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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

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重组治疗性乙型肝炎疫苗（YIC）的实验研究

闻玉梅,何丽芳,瞿涤,马张妹,姚忻

《中国工程科学》 1999年第1卷第1期页码 38-42

摘要：

研制了抗原-抗体复合物型乙肝治疗性疫苗。用小鼠实验证明这一治疗性疫苗的作用机理为：通过复合物中抗体Fc段与抗原呈递细胞表面的Fc受体结合，促进了细胞摄取抗原。复合物中的抗原经呈递后可比单纯抗原更有效地激活T细胞增殖，释放更多的γ-干扰素和白细胞介素-2，属TH1类型应答。复合物可在小鼠中诱生较单纯抗原诱生的抗-HBs高10倍以上。复合物还可诱生更强的细胞免疫，表现为经特异的抗原刺激后，γ-干扰素的mRNA量增多。还发现复合物可在对HBsAg低应答鼠系中（B 10.S）诱生与正常应答鼠相当的抗体效价。在HBsAg阳性转基因鼠中，复合物可使部分鼠的HBsAg转为阴性，并可产生抗-HBs，反映这一疫苗具有疗效。为制备人用乙肝治疗性疫苗建立了用重组酵母菌表达的HBsAg与人高效价抗乙肝免疫球蛋白组建治疗性疫苗的工艺，以及产品标化及效力的参比实验技术。

关键词：乙型肝炎治疗性疫苗抗原抗体复合物免疫应答

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CD176 single-chain variable antibody fragment inhibits the adhesion of cancer cells to endothelial cells

null

《医学前沿（英文）》 2016年第10卷第2期页码 204-211 doi: 10.1007/s11684-016-0443-1

摘要：

CD176 (Thomsen-Friedenreich antigen) is a tumor-associated carbohydrate epitope (glycotope) functionally involved in blood spread and liver metastasis of cancer cells by mediating the adhesion of cancer cells to endothelial cells and hepatocytes, respectively. CD176 could be a promising target for antitumor immunotherapy. We applied B lymphocytes obtained from mice immunized with CD176 antigen and constructed a phage display library. A positive clone of CD176 single-chain variable antibody fragment (scFv) was successfully screened from this library. The CD176 scFv was expressed in Escherichia coli and purified. The purified scFv can bind to the natural CD176 expressed on the surface of cancer cells. Furthermore, the CD176 scFv inhibits the adhesion of CD176⁺ cancer cells to endothelial cells and hepatocytes. This CD176 scFv provides a basis for future development of recombinant CD176-specific antibodies that can be used in therapeutic application.

关键词： CD176 Thomsen-Friedenreich antigen scFv cancer therapy adhesion metastasis

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HLA and lung transplantation

Liya Ju, Caroline Suberbielle, Xiaofan Li, Nuala Mooney, Dominique Charron

《医学前沿（英文）》 2019年第13卷第3期页码 298-313 doi: 10.1007/s11684-018-0636-x

摘要： Lung transplantation is increasingly practiced for patients with end-stage lung disease. The successful outcome of solid organ transplantation today is severely impeded by the production of alloantibodies, mainly directed against the protein products of the HLA complex of the organ donor. While the association between antibody mediated rejection and allograft damage has been well established in renal and heart transplantation, it has not yet been well characterized in lung transplantation. This review addresses the question of HLA matching in lung transplantation and current knowledge of the allogenicity of different HLA class I and II antigens. The role of the antibody mediated immune response is discussed as well as the importance of pre-transplant or post-transplant circulating antibodies. Finally, potential mechanisms, which may act individually or in combination, of antibody mediated damage to solid organ transplants are considered.

