Translational Science, Biomedical

翻译科学,生物医学
  • 文章类型: Journal Article
    过敏性疾病的患病率在全球范围内增加,其中2型炎症性疾病的子集发挥了重要作用。2型炎症性疾病的临床表现可能不同,但它们表现出共同的病理生理学,这是dupilumab独特的药理学所针对的。Dupilumab与白细胞介素(IL)-4受体α亚基(IL-4Rα)结合,阻断IL-4和IL-13信号传导,2型炎症的两个关键驱动因素。在这里,我们回顾了dupilumab的作用机制和药理学,以及导致dupilumab用于治疗多种2型炎症性疾病的监管批准的临床证据:特应性皮炎,哮喘,慢性鼻-鼻窦炎伴鼻息肉,嗜酸性粒细胞性食管炎,和结节性痒疹.
    Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)-4 receptor alpha subunit (IL-4Rα) that blocks IL-4 and IL-13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.
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  • 文章类型: Journal Article
    粮食不安全是一个普遍存在的问题,影响整个生命周期的健康和福祉。将粮食不安全与不良代谢和行为健康结果联系起来的人类研究本质上是相关的,并且随着时间的推移,家庭之间甚至同一家庭内部都存在高度的变异性。Further,粮食不安全受到社会和政治因素的影响,这些因素在很大程度上是个人无法控制的,这缩小了干预策略的范围。正在开发粮食不安全的动物模型,以解决机械研究的一些障碍。然而,动物模型在考虑人类状况的一些更复杂的社会因素方面的能力有限。我们认为,了解粮食不安全在摄入行为和慢性疾病中的作用需要一种真正的转化方法,了解这种复杂的社会现象对健康的影响需要了解其心理和生理层面。这篇简短的评论将概述粮食不安全的一些关键特征,强调那些可以用受控动物模型进行调查的人,并确定整合动物和人类研究的领域,可以提高我们对粮食不安全的心理负担和健康影响的理解。为了简洁起见,这次审查将主要集中在美国的粮食不安全问题上,因为导致粮食不安全的因素在全球范围内差异很大。
    Food insecurity is a pervasive problem that impacts health and well-being across the lifespan. The human research linking food insecurity to poor metabolic and behavioral health outcomes is inherently correlational and suffers from a high degree of variability both between households and even within the same household over time. Further, food insecurity is impacted by societal and political factors that are largely out of the control of individuals, which narrows the range of intervention strategies. Animal models of food insecurity are being developed to address some of the barriers to mechanistic research. However, animal models are limited in their ability to consider some of the more complex societal elements of the human condition. We believe that understanding the role that food insecurity plays in ingestive behavior and chronic disease requires a truly translational approach, and that understanding the health impacts of this complex social phenomenon requires understanding both its psychological and physiological dimensions. This brief review will outline some key features of food insecurity, highlighting those that are amenable to investigation with controlled animal models and identifying areas where integrating animal and human studies can improve our understanding of the psychological burden and health impacts of food insecurity. In the interest of brevity, this review will largely focus on food insecurity in the United States, as the factors that contribute to food insecurity vary considerably across the globe.
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  • 文章类型: Journal Article
    在这篇文章中,作者总结了食管癌和胃癌转化科学的现状。现有的靶向治疗,免疫疗法,并对最近发现的分子靶标进行了综述。作者介绍了循环肿瘤脱氧核糖核酸及其作为检测疾病复发的生物标志物的前景。作者提出了患者来源的类器官作为研究致癌作用和治疗反应的新模型。最后,我们讨论了类器官模型对精确肿瘤学的意义,并描述了将基因编辑技术应用于类器官的令人兴奋的新工作,以及使用3维共培养系统研究肿瘤-微环境相互作用。
    In this article, the authors summarize the current state of translational science for esophageal and gastric cancers. The available targeted therapies, immunotherapies, and recently discovered molecular targets are reviewed. The authors introduce circulating tumor deoxyribonucleic acid and its promise as a biomarker to detect disease recurrence. The authors present patient-derived organoids as a new model for studying carcinogenesis and treatment responses. Finally, we discuss the implications of organoid models for precision oncology and describe exciting new work applying gene editing technology to organoids and studying tumor-microenvironment interactions using 3-dimensional co-culture systems.
