RESUMO
Despite the intuitive value of adopting the Findable, Accessible, Interoperable, and Reusable (FAIR) principles in both academic and industrial sectors, challenges exist in resourcing, balancing long- versus short-term priorities, and achieving technical implementation. This situation is exacerbated by the unclear mechanisms by which costs and benefits can be assessed when decisions on FAIR are made. Scientific and research and development (R&D) leadership need reliable evidence of the potential benefits and information on effective implementation mechanisms and remediating strategies. In this article, we describe procedures for cost-benefit evaluation, and identify best-practice approaches to support the decision-making process involved in FAIR implementation.
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Descoberta de Drogas , Análise Custo-BenefícioRESUMO
MOTIVATION: The COVID-19 pandemic has prompted an impressive, worldwide response by the academic community. In order to support text mining approaches as well as data description, linking and harmonization in the context of COVID-19, we have developed an ontology representing major novel coronavirus (SARS-CoV-2) entities. The ontology has a strong scope on chemical entities suited for drug repurposing, as this is a major target of ongoing COVID-19 therapeutic development. RESULTS: The ontology comprises 2270 classes of concepts and 38 987 axioms (2622 logical axioms and 2434 declaration axioms). It depicts the roles of molecular and cellular entities in virus-host interactions and in the virus life cycle, as well as a wide spectrum of medical and epidemiological concepts linked to COVID-19. The performance of the ontology has been tested on Medline and the COVID-19 corpus provided by the Allen Institute. AVAILABILITYAND IMPLEMENTATION: COVID-19 Ontology is released under a Creative Commons 4.0 License and shared via https://github.com/covid-19-ontology/covid-19. The ontology is also deposited in BioPortal at https://bioportal.bioontology.org/ontologies/COVID-19. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
RESUMO
Bisphenol A (BPA) is a high production volume chemical with a broad application spectrum. As an endocrine disrupting chemical, mainly by modulation of nuclear receptors (NRs), BPA has an adverse impact on organisms and is identified as a substance of very high concern under the European REACH regulation. Various BPA substitution candidates have been developed in recent years, however, information concerning the endocrine disrupting potential of these substances is still incomplete or missing. In this study, we intended to investigate the endocrine potential of BPA substitution candidates used in environmentally relevant applications such as thermal paper or epoxy resins. Based on an extensive literature and patent search, 33 environmentally relevant BPA substitution candidates were identified. In order to evaluate the endocrine potential of the BPA replacements, a screening cascade consisting of biochemical and cell-based assays was employed to investigate substance binding to the NRs estrogen receptor α and ß, as well as androgen receptor, co-activator recruitment and NR-mediated reporter gene activation. In addition, a computational docking approach for retrospective prediction of receptor binding was carried out. Our results show that some BPA substitution candidates, for which so far no or only very few data were available, possess a substantial endocrine disrupting potential (TDP, BPZ), while several substances (BPS, D-8, DD70, DMP-OH, TBSA, D4, CBDO, ISO, VITC, DPA, and DOPO) did not reveal any NR binding.
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Compostos Benzidrílicos/química , Fenóis/química , Disruptores Endócrinos , Receptores Androgênicos , Estudos RetrospectivosRESUMO
Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 µM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 µM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.
Assuntos
Produtos Biológicos/farmacologia , Flavonóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Flavonóis/síntese química , Flavonóis/química , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/químicaRESUMO
Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health and healthcare for all Europeans.
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Pesquisa Biomédica/legislação & jurisprudência , Bases de Dados Factuais/normas , União Europeia/organização & administração , Pesquisa Biomédica/normas , Bases de Dados Factuais/legislação & jurisprudência , Implementação de Plano de Saúde , Humanos , Disseminação de Informação/legislação & jurisprudênciaRESUMO
Electronic images of histopathological changes are commonly and increasingly used in toxicologic pathology for morphological evaluation, illustration, peer review, or reporting. Toxicity studies in which cell proliferation is an end point are also pivotal in determining the carcinogenic potential of new molecules. In this article, we describe the approach of the European Cell Proliferation and Apoptosis working group (CEPA) for performing cell proliferation studies and morphometry using electronic images. The Society of Toxicologic Pathology (STP) has published a position statement on handling of pathology image data in compliance with 21 Code of Federal Regulations (CFR) Parts 58 and 11. CEPA supports the STP position and shares the issues involved in the use of electronic images in pathology. However, considering the experience and current know-how of members, particularly in conducting cell proliferation studies, CEPA would like to recommend in this article that electronic images acquired using state-of-the-art slide imaging techniques, including whole slide scanning, need not be considered as raw data, and therefore are not subject to 21 CFR Parts 58 and 11 regulations for archiving. In this article, we detail the reasons why we come to this proposal and we describe the measures that are taken to ensure Good Laboratory Practice-compliant execution of cell proliferation studies that include acquisition and validation of imaging and image analysis systems, development and validation of methods for their intended use, formulation, and use of standard operating procedures.
