National Institute of Health Dr. Ricardo Jorge
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Regulatory practices on the genotoxicity testing of nanomaterials and outlook for the future
No full textHighlights: - Genotoxicity testing of chemicals requires multiple tests to cover key endpoints; - NMs have distinct properties that require adaptations of conventional testing; - Approaches for genotoxicity testing of the NMs reviewed show challenges; - The level of harmonization between different frameworks is debated; - New approach methodologies are underlined to support NMs'regulation.The toxicity of nanomaterials(NMs) is closely tied to their physicochemical properties, such as size, shape, surface chemistry, stability in biological medium, and state of agglomeration as well to their uptake by cells. Key deficiencies in standardized testing approaches have been identified and tackled in recent years. Within the landscape of new approach methods (NAMs), the aim of this work is to review existing approaches for genotoxicity testing of the NMs under different regulatory domains, with a perspective on the development of NAMs that can solve longstanding difficulties in NMs’ risk assessment. It critically examines international and European Union guidelines, highlighting the need for harmonization and the potential of NAMs to drive next-generation risk assessment. However, further collaboration, research and validation are essential to gain wider acceptance and applicability. The contribution of innovative technological approaches based on big data, artificial intelligence and machine learning, may pave powerful comparisons among different sectors and grouping strategies that will furtherance innovation in the nanotoxicology research. The future outlook for the genotoxicity testing of NMs will depend on increased cooperation between regulatory agencies, researchers, and industry stakeholders. Key steps toward overcoming current obstacles include establishing clearer pathways for data sharing, standardizing testing protocols, and fostering greater international collaboration.This work was supported by the author’s institutions and by the Partnership for the Assessment of Risks from Chemicals (PARC) that has received funding from the European Union’s Horizon Europe Research and Innovation Programme under Grant Agreement No. 101057014.
This work is part of the PARC WP6.3 Case Study 11 entitled “Analysis and evaluation of genotoxicity and carcinogenicity assessment across legislations, with a special focus on (Q)SAR based approaches”, within the PARC. The authors thank the PARC WP6 Leaders and WP6 partners for fruitful discussions
The role of prenatal diagnosis and obstetric ultrasound in the diagnosis of congenital anomalies in Portugal: a national and regional analysis with data from 2011 and 2019
No full textA scoping review of the assessment reports of genetic or genomic tests reveals inconsistent consideration of key dimensions of clinical utility
No full textObjectives: Genetic and genomic tests are the cornerstone of personalized preventive approaches. Inconsistency in evaluating their clinical utility is often cited as a reason for their limited implementation in clinical practice. Previous reviews have primarily focused on theoretical frameworks used for clinical utility evaluations of genetic tests, rather than actual assessments and examined dimensions, rather than specific indicators within these dimensions. We aimed to review the dimensions and the specific indicators measured in published assessment reports of genetic or genomic tests.
Study design and setting: We conducted a scoping review of assessment reports of genetic and genomic tests used for prevention, searching through PubMed, Web of Science, Scopus, the websites of 20 different organizations, Google, and Google Scholar. From the included assessments, we extracted the reported indicators of clinical utility, compiling a list of disease-specific indicators that detailed their numerator, denominator, and calculation methods. We analyzed the extracted indicators by stratifying them according to ten comprehensive dimensions of clinical utility, the assessment framework used, and the type of indicator (categorized as quantitative, qualitative, reference, or no evidence reported). From these indicators, we then distilled a list of general indicators.
Results: We reviewed 3054 unique references and 12,000 results from gray literature searches, ultimately selecting 57 assessment reports. The reference frameworks used were health technology assessment (HTA) (42%), Evaluation of Genomic Applications in Practice and Prevention (EGAPP) (25%), ACCE (21%), and others (12%). We identified 951 disease-specific indicators. The dimensions most frequently evaluated (ie, had at least one indicator) were analytic validity (60%), clinical validity (79%), clinical efficacy (79%), and economic impact (58%). Only 12 assessments compared health outcomes between tested and untested groups, and fewer than 15% of the assessments addressed equity, acceptability, legitimacy, and personal value.