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  • 文章类型: Journal Article
    背景:我们旨在开发第一个机器学习模型来预测引文计数和翻译影响,定义为包含在指南或政策文件中,头痛研究,并评估哪些因素最具预测性。
    方法:文献计量数据和标题,摘要,我们使用了从3种面向头痛的期刊开始至2017年12月31日的8600种出版物的关键词.实施了一系列机器学习模型来预测三类5年引文计数间隔(0-5、6-14和,>14次引用);以及出版物的翻译影响。用受试者工作特征曲线下面积(AUC)对模型进行样品外评价。
    结果:性能最高的梯度增强模型预测正确的引用计数类别,样本外AUC为0.81。文献计量数据,如页数,引用的数量,第一个和最后一个作者引文计数和h指数是最重要的预测因子。当包括文献计量数据和标题信息时,翻译影响的预测效果最佳,抽象和关键字,表现最好的随机森林模型的样本外AUC为0.71。
    结论:引文计数最好通过文献计量数据来预测,虽然结合文献计量数据和出版物内容的模型确定了头痛研究的转化影响。
    BACKGROUND: We aimed to develop the first machine learning models to predict citation counts and the translational impact, defined as inclusion in guidelines or policy documents, of headache research, and assess which factors are most predictive.
    METHODS: Bibliometric data and the titles, abstracts, and keywords from 8600 publications in three headache-oriented journals from their inception to 31 December 2017 were used. A series of machine learning models were implemented to predict three classes of 5-year citation count intervals (0-5, 6-14 and, >14 citations); and the translational impact of a publication. Models were evaluated out-of-sample with area under the receiver operating characteristics curve (AUC).
    RESULTS: The top performing gradient boosting model predicted correct citation count class with an out-of-sample AUC of 0.81. Bibliometric data such as page count, number of references, first and last author citation counts and h-index were among the most important predictors. Prediction of translational impact worked optimally when including both bibliometric data and information from the title, abstract and keywords, reaching an out-of-sample AUC of 0.71 for the top performing random forest model.
    CONCLUSIONS: Citation counts are best predicted by bibliometric data, while models incorporating both bibliometric data and publication content identifies the translational impact of headache research.
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  • 文章类型: Review
    目标:如果没有战略行动支持,将科学研究证据转化为卫生政策往往缺乏或延迟。这篇综述系统地绘制和评估了卫生政策知识翻译(KT)领域的国家级战略文件,并开发了一个实用的模板,可以支持循证政策网络(EVIPNet)欧洲国家制定循证决策的国家战略。
    方法:以电子方式搜索在KT中负有战略责任的组织的网站,根据预先定义的标准,2017年7月至8月,并在2021年4月至6月进行了更新搜索。我们包括处理KT活动的国家战略或国家战略要素,以及以国家政策为重点的个别机构的类似战略。两名审稿人筛选了纳入战略。使用定性内容分析对数据进行分析。
    结果:总共确定了65个独特的文档,其中17人符合资格,并对其结构和内容进行了分析。在17份文件中,1份是国家卫生KT行动计划,6份是机构级KT战略。剩下的10个策略,其中还包括2个国家卫生战略,5个国家卫生研究战略和3个国家KT战略(并非仅针对卫生领域)。总之,从纳入的文件中确定了卫生政策KT战略的13个结构要素和7个主要主题。
    结论:卫生政策中的KT,正如我们的测绘所确定的国家战略所产生的那样,是基于政策相关研究的产生和可及性,其用于决策和与知识交流有关的活动的包装。KT战略在复杂和特定于环境的决策过程中可能发挥不同的作用。我们的研究结果表明,针对健康的循证政策文献的主要思想出现在这些策略中,但是它们的有效性取决于利益相关者使用它们的方式。具体的知识经纪机构和组织能力,关于使用证据的宣传,与主要利益攸关方的密切合作和共同决策对于促进研究成果的政策吸收至关重要。
    OBJECTIVE: Without strategic actions in its support, the translation of scientific research evidence into health policy is often absent or delayed. This review systematically maps and assesses national-level strategic documents in the field of knowledge translation (KT) for health policy, and develops a practical template that can support Evidence-informed Policy Network (EVIPNet) Europe countries in producing national strategies for evidence-informed policy-making.