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Processamento de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/normas , Testes de Toxicidade/métodos , Testes de Toxicidade/normas , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Eletrônica , Imuno-Histoquímica/normas , Microscopia , Patologia/normas , Projetos de Pesquisa , Toxicologia/normasRESUMO
Testicular tubular dilatation and degeneration and epididymal sperm granulomas were frequently seen in 4-week toxicity studies using different phosphodiesterase-4 (PDE4) inhibitors in Wistar rats, including the prototypic PDE4 inhibitor BYK169171. To investigate the pathogenesis of testicular and epididymal lesions, a time course study with BYK169171 was conducted with sequential necropsies after 7, 14, 21, and 28 days of treatment. After 7 days, a dilatation of efferent ducts and of the initial segment of the epididymis and a subacute interstitial inflammation were seen followed by a diffuse dilatation of seminiferous tubules in the testis. Dilatation and inflammation were most pronounced after 14 days. Single animals also exhibited vascular necrosis in the inflamed interstitium. Although dilatation decreased later in the study, the incidence and severity of tubular degeneration increased from 14 days onward. Sperm granulomas developed in efferent ducts and in the caput and cauda of the epididymis after 14 days. Our results demonstrate a clear time course of PDE4 inhibition-induced lesions, with dilatation preceding sperm granuloma formation. We conclude that the most likely mechanism of toxicity is a disturbance of fluid homeostasis in efferent and epididymal ducts resulting in abnormal luminal fluid and sperm contents, epithelial damage at specific sites of the excurrent duct system, sperm leakage, and granuloma formation.
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Dilatação Patológica/induzido quimicamente , Epididimo/efeitos dos fármacos , Doenças dos Genitais Masculinos/induzido quimicamente , Granuloma/induzido quimicamente , Inibidores da Fosfodiesterase 4/toxicidade , Testículo/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Dilatação Patológica/patologia , Epididimo/enzimologia , Epididimo/patologia , Doenças dos Genitais Masculinos/enzimologia , Doenças dos Genitais Masculinos/patologia , Granuloma/enzimologia , Granuloma/patologia , Histocitoquímica , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Testículo/enzimologia , Testículo/patologiaRESUMO
Inhibitors of phosphodiesterase type 4 (PDE4) are currently exploited as potent drugs for pulmonary diseases. Some PDE4 inhibitors induce necrotizing panarteritis in the mesentery of rats, comparable to spontaneous polyarteritis nodosa in rats and vascular alterations that are induced by various vasoactive compounds, such as fenoldopam and inhibitors of PDE3. The mechanism of toxicity is unknown. In order to investigate the development of arteritis in the splanchnic vasculature of rats, a time-course study was performed with high doses of a compound (BYK169171), specifically inhibiting PDE4. Rats were treated orally for 1-28 days, and alterations in the mesentery were evaluated by histology, morphometry, and immunohistology. As early as 3 days after the onset of treatment, a mesenteritis was found, characterized by macrophage infiltration, fibroblast proliferation, neovascularization, and loss of adipocytes. Incidence and severity of the mesenteritis were low during the first 2 weeks of treatment, but increased with duration of treatment, finally affecting 2/3 of all animals. A segmental necrotizing panarteritis was detected in some rats treated for 21 or 28 days, but always followed a mesenteritis, whereas many animals with mesenteric inflammation did not have vascular lesions. We postulate that PDE4 inhibitors do not cause a primary vasculitis/arteritis in rats, but induce a non-purulent inflammation as the predominant initial toxic effect in the mesentery. This renders their toxic effect distinct from that of PDE3 inhibitors.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Mesentério/efeitos dos fármacos , Peritonite/induzido quimicamente , Inibidores de Fosfodiesterase/toxicidade , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Fibrose/induzido quimicamente , Fibrose/patologia , Jejuno/efeitos dos fármacos , Jejuno/patologia , Masculino , Mesentério/patologia , Peritonite/patologia , Ratos , Ratos Wistar , Vasculite/induzido quimicamente , Vasculite/patologiaRESUMO
To investigate in an animal model whether preconceptual X-ray exposure leads to an altered tumor rate and spectrum in the offspring, a transgeneration carcinogenesis study was carried out. Female mice received X-ray irradiation (2 x 2 Gray) 2 weeks prior to mating with untreated males. After weaning, half of the descendants were exposed for 6 months to the immunomodulating and tumor-promoting compound cyclosporine A (CsA) by diet, the others remained untreated. The animals were maintained for their entire lifespan, terminal sacrifices were carried out after 28 months. Complete autopsy was performed, and three protocol organs (lung, liver and spleen) were examined histologically, together with any suspicious lesions in other organs. Fertility and the lifetime of the maternal mice were reduced by the X-ray irradiation, and their incidence of lung and liver tumors was increased as compared to non-irradiated mice. The descendants of all groups revealed comparable body weights and mortality rates. The incidence of hematopoietic/lymphoreticular tissue tumors increased in the female hybrids by 6 months of CsA-treatment. A higher incidence of lung and liver tumors in the sham-treated male progeny of irradiated mothers was detected, pointing to a possible germ cell-transmitted alteration initiated by the preconceptual maternal X-ray exposure.
