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Application of liquid biopsy in precision medicine: opportunities and challenges

null

《医学前沿（英文）》 2017年 第11卷 第4期   页码 522-527 doi: 10.1007/s11684-017-0526-7

摘要：

Precision medicine for cancer patients aims to adopt the most suitable treatment options during diagnosis and treatment of individuals. Detecting circulating tumor cell (CTC) or circulating tumor DNA (ctDNA) in plasma or serum could serve as liquid biopsy, which would be useful for numerous diagnostic applications. Liquid biopsies can help clinicians screen and detect cancer early, stratify patients to the most suitable treatment and real-time monitoring of treatment response and resistance mechanisms in the tumor, evaluate the risk for metastatic relapse, and estimate prognosis. We summarized the advantages and disadvantages of tissue and liquid biopsies. We also further compared and analyzed the advantages and limitations of detecting CTCs, ctDNAs, and exosomes. Furthermore, we reviewed the literature related with the application of serum or plasma CTCs, ctDNAs, and exosomes for diagnosis and prognosis of cancer. We also analyzed their opportunities and challenges as future biomarkers. In the future, liquid biopsies could be used to guide cancer treatment. They could also provide the ideal scheme to personalize treatment in precision medicine.

关键词： liquid biopsy     circulating tumor cells     cell-free ctDNA     exosomes     precision medicine    

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4-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murinetumor

Hui QIU, Hui ZHANG, Zuohua FENG

《医学前沿（英文）》 2009年 第3卷 第1期   页码 20-25 doi: 10.1007/s11684-009-0006-9

摘要： The interaction by co-stimulatory molecules 4-1BB and 4-1BB ligand (4-1BBL) plays an important role in the activation, proliferation and differentiation of T lymphocytes. The function of 4-1BB/4-1BBL expressed by the immune cells has been the focus for many tumor immunotherapy efforts. In this study, 4-1BBL was expressed in non-immune cells and non-tumor cells, and the role of 4-1BBL in lymphocyte activation and tumor suppression was investigated. The plasmid p4-1BBL containing the full length of mouse 4-1BBL cDNA sequence was constructed, and the plasmid was transfected into baby hamster kidney (BHK) cells and murine muscle cells by means of lipofectin-mediated or naked plasmid DNA injection into the muscle directly. The study demonstrated that the molecule 4-1BBL expressed by BHK cells could enhance the proliferation and cytotoxicity of lymphocytes, and it could increase the expression level of IL-2 and IFN-γ. The treatment with plasmid p4-1BBL revealed that the number of CD8 T cells in the peri-tumoral tissue increased markedly, and the growth rate of the tumor was significantly lower than that of control group. These findings suggest that expression of 4-1BBL by normal cells in the tumor microenvironment can enhance the proliferation and other functions of T lymphocytes. This therapeutic method may provide a promising approach for tumor immunotherapy.

关键词： 4-1BB ligand     tumor immunotherapy     tumor microenvironment    

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Identification of cancer stem cells provides novel tumor models for drug discovery

null

《医学前沿（英文）》 2012年 第6卷 第2期   页码 112-121 doi: 10.1007/s11684-012-0199-1

摘要：

Cancer stem cells (CSCs) have received considerable attention from the research community since they were first reported in human acute myeloid leukemia 15 years ago. Accumulating evidence suggests that CSCs are responsible for tumor initiation and progression, drug resistance, and metastasis in both liquid and solid tumors. These findings lead to the development of novel compounds targeting CSC populations that is becoming increasingly important for eradicating CSCs in heterogeneous tumor masses and to cure the cancer. Since 2003, we have participated in CSC studies and encountered crucial early events in the field. This article reviews the history of CSC biology, clarifies the term and its definition, and further addresses the issue of how to utilize CSCs in therapeutic target discovery and drug development based on our substantial experience.

