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1.
Gynecol Oncol ; 156(1): 251-259, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31767187

RESUMO

The majority of endometrial cancers are detected early with a favourable prognosis. However, for patients with advanced disease, chemotherapy response rates and overall survival remains poor. The endometrial cancer population is typically elderly with multiple co-morbidities and aggressive cytotoxic therapy may be hazardous. Therefore, there is an urgent need to define optimal treatment strategies for advanced and recurrent disease and personalise therapy based on individual tumour and patient characteristics. Three-dimensional (3D) models that preserve the tumour microenvironment and tumour-stromal interactions are increasingly important for translational research with the advent of immunotherapy and molecularly targeted agents. 3D patient-relevant pre-clinical models in endometrial cancer include spheroids, patient-derived organoids, microfluidic systems, patient-derived xenografts and patient-derived explants. Here we present a review of available 3D modelling systems in endometrial cancers, highlighting their current use, advantages, disadvantages and applications to translational research with a focus on the power of the patient-derived explant platform.


Assuntos
Técnicas de Cultura de Células/métodos , Neoplasias do Endométrio/patologia , Animais , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/patologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Xenoenxertos , Humanos , Transplante de Neoplasias/métodos , Organoides/patologia , Esferoides Celulares/patologia , Pesquisa Médica Translacional/métodos
2.
Bull Cancer ; 107(1): 30-40, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31466696

RESUMO

Primarily used in genetic studies of development, the zebrafish (Danio rerio) has rapidly emerged as a promising animal model of human cancer. Cancer cell transplantation in zebrafish constitutes a key platform for clinical research since it allows to study cellular and molecular events involved in various aspects of tumorigenesis and to evaluate the efficacy of therapeutic molecules in vivo. Applied to patient-derived cells, the xenotransplantation approach in zebrafish allows to define the most appropriate therapeutic strategies for specific alterations found in patients in the context of personalized medicine. This review discusses the zebrafish transplantation model for the study of cancer development and drug discovery.


Assuntos
Transplante de Neoplasias , Neoplasias Experimentais/etiologia , Medicina de Precisão/métodos , Pesquisa Médica Translacional/métodos , Peixe-Zebra , Imunidade Adaptativa , Animais , Animais Geneticamente Modificados , Transformação Celular Neoplásica , Modelos Animais de Doenças , Progressão da Doença , Descoberta de Drogas , Genes Neoplásicos , Xenoenxertos , Humanos , Imunossupressão/métodos , Neoplasias Experimentais/genética , Oncogenes , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/imunologia
3.
J Ethnopharmacol ; 247: 112255, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31568819

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Piper longum, commonly referred as 'Pippali', has found its traditional use in India, Malaysia, Singapore and other South Asian countries as an analgesic, carminative, anti-diarrhoeic, immunostimulant, post childbirth to check postpartum hemorrhage and to treat asthma, insomnia, dementia, epilepsy, diabetes, rheumatoid arthritis, asthma, spleen disorder, puerperal fever, leprosy etc. AIM OF THE REVIEW: This review offers essential data focusing on the traditional use, phytochemistry and pharmacological profile of Piper longum thereby identifying research gaps and future opportunities for investigation on this plant. MATERIALS AND METHODS: This systematic survey was accomplished as per the PRISMA guidelines. The information was collected from books, and electronic search (PubMed, Science Direct, Lilca and Scielo) during 1967-2019. RESULTS: Many phytochemicals have been identified till date, including alkaloids as its major secondary metabolites (piperine and piperlongumine), essential oil, flavonoids and steroids. These exhibit a wide range of activities including anti-inflammatory, analgesic, anti-oxidant, anti-microbial, anti-cancer, anti-parkinsonian, anti-stress, nootropic, anti-epileptic, anti-hyperglycemic, hepatoprotective, anti-hyperlipidemic, anti-platelet, anti-angiogenic, immunomodulatory, anti-arthritic, anti-ulcer, anti-asthmatic, anthelmintic action, anti-amebic, anti-fungal, mosquito larvicidal and anti-snake venom. CONCLUSION: Amongst various activities, bioscientific clarification in relation to its ethnopharmacological perspective has been evidenced mainly for anti-amebic, anthelminthic, anti-tumor and anti-diabetic activity. However, despite traditional claims, insufficient scientific validation for the treatment of insomnia, dementia, epilepsy, rheumatoid arthritis, asthma, spleen disorder, puerperal fever and leprosy, necessitate future investigations in this direction. It is also essential and critical to generate toxicological data and pharmacokinetics on human subjects so as to confirm its conceivable bio-active components in the body.


