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Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific

《医学前沿（英文）》 2022年 第16卷 第1期   页码 139-149 doi: 10.1007/s11684-021-0835-8

摘要： The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

关键词： B-cell acute lymphoblastic leukemia     bispecific antibody     trispecific antibody     CD19     CD20    

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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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供体来源的CD19靶向T细胞输注可以消除异基因造血干细胞移植后对供者淋巴细胞无反应的急性B淋巴细胞白血病微小残留病 Article

程翼飞, 陈育红, 闫晨华, 王昱, 赵翔宇, 陈瑶, 韩伟, 许兰平, 张晓辉, 刘开彦, 王莎莎, 张隆基, 肖磊, 黄晓军

《工程（英文）》 2019年 第5卷 第1期   页码 150-155 doi: 10.1016/j.eng.2018.12.006

摘要： 虽然供体来源的CD19 导向嵌合抗原受体（chimeric antigen receptor-modified，CAR）修饰T 细胞（CART19）可能治愈白血病，但输注此类细胞的效率与安全性尚未在经过在2014 年9 月至2018 年2 月期间，6 名患者均一次或多次输注了HSCT 供者提供的CD19 导向CAR 修饰T 细胞。

关键词： 供体来源的CD19靶向T细胞输注     造血干细胞移植     急性B淋巴细胞白血病     微小残留病    

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tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19

《医学前沿（英文）》 2023年 第17卷 第4期   页码 699-713 doi: 10.1007/s11684-022-0972-8

摘要： Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%–50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

关键词： anti-CD19 chimeric antigen receptor T     immunotherapy     diffuse large B cell lymphoma     tumor microenvironment     tumor-associated macrophage     metabolism    

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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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Clinical significance of CD34+CD117dim/CD34+CD117bri myeloblast-associated

Xueping Li, Yuting Dai, Bing Chen, Jinyan Huang, Saijuan Chen, Lu Jiang

《医学前沿（英文）》 2021年 第15卷 第4期   页码 608-620 doi: 10.1007/s11684-021-0836-7

摘要： t(8;21)(q22;q22) acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy with a high relapse rate in China. Two leukemic myeloblast populations (CD34 CD117 and CD34 CD117 ) were previously identified in t(8;21) AML, and CD34 CD117 cell proportion was determined as an independent factor for this disease outcome. Here, we examined the impact of CD34 CD117 /CD34 CD117 myeloblast-associated gene expression on t(8;21) AML clinical prognosis. In this study, 85 patients with t(8;21) AML were enrolled. The mRNA expression levels of CD34 CD117 -associated genes ( , , and ) and CD34 CD117 -associated genes ( , , and ) were measured using quantitative reverse transcription PCR. Associations between gene expression and clinical outcomes were determined using Cox regression models. Results showed that patients with high , , or expression had significantly inferior overall survival (OS), whereas those with high or expression showed relatively favorable prognosis. Univariate analysis revealed that CD19, CD34 CD117 proportion, mutation, minimal residual disease (MRD), and expression levels of , , , and were associated with OS. Multivariate analysis indicated that mutation, MRD and and expression levels were independent prognostic variables for OS. Identifying the clinical relevance of CD34 CD117 /CD34 CD117 myeloblast-associated gene expression may provide new clinically prognostic markers for t(8;21) AML.

关键词： t(8     21)(q22     q22) AML     CD34+CD117dim/ CD34+CD117bri cell population     gene expression     prognosis    

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Comparisons in subcellular and biochemical behaviors of cadmium between low-Cd and high-Cd accumulation

Meng XUE, Yihui ZHOU, Zhongyi YANG, Biyun LIN, Jiangang YUAN, Shanshan WU

《环境科学与工程前沿（英文）》 2014年 第8卷 第2期   页码 226-238 doi: 10.1007/s11783-013-0582-4

摘要： Subcellular distributions and chemical forms of cadmium (Cd) in the leaves, stems and roots were investigated in low-Cd accumulation cultivars and high-Cd accumulation cultivars of pakchoi ( L.). Root cell wall played a key role in limiting soil Cd from entering the protoplast, especially in the low-Cd cultivars. The high-Cd cultivars had significantly higher leaf and stem Cd concentrations than the low-Cd cultivars in cell wall fraction, chloroplast/trophoplast fraction, organelle fraction and soluble fraction. In low-Cd cultivars, which were more sensitive and thus had greater physiological needs of Cd detoxification than high-Cd cultivars, leaf vacuole sequestrated higher proportions of Cd. Cd in the form of pectate/protein complexes (extracted by 1 mol·L NaCl) played a decisive role in Cd translocation from root to shoot, which might be one of the mechanisms that led to the differences in shoot Cd accumulation between the two types of cultivars. Furthermore, the formation of Cd-phosphate complexes (extracted by 2% HAc) was also involved in Cd detoxification within the roots of pakchoi under high Cd stress, suggesting that the mechanisms of Cd detoxification might be different between low- and high-Cd cultivars.