Conclusion: Our study illustrates that, although dimensions such as equity and acceptability, are significantly emphasized in traditional evaluation frameworks, these are often not considered in the assessments. Additionally, our study has underscored a significant dearth of reported primary evidence concerning the clinical efficacy of these tests.Plain language summary: Genetic and genomic tests analyze a person's genes to predict health risks and guide healthcare decisions, potentially identifying who might benefit from certain treatments or check-ups. However, determining whether these tests are genuinely useful for wide use in health services is complex, because there is no standard way to define "clinical utility" of a genetic test. To understand how these tests are evaluated, we reviewed 57 evaluation reports from high-income countries, most of which focused on cancer-related genetic tests. We found that many evaluations looked mainly at how well a test predicted a condition (validity) and considered some form of effectiveness, yet often failed to measure whether the test truly improved patient health outcomes, such as lowering death rates or enhancing the quality of life. Moreover, factors like patient acceptance, equity, and personal relevance (eg, reducing anxiety) were frequently overlooked. Without including these broader considerations, evaluations risk missing critical evidence that would indicate whether a test is helpful, fair, and worth using. From over 900 unique indicators used to measure clinical utility, we created a simpler list of about 150 general indicators that can guide future evaluations. This consolidated list can help test developers decide which factors to investigate, evaluators determine what to measure, and policymakers identify what might be missing before deciding if a test should be adopted in healthcare. By highlighting the gaps-areas that should be assessed but currently are not-our study encourages a more comprehensive approach to evaluating genetic tests. If we fail to consider issues like equity, patient preferences, and proven health benefits, we risk investing in tests that may do little good or even harm patients. Ultimately, recognizing these shortcomings can lead to better-informed decisions, ensuring that genetic testing is used in ways that truly benefit patients and deliver safer, more personalized, and fairer healthcare for everyone.Highlights: - Few genetic test evaluations measure personal value, equity, and acceptability; - Genetic test evaluations rarely include evidence that show direct clinical efficacy; - We offer a catalog of indicators used for test evaluations.This research is supported by the ‘‘PROPHET - a PeRsOnalised Prevention roadmap for the future HEalThcare’’ project funded by the European Union (HORIZON Research and Innovation Actions no.
101057721). The UK participant in Horizon Europe Project PROPHET is supported by UKRI grant number 10040946 (Foundation for Genomics & Population Health)
Multi-country and intersectoral assessment of cluster congruence between pipelines for genomics surveillance of foodborne pathogens
No full textDifferent laboratories employ different Whole-Genome Sequencing (WGS) pipelines for Food and Waterborne disease (FWD) surveillance, casting doubt on the comparability of their results and hindering optimal communication at intersectoral and international levels. Through a collaborative effort involving eleven European institutes spanning the food, animal, and human health sectors, we aimed to assess the inter-pipeline clustering congruence across all resolution levels and perform an in-depth comparative analysis of cluster composition at outbreak level for four important foodborne pathogens: Listeria monocytogenes, Salmonella enterica, Escherichia coli, and Campylobacter jejuni. We found a general concordance between allele-based pipelines for all species, except for C. jejuni, where the different resolution power of allele-based schemas led to marked discrepancies. Still, we identified non-negligible differences in outbreak detection and demonstrated how a threshold flexibilization favors the detection of similar outbreak signals by different laboratories. These results, together with the observation that different traditional typing groups (e.g., serotypes) exhibit a remarkably different genetic diversity, represent valuable information for future outbreak case-definitions and WGS-based nomenclature design. This study reinforces the need, while demonstrating the feasibility, of conducting continuous pipeline comparability assessments, and opens good perspectives for a smoother international and intersectoral cooperation towards an efficient One Health FWD surveillance.INCD was funded by FCT and FEDER under the project 22153-01/SAICT/2016. We also thank the Italian Ministry of Health for supporting the acquisition of high-performance computing resources. This publication made use of the PubMLST website (https://pubmlst.org/) developed by Keith Jolley and sited at the University of Oxford. The development of that website was funded by the Wellcome Trust. This work was supported by co-funding from the European Union’s Horizon 2020 Research and Innovation program under grant agreement No 773830: One Health European Joint Programme (https://onehealthejp.eu/projects/foodborne-zoonoses/jrp-beone) (VB) and by the ISIDORe project (funding from the European Union’s Horizon Europe Research & Innovation Programme, Grant Agreement no. 101046133) (VB). VM contribution was funded by national funds through FCT - Foundation for Science and Technology, I.P., in the frame of Individual CEEC 2022.00851.CEECIND/CP1748/CT0001. JDS contribution was supported by the project “Sustainable use and integration of enhanced infrastructure into routine genome-based surveillance and outbreak investigation activities in Portugal'' (GENEO, https://www.insa.min-saude.pt/category/projectos/geneo/) on behalf of the EU4H programme (EU4H-2022-DGA-MS-IBA-1) (JPG). Research at the National Veterinary Research Institute (PIWet) Poland was supported by the Polish Ministry of Education and Science from the funds for science in the years 2018-2022 allocated for the implementation of a co-financed international project (EI)
Talc and Acrylonitrile
No full textThis publication represents the views and expert opinions of an IARC Working Group on the Identification of Carcinogenic Hazards to Humans, which met in Lyon, France, 11–18 June 2024.
