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111.
Jin Ding Hang Su Fan Wang Taiwei Chu 《Bioorganic & medicinal chemistry letters》2019,29(14):1791-1798
During the last four decades, nuclear medicine has undergone enormous growth, and positron emission tomography (PET) has been in the driving seat for most of the time. 18F-fluorodeoxyglucose (18F-FDG) is the most widely used agent for the detection of hibernating myocardium and metabolically active cancer tissue. But its cost and limited availability are the main limitations. For a long time different researchers and groups of pharmacists have tried to label glucose with a cheaper and long-acting radionuclide like 99mTc. However, they failed to achieve this goal owing to the chemical complexity of 99mTc and the lack of maintaining the physiological activity of diagnostic compounds. A pre-targeting strategy based on strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) reaction was applied to solve this problem. Functional click synthons were synthesized: 2-azido-2-deoxy-d-glucose (GlucN3) as a glucose analogue, and N- (2- (2- (2- (bis (pyridin-2-ylmethyl) amino) ethoxy) ethoxy) ethyl-2- (6H-11,12-didehydrodibenzo [a,e] cycloocten-5-ylideneaminooxy) acetamide (C7) as a 99mTc(CO)3 labeling and azido-binding group. The results of biodistribution experiments in mice bearing S180 tumor show the relatively high tumor/blood ratio (up to 2.95) and tumor/muscle ratio (up to 6.37), and both of them decreases significantly in the glucose blocking experiment. It indicates that GlucN3 behaves similarly to glucose and that in vivo SPAAC reactions can occur effectively. It is supposed that this pre-targeting strategy can indeed enhance target specificity and may be used for glucose metabolism imaging in tumor diagnosis. 相似文献
112.
Fabian Richter Oliver Seifert Andreas Herrmann Klaus Pfizenmaier Roland E. Kontermann 《MABS-AUSTIN》2019,11(4):653-665
The development of alternative therapeutic strategies to tumor necrosis factor (TNF)-blocking antibodies for the treatment of inflammatory diseases has generated increasing interest. In particular, selective inhibition of TNF receptor 1 (TNFR1) promises a more precise intervention, tackling only the pro-inflammatory responses mediated by TNF while leaving regenerative and pro-survival signals transduced by TNFR2 untouched. We recently generated a monovalent anti-TNFR1 antibody fragment (Fab 13.7) as an efficient inhibitor of TNFR1. To improve the pharmacokinetic properties of Fab 13.7, the variable domains of the heavy and light chains were fused to the N-termini of newly generated heterodimerizing Fc chains. This novel Fc heterodimerization technology, designated “Fc-one/kappa” (Fc1κ) is based on interspersed constant Ig domains substituting the CH3 domains of a γ1 Fc. The interspersed immunoglobulin (Ig) domains originate from the per se heterodimerizing constant CH1 and CLκ domains and contain sequence stretches of an IgG1 CH3 domain, destined to enable interaction with the neonatal Fc receptor, and thus promote extended serum half-life. The resulting monovalent Fv-Fc1κ fusion protein (Atrosimab) retained strong binding to TNFR1 as determined by enzyme-linked immunosorbent assay and quartz crystal microbalance, and potently inhibited TNF-induced activation of TNFR1. Atrosimab lacks agonistic activity for TNFR1 on its own and in the presence of anti-human IgG antibodies and displays clearly improved pharmacokinetic properties. 相似文献
113.
BackgroundComparative effectiveness studies of cancer therapeutics in observational data face confounding by patterns of clinical treatment over time. The validity of survival analysis in longitudinal health records depends on study design choices including index date definition and model specification for covariate adjustment.MethodsOverall survival in cancer is a multi-state transition process with mortality and treatment switching as competing risks. Parametric Weibull regression quantifies proportionality of hazards across lines of therapy in real-world cohorts of 12 solid tumor types. Study design assessments compare alternative analytic models in simulations with realistic disproportionality. The multi-state simulation framework is adaptable to alternative treatment effect profiles and exposure patterns.ResultsEvent-specific hazards of treatment-switching and death are not proportional across lines of therapy in 12 solid tumor types. Study designs that include all eligible lines of therapy per subject showed lower bias and variance than designs that select one line per subject. Confounding by line number was effectively mitigated across a range of simulation scenarios by Cox proportional hazards models with stratified baseline hazards and inverse probability of treatment weighting.ConclusionQuantitative study design assessment can inform the planning of observational research in clinical oncology by demonstrating the potential impact of model misspecification. Use of empirical parameter estimates in simulation designs adapts analytic recommendations to the clinical population of interest. 相似文献
114.
肿瘤转移是一个多阶段的恶性进展过程,涉及肿瘤细胞从原发部位逃逸,侵入脉管系统并在其中存活,随循环系统到达远处靶器官并穿出脉管系统播散定植,最终克隆性生长形成转移瘤。转移过程的每一阶段与肿瘤细胞本身遗传和表观遗传改变以及微环境中诸多因素的综合调控密切相关。本综述概要介绍了恶性肿瘤转移多步骤过程中所涉的分子调控机制以及肿瘤转移靶向干预新措施等方面的研究进展;同时,就未来肿瘤转移研究相关的新技术和新方向作一简单的展望。 相似文献
115.
