BackgroundAccumulation of macrocyclic gadolinium agents in children's brains remain to be determined.PurposeTo demonstrate whether there is an intracranial macrocyclic gadolinium deposition after multiple contrast‐enhanced MRI with gadoterate meglumine in a pediatric population.Study TypeRetrospective case–control.PopulationIn all, 45 children (age range: 5–17 years; mean, 13.7 ± 3.4 years) for the study group and 45 healthy children (age range: 5–17 years; mean, 13.7 ± 3.4 years) for the control group.Field Strength/SequenceT1‐ and T2‐weighted axial images on a 1.5T scanner.AssessmentChildren with at least three enhanced brain MRIs and an age‐ and sex‐matched control group with an unenhanced brain MRIs were compared in terms of T1 signal intensity (SI). All patients in the study group received gadoterate meglumine intravenously (0.1 mmol/kg). SI measurements were made by drawing six regions of interest (ROIs): dentate nuclei (DN), pons, globus pallidi (GP), frontal white matter (FWM), thalamus (T), clivus, and cerebrospinal fluid (CSF) for both groups on unenhanced T1‐weighted images.Statistical TestsStudent's t‐test was used for comparison of SI. The Pearson correlation was calculated for the correlation between the SI and the number of gadolinium administrations.ResultsA significant difference was detected between two groups for DN/CSF, pons/CSF, GP/CSF, thalamus/CSF, and FWM/CSF (P < 0.001, P < 0.001, P = 0.002, P = 0.002, P = 0.024, respectively). There was no significant difference between the two groups for clivus/CSF (P = 0.15). A good correlation between the number of gadoterate meglumine administrations and the SI for DN/CSF, pons/CSF, GP/CSF, and T/CSF (r = 0.80, r = 0.73, r = 0.91, and r = 0.90, respectively) was found.Data ConclusionA significant T1 SI increase reflecting gadolinium retention in the brain was detected for children with at least three gadoterate meglumine administrations in this series. The number of administrations correlated well with the increased SI.Level of Evidence: 3Technical Efficacy Stage: 5J. Magn. Reson. Imaging 2020;51:1471–1477.

2005-11-01·Biomaterials1区 · 工程技术

Ectopic bone formation in rat marrow stromal cell/titanium fiber mesh scaffold constructs: Effect of initial cell phenotype

1区 · 工程技术

Article

作者: Antonios G. Mikos ; Heidi L. Holtorf ; John A. Jansen

Titanium fiber mesh scaffolds have been shown to be a suitable material for culture of primary marrow stromal cells in an effort to create tissue engineered constructs for bone tissue replacement. In native bone tissue, these cells are known to attach to extracellular matrix molecules via integrin receptors for specific peptide sequences, and these attachments can be a source of cell signaling, affecting cell behaviors such as differentiation. In this study, we examined the ability of primary rat marrow stromal cells at two different stages of osteoblastic differentiation to further differentiate into osteoblasts both in vitro and in vivo when seeded on titanium fiber mesh scaffolds either with or without RGD peptide tethered to the surface. In vitro, the tethered RGD peptide resulted in reduced initial cell proliferation. In vivo, there was no effect of tethered RGD peptide on ectopic bone formation in a rat subcutaneous implant model. Scaffold/cell constructs exposed to dexamethasone for 4 days prior to implantation (+dex constructs) resulted in significant bone formation whereas no bone formation was observed in--dex constructs. These results show that the osteoblastic differentiation of marrow stromal cells was not dependent on surface tethered RGD peptide, and that the initial differentiation stage of implanted cells plays an important role in bone formation in titanium fiber mesh bone tissue engineering constructs.

