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OBJECTIVE: To assess the comparability of international ethics principles and practices used in regulating pediatric research as a first step in determining whether reciprocal deference for international ethics review is feasible. Prior studies by the authors focused on other aspects of international health research, such as biobanks and direct-to-participant genomic research. The unique nature of pediatric research and its distinctive regulation by many countries warranted a separate study. STUDY DESIGN: A representative sample of 21 countries was selected, with geographical, ethnic, cultural, political, and economic diversity. A leading expert on pediatric research ethics and law was selected to summarize the ethics review of pediatric research in each country. To ensure the comparability of the responses, a 5-part summary of pediatric research ethics principles in the US was developed by the investigators and distributed to all country representatives. The international experts were asked to assess and describe whether principles in their country and the US were congruent. Results were obtained and compiled in the spring and summer of 2022. RESULTS: Some of the countries varied in their conceptualization or description of one or more ethical principles for pediatric research, but overall, the countries in the study demonstrated a fundamental concordance. CONCLUSIONS: Similar regulation of pediatric research in 21 countries suggests that international reciprocity is a viable strategy.
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Bancos de Muestras Biológicas , Ética en Investigación , Niño , Humanos , Investigadores , Consentimiento InformadoRESUMEN
Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.
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Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Regiones no Traducidas 3'/genética , Empalme Alternativo/genética , Linfocitos B/metabolismo , Proteínas Portadoras/genética , Cromosomas Humanos Par 9/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Proteínas de Unión al ADN , Elementos de Facilitación Genéticos/genética , Genómica , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Factor de Transcripción PAX5/biosíntesis , Factor de Transcripción PAX5/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Factores de Transcripción/genéticaRESUMEN
Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.
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Genoma Humano/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Secuencia de Aminoácidos , Animales , Proteínas Portadoras/genética , Análisis Mutacional de ADN , Humanos , Carioferinas/genética , Datos de Secuencia Molecular , Factor 88 de Diferenciación Mieloide/química , Factor 88 de Diferenciación Mieloide/genética , Receptor Notch1/genética , Receptores Citoplasmáticos y Nucleares/genética , Reproducibilidad de los Resultados , Proteína Exportina 1RESUMEN
The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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Genética Médica/organización & administración , Genoma Humano/genética , Genómica/organización & administración , Cooperación Internacional , Neoplasias/genética , Metilación de ADN , Análisis Mutacional de ADN/tendencias , Bases de Datos Genéticas , Genes Relacionados con las Neoplasias/genética , Genética Médica/tendencias , Genómica/tendencias , Humanos , Propiedad Intelectual , Mutación , Neoplasias/clasificación , Neoplasias/patología , Neoplasias/terapiaRESUMEN
Many countries consider long-term implications for society.
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Investigación Biomédica , Revisión Ética , Humanos , Investigación Biomédica/ética , Comités de Ética en Investigación , Ética en Investigación , Cooperación InternacionalRESUMEN
Fecal microbiota transplantation (FMT) is an effective procedure against Clostridioides difficile infection (CDI), with promising but still suboptimal performance in other diseases, such as ulcerative colitis (UC). The recipient's mucosal immune response against the donor's microbiota could be relevant factor in the effectiveness of FMT. Our aim was to design and validate an individualized immune-based test to optimize the fecal donor selection for FMT. First, we performed an in vitro validation of the test by co-culturing lymphocytes obtained from the small intestine mucosa of organ donor cadavers (n=7) and microbe-associated molecular patterns (MAMPs) obtained from the feces of 19 healthy donors. The inflammatory response was determined by interleukin supernatant quantification using the Cytometric Bead Array kit (B&D). We then conducted a clinical pilot study with 4 patients with UC using immunocompetent cells extracted from rectal biopsies and MAMPs from 3 donor candidates. We employed the test results to guide donor selection for FMT, which was performed by colonoscopy followed by 4 booster instillations by enema in the following month. The microbiome engraftment was assessed by 16S rDNA massive sequencing in feces, and the patients were clinically followed-up for 16 weeks. The results demonstrated that IL-6, IL-8, and IL-1ß were the most variable markers, although we observed a general tolerance to the microbial insults. Clinical and colonoscopy remission of the patients with UC was not achieved after 16 weeks, although FMT provoked enrichment of the Bacteroidota phylum and Prevotella genus, with a decrease in the Actinobacteriota phylum and Agathobacter genus. The most relevant result was the lack of Akkermansia engraftment in UC. In summary, the clinical success of FMT in patients with UC appears not to be influenced by donor selection based on the explored recipient's local immunological response to FMT, suggesting that this approach would not be valid for FMT fecal donor optimization in such patients.
