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从药物开发的角度看工程化T细胞疗法 Review

Fang Chen, Joseph A. Fraietta, Carl H. June, 许中伟, J. Joseph Melenhorst, Simon F. Lacey

《工程（英文）》 2019年第5卷第1期页码 140-149 doi: 10.1016/j.eng.2018.11.010

摘要：例如，经基因修饰后，T 细胞可表达嵌合抗原受体（chimeric antigen receptor，CAR），使其能够识别并杀死肿瘤细胞，并形成一个记忆库，准备回击持续存在的恶性细胞。抗CD19 嵌合抗原受体T 细胞（CAR T cells，CART19）对某些恶性肿瘤具有显著的临床疗效。本文综述了基于生物标志物的分析方法在优化CAR结构、临床前研究和临床疗效评价、不良反应（AE）和CART19 细胞动力学方面的应用。同时还探讨了能够发现最佳靶标、新型CAR 结合结构域以及预测临床反应和不良反应的生物标志物的先进技术和计算工具。我们相信，就像胂凡纳明的发现开创了合成药物时代一样，CART19 的成功能够带来其他工程化T 细胞疗法的发展。

关键词：工程化T细胞疗法嵌合抗原受体药物开发过程生物标志物 CAR19 CART19

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Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function ofCD19-specific CAR T-cells via TGF-β signaling

《医学前沿（英文）》 doi: 10.1007/s11684-023-1010-1

摘要： Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-β signaling

关键词： exosomes induce activation impair function CD19 exosomal CD19 antigen

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Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large

《医学前沿（英文）》 2022年第16卷第2期页码 285-294 doi: 10.1007/s11684-021-0843-8

摘要： Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive efficacy in treating B-cell malignancies. A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR, a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule, for the treatment of patients with refractory diffuse large B-cell lymphoma (DLBCL). Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell (C-CAR011) treatment. The overall response rate was 20% and 50% at 4 and 12 weeks after the infusion of C-CAR011, respectively, and the disease control rate was 60% at 12 weeks after infusion. Treatment-emergent adverse events occurred in all patients. The incidence of cytokine release syndrome in all grades and grade≥3 was 90% and 0, respectively, which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel. Neurotoxicity or other dose-limiting toxicities was not observed in any dose cohort of C-CAR011 therapy. Antitumor efficacy was apparent across dose cohorts. Therefore, C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL, and further large-scale clinical trials are warranted.

关键词： CAR-T cell therapy refractory diffuse large B-cell lymphoma cytokine release syndrome dose-limiting toxicity

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中国私用轿车发展的现状与问题

郭孔辉

《中国工程科学》 2000年第2卷第8期页码 25-30

摘要：

目前国内对中国应不应该发展私用轿车，中国应着重发展什么样的轿车，中国应不应该发展自己的轿车工业，中国轿车工业的出路在哪里，以及应如何发展中国的轿车工业，……等等，讨论颇多，已经成为社会上普遍关心的问题。文章试图分析目前提出的有代表性的各种观点，并对有关问题提出笔者自己的见解，以供参考。笔者认为解决"汽车灾难"问题的根本出路不在抑制私用轿车的发展，而在于发展汽车高新技术，加强城市规划与交通管理。文章在肯定引进合资对提高我国汽车制造技术和管理水平的重要作用的同时，指出它的负面影响是逐渐丧失产品开发的主动权；提出中国汽车工业的总战略应是："自强不息加国际合作"，其中包括：高新技术战略、自主双赢战略、内联自强战略、自主品牌战略和跨越赶超战略。

关键词：中国汽车工业私用轿车家用轿车现状与问题

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CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells

null

《医学前沿（英文）》 2017年第11卷第4期页码 554-562 doi: 10.1007/s11684-017-0543-6

摘要：

T cells engineered with chimeric antigen receptor (CAR) have been successfully applied to treat advanced refractory B cell malignancy. However, many challenges remain in extending its application toward the treatment of solid tumors. The immunosuppressive nature of tumor microenvironment is considered one of the key factors limiting CAR-T efficacy. One negative regulator of T cell activity is lymphocyte activation gene-3 (LAG-3). We successfully generated LAG-3 knockout T and CAR-T cells with high efficiency using CRISPR-Cas9 mediated gene editing and found that the viability and immune phenotype were not dramatically changed during in vitro culture. LAG-3 knockout CAR-T cells displayed robust antigen-specific antitumor activity in cell culture and in murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates an efficient approach to silence immune checkpoint in CAR-T cells via gene editing.