IARC Monographs Working Group Members and Invited Specialists: Henriqueta Louro (National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal)This volume of the IARC Monographs provides evaluations of the carcinogenicity of talc and acrylonitrile.
Talc was defined as mineral (natural) or synthetic product, a hydrated magnesium silicate, that exists in both lamellar and fibrous (including asbestiform) types. Asbestiform talc is not asbestos; however, asbestos is present in some talc deposits and has been shown to contaminate some talc products. A mineral with a high production volume, talc is used in plastics, ceramics, paint, paper, roofing materials, rubber products, animal feed, food, fertilizers, cosmetics, and pharmaceuticals. It is also used in clinical settings for pleurodesis. Occupational exposure to talc dust occurs predominantly during mining and milling, mainly via inhalation, but can also occur among workers in downstream industries. The general population may be exposed via talc-based consumer products, and pathways of exposure include ingestion, inhalation, and dermal contact, including via the perineum.
Acrylonitrile is a chemical with a high production volume that is mostly used as a monomer to prepare polymers for the manufacture of fibres for textiles (acrylic fibres) used in clothing and carpets and other textiles, resins, synthetic rubber, and plastics. Occupational exposure occurs mainly in production industries via inhalation and dermal routes. The general population can be exposed to acrylonitrile via cigarette smoking, air pollution, and contact with contaminated consumer products.
An IARC Monographs Working Group reviewed evidence from epidemiological studies, cancer bioassays in experimental animals, and mechanistic studies to assess the carcinogenic hazard to humans of exposure to these agents and concluded that: - Talc is probably carcinogenic to humans (Group 2A); - Acrylonitrile is carcinogenic to humans (Group 1)
Functional characterization of 16 variants found in the LDL receptor gene
No full textFamilial hypercholesterolemia (FH) is a disorder of cholesterol metabolism characterized by elevated LDL-cholesterol levels. The most common cause of FH is pathogenic variants in the LDL receptor (LDLR) gene. To shed light on the functional impact of selected LDLR variants, we functionally characterized 16 LDLR genetic variants alongside 10 control variants. We performed in vitro assays based on transient expression of WT and mutant LDLRs in LDLR-deficient Chinese hamster ovary cells. We used flow cytometry to analyze the relative amount of LDLRs expressed on the cell surface and the relative amount of internalized LDL. In addition, we analyzed the expression and maturation of LDLR protein by Western blotting. Of the 16 studied variants, two variants (p.(Asn272Thr) and p.(Arg574Leu)) did not exhibit a defect in LDLR function, one variant (p.(Ala540Thr)) exhibited a defect in LDL binding and/or internalization despite normal LDLR cell surface expression, and the remaining 13 variants had a detrimental effect on both LDLR cell surface expression and LDL internalization. The information presented in this study contributes to the clinical classification of LDLR variants and a more precise diagnosis of FH patients, highlighting the type of defect each variant produces.The authors thank Prof Monty Krieger for kindly providing the CHO-ldlA7 cell line. They acknowledge the Flow Cytometry Laboratory at CEITEC MU supported by the EATRIS-ERIC-CZ research infrastructure (grant no.: LM2023053 funded by MEYS CR). Supported by the Ministry of Health of the Czech Republic in cooperation with the Czech Health Research Council under project no.: NU20-02-00261. This work was also supported by the project National Institute for Research of Metabolic and Cardio-vascular Diseases (Programme EXCELES, ID Project No.: LX22NPO5104)—funded by the European Union—Next Generation EU. This work also received funding for the conceptual development of a research organization (University Hospital Brno—FNBr, 65269705) by the Ministry of Health of the Czech Republic. The funders had no role in study design, data collection and analysis, decision to publish, or article preparation
The mechanism through which nonsense mutations are recognized as premature translation-termination codons
No full textAbout one third of the gene mutations found in human genetic disorders, including cancer, result in premature termination codons (PTCs) and the rapid degradation of their mRNAs by nonsense-mediated decay (NMD). NMD controls the quality of eukaryotic gene expression. The strength of the NMD response appears to reflect multiple determinants on a target mRNA. We have reported that human mRNAs with a PTC in close proximity to the translation initiation codon (AUG-proximal PTC), and thus, with a short open reading frame, can substantially escape NMD. Our data support a model in which cytoplasmic poly(A)-binding protein 1 (PABPC1) is brought into close proximity with an AUG-proximal PTC via interactions with the translation initiation complexes. This proximity of PABPC1 to the AUG-proximal PTC allows PABPC1 to interact with eRF3 with a consequent enhancement of the release reaction and repression of the NMD response. Here, we provide strong evidence that the eIF3 is involved in delivering eIF4G-associated PABPC1 into the vicinity of the AUG-proximal PTC. In addition, we dissect the biochemical interactions of the eIF3 subunits in bridging PABPC1/eIF4G complex to the 40S ribosomal subunit. Together, our data provide a framework for understanding the mechanistic details of PTC definition and mRNA translation initiation.FCT/PTDC/BIMONC/4890/2014N/
Modulation of protein translation mediated by upstream open reading frames (uORFs) in PERK mRNA
No full textObjective: PERK is one of the three sensor proteins from the ER that are responsible for inducing the Unfolded Protein Response (UPR)
when stress occurs (4). It is also the kinase responsible for phosphorylating eIF2α in these conditions (4). In this work we intended
to determine if PERK is regulated at the translational level by uORFs in normal and ER stress conditions, and understand the
impact of this regulation for the cell-stress response.Work partially supported by UID/MULTI/04046/2013 centre grant from FCT, Portugal (to BioISI). RF is recipient of a fellowship from BioSys PhD programme (Ref SFRH/BD/114392/2016) from FCT, Portugal.N/
Anthropometric Indices and Cardiovascular Risk: A Cross-Sectional Study in Portugal
No full textIntroduction: The relationship between abdominal obesity and cardiovascular risk is well established. The objective of this study was to determine the best anthropometric index to assess cardiovascular risk in the Portuguese population aged 40-69 years.
