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Gene therapy for hemophilia B mice with scAAV8-LP1-hFIX

null

《医学前沿(英文)》 2016年 第10卷 第2期   页码 212-218 doi: 10.1007/s11684-016-0438-y

摘要:

Hemophilia B is a hemorrhagic disease caused by the deficiency of clotting factor IX (FIX). Gene therapy might be the ultimate strategy for the disease. However, two main problems that should be solved in gene therapy for hemophilia B are immunity and safety. Self-complementary adeno-associated virus serotype 8 (scAAV8), a non-human primate AAV featuring low immunogenicity and high transfection efficiency in liver cells, might be a potential vector for hemophilia B gene therapy. A strong liver-specific promoter-1 (LP1) was inserted and mutant human FIX Arg338Ala was introduced into plasmid scAAV8-LP1 to develop an optimized AAV8 vector that expresses human clotting factor FIX (hFIX). The efficiency of scAAV8-LP1-hFIX administered through normal systemic injection or hydrodynamic injection was compared. A high expression was achieved using hydrodynamic injection, and the peak hFIX expression levels in the 5×1011 and 1×1011 virus genome (vg) cohorts were 31.94% and 25.02% of normal level, respectively, at 60 days post-injection. From the perspective of long-term (200 days) expression, both injection methods presented promising results with the concentration value maintained above 4% of normal plasma. The results were further verified by enzyme-linked immunosorbent assay and activated partial thromboplastin time. Our study provides a potential gene therapy method for hemophilia B.

关键词: hemophilia B     AAV8     hFIX     gene therapy    

Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B

null

《医学前沿(英文)》 2015年 第9卷 第1期   页码 90-99 doi: 10.1007/s11684-015-0390-2

摘要:

Gene therapy provides a potential cure for hemophilia B, and significant progress has been achieved in liver-directed gene transfer mediated by adeno-associated viral vectors. Recent clinical trials involving the use of a self-complementary adeno-associated virus serotype 8-human codon-optimized factor IX (AAV8-hFIXco) vector demonstrated encouraging efficacy with hFIX expression stabilized at 1% to 6% of normal level in patients, but safety concerns related to high vector doses are still present. Thus, further improvement of AAV vectors and hFIX expression cassette may positively contribute to the ultimate success of hemophilia B gene therapy. In this study, to obtain a higher expression level of hFIX that potentiates the coagulant capacity of recipients, human FIX expression vector was optimized by upgrading the codon adaption index and adjusting the GC content, inserting a Kozak sequence (GCCACC), and introducing a gain-of-function mutation, R338L (FIX Padua). The efficiency of the published and the presently constructed cassettes was compared through in vivo screening. In addition, the regulatory elements that control the FIX gene expression in these cassettes were screened for liver-specific effectiveness. Among all the constructed cassettes, scAAV-Pre-hFIXco-SIH-R338L, which was the construct under the control of the prothrombin enhancer and prealbumin promoter, resulted in the highest level of coagulant activity, and the expression levels of two constructed cassettes (scAAV-Chi-hFIXco-SIH-R338L and scAAV-Pre-hFIXco-SIH-R338L) were also higher than that of the published cassette (scAAV-LP1-hFIXco-SJ). In summary, our strategies led to a substantial increase in hFIX expression at the protein level or a remarkably elevated coagulant activity. Thus, these reconstructs of hFIX with AAV vector may potentially contribute to the creation of an efficacious gene therapy of hemophilia B.