关键词： CAR-T CRISPR-Cas9 LAG-3

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Thermal response of steel framing members in open car park fires

Xia YAN; Marion CHARLIER; Thomas GERNAY

《结构与土木工程前沿（英文）》 2022年第16卷第9期页码 1071-1088 doi: 10.1007/s11709-022-0879-0

摘要： For open car park structures, adopting a performance-based structural fire design is often justified and allowed because the fire does not reach flashover. However, this design approach requires an accurate assessment of temperatures in structural members exposed to car fires. This paper describes a numerical study on the thermal exposure on steel framing members in open car park fires. Steel temperatures are computed by the coupling of computational fluid dynamics and finite element modeling, and by analytical models from the Eurocodes. In addition, the influence of galvanization on the steel temperature evolution is assessed. Results show that temperatures in unprotected beams and columns are influenced by the section geometry, car fire scenario, modeling approach, and use of galvanization. Galvanization slightly delays and reduces peak temperature. Regarding the different models, CFD-FEM (CFD: computational fluid dynamics, FEM: finite-element method) coupled models predict lower temperatures than the Hasemi model, because the latter conservatively assumes that the fire flame continuously touches the ceiling. Further, the Hasemi model cannot account for the effect of reduced emissivity from galvanization on the absorbed heat flux. Detailed temperature distributions obtained in the steel members can be used to complete efficient structural fire designs based on the member sections, structure layout, and use of galvanization.

关键词： open car park localized fire steel frame numerical modeling computational fluid dynamics

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电动汽车市场加速发展

Chris Palmer

《工程（英文）》 2021年第7卷第2期页码 136-138 doi: 10.1016/j.eng.2020.12.009

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CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

《医学前沿（英文）》 2021年第15卷第6期页码 783-804 doi: 10.1007/s11684-021-0904-z

摘要： The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

关键词： CAR T cells hematological malignancies review

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虚实融合的协同工作环境CAR-CA工程技术研究进展

赵沁平

《中国工程科学》 2009年第11卷第10期页码 25-31

摘要：面向我国自行设计生产商用大飞机的需求，在863计划支持下，正在研制用于驾驶舱布局设计和飞机关键部件辅助拆装维护的虚实融合协同工作环境CAR-CA（collaborative augmented reality概要介绍CAR-CA的工程技术研究进展，包括体系结构、系统组成、关键技术研究和系统的应用前景等。

关键词：虚实融合协同工作驾驶舱设计维护

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A fully solid-state cold thermal energy storage device for car seats using shape-memory alloys

《能源前沿（英文）》 2023年第17卷第4期页码 504-515 doi: 10.1007/s11708-022-0855-3

摘要： Thermal energy storage has been a pivotal technology to fill the gap between energy demands and energy supplies. As a solid-solid phase change material, shape-memory alloys (SMAs) have the inherent advantages of leakage free, no encapsulation, negligible volume variation, as well as superior energy storage properties such as high thermal conductivity (compared with ice and paraffin) and volumetric energy density, making them excellent thermal energy storage materials. Considering these characteristics, the design of the shape-memory alloy based the cold thermal energy storage system for precooling car seat application is introduced in this paper based on the proposed shape-memory alloy-based cold thermal energy storage cycle. The simulation results show that the minimum temperature of the metal boss under the seat reaches 26.2 °C at 9.85 s, which is reduced by 9.8 °C, and the energy storage efficiency of the device is 66%. The influence of initial temperature, elastocaloric materials, and the shape-memory alloy geometry scheme on the performance of car seat cold thermal energy storage devices is also discussed. Since SMAs are both solid-state refrigerants and thermal energy storage materials, hopefully the proposed concept can promote the development of more promising shape-memory alloy-based cold and hot thermal energy storage devices.

关键词： shape-memory alloy (SMA) elastocaloric effect (eCE) cooled seat cold thermal energy storage

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A review of the safety and efficacy of current COVID-19 vaccines

《医学前沿（英文）》 2022年第16卷第1期页码 39-55 doi: 10.1007/s11684-021-0893-y

摘要： Vaccination is the most effective and feasible way to contain the coronavirus disease 2019 (COVID-19) pandemic. The rapid development of effective COVID-19 vaccines is an extraordinary achievement. This study reviewed the efficacy/effectiveness, immunogenicity, and safety profile of the 12 most progressed COVID-19 vaccines and discussed the challenges and prospects of the vaccine-based approaches in a global crisis. Overall, most of the current vaccines have shown safety and efficacy/effectiveness during actual clinical trials or in the real-world studies, indicating a development of pandemic control. However, many challenges are faced by pandemic control in terms of maximizing the effect of vaccines, such as rapid vaccine coverage, strategies to address variants with immune escape capability, and surveillance of vaccine safety in the medium- and long-terms.