    METHODS: Websites of organizations with strategic responsibilities in KT were electronically searched, on the basis of pre-defined criteria, in July-August 2017, and an updated search was carried out in April-June 2021. We included national strategies or elements of national strategies that dealt with KT activities, as well as similar strategies of individual institutions with a national policy focus. Two reviewers screened the strategies for inclusion. Data were analysed using qualitative content analysis.
    RESULTS: A total of 65 unique documents were identified, of which 17 were eligible and analysed for their structure and content. Of the 17, 1 document was a national health KT action plan and 6 documents were institution-level KT strategies. The remaining 10 strategies, which were also included were 2 national health strategies, 5 national health research strategies and 3 national KT strategies (not specific to the field of health alone). In all, 13 structural elements and 7 major themes of health policy KT strategies were identified from the included documents.
    CONCLUSIONS: KT in health policy, as emerged from the national strategies that our mapping identified, is based on the production and accessibility of policy-relevant research, its packaging for policy-making and the activities related to knowledge exchange. KT strategies may play different roles in the complex and context-specific process of policy-making. Our findings show that the main ideas of health-specific evidence-informed policy literature appear in these strategies, but their effectiveness depends on the way stakeholders use them. Specific knowledge-brokering institutions and organizational capacity, advocacy about the use of evidence, and close collaboration and co-decision-making with key stakeholders are essential in furthering the policy uptake of research results.
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  • 文章类型: Journal Article
    我很幸运地从现代分子生物学的曙光开始我的职业生涯,并将其应用于一个重要的健康问题。虽然我早期的工作重点是基础科学,更好地了解人类疾病并为研究发现找到实际应用的愿望,在接下来的几十年里,创造了一系列专门针对上皮癌的转化研究。只有通过多种合作才能做到这一点。这种团队科学最终将成为我职业生涯的标志。随着高通量分子技术的发展,研究和发现的步伐加快了,基于基因组学的个性化医疗概念现在正在实现。我希望我的遗产不会只反映我发表的作品,还将包括我对下一代科学家和临床科学家的发展产生的影响,他们的奉献精神激励了我,知识和热情。
    I was fortunate enough to start my career at what was the dawn of modern-day molecular biology and to apply it to an important health problem. While my early work focused on fundamental science, the desire to understand human disease better and to find practical applications for research discoveries resulted, over the following decades, in creating a stream of translational research directed specifically toward epithelial cancers. This could only have been possible through multiple collaborations. This type of team science would eventually become a hallmark of my career. With the development of higher throughput molecular techniques, the pace of research and discovery has quickened, and the concept of personalized medicine based on genomics is now coming to fruition. I hope my legacy will not just reflect my published works, but will also include the impact I have had on the development of the next generation of scientists and clinician scientists who inspired me with their dedication, knowledge, and enthusiasm.
