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Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ide

null

《医学前沿（英文）》 2017年第11卷第4期页码 502-508 doi: 10.1007/s11684-017-0590-z

摘要：

Although the efficacy of nucleos(t)ide analogue (NA) has been confirmed for treatment of chronic hepatitis B, long-term therapy has been recommended due to the high frequency of off-therapy viral DNA rebound and disease relapse. In this review, the RNA virion-like particles of hepatitis B virus (HBV) are integrated into the life cycle of HBV replication, and the potential significance of serum HBV RNA is systematically described. The production of HBV RNA virion-like particles should not be blocked by NA; in this regard, serum HBV RNA is found to be a suitable surrogate marker for the activity of intrahepatic covalently closed circular DNA (cccDNA), particularly among patients receiving NA therapy. Therefore, the concept of virological response is redefined as persistent loss of serum HBV DNA and HBV RNA. In contrast to hepatitis B surface antigen (HBsAg) that can originate from either the cccDNA or the integrated HBV DNA fragment, serum HBV RNA, with pregenomic RNA origination, can only be transcribed from cccDNA. Therefore, the loss of serum HBV RNA would likely be a promising predicator for safe drug discontinuation. The clinical status of consistent loss of serum HBV RNA accompanied with low serum HBsAg levels might be implicated as a “para-functional cure,” a status nearly close to the functional cure of chronic hepatitis B, to distinguish the “functional cure” characterized as serum HBsAg loss with or without anti-HBs seroconversion.

关键词： chronic hepatitis B serum HBV RNA nucleos(t)ide analogs virological response para-functional cure

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Impact of HBV replication in peripheral blood mononuclear cell on HBV intrauterine transmission

null

《医学前沿（英文）》 2017年第11卷第4期页码 548-553 doi: 10.1007/s11684-017-0597-5

摘要：

This study determined the effect of hepatitis B virus (HBV) replication in peripheral blood mononuclear cell (PBMC) from HBsAg-positive mothers on HBV intrauterine transmission. A total of 150 HBsAg-positive mothers and their neonates were recruited in this study. Within 24 h after birth, HBV serological markers, serum HBV DNA, PBMC HBV relaxed circular DNA (rcDNA), and covalently closed circular DNA (cccDNA) were measured in the HBsAg-positive mothers and their neonates before passive-active immune prophylaxis. The relationship between HBV replication in PBMC and HBV intrauterine transmission was examined through Chi-square test and logistic regression. The rate of HBV intrauterine transmission was 8.00% (12/150) in the 150 neonates born to HBsAg-positive mothers. The positivities of PBMC HBV rcDNA and cccDNA in the HBsAg-positive mothers were 36.67% (55/150) and 10% (15/150), respectively. Maternal PBMC HBV cccDNA was a risk factor of HBV intrauterine transmission (OR= 6.003, 95% CI: 1.249–28.855). Maternal serum HBeAg was a risk factor of PBMC HBV rcDNA (OR= 3.896, 95% CI: 1.929–7.876) and PBMC HBV cccDNA (OR= 3.74, 95% CI: 1.186–11.793) in the HBsAg-positive mothers. Administration of hepatitis B immune globulin was a protective factor of PBMC HBV cccDNA (OR= 0.312, 95% CI: 0.102–0.954) during pregnancy. The positivity of PBMC HBV rcDNA was related to that of cccDNA in the HBsAg-positive mothers (c²=5.087, P= 0.024). This study suggests that PBMC is a reservoir of HBV and an extrahepatic site for virus replication and plays a critical role in HBV intrauterine transmission.

关键词： PBMC HBV cccDNA HBV rcDNA HBV intrauterine transmission

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Current recommendations of managing HBV infection in preconception or pregnancy

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《医学前沿（英文）》 2014年第8卷第2期页码 158-165 doi: 10.1007/s11684-014-0340-4

