Despite reductions in AIDS-related deaths, registries show HIV＋ patients are still dying at a younger age than HIV-peers. Although overall mortality has declined in this population, a growing percent of deaths are du...Despite reductions in AIDS-related deaths, registries show HIV＋ patients are still dying at a younger age than HIV-peers. Although overall mortality has declined in this population, a growing percent of deaths are due to malignancy. Since the data demonstrating the growing percentage of deaths due to malignancy in the HIV＋ population is derived from registries, the study explores whether the subset dying from malignancy has particular characteristics that can be seen in a well-characterized cohort. In the well-characterized HIV＋ cohort, the percentage of deaths due to cancer was seen to increase over four years （2010-2013） from 21% to 24% to 38% to 40%. The mean CD4-count of those who died from malignancy was 252＋/-42 and 333＋/-36 in patients with death from other causes. The viral load was not suppressed in 26% of patients dying from malignancy. Of patients on integrase inhibitor therapy, 48% of deaths were due to malignancy while in patients not on this therapy, 10% of deaths were due to malignancy （relative risk = 4.8）. In HIV＋ patients, a low CD4-count, failure to achieve viral suppression, and use of integrase inhibitors were associated with malignancy as the cause of death. The association of a specific therapy, integrase inhibition, with malignancy is seen in the study.展开更多
An efficient procedure for the synthesis of caffeoyl- and galloyl-containing β-diketoacid derivatives linked by arylamide was reported by, in the key step, dissolving the corresponding phenyl methyl ketone in THF/DME...An efficient procedure for the synthesis of caffeoyl- and galloyl-containing β-diketoacid derivatives linked by arylamide was reported by, in the key step, dissolving the corresponding phenyl methyl ketone in THF/DME in the presence of NaOMe as base and dimethyl oxalate as oxalylation reagent, and then separating the sodium ketoenolate ester. The resulting β-diketoacids underwent further condensation reaction with o-phenylenediamine to generate quinoxalone derivatives in good yield, rather than 2-benzimidazol. The preliminary ion binding properties of quinoxalone derivatives were also investigated. UV-Vis spectra showed that these compounds could selectively recognize Cu^2 ＋ ion in ethanol and form a 1 ： 2 complex.展开更多
The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disr...The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.展开更多
HIV-1 integrase （IN）-mediated integration of viral DNA into the host chromosome is an essential step in the virus life cycle. Human lens epithelium-derived growth factor （LEDGF/p75） has been found to function as a...HIV-1 integrase （IN）-mediated integration of viral DNA into the host chromosome is an essential step in the virus life cycle. Human lens epithelium-derived growth factor （LEDGF/p75） has been found to function as a cellu- lar cofactor in this process. The LEDGF/p75-1N interaction hence represents an attractive target for anti-HIV ther- apy. In this study, natural products were virtually screened against the LEDGF/p75 binding pocket of HIV-1 IN. 24 compounds were selected and obtained from the National Compound Resource Center of China. AlphaScreen as- says characterized 8 of these 24 natural products as potent LEDGF/p75-IN interaction inhibitors. The active com- pounds whose ICs0 values ranged from 0.56 to 14.55 ~mol/L could be used as lead compounds for further investi- gation. This work confirmed that natural products are valuable resources for antiviral drug discovery.展开更多
目的评价HIV感染者基线CD4+T淋巴细胞(CD4细胞)计数和病毒载量对含整合酶抑制剂治疗方案疗效的影响。方法检索知网、万方、维普、PubMed以及Web of Science数据库,对符合纳入标准文献进行质量评价和原始数据提取,对基线CD4细胞计数(<...目的评价HIV感染者基线CD4+T淋巴细胞(CD4细胞)计数和病毒载量对含整合酶抑制剂治疗方案疗效的影响。方法检索知网、万方、维普、PubMed以及Web of Science数据库,对符合纳入标准文献进行质量评价和原始数据提取,对基线CD4细胞计数(<200/μL vs.≥200/μL)和HIV病毒载量(>10^(5)拷贝/mL vs.≤10^(5)拷贝/mL)进行亚组分析,评估各亚组治疗失败风险,采用R软件进行Meta分析。结果共纳入29篇文献。Meta分析结果显示,与基线CD4细胞计数≥200/μL组相比,<200/μL组治疗48周(OR=1.93,95%Cl:1.47~2.53,P=0.01)和96周(OR=1.53,95%Cl:1.13~2.09,P<0.01)的治疗失败风险更高;与基线病毒载量≤10^(5)拷贝/mL的HIV感染者相比,>10^(5)拷贝/mL的HIV感染者治疗48周后治疗失败风险更高(OR=1.82,95%Cl:1.37~2.42,P<0.01)。结论HIV感染者基线CD4细胞计数和病毒载量是影响含整合酶抑制剂治疗方案疗效的重要因素,应积极推行“发现即治疗”政策,促进HIV感染者的早检测、早诊断及早治疗。展开更多
文摘Despite reductions in AIDS-related deaths, registries show HIV＋ patients are still dying at a younger age than HIV-peers. Although overall mortality has declined in this population, a growing percent of deaths are due to malignancy. Since the data demonstrating the growing percentage of deaths due to malignancy in the HIV＋ population is derived from registries, the study explores whether the subset dying from malignancy has particular characteristics that can be seen in a well-characterized cohort. In the well-characterized HIV＋ cohort, the percentage of deaths due to cancer was seen to increase over four years （2010-2013） from 21% to 24% to 38% to 40%. The mean CD4-count of those who died from malignancy was 252＋/-42 and 333＋/-36 in patients with death from other causes. The viral load was not suppressed in 26% of patients dying from malignancy. Of patients on integrase inhibitor therapy, 48% of deaths were due to malignancy while in patients not on this therapy, 10% of deaths were due to malignancy （relative risk = 4.8）. In HIV＋ patients, a low CD4-count, failure to achieve viral suppression, and use of integrase inhibitors were associated with malignancy as the cause of death. The association of a specific therapy, integrase inhibition, with malignancy is seen in the study.