关键词： human leukocyte antigen class I and II lung transplantation mismatch obliterans bronchiolitis alloantibody antibody mediated rejection

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提升疗效的修饰型治疗性抗体国内外研究进展 Review

戴济民, 张雪芹, 戴竞耀, 杨向民, 陈志南

《工程（英文）》 2021年第7卷第11期页码 1529-1540 doi: 10.1016/j.eng.2020.06.030

摘要：

生物治疗药物市场的繁荣反映了治疗性抗体药物用于治疗癌症、炎性疾病和难治性感染的可行性和有效性。随着抗体药物临床试验和转化研究中出现的结合效率不高、效应功能降低和不良反应频发等问题的解决，治疗性抗体的修饰在抗体药物的研发进程中得到了前所未有的蓬勃发展。为了提升抗体的结合活性、循环中的半衰期、靶细胞的有效性，并最终实现改善抗体药物的疗效，抗体可主要通过以下途径修饰：①糖基化修饰；②抗体恒定区（Fc）改造；③抗体亚类重构；④构建抗体-药物偶联物（ADC）；⑤基于单链可变区片段（scFv）的嵌合抗原受体T细胞（CAR-T）；⑥双特异性抗体（bsAb）。过去几十年来全球在修饰型治疗性抗体的领域取得了许多成就，中国作为对于生物治疗药物需求巨大并且拥有巨大研发潜力的国家在该领域亦发挥了积极作用。本文概括了修饰型治疗性抗体在当前国际研究中取得的进展，并在单独的章节中重点介绍了中国在该领域取得的成果。

关键词：治疗性抗体抗体修饰疗效抗原抗体-药物偶联物双特异性抗体

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使用数据驱动模型优化抗体纯化策略 Article

刘松崧, Lazaros G. Papageorgiou

《工程（英文）》 2019年第5卷第6期页码 1077-1092 doi: 10.1016/j.eng.2019.10.011

摘要：

本工作致力于抗体片段纯化过程的多尺度优化。优化了生产过程中的色谱决策，包括色谱柱的数量及其大小，每批的循环数以及操作流速。使用基于微型实验数据的制造规模模拟数据集，建立了以负载质量、流速和柱床高度为输入的色谱通量数据驱动模型。与其他方法相比，分段线性回归建模方法具有简单、预测精度高的优点。提出了两种混合整数非线性规划（MINLP）模型，结合数据驱动模型，以最小化每克抗体纯化过程的总成本。然后，使用线性化技术和多参数分解将这些MINLP模型重新构造为混合整数线性规划（MILP）模型。研究了两个具有不同色谱柱尺寸替代品的工业相关案例，以证明所提出模型的适用性。

关键词：抗体纯化多尺度优化抗原结合片段混合整数规划数据驱动模型分段线性回归

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Polymerization of methyl methacrylate catalyzed by mono-/bis-salicylaldiminato nickel(II) complexes and

Jihong LU, Danfeng ZHANG, Qian CHEN, Buwei YU

《化学科学与工程前沿（英文）》 2011年第5卷第1期页码 19-25 doi: 10.1007/s11705-010-0546-1

摘要： Two types of salicylaldiminato-based nickel complexes, mono-ligated Ni(II) complexes ([O-C H - - C(H)=N-Ar]Ni(PPh )(Ph) ( ), [O-(3,5-Br )C H - -C(H)=N-Ar]Ni(PPh )(Ph) ( ), [O-(3- -Bu)C H - -C(H)=N-Ar]Ni(PPh )(Ph) ( )) and bis-ligated Ni(II) complexes ([O-(3,5-Br )C H - -C(H)=N-Ar] Ni ( ), [O-(3,5-Br )C H - -C(H)=N-2-C H (PhO)] Ni ( ), Ar=2,6-C H ( -Pr) ) were synthesized and characterized by Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), mass spectrography (MS) and elemental analysis (EA). In the presence of methylaluminoxane (MAO) as cocatalyst, all the nickel complexes exhibited high activities for the polymerization of methyl methacrylate (MMA) and syndiotactic-rich poly(methyl methacrylate) (PMMA) was obtained. The complexes with less bulky substituents on salicylaldiminato framework possessed higher activities, while with the same salicylaldiminato, the mono-ligated nickel complexes showed higher catalytic activity than bis-ligated ones.