摘要：

Hepatitis B remains a leading cause of cirrhosis, hepatocellular carcinoma and liver transplantation worldwide. Management of chronic hepatitis B during pregnancy is challenging. Transmission of hepatitis B to infants still occurs perinatally although immunoprophylaxis is widely available for infants born to mothers with chronic hepatitis B infection. The emerging data suggest that initiation of antiviral therapy in the beginning of the third trimester in highly viremic mothers can prevent immunoprophylaxis failure in their infants. The available drug safety data show that lamivudine, telbivudine and tenofovir are generally safe to be used during the pregnancy. In order to minimize the fetal exposure to the antiviral medication, antiviral therapy during the pregnancy should be limited to a selected group of patients with cirrhosis, high hepatitis B viral load, or prior history immunoprophylaxis failure. An elective Caesarean section may reduce the risk of perinatal transmission. For those females planning for pregnancy or in early stage of pregnancy, communication and follow-up among obstetrician, gastroenterologist, and primary care physician are important. In this article, we will review the features of hepatitis B infection before, during and after the pregnancy; the risk factors that increase mother-to-child transmission; safety data on antiviral drug use during pregnancy; and the potential role of Caesarean section in selected cases.

关键词： antiviral therapy Caesarean section cirrhosis hepatitis B immunoprophylaxis mother-to-child transmission pregnancy prevention

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Ribozyme and the mechanisms that underlie RNA catalysis

Timothy J. Wilson,Yijin Liu,David M. J. Lilley

《化学科学与工程前沿（英文）》 2016年第10卷第2期页码 178-185 doi: 10.1007/s11705-016-1558-2

摘要： Ribozymes are widespread, and catalyze some extremely important reactions in the cell. Mechanistically most fall into one of two classes, using either metal ions or general acid-base catalysis. The nucleolytic ribozymes fall into the latter class, mostly using nucleobases. A sub-set of these use a combination of guanine base plus adenine acid to catalyze the cleavage reaction. New ribozymes are still being discovered at regular intervals and we can speculate on the potential existence of ribozymes that catalyze chemistry beyond phosphoryl transfer reactions, perhaps using small-molecule coenzymes.

关键词： RNA catalysis RNA structure catalytic mechanism

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New perspective on the natural course of chronic HBV infection

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《医学前沿（英文）》 2014年第8卷第2期页码 129-134 doi: 10.1007/s11684-014-0339-x

摘要：

Chronic hepatitis B virus (HBV) infection is a significant threat to public health and an enormous burden on society. Mechanisms responsible for chronic HBV infection remain poorly understood. A better understanding of the natural course of chronic HBV infection may shed new light on the mechanisms underlying this disease and help in designing new antiviral strategies. Natural course of chronic HBV infection is conventionally viewed as an uninterrupted process that is usually marked by HBV e antigen (HBeAg) seroconversion or characterized by different phases associated with assumed host responses to HBV infection. However, none of these descriptions captures or highlights the core events that determine the natural course of chronic HBV infection. In this review, we briefly present the current knowledge on this subject and explain the significance and implication of events that occur during infection. A pre-core mutant becomes predominant in the viral population following elimination of the wild-type virus in duck hepatitis B virus-chronically infected animals. The coupled events in which first there is viral clearance that clears wild-type virus and then there is the reinfection of wild-type virus cleared livers with mutant virus are highly relevant to understanding of the natural course of chronic HBV infection under both treated and untreated conditions. In our new perspective, a general natural course of chronic HBV infection comprises cycles of viral clearance and reinfection, and such cycles prolong the chronic HBV infection course. Reviewing published data on the natural course of chronic HBV infection can reduce the possibility of missing important points in the initial data interpretation.

关键词： hepatitis B virus chronic HBV infection natural course hepatitis B seroconversion

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一种基于血液检测的诊断和预测HBV相关疾病的弹性方法 Article

侯格格, 陈云茹, 刘小静, 张东, 耿智敏, 司书宾

《工程（英文）》 2024年第32卷第1期页码 174-185 doi: 10.1016/j.eng.2023.06.013

摘要：

乙肝病毒(HBV)感染威胁着全球公共卫生安全，是导致肝脏相关疾病发病率和死亡率的主要原因。HBV持续感染引起的肝脏疾病检查方法包括实验室检测、超声、CT、核磁共振和肝活检等，重复的检查和多次诊断可能导致患者每次就医都面临高额费用。

关键词： HBV相关疾病功能弹性医疗资源利用率关键状态网络

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Eliminating mother-to-child transmission of HBV: progress and challenges in China