关键词: factor IX     hemophilia B     liver-specific regulatory elements     hydrodynamic gene transfer    

Long-term correction of hemorrhagic diathesis in hemophilia A mice by an AAV-delivered hybrid FVIII composed

《医学前沿(英文)》 2022年 第16卷 第4期   页码 584-595 doi: 10.1007/s11684-021-0844-7

摘要: Conventional therapies for hemophilia A (HA) are prophylactic or on-demand intravenous FVIII infusions. However, they are expensive and inconvenient to perform. Thus, better strategies for HA treatment must be developed. In this study, a recombinant FVIII cDNA encoding a human/rat hybrid FVIII with an enhanced procoagulant potential for adeno-associated virus (AAV)-delivered gene therapy was developed. Plasmids containing human FVIII heavy chain (hHC), human light chain (hLC), and rat light chain (rLC) were transfected into cells and hydrodynamically injected into HA mice. Purified AAV viruses were intravenously injected into HA mice at two doses. Results showed that the hHC+ rLC protein had a higher activity than the hHC+ hLC protein at comparable expression levels. The specific activity of hHC+ rLC was about 4- to 8-fold higher than that of their counterparts. Hydrodynamic injection experiments obtained consistent results. Notably, the HA mice undergoing the AAV-delivered hHC+ rLC treatment exhibited a visibly higher activity than those treated with hHC+ hLC, and the therapeutic effects lasted for up to 40 weeks. In conclusion, the application of the hybrid FVIII (hHC+ rLC) via an AAV-delivered gene therapy substantially improved the hemorrhagic diathesis of the HA mice. These data might be of help to the development of optimized FVIII expression cassette for HA gene therapy.

关键词: hemophilia A     adeno-associated virus (AAV)     human/rat hybrid factor VIII     gene therapy     dual chain strategy    

Current hepatitis B treatment guidelines and future research directions

null

《医学前沿(英文)》 2014年 第8卷 第2期   页码 145-157 doi: 10.1007/s11684-014-0335-1

摘要:

Hepatitis B virus (HBV) infection causes a tremendous clinical burden across the world with more than half a million people dying annually from HBV related disease. Significant advances have been made in HBV treatment in the past decade and several guidelines have been published by professional societies and expert panels. Although these recommendations have been valuable to help optimize HBV treatment, there is discordance in treatment criteria and many patients infected with HBV may fall outside of these recommendations. This paper systematically reviews the natural history of the disease and compares and contrasts the recommendations for initiation of treatment from the various societies. There is also discussion of special groups that require particular consideration and some of the open research questions and future research directions within the field.

关键词: chronic hepatitis B     HBV treatment guidelines     APASL guidelines     EASL guidelines     AASLD guidelines    

Clinical characteristics and risk factors of COVID-19 patients with chronic hepatitis B: a multi-center

《医学前沿(英文)》 2022年 第16卷 第1期   页码 111-125 doi: 10.1007/s11684-021-0854-5

摘要: The coronavirus disease 2019 (COVID-19) has spread globally. Although mixed liver impairment has been reported in COVID-19 patients, the association of liver injury caused by specific subtype especially chronic hepatitis B (CHB) with COVID-19 has not been elucidated. In this multi-center, retrospective, and observational cohort study, 109 CHB and 327 non-CHB patients with COVID-19 were propensity score matched at an approximate ratio of 3:1 on the basis of age, sex, and comorbidities. Demographic characteristics, laboratory examinations, disease severity, and clinical outcomes were compared. Furthermore, univariable and multivariable logistic and Cox regression models were used to explore the risk factors for disease severity and mortality, respectively. A higher proportion of CHB patients (30 of 109 (27.52%)) developed into severe status than non-CHB patients (17 of 327 (5.20%)). In addition to previously reported liver impairment markers, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin, we identified several novel risk factors including elevated lactate dehydrogenase (≥245 U/L, hazard ratio (HR) = 8.639, 95% confidence interval (CI) = 2.528–29.523; P <0.001) and coagulation-related biomarker D-dimer (≥0.5 μg/mL, HR= 4.321, 95% CI= 1.443–12.939; P = 0.009) and decreased albumin (<35 g/L, HR= 0.131, 95% CI= 0.048–0.361; P <0.001) and albumin/globulin ratio (<1.5, HR= 0.123, 95% CI= 0.017–0.918; P = 0.041). In conclusion, COVID-19 patients with CHB were more likely to develop into severe illness and die. The risk factors that we identified may be helpful for early clinical surveillance of critical progression.

