Proteolytic processing of the protein tyrosine phosphatase α extracellular domain is mediated by ADAM17/TACE

The receptor protein tyrosine phosphatase alpha (PTPα) is involved in the regulation of tyrosine kinases like the Src kinase and the insulin receptor. As with other PTPs, its function is determined by alternative splicing, dimerisation, phosphorylation and proteolytical processing. PTPα is cleaved by calpain in its intracellular domain, which decreases its potential to dephosphorylate Src kinase. Here, we demonstrate that PTPα is also processed in the extracellular domain. Extracellular processing was exclusively found for a splice variant containing an extra nine amino acid insert three residues amino-terminal from the transmembrane domain. Processing was sensitive to the metalloprotease-inhibitor Batimastat, and CHO-M2 cells lacking a disintegrin and metalloproteinase 17 (ADAM17; tumor-necrosis-factor α converting enzyme) activity were not able to cleave PTPα. After transient overexpression of ADAM17 and PTPα in these cells, processing was restored, proving that ADAM17 is involved in this process. Further characterization of the consequences of processing revealed that dephosphorylation of the insulin receptor or activation of Src was not affected but focus formation was reduced. We conclude that extracellular proteolytic processing is a novel mechanism for PTPα regulation.     

以重组TACE胞外功能域从噬菌体随机肽库中筛选TACE的抑制肽

肿瘤坏死因子转换酶 (TACE)是加工裂解TNF-α前体的关键酶 ,参与了许多炎症的发生发展过程。为通过肽库筛选得到TACE的抑制肽 ,首先制备筛选靶分子 ,用RT PCR从人外周血单核细胞中分别扩增出TACE的催化区 (T800 )和整个胞外区 (T1300 ) ,然后分别克隆至pET-28a和pET-28c中 ,转化大肠杆菌BL2-1(DE3) ,经IPTG诱导表达出带有His-tag的目的蛋白 ,两者均为包涵体 ,变性复性后过Ni²⁺-NTA亲和层析柱得到纯度达90%的重组蛋白。以纯化的重组T800和T1300分别筛选噬菌体展示随机 15肽库 ,对筛选克隆进行ELISA检测、竞争抑制实验和序列分析。从两个独立的筛选过程中得到一个相同的阳性克隆序列“TRWLVYFSRPYLVAT” ,固相Fmoc法合成该短肽 ,观察其在LPS诱导人单核细胞产生sTNF-α中的作用。结果表明 ,筛选到的短肽可显著抑制TACE的活性 ,减少TNF-α的分泌 ,抑制率可达 60.3% ,为抗炎小分子药物的设计和改造提供线索和依据。     

Feeling by sight or seeing by touch?

We have addressed the role of occipital and somatosensory cortex in a tactile discrimination task. Sight-ed and congenitally blind subjects rated the roughness and distance spacing for a series of raised dot patterns. When judging roughness, intermediate dot spacings were perceived as being the most rough, while distance judgments generated a linear relation. Low-frequency rTMS applied to somatosensory cortex disrupted roughness without affecting distance judgments, while rTMS to occipital cortex disrupted distance but not roughness judgments. We also tested an early blind patient with bilateral occipital cortex damage. Her performance on the roughness determination task was normal; however, she was greatly impaired with distance judgments. The findings suggest a double-dissociation effect in which roughness and distance are primarily processed in somatosensory and occipital cortex, respectively. The differential effect of rTMS on task performance and corroborative clinical evidence suggest that occipital cortex is engaged in tactile tasks requiring fine spatial discrimination.     

影响肝切除术后行TACE患者预后因素的分析

目的：对原发性肝细胞肝癌（HCC）肝部分切除术后行经肝动脉化疗栓塞（TACE）的病人和未行TACE病人影响其预后的多种因素进行分析和评价,为肝切除术后是否行TACE治疗寻找筛选条件。方法：对我院2003～2008年期间在我院肝胆外科行原发性肝细胞肝癌手术治疗221例（术后介入治疗103例,术后非介入治疗118例）患者进行全面随访了解患者的预后情况,分别对术后接受介入治疗和非介入治疗两组通过Kaplan-Meier及COX回归分析影响预后的因素,包括：年龄、性别、血清HBsAg、肿瘤直径、肿瘤大体分型、有无癌栓形成,肿瘤分期（TNM）共7项指标。结果：在1年生存期内介入治疗组中的性别、年龄、血清HBsAg、肿瘤直径、肿瘤大体分型无统计学意义（p〉0.05）,有无癌栓形成及肿瘤分期有意义（p〈0.05）;非介入组内年龄、性别、血清HBsAg无统计学意义,肿瘤直径、肿瘤大体分型、有无癌栓形成,肿瘤分期有意义;在3年生存期内介入治疗组中的以上指标无统计学意义,而非介入组在肿瘤直径、有癌栓形成及肿瘤分期方面与统计学意义。结论：对于肿瘤直径〉5cm及术后病理证实为低分化的患者给予积极TACE治疗可明显提高近期生存率。     