关键词： cancer stem cell     tumor model     drug discovery    

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基于飞秒激光的用于捕获肿瘤细胞的聚合物芯片实验室的智能程序 Article

Annalisa Volpe, Udith Krishnan, Maria Serena Chiriacò, Elisabetta Primiceri, Antonio Ancona, Francesco Ferrara

《工程（英文）》 2021年 第7卷 第10期   页码 1436-1442 doi: 10.1016/j.eng.2020.10.012

摘要：

由于聚合物芯片实验室具有高度的精准性和灵活性，将其用于设计和制造的快速原型制作方法正在兴起。例如，一个微流控平台可能需要优化阶段，而在此阶段需要不断修改结构和几何形状；然而，这只有在具有简易可控的制造方法和低成本材料的情况下才可能实现。本文描述了一个微流控工具的实现过程，从计算机辅助设计（CAD）到作为循环肿瘤细胞（CTC）捕获工具应用的概念验证。整个平台通过使用聚甲基丙烯酸甲酯（PMMA）及结合飞秒（fs）激光和微铣制造技术实现。该多层设备通过一种简便、低成本的溶剂辅助方法组装。然后通过固定能够在没有标记的情况下区分癌细胞与非癌细胞的捕获探针，实现蛇形微通道的直接生物功能化。由于低材料成本、可定制的方法以及可生物应用，已实现的平台成为即时医疗工业开发与应用的合适模型。

关键词： 芯片实验室     飞秒激光     循环肿瘤细胞     即时医疗     热键合     聚合物    

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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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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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Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

null

《医学前沿（英文）》 2018年 第12卷 第4期   页码 374-386 doi: 10.1007/s11684-018-0652-x

摘要：

A family of transcription factors known as Id proteins, or inhibitor of DNA binding and differentiation, is capable of regulating cell proliferation, survival and differentiation, and is often upregulated in multiple types of tumors. Due to their ability to promote self-renewal, Id proteins have been considered as oncogenes, and potential therapeutic targets in cancer models. On the contrary, certain Id proteins are reported to act as tumor suppressors in the development of Burkitt’s lymphoma in humans, and hepatosplenic and innate-like T cell lymphomas in mice. The contexts and mechanisms by which Id proteins can serve in such contradictory roles to determine tumor outcomes are still not well understood. In this review, we explore the roles of Id proteins in lymphocyte development and tumorigenesis, particularly with respect to inhibition of their canonical DNA binding partners known as E proteins. Transcriptional regulation by E proteins, and their antagonism by Id proteins, act as gatekeepers to ensure appropriate lymphocyte development at key checkpoints. We re-examine the derailment of these regulatory mechanisms in lymphocytes that facilitate tumor development. These mechanistic insights can allow better appreciation of the context-dependent roles of Id proteins in cancers and improve considerations for therapy.

关键词： Id proteins     lymphoma     leukemia     T cells     B cells     tumor suppressor     oncogene    

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Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive

《医学前沿（英文）》 doi: 10.1007/s11684-023-0999-5

摘要： Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.

关键词： thyroid carcinoma     mesenchymal stem cell     extracellular vesicle     GTF2I     FAT1     CDK4    

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Tumor growth and metastasis can be inhibited by maintaining genomic stability in cancer cells

