Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer

Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction-driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3- dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2-STAT3/STAT5.     

HSP70-肿瘤肽复合物的纯化及其对肝癌细胞株HepG-2增殖的作用

目的:应用快速蛋白液相色谱(FPLC)系统从肝癌组织中分离和纯4EHSP70-肽复合物,并研究其对肝癌细胞系HepG-2增殖的影响．方法:将组织进行匀浆、高速离心提取总蛋白后依次进行ConA-Sepharose亲和层析和 DEAE-Sephacel子交换层析分离纯化,所得蛋白经SDS-聚丙烯酰胺凝胶电泳和Western blot进行蛋白分子质量及性质鉴定,Bradford 法测定蛋白浓度;利用MTT方法检测HSP70- 肽复合物对HepG-2细胞增长的情况．结果:分离、纯化得到的蛋白经SDS-聚丙烯酰胺凝胶电泳、考马斯量蓝鉴定为单一带, 分子质量为70 kDa;Western blot结果证实为 HSP70,每10 g组织最终获得1．5 mg的HSP70; HSP70刺激组12,48,72 h与对照组的A值之间有显著差异(0．1 mg／L:t=-0．2500,P=0．00; t=-0．1777,P=0．001:t=-0．3094,P=0．001; 0．5 mg／L:t=-0．2878,P=0．00;t=-0．2044,P= 0．00;t=-0．3285,P=0．00;1 mg／L:t=-0．3118, P=0．00;t=-0．2592,P=0．00;t=-0．1994, P=0．025;5 mg／L:t=-0．4007,P=0．00;t= -0．1302,P=0．016;t=-0．2537,P=0．005),细胞存活率明显高于对照组(P<0．01)．结论:使用本分离纯化方法可获得高纯度 HSP70肽复合物;HSP70肽复合物可以促进 HepG-2细胞的生长．     

Effect of glutathione peroxidase mimic ebselen (PZ51) on endothelium and vascular structure of stroke-prone spontaneously hypertensive rats

BACKGROUND: To investigate whether extrinsic antioxidant seleno-glutathione peroxidase mimic ebselen (PZ51) can protect endothelium and vascular structure of stroke-prone spontaneously hypertensive rats (SHRsp) during the chronic process of hypertension. METHODS: Twenty-two 8-week-old SHRsp were randomized into a PZ51 group and a control group, and administered by gavage for 6 weeks. We examined the level of nitric oxide (NO) and malonaldehyde (MDA) in plasma. The intima-media thickness (IMT) of the common carotid artery (CCA) was measured by an image-analysis system. The endothelium of the CCA was observed by scanning electron microscopy. The eNOS protein of the major artery was assayed by immunohistochemistry and western blotting. RESULTS: Compared with the control group, PZ51 decreased plasma MDA (7.88+/-1.06 vs 10.88+/-1.73 nmol/l, p<0.001) and increased plasma NO (40.02+/-9.74 vs 22.22+/-10.05 micromol/l, p<0.001), increased eNOS protein expression (8.25+/-2.36 vs 4.46+/-3.14, p=0.026), decreased IMT (69.85+/-5.47 vs 76.60+/-6.53 microm, p<0.05) significantly and alleviated the damage to the endothelium of the CCA. CONCLUSION: Administration of PZ51 for 6 weeks can protect the endothelium and inhibit vascular remodeling, maybe due to its suppression of lipid peroxide formation and increase in eNOS protein expression.     

Amino acid transporters: Emerging roles in drug delivery for tumor-targeting therapy

Amino acid transporters,which play a vital role in transporting amino acids for the biosynthesis of mammalian cells,are highly expressed in types of tumors.Increasing studies have shown the feasibility of amino acid transporters as a component of tumortargeting therapy.In this review,we focus on tumor-related amino acid transporters and their potential use in tumor-targeting therapy.Firstly,the expression characteristics of amino acid transporters in cancer and their relationship with tumor growth are reviewed.Secondly,the recognition requirements are discussed,focusing on the“acidbase”properties,conformational isomerism and structural analogues.Finally,recent developments in amino acid transporter-targeting drug delivery strategies are highlighted,including prodrugs and nanocarriers,with special attention to the latest findings of molecular mechanisms and targeting efficiency of transporter-mediated endocytosis.We aim to offer related clues that might lead to valuable tumor-targeting strategies by the utilization of amino acid transporters.     

