笔者想从磁共振成像设备在塞姆斯 - 墨菲诊所，孟菲斯，田纳西州以及神经外科部门田纳西大学健康科学中心在孟菲斯大学，田纳西感谢工作人员。

凝胶幻影1。制备及染料<ol><li>通过以1,000 ml去离子水将2克0.1％的琼脂糖粉制备0.2％琼脂糖凝胶上。搅拌约1分钟，将溶液以保证适当的混合;并立即微波解决方案，在3分钟的间隔为9分钟，或直至清晰，间隔之间搅拌。 </li><li>而琼脂糖凝胶是液体，将溶液倒入5厘米×5厘米×5厘米的容器中。允许空间在容器的顶部，以加水，并允许琼脂糖凝胶冷却并沉降。 </li><li>一旦琼脂糖凝胶凝固后（约1-2小时），添加1厘米的水凝胶与冷藏的顶部。最好是在24-48小时的混合使用的凝胶，但它可以存储多达一周冷藏10。 </li><li>在60毫升注射器由50毫升0.017％溴酚蓝染料（BPB），和钆特醇无线电造影2mM的制备无线电对比染料。 <ol><li>结合8.5 BPB染料毫克50米升去离子水来创建0.017％BPB溶液。 </li><li>加入0.2毫升股票0.5M的钆特醇容量为50毫升0.017％BPB解决方案来创建一个2毫米钆特醇溶液。 </li></ol></li></ol> 2，准备输液系统<ol><li>注射泵的输注系统（优选方法）:用于注射器泵制剂，直接连接输液导管的注射器，通过该压力传感器，减少了输液管线的死体积。注射泵的排出功能可以用于使用大丸剂大于导管以10微升/分钟的速率填充量来清除空气中的行。 </li><li>管泵输注系统（另一种方法）:连接包含无线电造影剂的输液泵注射器。附加的压力传感器，以与连接到第四显示器换能器的泵出口。附加一个地下16输液导管与压力传感器的开口端。注意:在地下16输注导管的前端有一个内直径米为0.2毫米和0.35毫米的外径。尖端是由熔融二氧化硅和小费长度为3毫米。它增加至约0.75毫米，并继续于15 mm，导管那么步骤在一个锥形时尚到1.6毫米或16 G。 </li><li>通过清除系统约15分钟，在16.667微升/分钟，以除去任何气泡制备输注。不要超过16.667μL/ min的流速，因为机器会停止输液，由于高线压力。以下所附的输注导管的线离开的输液泵，空气通过使用输注泵"大丸剂"功能吹扫管线。 </li><li>装上输液导管安装和轨迹帧到凝胶假体容器（5厘米×5厘米×5厘米），发生在MRI检查。 </li></ol> 3，CED凝胶灌注及MR扫描<ol><li>零压力值（毫米汞柱）开始输液前录得的四显示器。 </li><li>插入输液导管进入琼脂糖凝胶瓦特第i个输液泵运行在最低流速可能的，在这种情况下，1.667微升/分钟。 </li><li>开始在MR ​​扫描中，使用表1中列出的参数，并不断注入以1.667微升/分钟的速率。注入的凝胶，以恒定速率输注，直至总体积达到60微升（约38分钟）。 </li><li>连续扫描凝胶在3分钟和50秒的间隔。记录压力读数，每隔60秒。一旦注入量达到60微升，关闭输液泵;和完整的MR扫描，同时继续记录压力读数。 </li></ol> 4，MR数据分析<ol><li>为了分析的MR图像，使用适当的DICOM浏览器与ROI分割功能。 </li><li>选择正确的帧中的每个扫描标记的导管， 如图1所示的横截面。 </li><li>使用"投资回报率 - 矩形"工具，选择凝胶，不包括任何的最大部分输注部位的部分。该软件将输出与标准偏差的平均像素密度。找到对应于三个标准偏差与平均值的值。此值被用作阈值，用于确定当对比度存在99.7％的置信度。 </li><li>使用"投资回报率 - 圈"的工具，环绕输注部位有一个足够大的圆圈，这给一个唯一的名称。 </li><li>选择圆和使用"ROI - 设置像素值"的工具，则在步骤4.3中找到输入到阈值"，如果当前值大于"框中，只要选中这一行。然后在"这个新的价值:"框中，输入一个较大的值（25,000）。重置像素密度来选择前面所定义的阈值所包围的区域。 </li><li>接下来，使用"投资回报率 - 成长区（2D/3D分割）"工具，选择2D的地区，与初始半径参数= 2的信心算法，刷的投资回报率。点击输注部位的软件来计算总面积的内径Ø上本地区。 </li><li>假设一个球形输液云，计算从该区域扩散通过下列公式的体积:V =4/3π（√（面积/π）），3 </li></ol>