基金Project supported by the National Natural Science Foundation of China （No. 20402001）, the Special Foundation for Beijing Municipal （No. 2004D0501520 and Beijing Novel Project （No. 2005B 10）.
文摘An efficient procedure for the synthesis of caffeoyl- and galloyl-containing β-diketoacid derivatives linked by arylamide was reported by, in the key step, dissolving the corresponding phenyl methyl ketone in THF/DME in the presence of NaOMe as base and dimethyl oxalate as oxalylation reagent, and then separating the sodium ketoenolate ester. The resulting β-diketoacids underwent further condensation reaction with o-phenylenediamine to generate quinoxalone derivatives in good yield, rather than 2-benzimidazol. The preliminary ion binding properties of quinoxalone derivatives were also investigated. UV-Vis spectra showed that these compounds could selectively recognize Cu^2 ＋ ion in ethanol and form a 1 ： 2 complex.
基金supported by the National Natural Science Foundation of China (No. 30472166)the Tianjin Commission of Science and Technology (06YFGZSH07000)
文摘The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.
基金supported by the Program for New Century Excellent Talents in University （No. NCET-08-0774）, the Innovation Program of Shanghai Municipal Education Commission （No. 10ZZ41）, the National Natural Science Foundation of China （No. 21072059）, and the Shanghai Committee of Science and Technology （No. 11DZ2260600）. We thank the National Compound Resource Center for providing compounds. The cDNA coding for HIV IN CCD （residues 50-212） including the F185K solubilizing-mutation was a gift from Prof. Robert Craigie （National Institutes of Health, Bethesda, MD）. The full-length plasmid pCPNat p75 was kindly provided by Prof. Zeger De- byser （Katholieke Universiteit Leuven, Belgium）.
文摘HIV-1 integrase （IN）-mediated integration of viral DNA into the host chromosome is an essential step in the virus life cycle. Human lens epithelium-derived growth factor （LEDGF/p75） has been found to function as a cellu- lar cofactor in this process. The LEDGF/p75-1N interaction hence represents an attractive target for anti-HIV ther- apy. In this study, natural products were virtually screened against the LEDGF/p75 binding pocket of HIV-1 IN. 24 compounds were selected and obtained from the National Compound Resource Center of China. AlphaScreen as- says characterized 8 of these 24 natural products as potent LEDGF/p75-IN interaction inhibitors. The active com- pounds whose ICs0 values ranged from 0.56 to 14.55 ~mol/L could be used as lead compounds for further investi- gation. This work confirmed that natural products are valuable resources for antiviral drug discovery.
文摘目的评价HIV感染者基线CD4+T淋巴细胞(CD4细胞)计数和病毒载量对含整合酶抑制剂治疗方案疗效的影响。方法检索知网、万方、维普、PubMed以及Web of Science数据库,对符合纳入标准文献进行质量评价和原始数据提取,对基线CD4细胞计数(<200/μL vs.≥200/μL)和HIV病毒载量(>10^(5)拷贝/mL vs.≤10^(5)拷贝/mL)进行亚组分析,评估各亚组治疗失败风险,采用R软件进行Meta分析。结果共纳入29篇文献。Meta分析结果显示,与基线CD4细胞计数≥200/μL组相比,<200/μL组治疗48周(OR=1.93,95%Cl:1.47~2.53,P=0.01)和96周(OR=1.53,95%Cl:1.13~2.09,P<0.01)的治疗失败风险更高;与基线病毒载量≤10^(5)拷贝/mL的HIV感染者相比,>10^(5)拷贝/mL的HIV感染者治疗48周后治疗失败风险更高(OR=1.82,95%Cl:1.37~2.42,P<0.01)。结论HIV感染者基线CD4细胞计数和病毒载量是影响含整合酶抑制剂治疗方案疗效的重要因素,应积极推行“发现即治疗”政策,促进HIV感染者的早检测、早诊断及早治疗。