Wenzhan Jing, Jue Liu, Min Liu

《医学前沿（英文）》 2020年第14卷第1期页码 21-29 doi: 10.1007/s11684-020-0744-2

摘要： China has the world’s largest burden of hepatitis B virus (HBV) infection, but the country has made considerable progress in preventing its mother-to-child transmission (MTCT) in the past three decades. This feat is made possible due to the high coverage of birth-dose hepatitis B vaccine (HepB,>95%), hepatitis B surface antigen (HBsAg) screening for pregnant women (>99%), and hepatitis B immunoglobulin plus HepB for newborns whose mothers are HBsAg positive (>99%). Studies on the optimal antiviral treatment regimen for pregnant women with high HBV-DNA load have also been conducted. However, China still faces challenges in eliminating MTCT of HBV. The overall HBsAg prevalence among pregnant women is considered an intermediate endemic. The prevalence of HBsAg among pregnant women from remote, rural, or ethnic minority areas is higher than that of the national level because of limited health resources and public health education for HBV. The coverage for maternal and child healthcare and immunization services should be improved, especially in western regions. Integration of current services to prevent MTCT of HBV with other relevant health services can increase the acceptability, efficiency, and coverage of these services, particularly in remote areas and ethnic minority areas. By doing so, progress toward key milestones and targets to eliminate hepatitis B as the main public health threat by 2030 can be achieved.

关键词： hepatitis B virus mother-to-child transmission progress challenge

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抗RNA病毒相关生物材料

姚康德,尹玉姬,张宝连,赵立国

《中国工程科学》 2003年第5卷第7期页码 17-23

摘要：

在介绍RNA病毒结构、生殖、复制和转录的基础上，综述了抗病毒策略，其中包括抗SARS药物设计，RNA干扰，DNA疫苗释放系统，调控蛋白与糖胺聚糖衍生物或类似物相互作用，天然药物及肺泡组织工程等。这些实例涵盖了RNA病毒与蛋白质、DNA及多糖等生物材料的相互作用。生物材料作为基质或载体正在向细胞或/和基因活化的第三代生物材料发展，可望在抗病毒中发挥作用。

关键词：抗RNA病毒蛋白质 DNA 多糖生物材料

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基于RNA的生物防治——一种作物保护新模式 Review

Matthew Bramlett, Geert Plaetinck, Peter Maienfisch

《工程（英文）》 2020年第6卷第5期页码 522-527 doi: 10.1016/j.eng.2019.09.008

摘要：在过去的几年中，RNA干扰（RNAi）过程被认为是一种非常有前景的新方法，可作为化学和生物害虫防治剂、植物保护剂等叶面喷施、土壤或种子处理的补充。基于RNA的活性成分（AI）具有独特的作用方式，可以通过基因修饰（GM）和生物防治两种途径来实现。由于基于RNA的AI可利用自然过程来发挥控制作用，同时它们具有高度选择性，降低了非目标生物（NTO）的风险，因此基于RNA的AI有望提供未来作物保护剂所需要的选择性和可持续性。本文讨论了基于RNA的生物防治的替代方案在作物保护中的优势和局限性，以及RNA生物防治科罗拉多马铃薯甲虫（CPB）、玉米根虫（CRW）和大豆臭虫（SSB）的最新研究进展。在实现各种基于RNA的产品及其广泛使用和应用的道路上，仍然存在许多挑战。尽管如此，我们仍可预期到，基于RNA的AI将成为有价值的新工具，以补充当前的农作物保护解决方案。

关键词：基于RNA的生物防治 RNA干扰（RNAi）科罗拉多马铃薯甲虫（CPB）玉米根虫（CRW）大豆臭虫（SSB）

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敲低特异性环状非编码RNA显著抑制骨肉瘤的进展 Article

王世东, 张红亮, 李博, 陈成龙, 任婷婷, 黄怡, 刘凯, 李敬敬, 郭卫

《工程（英文）》 2023年第21卷第2期页码 187-193 doi: 10.1016/j.eng.2021.12.007

摘要：异常表达的非编码环状RNA（circRNA）对骨肉瘤的发生和发展至关重要。本研究的目的是探索一种新的circRNA circ_000203 在骨肉瘤中的表达和作用，阐明其潜在机制。