关键词： late transition metal catalyst methyl methacrylate polymerization salicylaldiminato nickel complexes methylaluminoxane syndiotactic structure

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Exposure-response of Cr(III)-organic complexes to Saccharomyces cerevisiae

Nivedita CHATTERJEE, Zejiao LUO,

《环境科学与工程前沿（英文）》 2010年第4卷第2期页码 196-202 doi: 10.1007/s11783-010-0008-5

摘要： Hexavalent chromium [Cr(VI)] bioreduction produces soluble Cr(III)-organic complexes. The Cr(III)-organic complexes are relatively stable once they are formed, and no data about their toxicity were reported. Therefore, this study aims to investigate the bioavailability and toxicity of the soluble Cr(III)-organic complexes. L-1 wild type yeast strain was chosen as the model organism and Cr(III)-citrate was selected as the representative compound of the Cr(III)-organic complexes. The short-term chronic aquatic toxicity tests of the Cr(III)-citrate was explored by measuring growth inhibition, direct viable cell count, dry biomass, biosorption, and the amount of CO production. Cr(III)-citrate exerted a toxicity of 51mg/L with an , which was calculated from the percent growth inhibition. These toxicity data would be helpful to define the toxic potential of the organo-chromium-III compounds in the environment.

关键词： Cr(III)-organic complexes Saccharomyces cerevisiae toxicity EC50 bioavailability

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Synthesis of p -substituted tetraphenylporphyrins and corresponding ferric complexes with mixed-solvents

Zhicheng SUN, Yuanbin SHE, Rugang ZHONG,

《化学科学与工程前沿（英文）》 2009年第3卷第4期页码 457-461 doi: 10.1007/s11705-009-0169-6

摘要： By using mixed-solvents method, five kinds of -substituted tetraphenylporphyrin compounds [T(-R)PPH, R=NO, Cl, CH, OCH, OH] were synthesized by the condensation of -substituted benzaldehyde with pyrrole in mixed solvents (propionic acid, acetic acid and nitrobenzene), and corresponding ferric complexes [T(-R)PPFeCl] were synthesized in dimethylformamide. The above free base porphyrins were obtained in 30%–50% yields, metalation yields were up to 90% and total yields of ferric complexes were 27%–50%. Effects of reactive conditions, solvents and oxidants on yields of free base porphyrins were investigated and the relevant mechanism was discussed. Structures of the above porphyrin complexes were characterized by ultraviolet-visible (UV-Vis), infrared (IR) and far infrared (FIR) spectroscopy.

关键词： -substituted tetraphenylporphyrin condensation -substituted benzaldehyde dimethylformamide metalation

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Preparation, identification, and clinical application of anti-HBs monoclonal antibody that binds both

Fanghe LI BM , Chunyan ZHANG MS , Jinghua LIU MS , Xiaoyan ZHANG MS , Bing YAN , Bo ZHANG MS , Yongguo HUANG MS , Jingsong GONG BM , Yan CHEN BM ,

《医学前沿（英文）》 2009年第3卷第3期页码 277-283 doi: 10.1007/s11684-009-0047-0

摘要： Using a standard cellular fusion technique and indirect enzyme-linked immunosorbent assay (ELISA), a hybridoma cell line strain secreting anti-HBs monoclonal antibody (mAb) (defined G6 mAb) was obtained. The cells grew and secreted mAb stably. Antibody titers in the culture supernatant and ascites were 2.048×10 and 4.096×10, respectively. By applying the anti-HBs G6 mAb and horseradish peroxidase (HRP)-labeled goat anti-HBs antibody, we developed a sandwich ELISA (defined G6m ELISA) for detecting both wild-type and immune escape mutant HBsAgs (IEM HBsAg). The assay was performed to detect 17 species of genome recombinant expression HBsAg, including two wild-type species and 15 IEM HBsAg species, which varied in the “a” determinant, in a group of patients infected with hepatitis B virus (HBV). The patients previously had a lower ELISA detection signal [(absorbance of patients/absorbance of normal people (P/N): 1.0―4.5)]. The results demonstrated that the sensitivity of this assay to wild-type HBsAg was no less than 0.125g/L; 12 of 15 IEM HBsAg species (P/N≥2.5) were positive for G6 mAb. Of the positive IEM HBsAg species, two had a low absorbance value at 450nm (), one had an intermediate value and nine had a high value, which was 7.55%(mean), 59.4% and 92.1%―109.4% of the wild-type value, respectively. The two species with low value and the three negative species mutated at the bases 120―124 in the first loop of the HBV “a” determinant. Using the G6 ELISA and two commercial ELISA kits (A and B), 177 patients were tested. The G6 ELISA had a significantly higher detection rate than either commercial ELISAs (19.21% 14.89% and 6.21%, respectively; <0.01, <0.05, respectively).