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  • 文章类型: Journal Article
    背景:学术研究中用于知识翻译(KT)的常规方法和策略通常不足以有效地接触利益相关者,比如公民,从业者,和决策者,尤其是复杂的医疗问题。作为回应,越来越多的学者一直在接受基于艺术的知识翻译(ABKT),以瞄准具有不同背景和期望的更多样化的受众。尽管兴趣增加,利用率,在过去的三十年中,以艺术为基础的知识翻译文学,没有研究直接比较传统知识翻译和基于艺术的知识翻译方法。因此,我们的研究旨在评估和比较基于艺术的知识翻译干预-马戏团表演-与两种传统知识翻译干预(网络研讨会和研究报告)在意识方面的影响,可访问性,订婚,宣传/政策影响,和享受。
    方法:为了进行这种探索性的收敛混合方法研究,我们将162名参与者随机分配到三项干预措施中的一项.所有三种知识翻译方法都用于翻译同一研究项目:“农村紧急360:动员决策者,医疗保健专业人员,病人,和公民改善魁北克农村急诊室的医疗保健和服务(UR360)。\"
    结果:研究结果表明,马戏团表演在可访问性和娱乐性方面优于网络研讨会和研究报告,在提高认识方面同样有效,增加参与度,并影响宣传/政策。每种干预策略都展示了其独特的优势和劣势,马戏团表演迎合了不同的观众,而网络研讨会和研究报告的目标是更知情的参与者。这些结果强调了基于艺术的知识翻译的创新和包容性属性,展示其促进研究人员在不同背景下与更广泛的利益相关者接触的能力。
    结论:作为相关的第一步和补充资产,基于艺术的知识翻译在提高人们对关键健康问题的认识和动员方面具有巨大的潜力。
    BACKGROUND: The conventional methods and strategies used for knowledge translation (KT) in academic research often fall short in effectively reaching stakeholders, such as citizens, practitioners, and decision makers, especially concerning complex healthcare issues. In response, a growing number of scholars have been embracing arts-based knowledge translation (ABKT) to target a more diverse audience with varying backgrounds and expectations. Despite the increased interest, utilization, and literature on arts-based knowledge translation over the past three decades, no studies have directly compared traditional knowledge translation with arts-based knowledge translation methods. Thus, our study aimed to evaluate and compare the impact of an arts-based knowledge translation intervention-a circus show-with two traditional knowledge translation interventions (webinar and research report) in terms of awareness, accessibility, engagement, advocacy/policy influence, and enjoyment.
    METHODS: To conduct this exploratory convergent mixed method study, we randomly assigned 162 participants to one of the three interventions. All three knowledge translation methods were used to translate the same research project: \"Rural Emergency 360: Mobilization of decision-makers, healthcare professionals, patients, and citizens to improve healthcare and services in Quebec\'s rural emergency departments (UR360).\"
    RESULTS: The findings revealed that the circus show outperformed the webinar and research report in terms of accessibility and enjoyment, while being equally effective in raising awareness, increasing engagement, and influencing advocacy/policy. Each intervention strategy demonstrates its unique array of strengths and weaknesses, with the circus show catering to a diverse audience, while the webinar and research report target more informed participants. These outcomes underscore the innovative and inclusive attributes of Arts-Based Knowledge translation, showcasing its capacity to facilitate researchers\' engagement with a wider array of stakeholders across diverse contexts.
    CONCLUSIONS: As a relevant first step and a complementary asset, arts-based knowledge translation holds immense potential in increasing awareness and mobilization around crucial health issues.
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  • 文章类型: Review
    2023年8月,美国国家科学院,Engineering,和医学及时发表了题为“迈向健康和医学的公平创新:一个框架”的报告。\"这里,我们回顾了报告的一些主要贡献,关注公平的两个维度:投入公平和部署公平。然后,我们以治疗镰状细胞病(SCD)的新基因疗法为例,作为转化研究中投入和部署公平性的案例研究。SCD案例研究表明,需要一种对生活经验和临床现实以及高度经济和政策复杂性的深刻理解的转化生物伦理学。
    In August of 2023, the National Academies of Science, Engineering, and Medicine published a timely report titled \"Toward Equitable Innovation in Health and Medicine: A Framework.\" Here, we review some of the key contributions of the report, focusing on two dimensions of equity: input equity and deployment equity. We then use the example of new gene therapies to treat sickle cell disease (SCD) as a case study of input and deployment equity in translational research. The SCD case study illustrates the need for a kind of translational bioethics with deep understanding of lived experiences and clinical realities as well as a high degree of economic and policy sophistication.