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Exposição Materna , Neoplasias Induzidas por Radiação/etiologia , Óvulo/efeitos da radiação , Efeitos Tardios da Exposição Pré-Natal , Raios X/efeitos adversos , Animais , Carcinógenos/toxicidade , Cocarcinogênese , Ciclosporina/toxicidade , Modelos Animais de Doenças , Feminino , Fertilidade/efeitos da radiação , Hospedeiro Imunocomprometido , Fatores Imunológicos/toxicidade , Longevidade/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Neoplasias Induzidas por Radiação/imunologia , Neoplasias Induzidas por Radiação/patologia , Gravidez , RiscoRESUMO
Historical control tumor data are useful in the interpretation of long-term rodent carcinogenicity bioassays, especially to assess the occurrence of rare tumors and marginally increased tumor incidences. The major prerequisites to compare historical control data with studies under evaluation are the validity and consistency of the respective databases. The RITA (Registry of Industrial Toxicology Animal-data) database for historical data of tumors and pre-neoplastic lesions collects data according to highly standardized procedures including tissue sampling and trimming, histopathology according to internationally harmonized nomenclature and diagnostic criteria, and peer review. All lesions that are entered are unanimously diagnosed according to IARC (Intermational Agency for Research on Cancer)/WHO criteria. The validity of data is additionally confirmed by a complete peer review performed by a database pathologist. Equivocal diagnoses and selected cases are additionally submitted to a panel of RITA pathologists. In the RITA database, there are currently 10,896 rats from 106 studies with more than 17,604 primary tumors and 16,551 pre-neoplastic lesions. The RITA database for historical control data for Wistar and Sprague Dawley rats as well as for different mouse strains is briefly described. Based upon RITA background data, the survival rate of Wistar rats has been consistent over a period of 10 years. The occurrence of tumor-bearing animals also shows a stable percentage over a decade. Additionally, examples of how historical control data may support carcinogenic risk assessment in cases of rare tumors or marginally increased incidences of tumors and pre-neoplastic lesions are given.
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Órgãos Governamentais/normas , Indústrias/normas , Patologia/normas , Animais , Animais de Laboratório , Carcinógenos/toxicidade , Bases de Dados Factuais , Sistemas de Informação , Neoplasias Experimentais/patologia , Ratos , Padrões de Referência , Taxa de SobrevidaRESUMO
This prospective, observational study investigated the efficacy and tolerability of follitropin-alfa for ovarian stimulation in routine clinical practice. The study involved a large, unselected population of women. Stimulation parameters and treatment outcomes were documented for 767 patients who underwent a total of 1098 cycles of follitropin-alfa according to the clinic's standard protocol. Stimulation lasted a median of 11 days and used a cumulative dosage of 28 ampoules of 75 IU follitropin-alfa. Pituitary down-regulation was used in 81.2% of cycles, predominantly by the long protocol. The desired ovarian development was achieved in 99.5% of cycles and embryo transfer took place in 86.9% of cycles, with an average of 2.5 embryos transferred. The clinical pregnancy rate was 39.5% and the miscarriage rate was 12.2%. Ovarian hyperstimulation syndrome was observed in only 12 cycles (1.1%). In conclusion, follitropin-alfa is effective and well tolerated for ovarian stimulation during routine clinical practice.