关键词：非编码RNA 骨肉瘤 circRNA 分子机制敲低

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Blockage of receptor-interacting protein 2 expression by small interfering RNA in murine macrophages

LIU Hongchun, CAO Zhongwei, JIN Jianjun, WANG Jiyao

《医学前沿（英文）》 2008年第2卷第2期页码 166-170 doi: 10.1007/s11684-008-0030-1

摘要： This study aims to demonstrate that blocking the receptor-interacting protein2 (Rip2) expression can decrease inflammatory cytokine production by macrophage and protect mice from endotoxin lethality. Murine Rip2 small interfering RNA (siRNA) plasmids were constructed and transfected into macrophage and Rip2 expression was detected with reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Cell proliferation was assayed with MTT. TNF-? concentration was assayed with ELISA and high-mobility group box 1 protein (HMGB1) level with semi-quantitative western blot after lipopolysaccharide (LPS) stimulation. LPS challenge was given after the plasmids were injected into mice and the survival rate was calculated. Rip2 siRNA plasmid could block the mRNA and protein expression of Rip2 and promote cell proliferation. Blocking Rip2 could attenuate LPS-induced TNF-? and HMGB1 production. The HMGB1 expression in the liver decreased to (40.21 ± 11.03) pg/g, and serum TNF-? level decreased to (300.43 ± 59.26) ng/L ( < 0.05). The survival rate of mice from endotoxemia was also improved ( < 0.05). The results demonstrate that Rip2 siRNA plasmid can block the expression of Rip2, decrease the production of TNF-? and HMGB1 and protect mice from fatal endotoxemia.

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Effect of renal function and hemodialysis on the serum tumor markers in patients with chronic kidney

YU Xiaofang, XU Xialian, YE Zhibin

《医学前沿（英文）》 2007年第1卷第3期页码 308-311 doi: 10.1007/s11684-007-0059-6

摘要： In patients with chronic renal failure, whether they have had hemodialysis or not, the specificity of some of the serum tumor markers for the diagnosis of the corresponding tumors is decreased while others remain as valuable as they are in patients with normal kidney function. The detection of tumor markers is extensively used for the diagnosis of corresponding tumors. It has been recently shown that some tumor markers are higher in patients with chronic kidney disease (CKD) than in the normal population. The effects of renal function and hemodialysis were examined on serum levels of some of the tumor markers including CEA, CA, CA, AFP, CA, CA, CYFRA, NSE, SCC-Ag, PSA, and fPSA. The 232 non-dialysis patients with CKD and 37 chronic uremic patients treated with maintenance hemodialysis were enrolled in this study. The 232 non-dialysis patients were divided into three groups according to their Ccr. In group 1, Ccr was ≤25 mL/min. In group 2, Ccr was between 25 and 50 mL/min. In group 3, Ccr was ≥50 mL/min. The male patients were also divided into three groups to compare the serum levels of PSA and fPSA among the three groups. Nine tumor markers in 37 uremic patients were tested. For comparison, 37 non-dialysis patients with similar Ccr of the same age and gender served as controls. There existed significant differences in serum levels of CEA, CA, CYFRA, NSE, and SCC-Ag among different Ccr groups and the markers bore a negative correlation with Ccr. There were no significant differences among the three groups in the serum concentrations of CA, AFP, CA, CA, PSA and fPSA. The serum levels of CA and NSE were significantly higher (199, CYFRA, NSE, CA and SCC-Ag for the diagnosis of the corresponding tumors was decreased while serum AFP, CA, CA, PSA and fPSA were as valuable as they were in patients with normal kidney function. Hemodialysis further increased the serum level of CA and NSE.