Assuntos
Etnofarmacologia/métodos , Medicina Tradicional/métodos , Piper/química , Extratos Vegetais/farmacologia , Pesquisa Médica Translacional/métodos , Etnofarmacologia/tendências , Humanos , Índia , Malásia , Extratos Vegetais/uso terapêutico , Singapura , Pesquisa Médica Translacional/tendências
4.
Talanta ; 207: 120270, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594601

RESUMO

Since the disclosure of the fibrinogen degradation mechanism, around half a century ago, a significant number of papers have been published related to the clinical relevance of D-dimer, a molecule immune to additional enzymatic decomposition by plasmin. Due to the obliquity of regulating blood coagulation in pathological events, the number of diseases and conditions associated with abnormal levels of D-dimer includes deep vein thrombosis, pulmonary embolism, sepsis, myocardial infarction, disseminated intravascular coagulation, among many others. D-dimer not only is an important player in medical diagnosis but also its role as a prognosis biomarker is being revealed. However, the number of analytical alternative methods has not accompanied this trend, even though novel simple point-of-care devices would certainly boost the relevance of D-dimer in emergency medicine. Some reasons for that could be related to the fact that D-dimer is a challenging analyte present in complex samples like blood. In this manuscript, subsequent to a fibrinogen degradation process introduction, it is provided a historical overview of the early D-dimer assays, followed by an extended focus on innovative solutions, with a spotlight on the electrochemical bioanalytical devices. The discussion is accompanied with a critical analysis and concluding thoughts concerning future perspectives.


Assuntos
Técnicas Biossensoriais/métodos , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Laboratórios Hospitalares , Pesquisa Médica Translacional/métodos , Humanos
5.
PLoS One ; 14(12): e0226176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31846471

RESUMO

Discovery studies in animals constitute a cornerstone of biomedical research, but suffer from lack of generalizability to human populations. We propose that large-scale interrogation of these data could reveal patterns of animal use that could narrow the translational divide. We describe a text-mining approach that extracts translationally useful data from PubMed abstracts. These comprise six modules: species, model, genes, interventions/disease modifiers, overall outcome and functional outcome measures. Existing National Library of Medicine natural language processing tools (SemRep, GNormPlus and the Chemical annotator) underpin the program and are further augmented by various rules, term lists, and machine learning models. Evaluation of the program using a 98-abstract test set achieved F1 scores ranging from 0.75-0.95 across all modules, and exceeded F1 scores obtained from comparable baseline programs. Next, the program was applied to a larger 14,481 abstract data set (2008-2017). Expected and previously identified patterns of species and model use for the field were obtained. As previously noted, the majority of studies reported promising outcomes. Longitudinal patterns of intervention type or gene mentions were demonstrated, and patterns of animal model use characteristic of the Parkinson's disease field were confirmed. The primary function of the program is to overcome low external validity of animal model systems by aggregating evidence across a diversity of models that capture different aspects of a multifaceted cellular process. Some aspects of the tool are generalizable, whereas others are field-specific. In the initial version presented here, we demonstrate proof of concept within a single disease area, Parkinson's disease. However, the program can be expanded in modular fashion to support a wider range of neurodegenerative diseases.


Assuntos
Pesquisa Biomédica , Mineração de Dados , Doenças Neurodegenerativas , Pesquisa Médica Translacional/métodos , Animais , Humanos , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia
7.
Hist Philos Life Sci ; 41(4): 57, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31768774

RESUMO

Translational research is a buzzword which dominates discussions about the quality, the utilization, and the benefits of (bio)medical research. Yet, although translational research has become a prominent topic, no commonly agreed definition of this terminology exists. Instead, experts from different contexts such as biomedical research, clinical practice or nursing discuss translational research in multiple ways depending on how they define the problem that translational research is supposed to be the solution to. In this paper, we do not seek to find a 'correct' definition of translational research, but instead ask how actors using this terminology for describing their own research make sense of it. To do so, we asked three questions: Which actors are engaged in the debate about translational research? What kind of different meanings of translational research exist? And, which actors refer to which meaning of translational research when using the term? In answering these questions, we highlight the role this terminology plays in defining what medical science is about today.