关键词: COVID-19     chronic hepatitis B     liver injury     coagulation dysfunction    

Vaccine therapies for chronic hepatitis B: can we go further?

null

《医学前沿(英文)》 2014年 第8卷 第1期   页码 17-23 doi: 10.1007/s11684-014-0313-7

摘要:

Chronic hepatitis B is a major health burden worldwide. In addition to the recent progress in antiviral treatment, therapeutic vaccination is a promising new strategy for the control of chronic hepatitis B. On the basis of the major specific and non-specific immune dysregulations and defects in chronic hepatitis B patients, this paper presents the peptide and protein-based, DNA-based, cell-based, and antigen-antibody-based therapeutic vaccines, which have undergone clinical trials. The advantages, disadvantages, and future perspectives for these therapeutic vaccines are discussed.

关键词: chronic hepatitis B     therapeutic     antigen-antibody complexes     DNA     vaccine    

Chronic hepatitis B virus infection: epidemiology, prevention, and treatment in China

null

《医学前沿(英文)》 2014年 第8卷 第2期   页码 135-144 doi: 10.1007/s11684-014-0331-5

摘要:

Chronic hepatitis B is a major health problem in China. The universal vaccination program since 1992 has changed the epidemiology of hepatitis B virus infection in China from highly to moderately endemic. The most prevalent hepatitis B virus strains in China are genotypes B and C, whereas those in western provinces are genotypes D and C/D hybrid. Chronic hepatitis B poses a heavy burden to the society in China. Different treatment strategies have been explored to improve patient outcomes in a cost-effective manner. However, antiviral drugs with a low genetic barrier to resistance are still extensively used because of the generally low income and limited resources in China. Individualized antiviral therapy is closely associated with translational medicine, which utilizes information from studies on genomics, immune biomarkers, and fibrosis. The results of these studies are crucial in further improving treatment outcomes.

关键词: chronic hepatitis B     epidemiology     prevention     treatment    

基于PFM的B级钢侧架耐久性分析

李伟,李强,王平

《中国工程科学》 2011年 第13卷 第1期   页码 56-61

摘要:

基于概率断裂力学对B级钢货车侧架的圆角细节进行了模拟耐久性试验研究,提出了一种新的通用当量初始缺陷尺寸分布的计算方法,建立了裂纹超越概率模型

关键词: 耐久性     疲劳     B级钢     裂纹    

Impact analysis of compressor rotor blades of an aircraft engine

Y B SUDHIR SASTRY, B G KIROS, F HAILU, P R BUDARAPU

《结构与土木工程前沿(英文)》 2019年 第13卷 第3期   页码 505-514 doi: 10.1007/s11709-018-0493-3

摘要: Frequent failures due to foreign particle impacts are observed in compressor blades of the interceptor fighter MIG-23 aircraft engines in the Ethiopian air force, supplied by the Dejen Aviation Industry. In this paper, we made an attempt to identify the causes of failure and hence recommend the suitable materials to withstand the foreign particle impacts. Modal and stress analysis of one of the recently failed MIG-23 gas turbine compressor blades made up of the following Aluminum based alloys: 6061-T6, 7075-T6, and 2024-T4, has been performed, apart from the impact analysis of the rotor blades hit by a granite stone. The numerical results are correlated to the practical observations. Based on the modal, stress and impact analysis and the material properties of the three considered alloys, alloy 7075-T6 has been recommended as the blade material.

关键词: axial flow compressor     rotor and stator blades     aircraft engine     stress and impact analysis     aluminum alloys    

Comprehensive treatment of acute-on-chronic liver failure in a patient with hepatitis B: a case report

null

《医学前沿(英文)》 2014年 第8卷 第2期   页码 250-253 doi: 10.1007/s11684-014-0333-3

摘要:

The clinical data of a patient with acute-on-chronic liver failure were analyzed retrospectively. The patient has suffered from hepatitis B for 30 years. His liver function deteriorated, yielding Child-Pugh grade C and reaching a model for end-stage liver disease score of 33 points within a short period; this condition was complicated with highly active variceal bleeding and coagulation system failure (PT > 100 s). The patient also presented hepatocellular carcinoma. Comprehensive treatments included effective inhibition of hepatitis B virus replication and intensive care support. Piggyback orthotopic liver transplantation was performed as the final treatment. The patient recovered uneventfully and was discharged after surgery.

