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Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.
ABSTRACT
@#Protein arginine methyltransferases, which proceed the post-translational modification of both histones and non-histones, play an important role in many biological pathways. Protein arginine methyltransferase 5 (PRMT5) is a major enzyme responsible for symmetric di-methylation of arginine residues and has been suggested as a potential therapeutic target for tumors.In the past decade,the discovery and development of PRMT5 inhibitors have become one of the most important research fields.This article introduces the structure and biochemical function of PRMT5 and its correlation with cancer reviews, the binding modes and biological data of PRMT5 inhibitors under development, and discusses the clinical application potential of PRMT5 inhibitors in the treatment of cancer.
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Prodrug nanoassemblies, which can refrain from large excipients, achieve higher drug loading and control drug release, have been placed as the priority in drug delivery system. Reasoning that glutathione (GSH) and reactive oxygen species (ROS) are highly upgraded in tumor tissues which makes them attractive targets for drug delivery system, we designed and synthetized a novel prodrug which utilized mono thioether bond as a linker to bridge linoleic acid (LA) and docetaxel (DTX). This mono thioether-linked conjugates (DTX-S-LA) could self-assemble into nanoparticles without the aid of much excipients. The mono thioether endowed the nanoparticles redox sensitivity resulting in specific release at the tumor tissue. Our studies demonstrated that the nanoassemblies had uniform particle size, high stability and fast release behavior. DTX-S-LA nanoassemblies outperformed DTX solution in pharmacokinetic profiles for it had longer circulation time and higher area under curve (AUC). Compared with DTX solution, the redox dual-responsive nanoassemblies had comparable cytotoxic activity. Besides, the antitumor efficacy was evaluated in mice bearing 4T1 xenograft. It turned out this nanoassemblies could enhance anticancer efficacy by increasing the dose because of higher tolerance. Overall, these results indicated that the redox sensitivity nanoassemblies may have a great potential to cancer therapy.
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With the application of gene editing in medical treatment,food engineering,environmental protection,agriculture and forestry,it gives rise to a wide range of potential social risks.Both the advanced aspects and defects of this technology bring complicated social conflicts.It is undoubtedly crucial to coordinate the conflict of interests of all parties,improve the legal system and avoid the harmfulness and blindness of gene editing.Meanwhile,only that the ethical,legal and social concerns are introduced will govern the technical risk as a necessary condition in order to attain a virtuous cycle of technological improvement and social prosperity.
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ObjectiveTo evaluate the long-term outcomes of carotid endarterectomy versus carotid artery stenting for carotid stenosis.MethodsPubMed, EMBASE, and the Cochrane databases were retrieved.The randomized controlled trials of comparing CEA with CAS in patients with carotid artery stenosis were enrolled.The data such as the research basic characteristics and the long-term outcomes including stroke or death combined endpoints, any stroke or any death were extracted.The Stata software was used to conduct statistical analysis.ResultsA total of 7 randomized controlled trials and 8 210 patients were included.The median follow-up time was 2-7.4 years.The overall quality of the included studies was high and the risk of bias was low.The meta-analysis showed that the risks of the combined endpoint of stroke or death (hazard risk [HR] 1.21, 95% confidence interval [CI] 1.04-1.39), any stroke (HR 1.32, 95% CI 1.15-1.51) and ipsilateral stroke (HR 1.26, 95% CI 1.02-1.55) in the CAS group were significantly higher than those in the CEA group;the risks of death (HR 1.06, 95% CI 0.95-1.18), disabling stroke (HR 1.23, 95% CI 0.95-1.60), non-ipsilateral stroke (HR 1.12,95% CI 0.81-1.55) and restenosis (HR 1.18,95% CI 0.91-1.52) were not significantly different between between the CAS group and the CEA group.Conclusions CAS and CEA are associated with similar risks of long-term death, disabling stroke, non-ipsilateral stroke and restenosis.The risks of long-term combined endpoint of stroke or death, any stroke and ipsilateral stroke significantly higher with CAS.These results suggest that CEA remains the treatment of choice for carotid stenosis.
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Objective To evaluate the efficacy and safety of endovascular mechanical thrombectomy in patients with anterior circulation stroke. Methods PubMed, EMBASE, Cochrane database, Clinical Trials and the related supplement resources were retrieved. The randomized controled trials for comparing intravenous thrombolysis and endovascular mechanical thrombectomy in patients with anterior circulation stroke were selected. The bias risk assessment was performed. The basic characteristics of studies and the clinical outcome data at day 90, including good outcome (defined as the modified Rankin scale score 0-2), death and symptomatic intracranial hemorrhage (sICH) were extracted. Review Manager 5.3 software was used to conduct the statistical analysis. Results A total of 10 articles were enroled, including 1 557 patients in the endovascular mechanical thrombectomy group and 1 359 in the intravenous thrombolysis group. The overal quality of the included trials was higher. The risk of bias was lower. The good outcome rate in the endovascular mechanical thrombectomy group was significantly higher than that in the intravenous thrombolysis group (odds ratio [ OR] 2. 15, 95% confidence interval [ CI] 1. 34-3. 46; P < 0. 01). The death risk at day 90 was significantly lower than that in the intravenous thrombolysis group (OR 0. 86, 95% CI 0. 69-1. 06; P = 0. 16), and there was borderline statistical significance for the risk of sICH (OR 1. 35, 95% CI 1. 00- 1. 84; P = 0. 05 ). Conclusions The effectiveness of the endovascular mechanical thrombectomy is superior to the intravenous thrombolysis in patients with anterior circulation stroke;however, in terms of safety, further evaluation is needed.
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Objective To establish a determination method of phthalates in the drinking water used to monitor the pollution level of phthalates in the drinking water of Beijing. Methods 23 samples from drinking water plants in Beijing were determinated by GC-MS, using selective ion mode (SIM)with high sensitivity and internal standard quantitation method with high accuracy. Results In all samples, di(2-ethylhexyl) phthalate (DEHP) was detected out and the highest concentration was 24.5 ?g/L, dibutyl phthalate (DBP) was detected out in 7 samples and the highest concentration was 11.1 ?g/L, The other 3 kinds of phthalate were not detected out. The detection limit of DEHP and DOP was 8.0 ?g/L, DMP, DEP, DBP was 0.3 ?g/L, The recovery rate were 71.7%-96.0%, RSD were 2.8%-9.0%. Conclusion The main pollutants of phthalates are DEHP and DBP in drinking water of Beijing, GC-MS is suitable for determination of phthalates in drinking water.