影响肝切除术后行TACE 患者预后因素的分析

目的:对原发性肝细胞肝癌(HCC)肝部分切除术后行经肝动脉化疗栓塞(TACE)的病人和未行TACE病人影响其预后的多种因素进行分析和评价,为肝切除术后是否行TACE治疗寻找筛选条件。方法:对我院2003～2008年期间在我院肝胆外科行原发性肝细胞肝癌手术治疗221例(术后介入治疗103例,术后非介入治疗118例)患者进行全面随访了解患者的预后情况,分别对术后接受介入治疗和非介入治疗两组通过Kaplan-Meier及COX回归分析影响预后的因素,包括:年龄、性别、血清HBsAg、肿瘤直径、肿瘤大体分型、有无癌栓形成,肿瘤分期(TNM)共7项指标。结果:在1年生存期内介入治疗组中的性别、年龄、血清HBsAg、肿瘤直径、肿瘤大体分型无统计学意义(p>0.05),有无癌栓形成及肿瘤分期有意义(p<0.05);非介入组内年龄、性别、血清HBsAg无统计学意义,肿瘤直径、肿瘤大体分型、有无癌栓形成,肿瘤分期有意义;在3年生存期内介入治疗组中的以上指标无统计学意义,而非介入组在肿瘤直径、有癌栓形成及肿瘤分期方面与统计学意义。结论:对于肿瘤直径>5cm及术后病理证实为低分化的患者给予积极TACE治疗可明显提高近期生存率。     

TACE与手术治疗原发性大肝癌的临床疗效比较

目的:比较经导管肝动脉化疗栓塞(transcatheter arterial chemoembolization,TACE)和手术治疗原发性大肝癌(肿瘤最大直径≥5 cm)的临床疗效和安全性。方法:回顾性分析48例经TACE或手术(Operation)治疗的原发性大肝癌患者,其中TACE组25例,Operation组23例,治疗后随访24个月,评价和比较其治疗效果、生存曲线、镇痛剂的日平均用量及不良反应的发生情况。结果:治疗后3个月,TACE组患者的Karnofsky评分(P=0.033)显著高于Operation组,而血清甲胎蛋白(AFP)水平(P=0.022)显著低于Operation组。此外,TACE组的镇痛药杜冷丁的日均使用量显著低于Operation组(P=0.031),便秘的日均发生次数(P=0.045)显著少于Operation组。治疗后24个月,TACE组和Operation组的生存率分别为48.0%和17.4%,TACE组显著高于Operation组(P=0.0415,95%CI of ratio:1.006 to 1.994)。结论:TACE治疗原发性大肝癌的临床疗效可能优于手术治疗,且安全性高。     

TACE 联合其他介入手段治疗肝癌伴门静脉癌栓

肝癌是世界范围内恶性程度最高的恶性肿瘤之一。门静脉癌栓的出现加速了肝功衰竭以及门静脉高压的发生概率,严重影响了肝癌患者的预后,临床上对于肝癌合并门静脉癌栓的诊疗尤为棘手。传统的治疗手段对于肝癌合并门静脉癌栓的疗效欠佳,且创伤大、住院时间长、并发症多。介入治疗因其创伤小、住院时间短、并发症少,疗效确切等优势逐渐被人们认可。以往单独应用经导管肝动脉化疗栓塞术(Transcatheter Arterial Chemoembolization,TACE)治疗肝癌取得了可喜的成果,随着介入治疗的发展,TACE联合其他介入手段治疗肝癌伴门静脉癌栓引起了越来越多的学者重视。本文回顾了近几年来国内外的相关文献,对TACE联合其他介入手段治疗肝癌合并门静脉癌栓的方式及疗效做一综述,以期对肝癌的临床诊疗工作提供一些帮助。     