Assuntos
Pesquisa Médica Translacional/métodos , Humanos , Terminologia como Assunto
8.
Nat Rev Neurol ; 15(12): 732-745, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31728042

RESUMO

Over the past decade, we have witnessed a flourishing of novel strategies to enhance neuroplasticity and promote axon regeneration following spinal cord injury, and results from preclinical studies suggest that some of these strategies have the potential for clinical translation. Spinal cord injury leads to the disruption of neural circuitry and connectivity, resulting in permanent neurological disability. Recovery of function relies on augmenting neuroplasticity to potentiate sprouting and regeneration of spared and injured axons, to increase the strength of residual connections and to promote the formation of new connections and circuits. Neuroplasticity can be fostered by exploiting four main biological properties: neuronal intrinsic signalling, the neuronal extrinsic environment, the capacity to reconnect the severed spinal cord via neural stem cell grafts, and modulation of neuronal activity. In this Review, we discuss experimental evidence from rodents, nonhuman primates and patients regarding interventions that target each of these four properties. We then highlight the strengths and challenges of individual and combinatorial approaches with respect to clinical translation. We conclude by considering future developments and providing views on how to bridge the gap between preclinical studies and clinical translation.


Assuntos
Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/metabolismo , Pesquisa Médica Translacional/métodos , Animais , Axônios/fisiologia , Humanos , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/genética
10.
Expert Rev Clin Pharmacol ; 12(11): 1033-1036, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31633383

RESUMO

Introduction: In the era of 'precision' oncology, novel clinical trial designs have emerged, in order to better address the final goal of translating the above-mentioned preclinical discoveries into the clinic. Nonetheless, in aiming to achieve the greatest clinical benefit to patients, some limitations of these novel approaches from the statistical, methodological and practical point of view need to be overcome.Areas covered: In the present review, a short overview of basket trials, umbrella trials and platform trials are discussed, in particular advantages and disadvantages of such experimental approaches.Expert opinion: Master protocols represent the future of clinical oncology research. The possibility of investigating multiple biomarkers and therapeutic regimens under one study is a strong advantage over traditional trials, and it can lead to quick implementation of new, promising treatments or biomarkers into the clinic.


Assuntos
Ensaios Clínicos como Assunto/métodos , Neoplasias/terapia , Projetos de Pesquisa , Pesquisa Biomédica/métodos , Humanos , Medicina de Precisão/métodos , Pesquisa Médica Translacional/métodos
11.
Nat Commun ; 10(1): 4155, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519912

RESUMO

Zika virus (ZIKV) infection results in an increased risk of spontaneous abortion and poor intrauterine growth although the underlying mechanisms remain undetermined. Little is known about the impact of ZIKV infection during the earliest stages of pregnancy, at pre- and peri-implantation, because most current ZIKV pregnancy studies have focused on post-implantation stages. Here, we demonstrate that trophectoderm cells of pre-implantation human and mouse embryos can be infected with ZIKV, and propagate virus causing neural progenitor cell death. These findings are corroborated by the dose-dependent nature of ZIKV susceptibility of hESC-derived trophectoderm cells. Single blastocyst RNA-seq reveals key transcriptional changes upon ZIKV infection, including nervous system development, prior to commitment to the neural lineage. The pregnancy rate of mice is >50% lower in pre-implantation infection than infection at E4.5, demonstrating that pre-implantation ZIKV infection leads to miscarriage. Cumulatively, these data elucidate a previously unappreciated association of pre- and peri-implantation ZIKV infection and microcephaly.


Assuntos
Complicações Infecciosas na Gravidez/metabolismo , Infecção por Zika virus/complicações , Infecção por Zika virus/metabolismo , Zika virus/patogenicidade , Aborto Espontâneo/metabolismo , Aborto Espontâneo/fisiopatologia , Animais , Blastocisto/citologia , Blastocisto/metabolismo , Implantação do Embrião/fisiologia , Feminino , Desenvolvimento Fetal/genética , Desenvolvimento Fetal/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , RNA Viral/genética , Pesquisa Médica Translacional/métodos , Trofoblastos/citologia , Trofoblastos/metabolismo
12.
J Headache Pain ; 20(1): 94, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481015

