Preclinical.

  • 文章类型: Systematic Review
    多药耐药细菌感染的出现引起了严重的问题,涉及住院率和死亡率。本系统综述旨在回顾纳米粒子与传统使用的抗生素的联合抗菌作用。克服抗生素耐药性危机。在这个系统的搜索中,我们专注于使用动物模型的临床前研究,试验和评价在抗生素中添加纳米材料对耐碳青霉烯类革兰氏阴性菌的效果。Where,这种新形成的结构导致动物模型血清中细菌负荷的显著降低。此外,通过评估纳米材料的细胞毒性和炎症标志物,建立了有希望的结果,低毒性指数,支持这一新途径作为替代滥用抗生素的能力。我们的研究收集了各种数据,并显示出令人鼓舞的临床前使用纳米材料和抗生素。应该考虑这种不可否认的路线,由于其有助于治疗多药耐药细菌感染的能力。这些发现为未来的研究提供了基础,并加强了对纳米材料对细菌感染的安全性进行更多评估和测试的需求。
    The emergence of multi drug resistant bacterial infections has caused a critical problem with implication on hospitalization and mortality rates. This systematic review aims to review the combined antimicrobial effect of nanoparticles attached to the traditionally used antibiotics, to overcome the antibiotic resistance crisis. In this systematic search we focused on preclinical studies that have used animal models, to test and evaluate the effect of nanomaterials added to antibiotics against gram negative bacteria with carbapenem resistance. Where, this newly formed structure has led to significant decrease in bacterial load in animal model serum. Furthermore, by evaluating nanomaterial cytotoxicity and inflammatory markers, promising results were established, where low toxicity indices were presented, supporting the ability of this new pathway to be used as an alternative to abused antibiotics. Our research collected the various data and showed encouraging preclinical one for using nanomaterials with antibiotics. This undeniable route should be considered, due to its ability to contribute to the treatment of multi drug resistant bacterial infections. These findings provide base for future studies and reinforce the need for more evaluation and testing on the safety of nanomaterials against bacterial infections.
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  • 文章类型: Journal Article
    Accumulating evidence indicates that the failure to recover from the effects of proactive semantic interference [frPSI] represents an early cognitive manifestation of preclinical Alzheimer\'s disease. A limitation of this novel paradigm has been a singular focus on the number of targets correctly recalled, without examining co-occurring semantic intrusions [SI] that may highlight specific breakdowns in memory.
    We focused on SI and their relationship to amyloid load and regional cortical thickness among persons with amnestic mild cognitive impairment (aMCI).
    Thirty-three elders diagnosed with aMCI underwent F-18 florbetaben amyloid PET scanning with MRI scans of the brain. We measured the correlation of SI elicited on cued recall trials of the Loewenstein-Acevedo Scales for Semantic Interference and Learning [LASSI-L] with mean cortical amyloid load and regional cortical thickness in AD prone regions.
    SI on measures sensitive to frPSI was related to greater total amyloid load and lower overall cortical thickness [CTh]. In particular, SI were highly associated with reduced CTh in the left entorhinal cortex [r=-.71; p<.001] and left medial orbital frontal lobe [r=-.64; p<.001]; together accounting for 66% of the explained variability in regression models.
    Semantic intrusions on measures susceptible to frPSI related to greater brain amyloid load and lower cortical thickness. These findings further support the hypothesis that frPSI, as expressed by the percentage of intrusions, may be a cognitive marker of initial neurodegeneration and may serve as an early and distinguishing test for preclinical AD that may be used in primary care or clinical trial settings.
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  • 文章类型: Journal Article
    背景:胶质瘤是由神经胶质引起的脑肿瘤,中枢神经系统(CNS)的支持组织,并构成最常见的原发性恶性脑肿瘤。胶质瘤根据其在显微镜下的外观从I级到IV级分级。高级别胶质瘤最显著的不良特征之一是缺氧,当氧浓度变得不足以保证正常组织功能时发生的生物现象。由于肿瘤缺氧对患者预后有负面影响,靶向缺氧具有潜在的治疗意义,目前对测量缺氧的成像技术有很大的兴趣。
    目的:本综述的目的是提供关于通过正电子发射断层扫描(PET)测量脑肿瘤缺氧的放射性示踪剂的最新证据,最广泛研究的成像方法来量化缺氧。
    方法:该综述基于临床前和临床论文,并描述了不同可用放射性示踪剂的验证状态。
    结果:迄今为止,[F-18]氟异硝唑([18F]FMISO)仍然是最广泛使用的放射性示踪剂,用于脑肿瘤患者的缺氧成像,但是在过去的二十年中,与其他放射性示踪剂的经验已经扩展。在这些放射性药物可以在临床环境中广泛使用之前,缺氧放射性示踪剂的验证仍在进行且必不可少。
    结论:能够可靠地测量和绘制脑肿瘤中不同氧水平的非侵入性成像方法的可用性将为选择可能受益于针对缺氧的定制治疗策略的患者提供关键手段。
    BACKGROUND: Gliomas are brain tumours arising from the glia, the supportive tissue of the central nervous system (CNS), and constitute the commonest primary malignant brain tumours. Gliomas are graded from grade I to IV according to their appearance under the microscope. One of the most significant adverse features of high-grade gliomas is hypoxia, a biological phenomenon that develops when the oxygen concentration becomes insufficient to guarantee the normal tissue functions. Since tumour hypoxia influences negatively patient outcome and targeting hypoxia has potential therapeutic implications, there is currently great interest in imaging techniques measuring hypoxia.
