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Complex interplay between tumor microenvironment and cancer therapy

null

《医学前沿(英文)》 2018年 第12卷 第4期   页码 426-439 doi: 10.1007/s11684-018-0663-7

摘要:

Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

关键词: tumor microenvironment     therapy response     treatment resistance    

Nanovaccines for remodeling the suppressive tumor microenvironment: New horizons in cancer immunotherapy

Kai Shi, Matthew Haynes, Leaf Huang

《化学科学与工程前沿(英文)》 2017年 第11卷 第4期   页码 676-684 doi: 10.1007/s11705-017-1640-4

摘要: Despite limited successes in clinical development, therapeutic cancer vaccines have experienced resurgence in recent years due to an enhanced emphasis upon co-mitigating factors underlying immune response. Specifically, reversing the immune-suppressive effects of the tumor microenvironment, mediated by a variety of cellular and molecular signaling mechanisms, has become fundamental toward enhancing therapeutic efficacy. Therein, our lab has implemented various nano-vaccines based on the lipid-coated calcium phosphate platform for combined immunotherapy, in which antigenic, epitope-associated peptides as well as immune-suppression inhibitors can be co-delivered, often functioning through the same formulation. In probing the mechanism of action of such systems and , an improved effect synergy can be elucidated, inspiring future preclinical efforts and hope for clinical success.

关键词: vaccine     nanoparticle     tumor     immunotherapy     microenvironment    

Heterogeneity of the tumor immune microenvironment and clinical interventions

《医学前沿(英文)》 2023年 第17卷 第4期   页码 617-648 doi: 10.1007/s11684-023-1015-9

摘要: Heterogeneity of the tumor immune microenvironment and clinical interventions

关键词: Heterogeneity tumor immune    

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma

《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    

Distinct immune escape and microenvironment between RG-like and pri-OPC-like glioma revealed by single-cell

《医学前沿(英文)》 doi: 10.1007/s11684-023-1017-7

摘要: The association of neurogenesis and gliogenesis with glioma remains unclear. By conducting single-cell RNA-seq analyses on 26 gliomas, we reported their classification into primitive oligodendrocyte precursor cell (pri-OPC)-like and radial glia (RG)-like tumors and validated it in a public cohort and TCGA glioma. The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations, and the pri-OPC-like ones were prone to carrying TP53 mutations. Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes, suggesting their distinct immune evasion programs. Furthermore, the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners. Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes. For example, glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes, respectively. Their expression was positively correlated with those of immune checkpoint genes (e.g., LGALS3) and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells. This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.

关键词: single-cell RNA-seq     glioma     radial glia     primitive oligodendrocyte precursor cell     immune escape    

Intratumor heterogeneity, microenvironment, and mechanisms of drug resistance in glioma recurrence and

Zhaoshi Bao, Yongzhi Wang, Qiangwei Wang, Shengyu Fang, Xia Shan, Jiguang Wang, Tao Jiang

《医学前沿(英文)》 2021年 第15卷 第4期   页码 551-561 doi: 10.1007/s11684-020-0760-2

摘要: Glioma is the most common lethal tumor of the human brain. The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months. The World Health Organization classification of tumors of the central nervous system categorized gliomas into lower-grade gliomas and glioblastomas. Unlike primary glioblastoma that usually develop in the elderly, secondary glioblastoma enriched with an isocitrate dehydrogenase mutant typically progresses from lower-grade glioma within 5–10 years from the time of diagnosis. Based on various evolutional trajectories brought on by clonal and subclonal alterations, the evolution patterns of glioma vary according to different theories. Some important features distinguish the normal brain from other tissues, e.g., the composition of the microenvironment around the tumor cells, the presence of the blood-brain barrier, and others. The underlying mechanism of glioma recurrence and evolution patterns of glioma are different from those of other types of cancer. Several studies correlated tumor recurrence with tumor heterogeneity and the immune microenvironment. However, the detailed reasons for the progression and recurrence of glioma remain controversial. In this review, we introduce the different mechanisms involved in glioma progression, including tumor heterogeneity, the tumor microenvironment and drug resistance, and their pre-clinical implements in clinical trials. This review aimed to provide new insights into further clinical strategies for the treatment of patients with recurrent and secondary glioma.