RESUMO

Migraine is a complex brain disorder and initiating events for acute attacks still remain unclear. It seems difficult to explain the development of migraine headache with one mechanism and/or a single anatomical location. Cortical spreading depression (CSD) is recognized as the biological substrate of migraine aura and experimental animal studies have provided mechanisms that possibly link CSD to the activation of trigeminal neurons mediating lateralized head pain. However, some CSD features do not match the clinical features of migraine headache and there are gaps in translating CSD to migraine with aura. Clinical features of migraine headache and results from research are critically evaluated; and consistent and inconsistent findings are discussed according to the known basic features of canonical CSD: typical SD limited to the cerebral cortex as it was originally defined. Alternatively, arguments related to the emergence of SD in other brain structures in addition to the cerebral cortex or CSD initiated dysfunction in the thalamocortical network are proposed. Accordingly, including thalamus, particularly reticular nucleus and higher order thalamic nuclei, which functions as a hub connecting the visual, somatosensory, language and motor cortical areas and subjects to modulation by brain stem projections into the CSD theory, would greatly improve our current understanding of migraine.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Cefaleia/fisiopatologia , Enxaqueca com Aura/fisiopatologia , Pesquisa Médica Translacional/métodos , Animais , Córtex Cerebral/fisiopatologia , Cefaleia/diagnóstico , Humanos , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/fisiopatologia , Enxaqueca com Aura/diagnóstico , Núcleos Talâmicos/fisiopatologia
14.
Eur J Pediatr Surg ; 29(4): 361-367, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31430764

RESUMO

Hirschsprung's disease (HSCR) is caused by incomplete colonization of enteric neural crest-derived cell (ENCC) in the bowel, the failure of ENCCs to proliferate, differentiate, and migrate leads to an absence of enteric neurons in the distal colon, resulting in colonic motility dysfunction. Various animal models of HSCR have been important in the understanding of the anatomy and pathophysiology of the disease and in the discovery of genes involved in HSCR. Four types of HSCR animal models have been developed: teratogen-induced, surgically created, naturally occurring models, and knockout models. Mutations in several genes affect enteric nervous system (ENS) development and can have pleiotropic effects on this system. Furthermore, certain animal models are informative regarding how such molecules control the development and functional differentiation of the ENS. In this article, we summarize recent advances in this field and highlight opportunities for new discoveries.


Assuntos
Modelos Animais de Doenças , Doença de Hirschsprung , Pesquisa Médica Translacional/métodos , Animais , Doença de Hirschsprung/etiologia , Doença de Hirschsprung/patologia , Doença de Hirschsprung/fisiopatologia , Doença de Hirschsprung/terapia , Humanos
15.
Nature ; 572(7767): 43-50, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31367027

RESUMO

Science fiction notions of altering problematic memories are starting to become reality as techniques emerge through which unique memories can be edited. Here we review memory-editing research with a focus on improving the treatment of psychopathology. Studies highlight two windows of memory vulnerability: initial storage, or consolidation; and re-storage after retrieval, or reconsolidation. Techniques have been identified that can modify memories at each stage, but translating these methods from animal models to humans has been challenging and implementation into clinical therapies has produced inconsistent benefits. The science of memory editing is more complicated and nuanced than fiction, but its rapid development holds promise for future applications.


Assuntos
Memória/fisiologia , Psicopatologia/métodos , Pesquisa Médica Translacional/métodos , Animais , Humanos , Consolidação da Memória/fisiologia , Rememoração Mental/fisiologia , Modelos Animais , Psicopatologia/tendências , Pesquisa Médica Translacional/tendências
16.
EBioMedicine ; 47: 607-615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31466916

RESUMO

Big data problems are becoming more prevalent for laboratory scientists who look to make clinical impact. A large part of this is due to increased computing power, in parallel with new technologies for high quality data generation. Both new and old techniques of artificial intelligence (AI) and machine learning (ML) can now help increase the success of translational studies in three areas: drug discovery, imaging, and genomic medicine. However, ML technologies do not come without their limitations and shortcomings. Current technical limitations and other limitations including governance, reproducibility, and interpretation will be discussed in this article. Overcoming these limitations will enable ML methods to be more powerful for discovery and reduce ambiguity within translational medicine, allowing data-informed decision-making to deliver the next generation of diagnostics and therapeutics to patients quicker, at lowered costs, and at scale.