关键词： cadmium (Cd)     low-Cd cultivar     pakchoi (Brassica chinensis L.)     subcellular distribution     chemical forms    

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Cultivars and oil extraction techniques affect Cd/Pb contents and health risks in oil of rapeseed grownon Cd/Pb-contaminated farmland

《环境科学与工程前沿（英文）》 2023年 第17卷 第7期 doi: 10.1007/s11783-023-1687-z

摘要：

● Organic solvent extracted fewer Cd/Pb in rapeseed oil than physical pressing.

关键词： Rapeseed oil     Oil extraction technologies     Human health risk assessment     Cd/Pb-contaminated farmland     Substitute planting    

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Celecoxib in combination with retinoid CD437 inhibits melanoma A375 cell

Jianwen REN, Zhenhui PENG, Birong GUO, Min PAN

《医学前沿（英文）》 2009年 第3卷 第1期   页码 108-112 doi: 10.1007/s11684-009-0015-8

摘要： This study aimed to investigate the effects of celecoxib, synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437) and the combination of the two on cell proliferation, apoptosis, and cycle arrest of human malignant melanoma A375 cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-di-phenyltetrazoliumbromide assay (MTT assay) was applied to determine the anti-proliferative effects of the drugs on human malignant melanoma A375 cells. Flow cytometry was performed to investigate the influence of the drugs on cell cycle and cell apoptosis. Both celecoxib and CD437 could inhibit the growth of human malignant melanoma A375 cells in a dose-dependent manner. Celecoxib at 80 μmol/L inhibited proliferation, induced apoptosis and G /M cell cycle arrest of human malignant melanoma A375 cells after treatment for 24 h [proliferation inhibiting rate: (50.2±2.51)%, apoptosis rate: (35.91±1.80)%]. CD437 at 10 μmol/L inhibited proliferation, induced apoptosis and G /G cell cycle arrest of human malignant melanoma A375 cells after treatment for 24 h [proliferation inhibiting rate: (58.6±2.38)%, apoptosis rate: (28.03±0.77)%]. Celecoxib in combination with CD437 could significantly enhance the effects of inhibiting proliferation and inducing apoptosis of human malignant melanoma A375 cells 24 h after treatment compared with the drug alone [proliferation inhibiting rate: (68.92±1.72)%, apoptosis rate: (42.09±1.05)%, both <0.05] and could decrease the proportion of the S phase in the cell cycle. Celecoxib could inhibit the growth of human malignant melanoma A375 cells by inducing apoptosis and G /M cycle arrest. CD437 could inhibit the growth of human malignant melanoma A375 cells by inducing apoptosis and G /G cycle arrest. Celecoxib exhibited additive effects with CD437 on retarding the growth and inducing apoptosis of human malignant melanoma A375 cells. Celecoxib in combination with CD437 may become an effective method for prevention and treatment of human melanoma.

关键词： celecoxib     CD437     melanoma A375 cell     apoptosis     cycle arrest    

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Growth responses of the newly-discovered Cd-hyperaccumulator Rorippa globosa and its accumulation characteristicsof Cd and As under joint stress of Cd and As

SUN Yuebing, ZHOU Qixing, WEI Shuhe, REN Liping

《环境科学与工程前沿（英文）》 2007年 第1卷 第1期   页码 107-113 doi: 10.1007/s11783-007-0020-6

摘要： has been identified as a newly-found Cd-hyperaccumulating species. In the present study, growth responses of and its accumulation characteristics of Cd and As were examined under joint stress of Cd and As. The results showed that Cd and As had an antagonistic effect on enhancing the growth of plants and Cd uptake and accumulation under the low concentration Cd and As treatments. When the concentration of Cd in the soil was 10 mg/kg and the concentration of As was 50 mg/kg, the highest growing height of the plant was up to 35.9 cm and the dry weight of the shoots was up to 2.2 g/pot, respectively. Meanwhile, the accumulation of Cd in the leaves under the joint stress was higher than that at the same level under single Cd pollution. However, there were synergic adverse effects on plant growth and Cd uptake under the combined pollution from a high concentration of Cd and As. Meanwhile, the accumulation of As in the roots was greater than that in the shoots, the translocation factor (TF) was "d0.3 and the bioaccumulation factor (BF) was "d0.6, thus showing that had an excluding effect on As uptake. These results confirmed that had a strong tolerant ability to the joint stress of Cd and As, and the potential for phytoremediation of soils contaminated by Cd and As.

关键词： synergic adverse     stress     present study     potential     weight    

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Changes of phenotype and function of human CD4 CD25 T cells induced by transfection of Foxp3

WU Kui, BI Yutian, WANG Yaoli, WANG Changzheng

《医学前沿（英文）》 2008年 第2卷 第4期   页码 366-369 doi: 10.1007/s11684-008-0070-6

摘要： The aim of this paper is to explore the effects of transfection of Foxp3 gene on the phenotype and function of naive CD4 T cells. The pMSCV-Foxp3 retroviral vector encoding Foxp3 gene was transduced into the PT67 packaging cell line. Virus-containing supernatant was applied to differentiate CD4CD25 T cells. The resulting cells were sorted with flow cytometry. The expressions of CD25, CD127, CTLA-4 and the proliferation of transfected T cells were examined. The effect of transfected CD4 T cells on the proliferation and cytokine production of CD4CD25 T cells was examined. Foxp3-gene transfected CD4 T cells could express Foxp3 and transfection of Foxp3 gene up-regulated the expressions of CD25 and CTLA-4, but down-regulated CD127 expression. After transfection, the proliferation of CD4 T cells was eliminated. Transfected T cells inhibited the proliferation of CD4CD25 T cells. CD4CD25 T cells acquired a regulatory phenotype and function after it was transduced with the Foxp3 gene. This suggested a key role of Foxp3 in the generation of CD4CD25 regulatory T cells.
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CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer

《医学前沿（英文）》 2023年 第17卷 第1期   页码 105-118 doi: 10.1007/s11684-022-0934-1

摘要： The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of “eat me” signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.