项与 RO-7075573 相关的新闻（医药）

2024-01-05

·奇点网

《自然》重磅：等了50年，克星终于来了！罗氏/哈佛团队发现全新抗生素，可抑制内毒素脂多糖外排，让耐药鲍曼不动杆菌自杀丨科学大发现

*仅供医学专业人士阅读参考2017年，世界卫生组织发布了一个“追杀”名单。名单按照紧急程度，列举了多种亟需开发新抗生素的耐药细菌。其中排名第一的是多重/广泛耐药的结核分枝杆菌，排名第二的是耐碳青霉烯鲍曼不动杆菌（CRAB）。虽然鲍曼不动杆菌的知名度不如结核分枝杆菌高，但是对被誉为人类对抗细菌感染“最后一道防线”的碳青霉烯类抗生素因耐药的CRAB，仍让医生胆寒。据估算，侵袭性CRAB感染的死亡率在40%到60%之间，缺少有效治疗方法是其推高死亡率的主要原因之一。更可怕的是，FDA已经有50多年没有批准治疗CRAB感染的新抗生素上市了。好消息是，近日由罗氏Kenneth A. Bradley和Michael A. Lobritz领衔的研究团队，在顶级期刊《自然》上发表了一项突破性研究成果[1]。他们宣布找到了一个以脂多糖转运体为靶点的新型抗生素zosurabalpin，它可以抑制CRAB合成的内毒素脂多糖外排，导致细胞内脂多糖浓度过高，CRAB中毒身亡。论文首页截图值得注意的是，由哈佛大学Daniel Kahne和哈佛医学院Andrew C. Kruse领衔的研究团队，从结构生物学、生物化学和遗传学的角度，详细阐述了zosurabalpin抑制脂多糖转运体外排脂多糖的机制[2]，进一步证实了这一全新机制的存在。据了解，这也是科学家首次发现脂多糖转运体可以作为抗生素的作用靶点。论文首页截图正如前文所言，耐碳青霉烯鲍曼不动杆菌（CRAB）感染导致的超高死亡率是临床医生的噩梦。为了找到对抗CRAB的新型抗生素，Bradley团队对Tranzyme Pharma公司生产的44985种大环肽（MCPs）进行筛选。他们发现其中一个编号为RO7036668的大环肽对鲍曼不动杆菌有活性，但对其他革兰氏阴性菌无活性，对革兰氏阳性菌和酵母菌的活性也非常有限，且没有发现细胞毒性。为了进一步提高这个大环肽的杀菌活性，研究人员对它做了初步改造，得到了先导化合物RO7075573。两种化合物的分子结构在改造之后，RO7075573对一组鲍曼不动杆菌的药效是RO7036668的4到64倍，而且选择性变得更强了。由于RO7075573对抗生素敏感型和多耐药（MDR）型鲍曼不动杆菌的抗菌活性相似，Bradley团队推测RO7075573可能作用于一个新的靶点。基于小鼠模型的研究也证实，RO7075573在体内也有与体外相似的强大抗菌活性。这也促使研究团队有信心进一步开发这个大环肽。体内药代动力学显示，RO7075573具有良好的吸收、分布、代谢和消除特性，但是耐受性似乎不行，会导致血脂异常，进而导致模式动物死亡。于是他们进一步对RO7075573做了改造，降低它的亲脂性，得到了zosurabalpin（ZAB）。研究结果显示，模式动物对zosurabalpin耐受良好。ZAB本尊接下来的工作就是寻找zosurabalpin的作用靶点，以及它在体内的疗效。Bradley团队寻找作用靶点的方法简单粗暴，就是通过不断提升培养基中zosurabalpin的浓度，让鲍曼不动杆菌自己进化出自发耐药，然后通过基因测序分析突变的位点。在汇总测序结果之后，他们发现突变主要发生在编码脂多糖（LPS）转运和生物合成的基因中，尤其是构成脂多糖转运系统的LptB2FGC复合物中的多种蛋白（LptF和LptG等）。显然，zosurabalpin肯定是影响了脂多糖的转运。随后的生化实验证实了zosurabalpin是以内膜LptB2FGC复合物为靶点，阻断了脂多糖的转运，导致这种内毒素在细胞内积累，最终导致细菌的死亡。哈佛大学Daniel Kahne和哈佛医学院Andrew C. Kruse团队，进一步从结构生物学角度证实了上述发现。值得注意的是，这个靶点之前没有被当做抗生素的靶点。作用机制示意图[3]在研究的最后，Bradley团队测试了zosurabalpin治疗严重侵袭性CRAB感染的潜力。他们对分离自患者不同感染部位的129株鲍曼不动杆菌分离株进行了体外活性评估，其中78%是难治性鲍曼不动杆菌，80%属于多耐药鲍曼不动杆菌。体外数据显示，zosurabalpin对这些菌株有极强的抑菌活性。将上述菌株接种到模式小鼠体内之后，zosurabalpin仍有强大的抑菌活性，而且细菌的负担呈剂量依赖性下降。不同剂量zosurabalpin的治疗效果总的来说，Bradley团队发现了一种对耐碳青霉烯鲍曼不动杆菌和泛耐药鲍曼不动杆菌有强力抑菌活性的抗生素，并发现了一个之前不为人所知的新的抗生素靶点LptB2FGC复合物，这也为铜绿假单胞菌、肺炎克雷伯菌和大肠杆菌等革兰氏阴性菌抗生素的开发提供了思路。需要指出的是，虽然zosurabalpin是个作用于全新靶点的抗生素，按理说现阶段临床上不会出现耐药的情况；但是在抗生素的压力之下，几乎所有的抗生素最终都会面临耐药问题，正如在本研究中，Bradley团队自己也筛选出了耐药株。不过，在合理使用的情况下，必定会减轻耐药性的发生。据了解，目前zosurabalpin已经进入临床测试阶段。如果试验顺利，耐碳青霉烯鲍曼不动杆菌给临床医生带来的噩梦有可能就此终结。参考文献：[1].Zampaloni, C., Mattei, P., Bleicher, K. et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature. 2024. doi: 10.1038/s41586-023-06873-0[2].Pahil, K.S., Gilman, M.S.A., Baidin, V. et al. A new antibiotic traps lipopolysaccharide in its intermembrane transporter. Nature. 2024. doi: 10.1038/s41586-023-06799-7[3].Gugger MK, Hergenrother PJ. A new type of antibiotic targets a drug-resistant bacterium. Nature. 2024. doi:10.1038/d41586-023-03988-2本文作者丨BioTalker

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