Assuntos
Inteligência Artificial , Aprendizado de Máquina , Pesquisa Médica Translacional , Animais , Descoberta de Drogas , Genômica/métodos , Humanos , Imagem Molecular , Medicina de Precisão , Reprodutibilidade dos Testes , Pesquisa Médica Translacional/métodos
17.
Eur J Pediatr Surg ; 29(4): 336-341, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31412364

RESUMO

Biliary atresia (BA) is a fibro-obliterative cholangiopathy of unknown etiology. While Kasai portoenterostomy achieves temporary biliary drainage in some cases, BA remains the most common indication for liver transplantation during childhood. During the last few decades, observations on BA, like cholestatic diseases in animals and the introduction of different animal models for BA, have not achieved the anticipated results, and we are still not able to translate the basic research to the patient's bedside. This article presents a review of the literature on available BA animal models and gives a glimpse of future developments.


Assuntos
Atresia Biliar/terapia , Modelos Animais de Doenças , Pesquisa Médica Translacional/métodos , Animais , Animais Selvagens , Atresia Biliar/etiologia , Humanos , Camundongos
18.
Eur J Pediatr Surg ; 29(4): 317-327, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31365938

RESUMO

Congenital diaphragmatic hernia (CDH) is a devastating disease that still carries a high mortality and morbidity rate. Poor outcomes for fetuses and infants with CDH are mainly related to pulmonary hypoplasia (PH) and pulmonary vascular remodeling that leads to pulmonary hypertension (PHTN). Over the last five decades, research efforts have focused on modeling CDH not only to study the pathophysiology of the diaphragmatic defect, pulmonary hypoplasia, and pulmonary hypertension, but also to identify therapies that would promote lung growth and maturation, and correct vascular remodeling. As CDH is a multifactorial condition whose etiology remains unknown, there is not a single model of CDH, rather several ones that replicate different aspects of this disease. While small animals like the mouse and the rat have mainly been used to uncover biological pathways underlying the diaphragmatic defect and poor lung growth, larger animals like the lamb and the rabbit models have been instrumental for pursuing medical and surgical interventions. Overall, the use of animal models has indeed advanced our knowledge on CDH and helped us test innovative therapeutic options. For example, the lamb model of CDH has been the paradigm for testing fetal surgical procedures, including tracheal occlusion, which has been translated to clinical use. In this review, we outline the induction protocols of CDH in animals with the use of chemicals, dietary changes, genetic alterations, and surgical maneuvers, and we describe the studies that have translated experimental results to the bedside.


Assuntos
Modelos Animais de Doenças , Hérnias Diafragmáticas Congênitas , Pesquisa Médica Translacional/métodos , Animais , Terapias Fetais/métodos , Hérnias Diafragmáticas Congênitas/etiologia , Hérnias Diafragmáticas Congênitas/terapia , Humanos
19.
Eur J Pediatr Surg ; 29(4): 328-335, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31426114

RESUMO

Long-gap esophageal atresia is one of the most challenging diseases in the field of pediatric surgery. There is no optimal therapy, and thus many potential therapies and techniques are being actively explored, both in animal models and in neonates. This article will review the available experimental treatment options with a focus on novel techniques.


Assuntos
Modelos Animais de Doenças , Atresia Esofágica/terapia , Pesquisa Médica Translacional/métodos , Animais , Humanos
20.
Eur J Pediatr Surg ; 29(4): 352-360, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31426115

RESUMO

Necrotizing enterocolitis (NEC) is a devastating intestinal disease that continues to have high morbidity and mortality among preterm neonates, despite medical advancements in neonatology and neonatal care. To investigate the pathogenesis of the disease and explore novel form of treatment, a variety of experimental models of NEC have been developed and used by various investigators. These experimental models range from in vitro evaluation of intestinal epithelial cells and intestinal organoids to in vivo models of the disease in neonatal mice, rats, and piglets. Most recently, human-derived intestinal organoids have also been developed and investigated. In this review, we will briefly discuss these experimental models and the contributions that they have made to our understanding of NEC. We will also point to the ischemia/reperfusion (I/R) model of intestinal injury which has been used as an indirect model of NEC by some investigators. Advancements in laboratory research into this devastating disease have continued to expand our knowledge on the pathogenesis and prevention of NEC as well as the effectiveness of therapeutic options for management of this severe disease.


Assuntos
Modelos Animais de Doenças , Enterocolite Necrosante , Pesquisa Médica Translacional/métodos , Animais , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/patologia , Enterocolite Necrosante/terapia , Humanos
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