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  • 文章类型: Journal Article
    脊髓小脑共济失调(SCA)包括一组遗传性神经退行性疾病。Machado-Joseph病(MJD)或脊髓小脑共济失调3(SCA3)是最常见的常染色体显性形式,由ataxin-3(ATXN3)基因内CAG重复序列的扩展引起。该突变导致含有长的聚谷氨酰胺(polyQ)延伸的异常蛋白质的表达,所述长的聚谷氨酰胺(polyQ)延伸赋予毒性功能增益,并导致ATXN3在神经元中的错误折叠和聚集。作为神经退行性过程的结果,SCA3患者严重残疾并过早死亡。几种筛查方法,例如,已经进行了药物全基因组和药物库筛选,集中于稳定过表达的ATXN3(polyQ)蛋白的减少和由此产生的毒性的改善。然而,毒性ATXN3的转基因过表达模型,错过了内源性ATXN3调节的潜在调节剂。在使用CRISPR/Cas9修饰的SK-N-SH野生型细胞系鉴定内源ATXN3表达的修饰剂的另一种方法中,在内源ATXN3启动子的控制下,使用GFP-T2A-荧光素酶(LUC)盒,四种他汀类药物被鉴定为潜在的表达激活剂。我们在这里提供了高通量筛选方法的概述,这些方法在不同的SCA3模型生物和细胞系中找到ATXN3(polyQ)毒性的化合物或基因组修饰剂,以改善和阻止患者的SCA3进展。此外,讨论了胆固醇在神经退行性疾病(NDDs)中的一般作用,特别是SCA3。
    The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado-Joseph Disease (MJD) or spinocerebellar ataxia 3 (SCA3) is the most common autosomal dominant form, caused by the expansion of CAG repeats within the ataxin-3 (ATXN3) gene. This mutation results in the expression of an abnormal protein containing long polyglutamine (polyQ) stretches that confers a toxic gain of function and leads to misfolding and aggregation of ATXN3 in neurons. As a result of the neurodegenerative process, SCA3 patients are severely disabled and die prematurely. Several screening approaches, e.g., druggable genome-wide and drug library screenings have been performed, focussing on the reduction in stably overexpressed ATXN3(polyQ) protein and improvement in the resultant toxicity. Transgenic overexpression models of toxic ATXN3, however, missed potential modulators of endogenous ATXN3 regulation. In another approach to identify modifiers of endogenous ATXN3 expression using a CRISPR/Cas9-modified SK-N-SH wild-type cell line with a GFP-T2A-luciferase (LUC) cassette under the control of the endogenous ATXN3 promotor, four statins were identified as potential activators of expression. We here provide an overview of the high throughput screening approaches yet performed to find compounds or genomic modifiers of ATXN3(polyQ) toxicity in different SCA3 model organisms and cell lines to ameliorate and halt SCA3 progression in patients. Furthermore, the putative role of cholesterol in neurodegenerative diseases (NDDs) in general and SCA3 in particular is discussed.
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  • 文章类型: Journal Article
    流式细胞术是细胞生物学研究的主要技术,用于混合细胞群的表型分析。定量方法已经解锁了流式细胞术在药物发现研究中的更深层次的价值。随着药物模式和药物机制的增加,识别有意义的生物标志物的动力越来越强,评估药代动力学和药效学(PK/PD)之间的关系,并将这些见解转化为对参加早期临床试验的患者的评估。在这次审查中,我们讨论了流式细胞术在翻译环境中的新兴作用,支持新化合物在临床中的转变和评估。
    Flow cytometry is a mainstay technique in cell biology research, where it is used for phenotypic analysis of mixed cell populations. Quantitative approaches have unlocked a deeper value of flow cytometry in drug discovery research. As the number of drug modalities and druggable mechanisms increases, there is an increasing drive to identify meaningful biomarkers, evaluate the relationship between pharmacokinetics and pharmacodynamics (PK/PD), and translate these insights into the evaluation of patients enrolled in early clinical trials. In this review, we discuss emerging roles for flow cytometry in the translational setting that supports the transition and evaluation of novel compounds in the clinic.
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