关键词: acute-on-chronic liver failure     submassive necrosis     viral hepatitis B     esophageal variceal bleeding     liver transplantation    

带约束条件的C-Bézier曲面最优降多阶逼近 Article

Lian ZHOU, Xin-hui LIN, Hong-yan ZHAO, Jun CHEN

《信息与电子工程前沿(英文)》 2017年 第18卷 第12期   页码 2009-2016 doi: 10.1631/FITEE.1700458

摘要: 本文提出了一种在L2范数下C-Bézier曲面带约束条件的降多阶逼近最优方法。利用C-Bézier基函数的转换矩阵,得到了降阶曲面控制顶点的显式矩阵表示。

关键词: C-Bézier曲面;降阶;边界约束    

MicroRNA-148b promotes proliferation of hair follicle cells by targeting

Wanbao YANG,Qinqun LI,Bo SU,Mei YU

《农业科学与工程前沿(英文)》 2016年 第3卷 第1期   页码 72-80 doi: 10.15302/J-FASE-2016089

摘要: MicroRNAs (miRNAs), small non-coding RNAs, are involved in many aspects of biological processes. Previous studies have indicated that miRNAs are important for hair follicle development and growth. In our study, we found by qRT-PCR that miR-148b was significantly upregulated in sheep wool follicle bulbs in anagen phase compared with the telogen phase of the hair follicle cycle. Overexpression of miR-148b promoted proliferation of both HHDPC and HHGMC. By using the TOPFlash system we demonstrated that miR-148b could activate Wnt/β-catenin pathway and , , and were consistently upregulated accordingly. Furthermore, transcript factor nuclear factor of activated T cells type 5 ( ) and were predicted to be the target of miR-148b and this was substantiated using a Dual-Luciferase reporter system. Subsequently was further identified as the target of miR-148b using western blotting. These results were considered to indicate that miR-148b could activate the Wnt/β-catenin signal pathway by targeting to promote the proliferation of human hair follicle cells.

关键词: miR-148b     hair follicle     proliferation     NFAT5     Wnt10b    

Correlation between viral load and liver cirrhosis in chronic hepatitis B patients

Lili LIU MM , Jiyao WANG MD , Weimin SHE MM ,

《医学前沿(英文)》 2009年 第3卷 第3期   页码 271-276 doi: 10.1007/s11684-009-0054-1

摘要: The aim of this paper is to investigate the relationship between hepatitis B virus (HBV) DNA levels during the course and the progression to cirrhosis with chronic hepatitis B. A total of 239 chronic hepatitis B patients confirmed by liver biopsy between 2001 and 2007 were followed up for a median of 28 months. Compared with the patients without cirrhosis, the patients progressed to cirrhosis were older and with higher HBV-DNA levels at end point. However, there was no significant difference in cirrhosis progression between different HBV-DNA groups at baseline ( = 0.531). Kaplan-Meier analysis showed higher HBV-DNA level at endpoint had increasing risk of cirrhosis ( = 0.019). The results of Cox model indicated that HBV-DNA levels at endpoint, stage of fibrosis, negative hepatitis B e antigen, and γ-glutamyl transpeptidase at baseline were independent risk factors of cirrhosis. The relative risk ratios were 1.898, 1.918, 8.976, and 1.006, respectively. Progression to cirrhosis in chronic hepatitis B patients is correlated with HBV-DNA levels during follow-up.