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作者宣称，他们有没有竞争的财务权益。

<html>为确保输液成功的关键步骤是:吹扫气的输液管，混合琼脂糖凝胶，分析的MR数据，使用小的内导管的直径，使用阶梯导管设计，以减少回流，并最小化所感受到的压力凝胶或组织到其中的药物被注入。如前所述，主要损害输液的成功是输液管的空气。正确地和彻底吹扫空气的输液管是至关重要的，以确保没有空气进入输液。同样重要的是混合的琼脂糖凝胶电泳图谱。不当合成的凝胶可能导致?...

对流增强输送（CED）已被提议作为用于神经病症包括恶性脑瘤，癫痫，代谢疾病，神经变性疾病（如帕金森病）1，中风和创伤2的广谱治疗选择。 CED采用正压主体流动的药物或其它输注液的分布。 CED提供安全，可靠，且均匀交付分子量化合物，从低到高，在临床相关卷3。传统的药物递送到脑组织受到严重的血-脑屏障4的限制。由内皮细胞间的紧密连接构成的毛细血管在大脑中，血 - 脑屏障块极性和高分子量的分子进入大脑实质内形成。通过海关直接实质内脑灌注可以克服以前的治疗药物传递方式的局限性并允许使用的治疗剂，不会穿过血-脑屏障，因此，此前已作为可行的治疗方案5不可用。 从健康的美国国立卫生研究院（NIH）的研究人员描述土木工程署在上世纪90年代初，作为实现更大的治疗药物浓度的方法比单纯扩散6-8。 CED的第一方法涉及植入一个或多个导管进入大脑，连接输液泵的导管，并直接泵送治疗剂进入目标区域。增加的分布分数和相对稳定的浓度被报道发生如由输液泵产生的正压引起的组织扩张，并允许该药物9的渗透。 最根本的技术CED在很大程度上仍然是它第一次描述的相同。在导管设计10，输液技术进展<su对&gt; 11，管路压力监测2，并实时MRI监测来纠正脑移位12，13，优化多个共线输注14，并监测输液损失15都增加了治疗10的安全性和有效性。额外的重要性已经被放置在导管的设计和输注策略，包括流速。成功的CED，用有限的导管回流和组织损伤，已与相关导管设计和输注速度。使用的导管的具有窄的直径和低输注率，以限制沿脑导管接口倒流以及损坏限制在导管末端16。磁共振成像提供了正确的位置，输液导管置入的视觉确认，因而给药，同时还允许修正输液回流或异常分娩17。 MR图像，也可以用于近似和跟踪分配的体积（VD输注的药物）。在VD是使 ​​用磁共振成像信号强度值大于上述平均值与周围非灌注胶为18分割阈值三个标准差来计算。在Vd为CED为一种有用的测量，因为它代表分布在大脑中的药物的体积。随着输注（六）音量，比率可以生成（VD / VI）量化所涵盖的输注药物的体积。 琼脂糖凝胶体模模仿人类大脑的理解CED等重要几个关键的机械性能:VD，凝胶导管相互作用，多孔弹性性能，并输注云形态10。的0.2％琼脂糖凝胶的混合物已经显示模拟体内由于CED引起凝胶扩张改变当地的孔隙分数。类似的毛孔小部分人脑类似的促进互动和VD 19的精确测量。此外，类似浓度的garose凝胶如0.6％和0.8％也显示类似输液压力分布至脑20。另外，透光性琼脂糖凝胶中提供的导管放置和输注回流的实时可视化的优点。琼脂糖凝胶假体是相对廉价的生产。琼脂糖凝胶假体的费用可能是关键，在整个神经外科未来的广泛培训。由于这些特性，琼脂糖凝胶提供了一个有用的替代，复制了许多人的大脑注入的关键属性，而无需使用脑组织。 如上所述，图像引导到CED琼脂糖凝胶模型提供的体外方法进行测试，研究和培训一个有益的。本文的目的是描述如何重新琼脂糖凝胶假体，勾勒适当CED测试和分析方案，并解决在CED输注用于神经系统疾病的治疗面临的常见错误。