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Colitis Ulcerosa/inmunología , Colitis Ulcerosa/terapia , Selección de Donante , Trasplante de Microbiota Fecal , Adulto , Anciano , Toma de Decisiones Clínicas , Colitis Ulcerosa/diagnóstico , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field.
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Biomarcadores de Tumor/análisis , Investigación Biomédica/métodos , Quinasa de Linfoma Anaplásico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Investigación Biomédica/normas , Estudios Clínicos como Asunto , Ensayos Clínicos como Asunto , Receptores ErbB/genética , Humanos , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptor ErbB-2/análisis , Proteínas ras/genéticaRESUMEN
The Spanish legal framework for the processing of samples and data with biomedical research purposes has sought to encourage scientific research, protect the right to freedom of research, and guarantee the interests of donors. The pillars of this legal framework are firstly, the duty to inform the donor in order to ensure that he or she is aware of the importance and the consequences of the donation; secondly, the control by ethics committees (RECs and External Ethics Committees of biobanks); and third, the supplementary application of the general rules on data protection. There are three different possibilities for processing samples (project, collection, and biobanks) - each one reinforcing specific consent or requiring other added guarantees. This system, which is applied consistently in the entire national territory, is producing very satisfactory results. However, there are some issues that need further policies or legal development, as the specific conditions and procedures for the international transfer of samples and data with research purposes.
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Acceso a la Información/legislación & jurisprudencia , Bancos de Muestras Biológicas/legislación & jurisprudencia , Confidencialidad/legislación & jurisprudencia , Investigación Biomédica/legislación & jurisprudencia , Humanos , EspañaRESUMEN
Degradation of human DNA extracted from forensic stains is, in most cases, the result of a natural process due to the exposure of the stain samples to the environment. Experiences with degraded DNA from casework samples show that every sample may exhibit different properties in this respect, and that it is difficult to systematically assess the performance of routinely used typing systems for the analysis of degraded DNA samples. Using a batch of artificially degraded DNA with an average fragment size of approx. 200 bp a collaborative exercise was carried out among 38 forensic laboratories from 17 European countries. The results were assessed according to correct allele detection, peak height and balance as well as the occurrence of artefacts. A number of common problems were identified based on these results such as strong peak imbalance in heterozygous genotypes for the larger short tandem repeat (STR) fragments after increased PCR cycle numbers, artefact signals and allelic drop-out. Based on the observations, strategies are discussed to overcome these problems. The strategies include careful balancing of the amount of template DNA and the PCR cycle numbers, the reaction volume and the amount of Taq polymerase. Furthermore, a careful evaluation of the results of the fragment analysis and of automated allele calling is necessary to identify the correct alleles and avoid artefacts.
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Técnicas de Laboratorio Clínico/normas , Dermatoglifia del ADN/normas , Fragmentación del ADN , Reacción en Cadena de la Polimerasa/métodos , Secuencias Repetidas en Tándem , Alelos , Conducta Cooperativa , ADN/análisis , Europa (Continente) , Humanos , Reacción en Cadena de la Polimerasa/estadística & datos numéricosRESUMEN
International transfers of human biological material (biospecimens) and data are increasing, and commentators are starting to raise concerns about how donor wishes are protected in such circumstances. These exchanges are generally made under contractual material transfer agreements (MTAs). This paper asks what role, if any, should research ethics committees (RECs) play in ensuring legal and ethical conduct in such exchanges. It is recommended that RECs should play a more active role in the future development of best practice MTAs involving exchange of biospecimens and data and in monitoring compliance.