关键词: hepatitis B     chronic     viral load     liver cirrhosis    

感存算一体化智能视觉芯片展望

潘汶, 郑纪元, 汪莱, 罗毅

《工程(英文)》 2022年 第14卷 第7期   页码 19-21 doi: 10.1016/j.eng.2022.01.009

Detection of maternal serum thromboxane B2 in different durations of pregnancy and prediction of preeclampsia

Geqing XIA MD, Zehua WANG MD, Li ZOU MD, Chaoying WU MS, Yu HU MD,

《医学前沿(英文)》 2010年 第4卷 第2期   页码 235-240 doi: 10.1007/s11684-010-0002-0

摘要: This study was aimed to detect maternal serum levels of thromboxane B2 (TXB2) in different durations of pregnancy and explore the predictive value of TXB2 for preeclampsia. By employing a prospective and double-blind study method, 180 pregnant women with previously normal blood pressures during their progestation were included in the study. Peripheral venous blood samples were obtained during 10–14 (period I), 20–24 (period II) and 30–34 (period III) weeks of gestation. Maternal serum levels of TXB2 were measured by enzyme-linked immunoassay. The pathogenetic condition and pregnancy outcomes of these cases were observed. (1) Among the 180 previously normotensive women, ten developed preeclampsia (case group; four severe and six mild preeclampsia). One hundred and seventy remained normal till the end of pregnancy (control group). (2) With development of pregnancy, the levels of maternal serum TXB2 in the 180 cases gradually ascended as seen through the Wilcoxon Signed Ranks Test. There was a statistical significance in maternal TXB2 levels between two different gestational stages (<0.01). (3) The levels of maternal serum TXB2 were slightly higher in the case group than in the control group during period I of gestation, but the difference was not statistically significant (>0.05); the levels of TXB2 were significantly higher in the case group than in the control group during periods II and III of gestation (both <0.05). (3) The best cutoff points of maternal TXB2 were 3750 and 4400ng/mL during periods II and III of gestation by receiver operator characteristic (ROC) curve; and the sensitivity, specificity, positive predictive value, negative predictive value and odds radio of TXB2 in predicting preeclampsia were 80%, 69.5%, 13.3%, 98.33%, 9.11 and 90%, 68.82%, 13.84%, 99.13, 19.86, respectively. Higher levels of maternal serum TXB2 were detected a long time before clinical symptoms appeared. The maternal serum TXB2 after 20 weeks of gestation had predictive value, and the index after 30 weeks was superior to that prior to 30 weeks .

关键词: thromboxane B2     preeclampsia    

标题 作者 时间 类型 操作

Gene therapy for hemophilia B mice with scAAV8-LP1-hFIX

null

期刊论文

Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B

null

期刊论文

Long-term correction of hemorrhagic diathesis in hemophilia A mice by an AAV-delivered hybrid FVIII composed

期刊论文

Current hepatitis B treatment guidelines and future research directions

null

期刊论文

Clinical characteristics and risk factors of COVID-19 patients with chronic hepatitis B: a multi-center

期刊论文

Vaccine therapies for chronic hepatitis B: can we go further?

null

期刊论文

Chronic hepatitis B virus infection: epidemiology, prevention, and treatment in China

null

期刊论文

基于PFM的B级钢侧架耐久性分析

李伟,李强,王平

期刊论文

Impact analysis of compressor rotor blades of an aircraft engine

Y B SUDHIR SASTRY, B G KIROS, F HAILU, P R BUDARAPU

期刊论文

Comprehensive treatment of acute-on-chronic liver failure in a patient with hepatitis B: a case report

null

期刊论文

带约束条件的C-Bézier曲面最优降多阶逼近

Lian ZHOU, Xin-hui LIN, Hong-yan ZHAO, Jun CHEN

期刊论文

MicroRNA-148b promotes proliferation of hair follicle cells by targeting

Wanbao YANG,Qinqun LI,Bo SU,Mei YU

期刊论文

Correlation between viral load and liver cirrhosis in chronic hepatitis B patients

Lili LIU MM , Jiyao WANG MD , Weimin SHE MM ,

期刊论文

感存算一体化智能视觉芯片展望

潘汶, 郑纪元, 汪莱, 罗毅

期刊论文

Detection of maternal serum thromboxane B2 in different durations of pregnancy and prediction of preeclampsia

Geqing XIA MD, Zehua WANG MD, Li ZOU MD, Chaoying WU MS, Yu HU MD,

期刊论文