肌硬膜桥的研究进展

正1995年, Hack等[1]发现了肌硬膜桥(myodural bridges,MDBs),随着对其相关研究的不断深入,越来越多的学者开始关注和研究肌硬膜桥,本文通过对肌硬膜桥相关文献资料的整理总结和分析,目的在于对肌硬膜桥有更加系统和深入的认识,为今后肌硬膜桥的研究提供参考和思路。     

预防冠状动脉支架植入术术后低分子肝素皮下出血的前瞻性临床研究

目的 低分子肝素皮下注射后注射部位出血率高达34％～42％,十分影响患者就医体验及依从性,本文将探讨一种按压贴预防低分子肝素皮下出血的效果.方法 本研究采用前瞻性自身对照实验设计,研究收集2019年2月-10月某院急诊行冠状动脉支架植入术(Percutaneous coronary intervention,PCI)的急性冠脉综合征(Acute coronary syndrome,ACS)患者,对于术中发现慢血流或多支血管病变的患者,临床通常在术后会皮下注射3天(Q12h,共6针)低分子肝素,将这6针随机分为对照组和实验组(每组3针),对照组皮下注射后常规不按压,实验组采用自制按压贴在注射后进行物理按压,比较两组的皮下出血发生率及出血面积的差异.结果 本研究纳入171例患者共1026针次低分子肝素皮下注射,实验组和对照组各513针次.实验组不仅皮下出血发生率显著低于对照组(14.42％VS.44.83％,P＜0.01),且实验组皮下出血患者的平均出血面积也显著小于对照组[(56±12)mm2 VS.(719±170)mm2,P＜0.01].亚组分析中发现对照组中高龄患者(≥60岁)的皮下出血率较非高龄患者(＜60岁)高(50.81％VS.44.30％,PP＜0.05),女性患者皮下出血率高于男性(48.81％VS.44.06％,P＜0.05).围术期抗血小板方案对低分子肝素皮下出血发生率无显著影响.结论 按压贴可有效预防ACS患者PCI术后低分子肝素皮下出血的发生率及显著减少出血后的出血面积,有利于改善患者就医体验,且使 用按压贴较传统手工按压可显著降低护理工作量,有一定临床推广价值.     

Effect of high volume hemofiltration on CHOP protein from a canine model of multiple organ dysfunction syndrome

Objective To observe the effect of high volume hemofiltration (HVHF) on the expression of CCAAT enhancer binding protein(CHOP) during the treatment of multiple organ dysfunction syndrome (MODS). To investigate the role of CHOP protein act in apoptosis pathway mediated by the endoplasmic reticulum stress. Methods Twelve Beagle dogs were subjected to hemorrhagic shock plus resuscltation and endotixemia to establish MODS model, then they were randomly divided into two groups: HVHF group (n=6) and MODS group (n=6). After endotoxin injection completed, the HVHF group received HVHF treatment for 24 hours; MODS group did not receive. Vivo experiments: Blood samples were obtained at different time points(before operation, 0 h, 6 h, 12 h, 24 h after the injection of endotoxin). The dogs were killed and the tissue samples from lung, liver and kidney were took, then the expression of CHOP mRNA was determined. Vitro experiments: human umbilical vein endothelial cells (HUVECs) were induced by two groups’ blood samples to establish the apoptosis model. Gene expression, protein quantification and cell apoptosis rate were determined before and after the interference. Results Vivo experiments: The levels of CHOP mRNA from lung, liver and kidney had no significant difference between the two groups (P＞0.05). Vitro experiments: (1)The expression of CHOP mRNA: Compared with MODS group, the expression levels of CHOP mRNA were significantly decreased in HVHF group at 6 h, 24 h after the injection of endotoxin (P＜0.05). Compared with before, the expression levels of CHOP mRNA in the two groups were both significantly decreased after CHOP siRNA interference (P＜0.05). (2)The expression of CHOP protein: Compared with MODS group, the expression levels of CHOP protein were significantly decreased in HVHF group at each time points (P＜0.05). Compared with before, the expression levels of CHOP protein in the two groups were both significantly decreased after CHOP siRNA interference(P＜0.05). (3)Endothelial cell apoptosis rate: Compared with the preoperative rate, the two group’s endothelial cell apoptosis rate was decreased significantly at each time points(P＜0.05). Compared with MODS group, the endothelial cell apoptosis rate was significantly decreased in HVHF group at each time points(P＜0.05). Compared with before, the endothelial cell apoptosis rate in the two groups was both significantly decreased after CHOP siRNA interference(P＜0.05). Conclusion In the treatment of MODS process, HVHF can reduce endothelial cell apoptosis which may be related to the inhibition of CHOP mRNA expression and protein synthesis.     

Management of bisphosphonate‐related osteonecrosis of the jaw: a literature review

Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of malignancy, metastatic bone disease and multiple myeloma, although recently this complication has also been reported in patients under non‐bisphosphonate medication, such as denosumab and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high‐dose iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains unclear. As treatment protocols based on randomized controlled trials (RCTs) do not exist, we critically reviewed the existing data concerning the management of bisphosphonate‐related osteonecrosis of the jaw, including the most recent data for the use of teriparatide and hyperbaric oxygen.