关键词： COVID-19 SARS-CoV-2 vaccine safety efficacy effectiveness immunogenicity

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Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

Xiaohui Wang, Zhiqiang Wu, Wei Qiu, Ping Chen, Xiang Xu, Weidong Han

《医学前沿（英文）》 2020年第14卷第6期页码 726-745 doi: 10.1007/s11684-020-0746-0

摘要： Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.

关键词： CAR T cells immunoregulatory molecules endogenous immune response solid malignancies

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Innovation-driven trend shaping COVID-19 vaccine development in China

《医学前沿（英文）》 doi: 10.1007/s11684-023-1034-6

摘要： Confronted with the coronavirus disease 2019 (COVID-19) pandemic, China has become an asset in tackling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and mutation, with several innovative platforms, which provides various technical means in this persisting combat. Derived from collaborated researches, vaccines based on the spike protein of SARS-CoV-2 or inactivated whole virus are a cornerstone of the public health response to COVID-19. Herein, we outline representative vaccines in multiple routes, while the merits and plights of the existing vaccine strategies are also summarized. Likewise, new technologies may provide more potent or broader immunity and will contribute to fight against hypermutated SARS-CoV-2 variants. All in all, with the ultimate aim of delivering robust and durable protection that is resilient to emerging infectious disease, alongside the traditional routes, the discovery of innovative approach to developing effective vaccines based on virus properties remains our top priority.

关键词： SARS-CoV-2 COVID-19 vaccine vaccine development

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CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a

《医学前沿（英文）》 2022年第16卷第3期页码 322-338 doi: 10.1007/s11684-021-0901-2

摘要： Immune-based therapies have experienced a pronounced breakthrough in the past decades as they acquired multiple US Food and Drug Administration (FDA) approvals for various indications. To date, six chimeric antigen receptor T cell (CAR-T) therapies have been permitted for the treatment of certain patients with relapsed/refractory hematologic malignancies. However, several clinical trials of solid tumor CAR-T therapies were prematurely terminated, or they reported life-threatening treatment-related damages to healthy tissues. The simultaneous expression of target antigens by healthy organs and tumor cells is partly responsible for such toxicities. Alongside targeting tumor-specific antigens, targeting the aberrantly glycosylated glycoforms of tumor-associated antigens can also minimize the off-tumor effects of CAR-T therapies. Tn, T, and sialyl-Tn antigens have been reported to be involved in tumor progression and metastasis, and their expression results from the dysregulation of a series of glycosyltransferases and the endoplasmic reticulum protein chaperone, Cosmc. Moreover, these glycoforms have been associated with various types of cancers, including prostate, breast, colon, gastric, and lung cancers. Here, we discuss how underglycosylated antigens emerge and then detail the latest advances in the development of CAR-T-based immunotherapies that target some of such antigens.

关键词： cancer immunotherapy chimeric antigen receptor solid tumors tumor-associated antigen glycosylation O-glycans adoptive cell therapy

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SARS-CoV-2 vaccine research and immunization strategies for improved control of the COVID-19 pandemic

《医学前沿（英文）》 2022年第16卷第2期页码 185-195 doi: 10.1007/s11684-021-0913-y

摘要： The record speed at which Chinese scientists identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and shared its genomic sequence with the world, has greatly facilitated the development of coronavirus disease (COVID-19) diagnostics, drugs, and vaccines. It is unprecedented in pandemic control history to develop a dozen successful vaccines in the first year and to immunize over half of the global population in the second year, due to the efforts of the scientific community, biopharmaceutical industry, and regulatory agencies worldwide. The challenges are both great and multidimensional due to the rapid emergence of virus variants and waning of vaccine immunity. Vaccination strategies need to adapt to these challenges to keep population immunity above the herd immunity threshold, by increasing vaccine coverage, especially for older adults and young people, and providing timely booster doses with homologous or heterologous vaccine boosts. Further research should be undertaken to develop more effective vaccines against SARS-CoV-2 variants and to understand the best prime-boost vaccine combinations and immunization strategies to provide sufficient and sustainable immune protection against COVID-19.

关键词： COVID-19 pandemics SARS-CoV-2 vaccination