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			<td height="21" style="height:21px;width:205px;">Prohance</td>
			<td style="width:71px;">Bracco</td>
			<td style="width:119px;"></td>
			<td style="width:195px;">Gadoteridol radio contrast media</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:205px;">Bromophenol Blue Dye</td>
			<td style="width:71px;">Biorad</td>
			<td style="width:119px;">161-0404</td>
			<td>Dye for infusate visualization</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:205px;">Agarose Gel Powder</td>
			<td style="width:71px;">Biorad</td>
			<td style="width:119px;">161-3101EDU</td>
			<td>Agarose powder for creating gels</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:205px;">Medrad Veris MR Vital Signs Monitor</td>
			<td style="width:71px;">Medrad</td>
			<td style="width:119px;"></td>
			<td>MR safe infusion pressure monitor</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:205px;">16 Gauge SmartFlow Catheter</td>
			<td style="width:71px;">SurgiVision</td>
			<td style="width:119px;"></td>
			<td>Infusion catheter</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:205px;">Medrad Continuum MR Infusion System</td>
			<td style="width:71px;">Medrad</td>
			<td style="width:119px;"></td>
			<td>MR safe infusion pump</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:205px;">SMART Frame MRI Guided Trajectory Frame</td>
			<td style="width:71px;">ClearPoint</td>
			<td style="width:119px;"></td>
			<td>Infusion catheter frame</td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:205px;">Osirix Imaging Software and DICOM Viewer</td>
			<td style="width:71px;">Osirix Imaging Software</td>
			<td style="width:119px;"></td>
			<td>OsiriX 32-bit DICOM Viewer</td>
		</tr>
	</tbody>
</table>

image-guided convection-enhanced delivery into agarose gel models of the brain

对流增强交付（CED）已被提议作为一个广泛的神经系统疾病的治疗选择。 Neuroinfusion导管海关允许正压大量流量，提供更大量疗法比传统给药方法颅内目标。实时磁共振成像的临床应用指导CED（rCED）在于准确瞄准，监测治疗，并确定并发症的能力。与训练，rCED是有效和并发症可以被最小化。大脑的琼脂糖凝胶模型提供了一种方便的工具CED测试，研究和培训。模拟大脑rCED允许模拟手术的做法，同时还提供可视化的输液反馈。输注的分析允许对分布分数（VD / VI）使学员以验证模型的相似性相比，人脑组织的计算。本文介绍了我们的琼脂糖凝胶假体脑并概述重要的我在同时解决过程中的CED输液面临神经系统疾病的治疗常见的陷阱，一个CED输液和分析协议trics。

解释和分析CED输液涉及的几个重要因素，如分配分数和输液回流。分配比例计算很大程度上取决于Vd的计算。因此，MR图像的准确解释是关键。我们提出了用于可靠地再现这些测量如上面列出的半自动化方法。这些方法客观地确定输液云和横截面面积的大致半径。而可变，在琼脂糖凝胶输液云往往被证明是球形的。假设一个球形输液云，该半径可以被用来确定在VD为CED输注。 VD / VI的琼脂糖凝胶输?...

Watch this Scientific Journal Video about Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain at JoVE.com

Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

对流增强交付（CED）已被提议作为一个广泛的神经系统疾病的治疗选择。为了准备专业医护人员采用CED的，需要访问的培训模式。我们描述了使用琼脂糖凝胶作为人脑的这样的试验，研究和训练的模型。

图像引导的对流增强交付到大脑的琼脂糖凝胶模型

Convection-enhanced delivery (CED) has been proposed as a treatment option for a wide range of neurological diseases. Neuroinfusion catheter CED allows ...

image-guided-convection-enhanced-delivery-into-agarose-gel-models

Research

JoVE Journal

Medicine

11.3K 次观看.  University of Tennessee Health Science Center. 对流增强交付（CED）已被提议作为一个广泛的神经系统疾病的治疗选择。为了准备专业医护人员采用CED的，需要访问的培训模式。我们描述了使用琼脂糖凝胶作为人脑的这样的试验，研究和训练的模型。 