脾多肽注射液联合TACE治疗原发性肝癌的效果分析

为探讨脾多肽注射液联合经导管动脉化疗栓塞术治疗原发性肝癌的效果,本研究选取我院肝胆外科收治的原发性肝癌患者168例,按随机数字表法分为对照组和研究组。对照组84例予以经导管动脉化疗栓塞术(TACE)治疗,研究组84例在对照组基础上予以脾多肽注射液治疗。检查记录两组间肿瘤血供情况、血清肿瘤标志物水平、外周血免疫细胞水平,同时比较临床疗效及不良反应发生率。分析表明,其中研究组的治疗总有效率61.91%,远高于对照组,二者之间的差异显著(p0.05);研究组和对照组相比,在治疗后肿瘤内动脉、肿瘤周边动脉血流分级水平较低,肿瘤周边门脉血流分级水平较高,治疗后血清AFP、CA19-9、GGT、AFU水平较低,治疗后外周血NK细胞、CD4~+、CD4~+/CD8~+比值水平较高,CD8~+T淋巴细胞水平较低,具有统计学意义(p0.05);研究组恶心呕吐、食欲不振、白细胞减少、发热、乏力疲劳等不良反应的发生率低于对照组,具有统计学意义(p0.05)。本研究表明,脾多肽注射液联合TACE治疗对于减少原发性肝癌患者肿瘤组织的血供,降低AFP、CA19-9、GGT、AFU水平,以及减轻TACE治疗对免疫功能的抑制作用,值得在临床上推广使用。     

Neuronal death induced by nanomolar amyloid β is mediated by primary phagocytosis of neurons by microglia

Alzheimer disease is characterized by neuronal loss and brain plaques of extracellular amyloid β (Aβ), but the means by which Aβ may induce neuronal loss is not entirely clear. Although high concentrations of Aβ (μM) can induce direct toxicity to neurons, we find that low concentration (nM) induce neuronal loss through a microglia-mediated mechanism. In mixed neuronal-glial cultures from rat cerebellum, 250 nM Aβ1-42 (added as monomers, oligomers or fibers) induced about 30% loss of neurons between 2 and 3 days. This neuronal loss occurred without any increase in neuronal apoptosis or necrosis, and no neuronal loss occurred with Aβ42-1. Aβ greatly increased the phagocytic capacity of microglia and induced phosphatidylserine exposure (an "eat-me" signal) on neuronal processes. Blocking exposed phosphatidylserine by adding annexin V or an antibody to phosphatidylserine or inhibiting microglial phagocytosis by adding either cytochalasin D (to block actin polymerization) or cyclo(RGDfV) (to block vitronectin receptors) significantly prevented neuronal loss. Loss of neuronal synapses occurred in parallel with loss of cell bodies and was also prevented by blocking phagocytosis. Inhibition of phagocytosis prevented neuronal loss with no increase in neuronal death, even after 7 days, suggesting that microglial phagocytosis was the primary cause of neuronal death induced by nanomolar Aβ.     

基于CBCT的三维重建技术在原发性肝癌TACE治疗中的应用

为了深入了解基于CBCT的三维重建技术在原发性肝癌TACE治疗中的应用,本研究对在我院进行TACE治疗的原发性肝癌患者,分别采用基于CBCT的三维重建技术和常规的DSA技术进行分析比较。我们选取我院2013年1月~2015年10月确诊的67例原发性肝癌患者,采用随机数字表法分为CBCT组34例、血管造影(DAS组)33例,两组均采用TACE治疗,术中分别给予CBCT及三维重建、DSA技术进行手术指指导。研究表明:CBCT组对肿瘤供血动脉检出正确率、超选择动脉插管成功率、碘油在病灶中完全沉积率均高于DSA组(p0.05);CBCT组的手术时间、辐射总剂量均高于DSA组(p0.05);术后一个月复查,CBCT组CR 17.65%、PR 73.53%、SD 8.82%,DSA组CR 6.06%、PR 66.67%、SD 21.21%、PD 6.06%,两组比较差异具有统计学意义(p0.05);术后一个月复查,CBCT组血清AFP水平低于DSA组(p0.05);两组患者的KPS评分较本组术前均显著的提高(p0.05),两组间的KPS评分差异无统计学意义(p0.05)。我们的研究初步得出结论:基于CBCT的三维重建技术在原发性肝癌TACE治疗中较DSA技术能够更好的检出肿瘤的供血动脉、指导手术更加便捷和精确,能达到更好的手术效果。     