Didymocarpus pedicellata R. Br. (Gesneriaceae) is widely used in traditional Indian medicines against renal afflictions. In the present study, we have revealed ethanolic extract of aerial parts of D. pedicellata to possess significant antioxidant activity and protect against ferric nitrilotriacetate (Fe-NTA) mediated renal oxidative stress, nephrotoxicity and tumor promotion response. D. pedicellata extract was found to possess a high content of total polyphenolics, exhibit potent reducing power and significantly scavenge free radicals including several reactive oxygen species (ROS) and reactive nitrogen species (RNS). The extract also significantly and dose-dependently protected against Fe-NTA plus H(2)O(2)-mediated damage to lipids and DNA. Protective efficacy of the extract was also tested in vivo against Fe-NTA mediated nephrotoxicity and tumor promotion response. Administration of Fe-NTA (9 mg/kg body weight, i.p.) to Swiss albino mice depleted renal glutathione content and activities of antioxidant and phase II metabolizing enzymes with concomitant induction of oxidative damage. Fe-NTA also incited hyperproliferation response elevating ornithine decarboxylase activity and [(3)H]-thymidine incorporation into DNA. Elevation in serum creatinine (SCr) and blood urea nitrogen (BUN), and histopathological changes were also evident and suggested Fe-NTA to afflict damage to kidney. Pretreatment of mice with D. pedicellata extract (100-200 mg/kg body weight) for 7 days not only restored antioxidant armory near normal values but also significantly protected against renal oxidative stress and damage restoring normal renal architecture and levels of renal damage markers, viz., BUN and SCr. The results of the present study indicate D. pedicellata to possess potent antioxidant and free radical scavenging activities and preclude oxidative damage and hyperproliferation in renal tissues. 相似文献
116.
117.
Knisely JM Li Y Griffith JM Geuze HJ Schwartz AL Bu G 《Experimental cell research》2007,313(15):3298-3307
The LDL receptor-related protein 1B (LRP1B) is a putative tumor suppressor homologous to LRP1. Both LRP1 and LRP1B contain cytoplasmic tails with several potential endocytosis motifs. Although the positions of these endocytic motifs are similar in both receptors, LRP1B is internalized at a 15-fold slower rate than LRP1. To determine whether the slow endocytosis of LRP1B is due to the utilization of an endocytosis motif other than the YATL motif used by LRP1, we tested minireceptors with mutations in each of the five potential motifs in the LRP1B tail. Only mutation of both NPXY motifs together abolished LRP1B endocytosis, suggesting that LRP1B can use either of these motifs for internalization. LRP1B contains a unique insertion of 33 amino acids not present in LRP1 that could lead to altered recognition of trafficking motifs. Surprisingly, deletion of this insertion had no effect on the endocytosis rate of LRP1B. However, replacing either half of the LRP1B tail with the corresponding LRP1 sequence markedly accelerated LRP1B endocytosis. From these data, we propose that both halves of the LRP1B cytoplasmic tail contribute to a unique global conformation, which results in less efficient recognition by endocytic adaptors and a slow endocytosis rate. 相似文献
118.
The sporogonic development of the malaria parasite takes place in the mosquito and a wide range of factors modulates it. Among those, the contents of the blood meal can influence the parasite development directly or indirectly through the mosquito response to the infection. We have studied the effect of a second blood meal in previously infected mosquitoes and the effect of anti-sporozoite immune serum on parasite development and mosquito response to the infection. The prevalence and intensity of infection and gene expression of both Plasmodium yoelii and Anopheles stephensi was analyzed. We verified that a second blood meal and its immune status interfere with parasite development and with Plasmodium and mosquito gene expression. 相似文献
119.
120.
目的:探讨用表面增强激光解吸电离飞行时间质谱(SELDI-TOF-MS)技术筛查肺癌血清特异性蛋白质的临床意义。方法:应用SELDI-TOF-MS对35例正常对照组、43例治疗前肺癌病人的血清样品进行蛋白质指纹图谱测定,用BioMarker Wizard 3.01及BioMarker Parrern System 5.01分析软件对测得的数据进行处理及建立诊断模型。结果:共检测到251个蛋白质峰,筛选出差异蛋白质峰11个,以质荷比(m/z)分别为M2799_26,M3227_41,M5739_70和M8164_30的4个蛋白质峰为依据组合构建分类决策树模型,分出5个终节点。决策树模型的原始判别总准确率为91.0%(71/78),敏感性为88.4%(38/43),特异性为94.3%(33/35);交叉验证总准确率为85.9%(67/78),敏感性为88.4%(38/43),特异性为82.9%(29/35)。结论:SELDI-TOF-MS在肺癌血清特异性蛋白质的筛选及诊断模型的建立有一定的临床意义。 相似文献