关键词： CKD non-dialysis valuable detection chronic

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Overexpressed long noncoding RNA CRNDE with distinct alternatively spliced isoforms in multiple cancers

Xuefei Ma, Wei Zhang, Rong Zhang, Jingming Li, Shufen Li, Yunlin Ma, Wen Jin, Kankan Wang

《医学前沿（英文）》 2019年第13卷第3期页码 330-343 doi: 10.1007/s11684-017-0557-0

摘要： Alternative splicing is a tightly regulated process that contributes to cancer development. CRNDE is a long noncoding RNA with alternative splicing and is implicated in the pathogenesis of several cancers. However, whether deregulated expression of CRNDE is common and which isoforms are mainly involved in cancers remain unclear. In this study, we report that CRNDE is aberrantly expressed in the majority of solid and hematopoietic malignancies. The investigation of CRNDE expression in normal samples revealed that CRNDE was expressed in a tissue- and cell-specific manner. Further comparison of CRNDE expression in 2938 patient samples from 15 solid and hematopoietic tumors showed that CRNDE was significantly overexpressed in 11 malignancies, including 3 reported and 8 unreported, and also implicated that the overexpressed isoforms differed in various cancer types. Furthermore, anti-cancer drugs could efficiently repress CRNDE overexpression in cancer cell lines and primary samples, and even had different impacts on the expression of CRNDE isoforms. Finally, experimental profiles of 12 alternatively spliced isoforms demonstrated that the spliced variant CRNDE-g was the most highly expressed isoform in multiple cancer types. Collectively, our results emphasize the cancer-associated feature of CRNDE and its spliced isoforms, and may provide promising targets for cancer diagnosis and therapy.

关键词： long noncoding RNA CRNDE alternative splicing

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Direct acting antiviral-induced dynamic reduction of serum

Tung Huynh, Ke-Qin Hu

《医学前沿（英文）》 2019年第13卷第6期页码 658-666 doi: 10.1007/s11684-019-0707-7

摘要： Direct acting antiviral (DAA) treatments may reduce the elevated α fetoprotein (AFP), but data on how these treatments affect elevated AFP in patients with chronic hepatitis C (CHC) remain insufficient. In the present study, the frequency of baseline AFP elevations and their related factors, AFP dynamics during and after DAA treatment, and factors associated with AFP reduction was assessed. This retrospective study included 141 patients with CHC without hepatocellular carcinoma who received DAA and achieved sustained virological response. The details are as follows: mean post-treatment follow-up was 99 weeks (12–213); mean age, 57.8 years old; 52%, males; 79%, genotype (GT) 1; and 47%, cirrhosis. Pre-treatment AFP elevation (>5.5 ng/mL) was seen in 48.2% patients. On multivariate analysis, baseline AFP>5.5 was associated with the presence of cirrhosis ( =0.001), co-existing non-alcoholic steatohepatitis (NASH) ( = 0.035), and GT 1 ( = 0.029). AFP normalization was seen in 28.2% patients at treatment week 2, in 52% at the end of treatment, and in 73.4% at the end of follow-up. Post-treatment week 24 AFP normalization was associated with the absence of cirrhosis ( = 0.003), Child–Pugh score<6 ( = 0.015), and baseline AFP<10 ( = 0.015). AFP elevation is common in patients with CHC and independently associated with NASH, cirrhosis, and GT 1. DAA treatment resulted in AFP normalization as early as treatment week 2. Post-treatment week 24 AFP normalization is independently associated with the absence of cirrhosis, Child–Pugh score<6, and baseline AFP<10.

关键词： chronic hepatitis C α fetoprotein direct acting antiviral treatment cirrhosis

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Proteomics study of Mycoplasma pneumoniae pneumonia reveals the Fc fragment of the IgG-binding protein as a serum

《医学前沿（英文）》 2022年第16卷第3期页码 378-388 doi: 10.1007/s11684-021-0840-y

摘要： Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP (SMPP). SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans. Therefore, identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency. In this study, serum samples were collected from patients with general MPP (GMPP) and SMPP to conduct proteomics profiling. The Fc fragment of the IgG-binding protein (FCGBP) was identified as the most promising indicator of SMPP. Biological enrichment analysis indicated uncontrolled inflammation in SMPP. ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP. Furthermore, the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression. Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment. Among them, a mechanistic target of rapamycin kinase (mTOR) inhibitor, which is a macrolide compound and a cell proliferation inhibitor, was the most promising candidate for targeting SMPP. To our knowledge, this study was the first proteomics-based characterization of patients with SMPP and GMPP.

关键词： severe Mycoplasma pneumoniae pneumonia children proteomics Fc fragment of the IgG-binding protein mechanistic target of rapamycin kinase inhibitor