TACE联合RFA疗法可有效提高原发性肝癌患者的疗效

为了探讨肝动脉栓塞化疗(TACE)联合射频消融(RFA)对原发性肝癌患者疗效的影响,本研究选取了2016年1月至2016年12月我院收治的原发性肝癌患者60例,随机分为两组,对照组应用TACE治疗,研究组应用TACE联合RFA治疗。通过对比两组患者治疗效果及Th1、Th2细胞因子水平,我们发现研究组患者的治疗有效率显著优于对照组(p0.05);治疗前两组患者的Th1、Th2型细胞因子的水平无明显区别(p0.05),治疗后均得到一定改善,研究组显著优于对照组(p0.05);治疗前两组患者的免疫细胞因子的水平无明显区别(p0.05),治疗后两组均得到一定改善,且研究组显著优于对照组(p0.05)。本研究表明,TACE联合RFA治疗原发性肝癌患者,有利于提高近期有效率,改善患者的Th1、Th2细胞因子水平。我们的研究为肝动脉栓塞化疗联合射频消融疗法在原发性肝癌患者临床治疗中的应用提供了一定的理论依据。     

乳果糖对肝癌TACE后肠黏膜损伤的保护作用研究

目的了解乳果糖对肝癌TACE后患者肠黏膜损伤的保护作用。方法将54例患者随机分为2组,治疗组按常规治疗加服乳果糖,对照组按常规治疗,服药后观察全身和肠道情况并检测二胺氧化酶(DAO)的内毒素水平。结果治疗组血二胺氧化酶水平与术前相比差异无显著性(P>0.05),未应用乳果糖组血内毒素水平比术前降低(P<0.05);治疗组血内毒素水平与术前相比差异无显著性(P>0.05),而未应用乳果糖组血内毒素水平比术前升高(P<0.05)。结论乳果糖增强了肠道黏膜的屏障作用,在避免肝癌TACE后的肠道细菌易位,内毒素血症起到积极作用。     

Some properties of auditory neuron’s model trained by firing caused by tones modulated by low-frequency noise

In many sensory systems the formation of burst firing can be observed along a way from the periphery to the central nuclei. We investigate the putative transformation of spontaneous activity in the auditory pathway using a neuron model trained by real firing recorded in the auditory nuclei of the frog. The model has 200 separate inputs (neuronal spines). It is supposed that every spine is a coincidence detector. Its output (synaptic potential) sharply increases at emergence of the precisely certain interpulse interval in an input pulse sequence. If the total synaptic potentials excess a threshold, the model generates output spike, which changes weight of all spines according to the simplified Hebb principle. The model was trained by real firing caused in the auditory nuclei of the frog by tones modulated by low-frequency noise in the frequency ranges of 0–15 Hz, 0–50 Hz or 0–150 Hz. After that training the synaptic weights of every spine essentially changed. Thus, along with some increase of weights of spines tuned to boundary frequencies of modulating noise, the most characteristic change was the emphasizing weights of spines tuned to short interpulse intervals. As a result the spontaneous activity passed through the trained model became much more bursting. Efficiency of a signal transmission in model was higher when input spontaneous activity of real cells contains bursts of spikes. Results of modeling are discussed in connection with modern physiological data demonstrating the functional advantage of bursting.     

Formation of Three New Trisaccharide-azoxyglycosides by Transglucosylation by Cycad β-Glucosidase

transglucosylation by a β-d-glucosidase from cycad seeds. These azoxyglycosides, named neocycasin H, I, and J, were identified as O-β-d-glucopyranosyl-(1→4)-O-β-d-glucopyranosyl-(l→3)-O-β-d-glucopyranoside of methylazoxymethanol (MAM), O-β-d-glucopyranosyl-(1→3)-[O-β-d-glucopyranosyl-(1→6)]-O-β-d-glucopyranoside of MAM, and O-β-d-glucopyranosyl-(1→3)-[O-β-d-xylopyranosyl-(1→6)]-O-β-d-glucopyranoside of MAM, respectively. On the basis of their structures, the mechanism of the formation of these neocycasins is also discussed.     

BAFfled by Poxviruses?

Successful viruses engage in a dynamic interplay with their hosts, where both utilize diverse strategies to impose their supremacy. In this issue of Cell Host & Microbe, Wiebe and Traktman describe a novel interaction between vaccinia virus and mammalian cells. A host protein called BAF can bind ectopic cytoplasmic DNA and block viral DNA replication, whereas vaccinia in turn counteracts this inhibition with a virus-encoded serine threonine kinase that inactivates BAF.