null

《医学前沿（英文）》 2015年 第9卷 第1期   页码 57-62 doi: 10.1007/s11684-015-0389-8

摘要：

The existence of cancer stem cells, stem-like cancer cells (SLCCs), or tumor-initiating cells is considered as the cause of tumor formation and recurrence, indicating the importance of studying novel therapy that targets SLCCs. The origin of SLCCs is controversial because of two competing hypotheses: SLCCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Our previous research demonstrates that SLCCs are inducible by increasing genomic instability in cancer cells. In this study, to block the emergence of SLCCs, aminoethyl isothiourea (AET), a compound that clears free radicals and is used to protect patients from radioactive exposure, was used as an agent that maintains genomic stability in combination with mitomycin C (MMC), a commonly used chemotherapeutic drug that damages DNA. Using a rabbit tumor model with VX2 hepatic carcinoma, we found that MMC alone increased lung metastases and disadvantaged survival outcome, but the combination of MMC and AET reversed this effect and even prolonged overall survival. Moreover, in a VX2 xenograft model by immunocompromised mice, MMC alone enriched tumor-initiating cells, but the administration of MMC in combination with AET eliminated tumor cells effectively. Furthermore, MMC alone enhanced genomic instability, but MMC combined with AET attenuated the extent of genomic instability in primary VX2 tumor tissue. Taken together, our data suggest that the genomic protector AET can inhibit the induction of SLCCs, and this combination treatment by AET and cytotoxic agents should be considered as a promising strategy for future clinical evaluation.

关键词： rabbit VX2 liver tumor     mitomycin C     AET     stem-like cancer cells     genomic instability    

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Immunotherapeutic effects on murine pancreatic carcinoma by β-elemene combined with dendritic cells modified

TAN Guang, WANG Zhongyu, CHE Luanqing, YIN Shuo

《医学前沿（英文）》 2007年 第1卷 第1期   页码 41-45 doi: 10.1007/s11684-007-0008-4

摘要： The dendritic cell vaccine is a treatment vaccine with potent clinical applications. Functional cytokines can enhance dendritic cell anti-tumor immune responses. This experiment was conducted to study the effects of bone marrow-deriv

关键词： Functional     experiment     anti-tumor     dendritic     clinical    

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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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Inhibition of TNF-alpha secretion from peripheral blood monocular cells by triptolid is associated with

Xiu-Liang TAO MM, Sheng-Hao TU MD, Ri-Bo XIONG MM, Yong-Hong HU BM,

《医学前沿（英文）》 2010年 第4卷 第2期   页码 220-224 doi: 10.1007/s11684-010-0025-6

摘要： This study examined the inhibitory effect of triptolid (TP) on tumor necrosis factor-α (TNF-α) secreted from peripheral blood monocular cells (PBMCs) and the association of the inhibitory effect with TNF-α-308 gene polymorphisms in rheumatoid arthritis (RA) patients. Gene polymorphism at A-G site 308 in the promoter region of TNF-α gene was detected in 42 RA patients by using allele specific polymerase chain reaction (AS-PCR) assay. PBMCs were harvested from these patients and treated first with lipopolysaccharides (LPS) and then with different doses of TP (1, 5.4 and 15 ng/mL). The TNF-α level in the supernatants was measured by enzyme-linked immunosorbent assay (ELISA). The results showed that TNF-α level in the supernatants of TP (1 ng/mL)-treated PBMCs was decreased by 3.80% and 4.91%, respectively, in the patients with AA and AG genotypes, when compared with those treated with LPS alone (>0.05). Moreover, the TNF-α level in the patients with GG genotype was reduced by 20.74% (<0.05). When PBMCs were treated with TP at 5.4 ng/mL, TNF-α levels in the patients with AA, AG, and GG genotypes were decreased by 20.42%, 34.73%, and 41.69%, respectively (<0.05). The TNF-α level was slightly higher in the PBMCs treated with 15 ng/mL of TP than those in the two TP groups in the patients carrying AA, AG, and GG genotypes (>0.05). It was concluded that gene polymorphism at TNF-α-308 sites may relate to the secretion of TNF-α in RA patients. TP has different inhibitory effects on the secretion of TNF-α in the patients harboring different genotypes, which may be one of the reasons for individual variation in response to TP.

