panóplia de eventos que ocorrem ao longo de
todo o processo permita que a produção proteica seja controlada a vários níveis,
também torna a expressão génica vulnerável a erros. As células eucarióticas
desenvolveram mecanismos elaborados de controlo de qualidade do mRNA que
reconhecem e degradam transcritos anómalos. Dois exemplos destes
mecanismos são o decaimento do mRNA mediado por mutações nonsense
(NMD), que detecta mRNAs com codões de terminação da tradução prematuros
(PTCs), e o decaimento do mRNA nonstop (NSD), que elimina mRNAs que não
possuem codões de terminação da tradução em fase na grelha de leitura. A
SMG6 e a PM/Scl100 são ambas ribonucleases já implicadas em vias de
degradação do mRNA. Um dos mecanismos propostos para o NMD em
mamíferos envolve a clivagem endonucleolítica dos transcritos na proximidade
do PTC, catalizada pela SMG6. Por outro lado, o exossoma humano, que inclui
a subunidade catalítica PM/Scl100, já foi associado não só com mecanismos de
vigilância do mRNA, mas também com o turnover do mRNA. No entanto,
questões relativas à especificidade ou indispensabilidade destas enzimas nos
mecanismos nos quais participam ainda não têm resposta. O presente trabalho
teve como objectivo explorar o papel das ribonucleases SMG6 e da PM/Scl100
na degradação de mRNAs normais ou sensíveis ao NSD e ao NMD. Os
resultados obtidos apontam para o envolvimento da SMG6, não só no NMD,
mas também no NSD e no turnover do mRNA. Para além disso, sugerem
também que a SMG6 desempenha um papel indirecto na degradação de alvos
do NMD. A PM/Scl100 também parece intervir no NMD, no NSD e no turnover
do mRNA; no entanto; os resultados aqui apresentados sugerem que a principal
contribuição para a degradação 3’→5’ de transcritos que desencadeiam o NMD
é oferecida por outras exoribonucleases.N/
Mechanistic aspects of nonsense-mediated mRNA decay in human cells
No full textThe nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs carrying a premature translation-termination codon but also regulates the abundance of a large number of physiological RNAs that encode full-length proteins. NMD results from improper translation termination at stop codons, and thus, it is a cytoplasmic and translation-dependent process. In human cells, mRNA decay inherent to NMD involves an endonucleolytic cleavage near the stop codon and exonucleolytic degradation from both 5’ and 3’ ends. This is done by a process not yet completely understood that recruits decapping and 5’-to-3’ exonuclease activities, as well as deadenylating and 3’-to-5’ exonuclease exosome activities. In yeast, DIS3/Rrp44 protein is the catalytic subunit of the exosome, but in humans, there are three known paralogues of this enzyme: DIS3, DIS3L1, and DIS3L2. However, DIS3L2 exoribonuclease activity is independent of the exosome. DIS3L1 and DIS3L2 exoribonucleases localize in the same compartment where NMD occurs, however little is known about their role in this process. In order to unveil the role of DIS3L2 in NMD, we performed its knockdown in HeLa cells and measured the mRNA levels of various natural NMD-targets. Our results show that some NMD-targets accumulate in DIS3L2-depleted cells. In addition, mRNA half-life analysis indicated that these NMD-targets are direct DIS3L2 substrates. Besides, we observed that DIS3L2 acts over full-length transcripts, being DIS3L2-mediated decay dependent on the activity of the terminal uridylyl transferases (TUTases) Zcchc6/11 (TUT7/4). Together, our findings establish the role of DIS3L2 and uridylation over human NMD-targets.PTFC/BIM-MEC/3749/2014; UID/MULTI/04046/2013N/