关键词： osimertinib     anti-CD47 antibody     combination strategy     ADCP     EGFR    

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Response of indigenous Cd-tolerant electrochemically active bacteria in MECs toward exotic Cr(VI) based

Xia Hou, Liping Huang, Peng Zhou, Hua Xue, Ning Li

《环境科学与工程前沿（英文）》 2018年 第12卷 第4期 doi: 10.1007/s11783-018-1057-4

摘要：

Cell membrane of indigenous Cd-tolerant EAB harbored more cadmium than chromium.

Indigenous Cd-tolerant EAB cytoplasm located more chromium than cadmium.

Simultaneously quantitatively imaging Cd(II) and Cr(III) ions in EAB was achieved.

Current accelerated the harboring of cadmium in EAB at an initial 2 h.

Current directed the accumulation of more chromium in EAB over time.

关键词： Microbial electrolysis cell     Electrochemically active bacteria     Cd-tolerant bacteria     Cd(II) and Cr(VI)     Fluorescence probe    

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Downregulation effects of beta-elemene on the levels of plasma endotoxin, serum TNF-alpha, and hepatic CD14

null

《医学前沿（英文）》 2011年 第5卷 第1期   页码 101-105 doi: 10.1007/s11684-011-0111-4

摘要：

It has been demonstrated that β-elemene could protect against carbon tetrachloride (CCl4)-induced liver fibrosis in our laboratory work, and the aim of this paper is to reveal the protective mechanisms of β-elemene. The hepatic fibrosis experimental model was induced by the hypodermical injection of CCl4 in Wistar male rats. β-elemene was intraperitoneally administered into rats for 8 weeks (0.1 mL/100 g bodyweight per day), and plasma endotoxin content was assayed by biochemistry. The serum TNF-α level was detected using radioactive immunity. CD14 expression in rat livers was measured by immunohistochemistry and Western blot. The results showed that β-elemene can downregulate the levels of plasma endotoxins, serum TNF-α, and hepatic CD14 expression in rats with liver fibrosis. β-elemene plays an important role in downregulating the lipopolysaccharide signal transduction pathway, a significant pathway in hepatic fibrosis development.

关键词： liver fibrosis     beta-elemene     endotoxin     CD14    

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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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标题 作者 时间 类型 操作

Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific

期刊论文

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

期刊论文

供体来源的CD19靶向T细胞输注可以消除异基因造血干细胞移植后对供者淋巴细胞无反应的急性B淋巴细胞白血病微小残留病

程翼飞, 陈育红, 闫晨华, 王昱, 赵翔宇, 陈瑶, 韩伟, 许兰平, 张晓辉, 刘开彦, 王莎莎, 张隆基, 肖磊, 黄晓军

期刊论文

tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19

期刊论文

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

期刊论文

Clinical significance of CD34+CD117dim/CD34+CD117bri myeloblast-associated

Xueping Li, Yuting Dai, Bing Chen, Jinyan Huang, Saijuan Chen, Lu Jiang

期刊论文

Comparisons in subcellular and biochemical behaviors of cadmium between low-Cd and high-Cd accumulation

Meng XUE, Yihui ZHOU, Zhongyi YANG, Biyun LIN, Jiangang YUAN, Shanshan WU

期刊论文

Cultivars and oil extraction techniques affect Cd/Pb contents and health risks in oil of rapeseed grownon Cd/Pb-contaminated farmland

期刊论文

Celecoxib in combination with retinoid CD437 inhibits melanoma A375 cell

Jianwen REN, Zhenhui PENG, Birong GUO, Min PAN

期刊论文

Growth responses of the newly-discovered Cd-hyperaccumulator Rorippa globosa and its accumulation characteristicsof Cd and As under joint stress of Cd and As

SUN Yuebing, ZHOU Qixing, WEI Shuhe, REN Liping

期刊论文

Changes of phenotype and function of human CD4 CD25 T cells induced by transfection of Foxp3

WU Kui, BI Yutian, WANG Yaoli, WANG Changzheng

期刊论文

CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer

期刊论文

Response of indigenous Cd-tolerant electrochemically active bacteria in MECs toward exotic Cr(VI) based

Xia Hou, Liping Huang, Peng Zhou, Hua Xue, Ning Li

期刊论文

Downregulation effects of beta-elemene on the levels of plasma endotoxin, serum TNF-alpha, and hepatic CD14

null

期刊论文

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

期刊论文