视频: Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

MRI and PET in Mouse Models of Myocardial Infarction

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ideal model for testing novel therapeutic strategies.
In vivo magnetic resonance imaging (MRI) gives excellent views of the heart noninvasively with clear anatomical detail, which can be used for accurate functional assessment. Contrast agents can provide basic measures of tissue viability but these are nonspecific. Positron emission tomography (PET) is a complementary technique that is highly specific for molecular imaging, but lacks the anatomical detail of MRI. Used together, these techniques offer a sensitive, specific and quantitative tool for the assessment of the heart in disease and recovery following treatment.
In this paper we explain how these methods are carried out in mouse models of acute myocardial infarction. The procedures described here were designed for the assessment of putative protective drug treatments. We used MRI to measure systolic function and infarct size with late gadolinium enhancement, and PET with fluorodeoxyglucose (FDG) to assess metabolic function in the infarcted region. The paper focuses on practical aspects such as slice planning, accurate gating, drug delivery, segmentation of images, and multimodal coregistration. The methods presented here achieve good repeatability and accuracy maintaining a high throughput.

We describe how to perform MRI and PET imaging of the mouse heart. The protocol is tailored to assess treatment efficacy in models of myocardial infarction and heart failure.

MRI和PET心肌梗死小鼠模型

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ...

科研

医学

DNBS/TNBS Colitis Models: Providing Insights Into Inflammatory Bowel Disease and Effects of Dietary Fat

Inflammatory Bowel Diseases (IBD), including Crohn&#39;s Disease and Ulcerative Colitis, have long been associated with a genetic basis, and more recently host immune responses to microbial and environmental agents. Dinitrobenzene sulfonic acid (DNBS)-induced colitis allows one to study the pathogenesis of IBD associated environmental triggers such as stress and diet, the effects of potential therapies, and the mechanisms underlying intestinal inflammation and mucosal injury. In this paper, we investigated the effects of dietary n-3 and n-6 fatty acids on the colonic mucosal inflammatory response to DNBS-induced colitis in rats. All rats were fed identical diets with the exception of different types of fatty acids [safflower oil (SO), canola oil (CO), or fish oil (FO)] for three&#160;weeks prior to exposure to intrarectal DNBS. Control rats given intrarectal ethanol continued gaining weight over the 5 day study, whereas, DNBS-treated rats fed lipid diets all lost weight with FO and CO fed rats demonstrating significant weight loss by 48&#160;hr and rats fed SO by 72&#160;hr. Weight gain resumed after 72&#160;hr post DNBS, and by 5 days post DNBS, the FO group had a higher body weight than SO or CO groups. Colonic sections collected 5&#160;days post DNBS-treatment showed focal ulceration, crypt destruction, goblet cell depletion, and mucosal infiltration of both acute and chronic inflammatory cells that differed in severity among diet groups. The SO fed group showed the most severe damage followed by the CO, and FO fed groups that showed the mildest degree of tissue injury. Similarly, colonic myeloperoxidase (MPO) activity, a marker of neutrophil activity was significantly higher in SO followed by CO fed rats, with FO fed rats having significantly lower MPO activity. These results demonstrate the use of DNBS-induced colitis, as outlined in this protocol, to determine the impact of diet in the pathogenesis of IBD.

DNBS/TNBS induced colitis offers an alternative and inexpensive method to study the pathobiology of inflammatory bowel disease. The protocol discussed in this paper outlines the successful application of DNBS to induce colitis in mice and rats and allows one to thoroughly study host-mediated intestinal responses.

二硝基苯磺酸/ TNBS结肠炎模型:提供洞察炎症性肠病和膳食脂肪的影响

Inflammatory Bowel Diseases (IBD), including Crohn&#39;s Disease and Ulcerative Colitis, have long been associated with a genetic basis, and more recently ...