关键词： arthritis     rheumatoid     molonuclear cells     tumor necrosis factor     gene polymorphisms     triptolid    

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Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cellsenriched with tumor spheroids from a non-small cell lung cancer cell line

null

《医学前沿（英文）》 2013年 第7卷 第4期   页码 462-476 doi: 10.1007/s11684-013-0270-6

摘要：

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

关键词： drug resistance     cancer stem cell     checkpoint kinase 1 (CHK1)     PF-00477736     lung cancer     tumorigenicity    

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Modeling of solids segregation in circulating fluidized bed boilers

Xuan YAO, Tao WANG, Jia ZHAO, Hairui YANG, Hai ZHANG

《能源前沿（英文）》 2011年 第5卷 第1期   页码 115-119 doi: 10.1007/s11708-010-0103-0

摘要： Segregation always occurs in a circulating fluidized bed (CFB) because of the wide distribution of particle size and density of the bed material. Terminal velocity has a significant influence on solids segregation; thus, it is convenient to describe the segregation tendency using single particle terminal velocity . This paper proposes a segregation model in CFB boilers based on the Cell Model. In each cell along the riser, varied-sized particles have different tendencies toward segregation; finer particles are carried out more easily, while coarser ones tend to sink into the cell. It is assumed that the average terminal velocity , corresponding to the mean particle size in the cell, has a segregation index of = 1.0 as the reference point. The segregation index of particles with higher terminal velocity is lower than 1.0, while that for finer particles is larger than 1.0. The empirical formulae of segregation parameters, namely and , are derived by optimizing experimental data in published literature. The test result of ash size distribution in a 220 t/h CFB boiler validates the reasonableness of the model.

关键词： segregation     model     terminal velocity     circulating fluidized bed (CFB)    

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Flow boiling heat transfer in circulating fluidized bed

Xiaoguang REN , Jiangdong ZHENG , Sefiane KHELLIl , Arumemi-Ikhide MICHAEL ,

《能源前沿（英文）》 2009年 第3卷 第1期   页码 85-89 doi: 10.1007/s11708-008-0067-5

摘要： In order to enhance heat transfer and mitigate contamination in the boiling processes, a new type of vapor-liquid-solid (3-phase) circulating fluidized bed boiling system has been designed, combining a circulating fluidized bed with boiling heat transfer. Experimental results show an enhancement of the boiling curve. Flow visualization studies concerning flow hydrodynamics within the riser column are also conducted whose results are presented and discussed.

关键词： vapor-liquid-solid three phase     flow boiling heat transfer     circulating fluidized bed    

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标题 作者 时间 类型 操作

Application of liquid biopsy in precision medicine: opportunities and challenges

null

期刊论文

4-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murinetumor

Hui QIU, Hui ZHANG, Zuohua FENG

期刊论文

Identification of cancer stem cells provides novel tumor models for drug discovery

null

期刊论文

基于飞秒激光的用于捕获肿瘤细胞的聚合物芯片实验室的智能程序

Annalisa Volpe, Udith Krishnan, Maria Serena Chiriacò, Elisabetta Primiceri, Antonio Ancona, Francesco Ferrara

期刊论文

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

期刊论文

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

期刊论文

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

null

期刊论文

Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive

期刊论文

Tumor growth and metastasis can be inhibited by maintaining genomic stability in cancer cells

null

期刊论文

Immunotherapeutic effects on murine pancreatic carcinoma by β-elemene combined with dendritic cells modified

TAN Guang, WANG Zhongyu, CHE Luanqing, YIN Shuo

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

Inhibition of TNF-alpha secretion from peripheral blood monocular cells by triptolid is associated with

Xiu-Liang TAO MM, Sheng-Hao TU MD, Ri-Bo XIONG MM, Yong-Hong HU BM,

期刊论文

Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cellsenriched with tumor spheroids from a non-small cell lung cancer cell line

null

期刊论文

Modeling of solids segregation in circulating fluidized bed boilers

Xuan YAO, Tao WANG, Jia ZHAO, Hairui YANG, Hai ZHANG

期刊论文

Flow boiling heat transfer in circulating fluidized bed

Xiaoguang REN , Jiangdong ZHENG , Sefiane KHELLIl , Arumemi-Ikhide MICHAEL ,

期刊论文