关键词： hepatitis B virus gene variation hepatitis B surface antigen immune escape enzyme-linked immunosorbent assay

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Synthesis of iron(II) complexes with asymmetric N

Wolfgang Bauer, Tanja Ossiander, Birgit Weber

《化学科学与工程前沿（英文）》 2018年第12卷第3期页码 400-408 doi: 10.1007/s11705-018-1753-4

摘要：

The synthesis of new Schiff base-like ligands with asymmetric substituents pattern and their iron complexes with pyridine as axial ligand is described. Two of the ligands and one of the iron(II) complexes were characterized by single crystal X-ray structure analysis. One of the the iron(II) complexes shows spin crossover behavior while the others remain in the high spin state. The influence of the reduced symmetry of the ligand on the properties of the complexes is discussed.

关键词： iron Schiff base-like ligands magnetism spin crossover X-ray structures

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Chimeric antigen receptor T cell therapies for acute myeloid leukemia

Bin Gu, Jianhong Chu, Depei Wu

《医学前沿（英文）》 2020年第14卷第6期页码 701-710 doi: 10.1007/s11684-020-0763-z

摘要： Abstract Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

关键词： acute myeloid leukemia CAR T immunotherapy

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Advancement of human leukocyte antigen-partially matched related hematopoietic stem cell transplantation

null

《医学前沿（英文）》 2013年第7卷第3期页码 306-315 doi: 10.1007/s11684-013-0279-x

摘要：

Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective options for hematological malignancies, and human leukocyte antigen-partially matched related donors (PMRDs) are a valuable option for HSCT. Several protocols (with or without ex vivo T-cell depletion (TCD)) have been established worldwide. TCD including CD34⁺positive selection and CD3/CD19 depletion has successfully overcome the human leukocyte antigen disparity. However, TCD is associated with prolonged immune deficiencies, increased risks of infectious complications, and high transplantation-related mortality. PMRD HSCT without ex vivo TCD is well developed, and numerous patients have benefitted from it. Here, we review the literature on PMRD HSCT.

关键词： partially matched related donor hematopoietic stem cell transplantation allogeneic

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BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation

《医学前沿（英文）》 doi: 10.1007/s11684-023-0996-8

摘要： OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40–OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

关键词： BGB-A445 OX40 agonistic antibody OX40L noncompetitive

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Passive antibody therapy in emerging infectious diseases

《医学前沿（英文）》 doi: 10.1007/s11684-023-1021-y

摘要： The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 and its variants of concern (VOCs) has been ongoing for over 3 years. Antibody therapies encompassing convalescent plasma, hyperimmunoglobulin, and neutralizing monoclonal antibodies (mAbs) applied in passive immunotherapy have yielded positive outcomes and played a crucial role in the early COVID-19 treatment. In this review, the development path, action mechanism, clinical research results, challenges, and safety profile associated with the use of COVID-19 convalescent plasma, hyperimmunoglobulin, and mAbs were summarized. In addition, the prospects of applying antibody therapy against VOCs was assessed, offering insights into the coping strategies for facing new infectious disease outbreaks.

关键词： SARS-CoV-2 COVID-19 convalescent plasma hyperimmunoglobulin neutralizing monoclonal antibodies