Heterotopic Mucosal Engrafting Procedure for Direct Drug Delivery to the Brain in Mice

Delivery of therapeutics into the brain is impeded by the presence of the blood-brain barrier (BBB) which restricts the passage of polar and high molecular weight compounds from the bloodstream and into brain tissue. Some direct delivery success in humans has been achieved via implantation of transcranial catheters; however this method is highly invasive and associated with numerous complications. A less invasive alternative would be to dose the brain through a surgically implanted, semipermeable membrane such as the nasal mucosa that is used to repair skull base defects following endoscopic transnasal tumor removal surgery in humans. Drug transfer though this membrane would effectively bypass the BBB and diffuse directly into the brain and cerebrospinal fluid. Inspired by this approach, a surgical approach in mice was developed that uses a donor septal mucosal membrane engrafted over an extracranial surgical BBB defect. This model has been shown to effectively allow the passage of high molecular weight compounds into the brain. Since numerous drug candidates are incapable of crossing the BBB, this model is valuable for performing preclinical testing of novel therapies for neurological and psychiatric diseases.

A mouse model of human endoscopic skull base reconstruction has been developed that creates a semipermeable interface between the brain and nose using nasal mucosal grafts. This method allows researchers to study delivery to the central nervous system of high molecular weight therapeutics which are otherwise excluded by the blood-brain barrier when administered systemically.

异位黏膜移植程序直接给药到小鼠的大脑

Delivery of therapeutics into the brain is impeded by the presence of the blood-brain barrier (BBB) which restricts the passage of polar and high ...

Mouse Kidney Transplantation: Models of Allograft Rejection

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique.

Here, we present a protocol to study the immunology of rejection. The surgical model presented reports a short operating time and a concise technique. Depending on the donor-recipient strain combination, the transplanted kidney may develop acute cellular rejection or chronic allograft damage, defined by interstitial fibrosis and tubular atrophy.

鼠肾移植:移植排斥反应模型

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely ...

Transposon Mediated Integration of Plasmid DNA into the Subventricular Zone of Neonatal Mice to Generate Novel Models of Glioblastoma

An urgent need exists to test the contribution of new genes to the pathogenesis and progression of human glioblastomas (GBM), the most common primary brain tumor in adults with dismal prognosis. New potential therapies are rapidly emerging from the bench and require systematic testing in experimental models which closely reproduce the salient features of the human disease. Herein we describe in detail a method to induce new models of GBM with transposon-mediated integration of plasmid DNA into cells of the subventricular zone of neonatal mice. We present a simple way to clone new transposons amenable for genomic integration using the Sleeping Beauty transposon system and illustrate how to monitor plasmid uptake and disease progression using bioluminescence, histology and immuno-histochemistry. We also describe a method to create new primary GBM cell lines. Ideally, this report will allow further dissemination of the Sleeping Beauty transposon system among brain tumor researchers, leading to an in depth understanding of GBM pathogenesis and progression and to the timely design and testing of effective therapies for patients.

Here we describe an efficient and versatile protocol to induce, monitor and analyze novel glioblastomas (GBM) using transposon DNA injected into the ventricles of neonatal mice. Cells of the subventricular zone, which take up the plasmid, transform, proliferate and generate tumors with histo-pathological characteristics of human GBM.

质粒DNA转座子介导整合到新生小鼠的脑室下区，以生成胶质母细胞瘤的新模型

An urgent need exists to test the contribution of new genes to the pathogenesis and progression of human glioblastomas (GBM), the most common primary ...

Surgical Models of Gastroesophageal Reflux with Mice

Multiple surgical procedures have been reported to induce gastroesophageal reflux in animals. Herein, we report three surgical models with mice aiming to induce reflux of gastric contents, duodenal contents or mixed contents. Surgical procedures and general principles have been described in detail. A researcher with surgical experience should be able to grasp the technique after a short period of practice. After surgery, most mice can survive and develop reflux esophagitis similar to that in humans. However, it should be noted that histological differences between mouse and human esophagus are the inherent limitations of these surgical models. If used for research on Barrett&#8217;s esophagus and adenocarcinoma, these procedures may need to be combined with genetic modifications.

This article demonstrates surgical procedures of gastroesophageal reflux with mice. These models are useful tools for research on mechanisms and treatment of gastroesophageal reflux disease and potentially Barrett&#8217;s esophagus and esophageal adenocarcinoma.

胃食管反流与小鼠手术模型

Multiple surgical procedures have been reported to induce gastroesophageal reflux in animals. Herein, we report three surgical models with mice aiming to ...

Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients

Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening pulmonary manifestations. Ivacaftor (IVA) and ivacaftor-lumacaftor (LUMA) combination are two new breakthrough CF drugs that directly modulate the activity and trafficking of the defective CFTR-protein. However, there is still a dearth of understanding on pharmacokinetic/pharmacodynamic parameters and the pharmacology of ivacaftor and lumacaftor. The HPLC-MS technique for the simultaneous analysis of the concentrations of ivacaftor, hydroxymethyl-ivacaftor, ivacaftor-carboxylate, and lumacaftor in biological fluids in patients receiving standard ivacaftor or ivacaftor-lumacaftor combination therapy has previously been developed by our group and partially validated to FDA standards. However, to allow the high-throughput analysis of a larger number of patient samples, our group has optimized the reported method through the use of a smaller pore size reverse-phase chromatography column (2.6 &#181;m, C8 100 &#197;; 50 x 2.1 mm) and a gradient solvent system (0-1 min: 40% B; 1-2 min: 40-70% B; 2-2.7 min: held at 70% B; 2.7-2.8 min: 70-90% B; 2.8-4.0 min: 90% B washing; 4.0-4.1 min: 90-40% B; 4.1-6.0 min: held at 40% B) instead of an isocratic elution. The goal of this study was to reduce the HPLC-MS analysis time per sample dramatically from ~15 min to only 6 min per sample, which is essential for the analysis of a large amount of patient samples. This expedient method will be of considerable utility for studies into the exposure-response relationships of these breakthrough CF drugs.

Ivacaftor and ivacaftor-lumacaftor combination are two new CF drugs. However, there is still a dearth of understanding on their PK/PD and pharmacology. We present an optimized HPLC-MS technique for the simultaneous analysis of ivacaftor and its major metabolites, and lumacaftor.

经优化的 LC/ms 方法对囊性纤维化患者 Ivacaftor 及其主要代谢物和 Lumacaftor 的高通量分析

Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening ...

Improved Method for the Establishment of an In Vitro Blood-Brain Barrier Model Based on Porcine Brain Endothelial Cells

The aim of this protocol presents an optimized procedure for the purification and cultivation of pBECs and to establish in vitro blood-brain barrier (BBB) models based on pBECs in mono-culture (MC), MC with astrocyte-conditioned medium (ACM), and non-contact co-culture (NCC) with astrocytes of porcine or rat origin. pBECs were isolated and cultured from fragments of capillaries from the brain cortices of domestic pigs 5-6 months old. These fragments were purified by careful removal of meninges, isolation and homogenization of grey matter, filtration, enzymatic digestion, and centrifugation. To further eliminate contaminating cells, the capillary fragments were cultured with puromycin-containing medium. When 60-95% confluent, pBECs growing from the capillary fragments were passaged to permeable membrane filter inserts and established in the models. To increase barrier tightness and BBB characteristic phenotype of pBECs, the cells were treated with the following differentiation factors: membrane permeant 8-CPT-cAMP (here abbreviated cAMP), hydrocortisone, and a phosphodiesterase inhibitor, RO-20-1724 (RO). The procedure was carried out over a period of 9-11 days, and when establishing the NCC model, the astrocytes were cultured 2-8 weeks in advance. Adherence to the described procedures in the protocol has allowed the establishment of endothelial layers with highly restricted paracellular permeability, with the NCC model showing an average transendothelial electrical resistance (TEER) of 1249 &#177; 80 &#937; cm2, and paracellular permeability (Papp) for Lucifer Yellow of 0.90 10-6 &#177; 0.13 10-6 cm sec-1 (mean &#177; SEM, n=55). Further evaluation of this pBEC phenotype showed good expression of the tight junctional proteins claudin 5, ZO-1, occludin and adherens junction protein p120 catenin. The model presented can be used for a range of studies of the BBB in health and disease and, with the highly restrictive paracellular permeability, this model is suitable for studies of transport and intracellular trafficking.

Improved Method for the Establishment of an In Vitro Blood-Brain Barrier Model Based on Porcine Brain Endothelial Cells

The aim of the protocol is to present an optimized procedure for the establishment of an in vitro blood-brain barrier (BBB) model based on primary porcine brain endothelial cells (pBECs). The model shows high reproducibility, high tightness, and is suitable for studies of transport and intracellular trafficking in drug discovery.