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Investigación Biomédica/ética , Comités de Ética en Investigación , Contrato de Transferencia , Ética en Investigación , HumanosAsunto(s)
Investigación Biomédica/ética , Investigación Biomédica/legislación & jurisprudencia , Genómica , Internacionalidad/legislación & jurisprudencia , Selección de Paciente , Informe de Investigación , Bancos de Muestras Biológicas , Confidencialidad/legislación & jurisprudencia , Pruebas Dirigidas al Consumidor/legislación & jurisprudencia , Comités de Ética en Investigación/legislación & jurisprudencia , Pruebas Genéticas/legislación & jurisprudencia , Sustancias Peligrosas , Humanos , Internet , Formulación de Políticas , Investigadores/psicología , Encuestas y CuestionariosRESUMEN
There is a noticeable lack of international regulation on personal data exchange and management in research. This article sheds light in this area by describing how the International Cancer Genome Consortium is developing policies and procedures to address the ethical and legal issues raised by the international transfer of data and results. These policies and procedures aim, first and most importantly, to safeguard the interests of the research participants and other involved stakeholders and, secondly, to facilitate the sharing of data and results to realize greater benefits from this kind of internationally collaborative genetic research.
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Investigación Biomédica/legislación & jurisprudencia , Bases de Datos Genéticas/legislación & jurisprudencia , Investigación Genética/legislación & jurisprudencia , Bases de Datos Genéticas/ética , Agencias Internacionales , InternacionalidadRESUMEN
The obtaining and use of genetic data have several particular implications for the rights of the patients and their relatives, and frequently practitioners and researchers face some new conflicts to which law and ethics try to give an answer. Some countries have enacted national laws related to genetic analysis. At the international level a great effort has been done to develop a common regulatory framework taking into account the rights of the patients/subjects of the research and other rights and interests. In the field of genetic analysis, both diagnostic and research purposes frequently go hand in hand. The scientific interest in the use of biological samples as a research tool has increased simultaneously with the knowledge of human genetics. The regulations related to the rights of the patients in the use of biological samples need to be abided.
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Privacidad Genética/ética , Pruebas Genéticas/ética , Pruebas Genéticas/legislación & jurisprudencia , Confidencialidad/ética , Confidencialidad/legislación & jurisprudencia , Privacidad Genética/legislación & jurisprudencia , Derechos Humanos/legislación & jurisprudencia , Humanos , Cobertura del Seguro/ética , Cobertura del Seguro/legislación & jurisprudencia , Internacionalidad , PrejuicioAsunto(s)
Seguridad Computacional , Privacidad Genética/organización & administración , Genética Médica/organización & administración , Genética/organización & administración , Genómica/organización & administración , Oncología Médica/organización & administración , Política Organizacional , Predicción , Agencias Internacionales/organización & administración , Sociedades/organización & administraciónRESUMEN
The specific characteristics of genetic data lead to ethical-legal conflicts in the framework of genetic diagnosis. Several international organisations, including UNESCO and the Council of Europe, have enacted rules referring to the use of genetic information. This paper discusses possible legal and ethical criteria that could be used in genetic testing.
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Group 5 metal complexes [M(eta5-C5H5)[eta5-C5H4SiMe2(CH2-eta]2-CH=CH2)]X] (M = Nb, X = Me, CH2Ph, CH2SiMe3; M = Ta, X = Me, CH2Ph) and [Ta(eta5-C5Me5)[eta5-C5H4SiMe2(CH2-eta2-CH=CH2)]X] (X = Cl, Me, CH2Ph, CH2SiMe3) containing a chelating alkene ligand tethered to a cyclopentadienyl ring have been synthesized in high yields by reduction with Na/Hg (X = Cl) and alkylation with reductive elimination (X = alkyl) of the corresponding metal(iv) dichlorides [M(eta5-Cp)[eta5-C5H4SiMe2(CH2CH=CH2)]Cl2] (Cp = C5H5, M = Nb, Ta, Cp = C5Me5, M = Ta). These chloro- and alkyl-alkene coordinated complexes react with CO and isocyanides [CNtBu, CN(2,6-Me2C6H3)] to give the ligand-substituted metal(III) compounds [M(eta5-Cp)[eta5-C5H4SiMe2(CH2CH=CH2)]XL] (X = Cl, Me, CH2Ph, CH2SiMe3). Reaction of the chloro-alkene tantalum complex with LiNHtBu results in formation of the imido hydride derivative [Ta(eta5-C5Me5)[eta5-C5H4SiMe2(CH2CH=CH2)]H(NtBu)]. NMR studies for all of the new compounds and DFT calculations for the alkene-coordinated metal complexes are compared with those known for related group 4 metal cations.