Materials and methods: Data from the 1st National Health Examination Survey 2015 were used. The analyzed anthropometric indices included Body Mass Index (BMI), Waist Circumference (WC), Waist-to-Height Ratio (WHtR), Waist-to-Hip Ratio (WHR), and A Body Shape Index (ABSI). The subsample consisted of 2780 individuals who met the inclusion criteria: aged 40-69 years, not pregnant, available information on sex, age, smoking status, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, and anthropometric measures (weight, height, WC, hip circumference). Individuals receiving cancer treatment were not included in the study. Those with a previous diagnosis of acute myocardial infarction, stroke, diabetes, chronic kidney disease, or undergoing medication therapy for these conditions were excluded from the analysis due to their already high or very high cardiovascular risk, being the use of SCORE2 inappropriate. The area under the curve (AUC) of the receiver operating characteristic (ROC) was calculated, stratified by sex, to determine the best index for assessing cardiovascular risk.
Results: In females, WHR exhibited the highest discriminatory power with an AUC of 0.67 (95% CI: 0.63 to 0.71), closely followed by WHtR with an AUC of 0.66 (95% CI: 0.61 to 0.70) and ABSI with an AUC of 0.65 (95% CI: 0.60 to 0.70). In males, WHtR displayed the highest discriminatory power with an AUC of 0.64 (95% CI: 0.59 to 0.68), closely followed by WHR with an AUC of 0.63 (95% CI: 0.58 to 0.67), and WC had an AUC of 0.62 (95% CI: 0.57 to 0.67).
Discussion: Previous research has produced diverse findings regarding the choice of anthropometric indices, with variations across genders. In the present study the AUC values for the analyzed indices encountered for both genders had overlapping confidence intervals, indicating no statistically significant difference in predictive power.
Conclusion: In women, the best index was WHR, and in men it was WHtR. However, due to a lack of statistical significance, it was not possible to determine which index had the best predictive ability. Nevertheless, this doesn't invalidate the previously well-established link between abdominal obesity and cardiovascular risk. Cardiovascular disease has a multifactorial etiology, and attempting to find only one variable that predicts the risk of a cardiovascular event can be overly simplistic and limiting.N/
Re‐evaluation of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additives
No full textEFSA FAF Panel members: Henriqueta Louro (INSA)The Panel on Food Additives and Flavourings (FAF) provides a scientific opinion re‐evaluating the safety of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additives. Butane, isobutane and propane are short‐chain (C3–C4) alkanes, which are in gaseous state at room temperature. Their currently permitted use in food is in vegetable oil pan spray (for professional use only) and water‐based emulsion spray as propellants at quantum satis. They can also be used in food colour preparations with a maximum residual limit of 1 mg/kg in food. Two interested business operators (IBOs) provided information in response to the call for data published by EFSA reporting typical and maximum use levels. The toxicological hazards of the three gases via inhalation are known, however this route of exposure is not considered relevant for their safety assessment as food additives. Existing EU specifications for the three food additives already contain limits for the toxic impurity 1,3‐butadiene (1,3‐BD), however due to a lack of information on the manufacturing processes used, uncertainties do remain regarding the potential presence of other impurities not listed in the current EU specifications for food additives. Based on their physicochemical properties, the three gases are considered by the Panel to be of low toxicological concern when used as food additives and their dietary exposure very low. The Panel concluded that the use of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additives at the currently permitted uses and use levels does not raise a safety concern. The Panel made some recommendations for amending existing EU specifications for butane (E 943a), isobutane (E 943b) and propane (E 944)