一种基于猪脑内皮细胞的体外血脑屏障模型的改进方法

The aim of this protocol presents an optimized procedure for the purification and cultivation of pBECs and to establish in vitro blood-brain barrier (BBB) ...

Image-Guided Resection of Glioblastoma and Intracranial Implantation of Therapeutic Stem Cell-seeded Scaffolds

Glioblastoma (GBM), the most common and aggressive primary brain cancer, carries a life expectancy of 12-15 months. The short life expectancy is due in part to the inability of the current treatment, consisting of surgical resection followed by radiation and chemotherapy, to eliminate invasive tumor foci. Treatment of these foci may be improved with tumoricidal human mesenchymal stem cells (MSCs). MSCs exhibit potent tumor tropism and can be engineered to express therapeutic proteins that kill tumor cells. Advancements in preclinical models indicate that surgical resection induces premature MSC loss and reduces therapeutic efficacy. Efficacy of MSC treatment can be improved by seeding MSCs on a biodegradable poly(lactic acid) (PLA) scaffold. MSC delivery into the surgical resection cavity on a PLA scaffold restores cell retention, persistence, and tumor killing. To study the effects of MSC-seeded PLA implantation on GBM, an accurate preclinical model is needed. Here we provide a preclinical surgical protocol for image-guided tumor resection of GBM in immune-deficient mice followed by MSC-seeded scaffold implantation. MSCs are engineered with lentiviral constructs to constitutively express and secrete therapeutic TNF&#945;-related apoptosis-inducing ligand (TRAIL) as well as green fluorescent protein (GFP) to allow fluorescent tracking. Similarly, the U87 tumor cells are engineered to express mCherry and firefly luciferase, providing dual fluorescent/luminescent tracking. While currently used for investigating stem cell mediated delivery of therapeutics, this protocol could be modified to investigate the impact of surgical resection on other GBM interventions.

Tumor-seeking therapeutic mesenchymal stem cells (MSCs) show promise as a treatment for invasive glioblastoma. Optimal transplantation involves delivery of MSCs into the tumor resection cavity on scaffolds. Here, preclinical techniques to study MSC treatment of glioblastoma are provided including: image-guided tumor resection; implantation of MSC-seeded scaffolds; and postoperative therapy tracking.

影像引导切除治疗干细胞种子支架的胶质母细胞瘤和颅内植入术

Glioblastoma (GBM), the most common and aggressive primary brain cancer, carries a life expectancy of 12-15 months. The short life expectancy is due in ...

Predicting Treatment Response to Image-Guided Therapies Using Machine Learning: An Example for Trans-Arterial Treatment of Hepatocellular Carcinoma

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. The objective of this study was to develop a method to predict response to intra-arterial treatment prior to intervention.
The method provides a general framework for predicting outcomes prior to intra-arterial therapy. It involves pooling clinical, demographic and imaging data across a cohort of patients and using these data to train a machine learning model. The trained model is applied to new patients in order to predict their likelihood of response to intra-arterial therapy.
The method entails the acquisition and parsing of clinical, demographic and imaging data from N patients who have already undergone trans-arterial therapies. These data are parsed into discrete features (age, sex, cirrhosis, degree of tumor enhancement, etc.) and binarized into true/false values (e.g., age over 60, male gender, tumor enhancement beyond a set threshold, etc.). Low-variance features and features with low univariate associations with the outcome are removed. Each treated patient is labeled according to whether they responded or did not respond to treatment. Each training patient is thus represented by a set of binary features and an outcome label. Machine learning models are trained using N - 1 patients with testing on the left-out patient. This process is repeated for each of the N patients. The N models are averaged to arrive at a final model.
The technique is extensible and enables inclusion of additional features in the future. It is also a generalizable process that may be applied to clinical research questions outside of interventional radiology. The main limitation is the need to derive features manually from each patient. A popular modern form of machine learning called deep learning does not suffer from this limitation, but requires larger datasets.

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. A method for predicting response to these therapies is proposed. The technique uses pre-procedural clinical, demographic, and imaging information to train machine learning models capable of predicting response prior to treatment.

用机器学习预测图像引导疗法的治疗反应--肝细胞癌的跨动脉治疗实例

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. The objective of this ...