    OBJECTIVE: The aim of this review is to provide up to date evidence on the radiotracers available for measuring hypoxia in brain tumours by means of positron emission tomography (PET), the most extensively investigated imaging approach to quantify hypoxia.
    METHODS: The review is based on preclinical and clinical papers and describes the validation status of the different available radiotracers.
    RESULTS: To date, [F-18] fluoromisonidazole ([18F]FMISO) remains the most widely used radiotracer for imaging hypoxia in patients with brain tumours, but experience with other radiotracers has expanded in the last two decades. Validation of hypoxia radiotracers is still on-going and essential before these radiopharmaceuticals can become widely used in the clinical setting.
    CONCLUSIONS: Availability of a non-invasive imaging method capable of reliably measuring and mapping different levels of oxygen in brain tumours would provide the critical means of selecting patients that may benefit from tailored treatment strategies targeting hypoxia.
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  • 文章类型: Comparative Study
    人诱导的多能干细胞心肌细胞(hiPSC-CM)是开发预测性电生理安全性筛选测定法的潜在来源。已发表的研究表明,相关的生理学和药理学存在,但没有显示干细胞心肌细胞试验和其他临床前安全性筛选试验之间的翻译,这对药物发现和安全性科学家和监管机构至关重要。我们的研究首次显示了离子通道阻滞的药理学,并将其与现有的功能性心脏电生理学研究进行了比较。10种化合物(纯hERG[E-4031和西沙必利]的混合物,hERG和钠[氟卡尼,美西律,奎尼丁,和特非那定],钙通道阻滞剂[硝苯地平和维拉帕米],和两种专有化合物[GSKA和B])进行了测试,使用综合风险评估图,将在多电极阵列(MEA)上研究的hiPSC-CM的结果与其他临床前模型以及临床药物浓度和效果进行了比较。所有离子通道阻断剂均产生(1)对IC25和IC50值附近的复极化和去极化的功能作用,以及(2)过度阻断hERG和/或阻断钠电流诱发的心律失常。我们的MEA数据表明,hiPSC-CM表现出相关的药理学,并显示出与当前功能性心脏电生理研究的良好相关性。基于这些结果,使用iPSC-CM的MEA检测提供了一种可靠的、成本有效,并替代临床前体外测试,除了3R(精炼,reduce,并在研究中取代动物)受益。
    Human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) are a potential source to develop assays for predictive electrophysiological safety screening. Published studies show that the relevant physiology and pharmacology exist but does not show the translation between stem cell cardiomyocyte assays and other preclinical safety screening assays, which is crucial for drug discovery and safety scientists and the regulators. Our studies are the first to show the pharmacology of ion channel blockade and compare them with existing functional cardiac electrophysiology studies. Ten compounds (a mixture of pure hERG [E-4031 and Cisapride], hERG and sodium [Flecainide, Mexiletine, Quinidine, and Terfenadine], calcium channel blockers [Nifedipine and Verapamil], and two proprietary compounds [GSK A and B]) were tested, and results from hiPSC-CMs studied on multielectrode arrays (MEA) were compared with other preclincial models and clinical drug concentrations and effects using integrated risk assessment plots. All ion channel blockers produced (1) functional effects on repolarization and depolarization around the IC25 and IC50 values and (2) excessive blockade of hERG and/or blockade of sodium current precipitated arrhythmias. Our MEA data show that hiPSC-CMs demonstrate relevant pharmacology and show excellent correlations to current functional cardiac electrophysiological studies. Based on these results, MEA assays using iPSC-CMs offer a reliable, cost effective, and surrogate to preclinical in vitro testing, in addition to the 3Rs (refine, reduce, and replace animals in research) benefit.
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