关键词: glioma     evolution mechanism     strategies     tumor heterogeneity     secondary glioma    

Immunometabolism: a new dimension in immunotherapy resistance

《医学前沿(英文)》 2023年 第17卷 第4期   页码 585-616 doi: 10.1007/s11684-023-1012-z

摘要: Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

关键词: immune cell     immunometabolism     metabolic reprogramming     immunotherapy     resistance     tumor microenvironment     immune checkpoint inhibitor    

Translational medicine in hepatocellular carcinoma

null

《医学前沿(英文)》 2012年 第6卷 第2期   页码 122-133 doi: 10.1007/s11684-012-0193-7

摘要:

Hepatocellular carcinoma (HCC) is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy. Consequently, there is an urgent need for the development of new treatment strategies for this devastating disease. In the past decade, tremendous progress has been achieved in the molecular stratification of HCCs for diagnosis, prognosis, and therapeutic decision-making. To date, the molecular classification of HCCs has been carried out through transcriptomic, genetic and epigenetic profiling of tumors. Such research has led to identification of several potential molecular targets in HCC, and subsequently, development of novel systemic agents for the treatment of HCC has begun in earnest. In this article, we review the current knowledge of the molecular pathogenesis of HCC and outline potential areas for application of this knowledge in a clinical setting. As a typical virus and inflammation-associated cancer, both host immune response and tumor microenvironment have crucial roles in HCC pathogenesis. In addition, we examine the potential of immunotherapy and strategies targeting various components of the tumor microenvironment, as well as novel molecular and cellular targets in HCC such as cancer stem cells.

关键词: hepatocellular carcinoma     molecular classification     molecular targeted therapies     tumor microenvironment     immunotherapy    

Immunological effects of nano-enabled hyperthermia for solid tumors: opportunity and challenge

《化学科学与工程前沿(英文)》 2022年 第16卷 第3期   页码 333-344 doi: 10.1007/s11705-021-2059-5

摘要: Compared to conventional hyperthermia that is limited by low selectivity and severe side effects, nano-enabled hyperthermia yields great potentials to tackle these limitations for cancer treatment. Another major advance is the observation of immunological responses associated with nano-enabled hyperthermia, which introduces a new avenue, allowing a potential paradigm shift from the acutely effective and cytotoxicity-centric response to the next-phase discovery, i.e., long-lasting and/or systemic anti-tumor immunity. This perspective first discusses the temperature-gradient and the spatially-structured immunological landscape in solid tumors receiving nano-enabled hyperthermia. This includes the discussion about underlying mechanism such as immunogenic cell death, which initiates a profound immunological chain reaction. In order to propagate the immune activation as a viable therapeutic principle, we further discussed the tumor type-specific complexity in the immunological tumor microenvironment, including the creative design of nano-enabled combination therapy to synergize with nano-enabled hyperthermia.

关键词: nano-enabled hyperthermia     immunogenic cell death     heterogeneous immunological landscape     tumor microenvironment    

Quantitative proteomics revealed extensive microenvironmental changes after stem cell transplantation in ischemic stroke

《医学前沿(英文)》 2022年 第16卷 第3期   页码 429-441 doi: 10.1007/s11684-021-0842-9

摘要: The local microenvironment is essential to stem cell-based therapy for ischemic stroke, and spatiotemporal changes of the microenvironment in the pathological process provide vital clues for understanding the therapeutic mechanisms. However, relevant studies on microenvironmental changes were mainly confined in the acute phase of stroke, and long-term changes remain unclear. This study aimed to investigate the microenvironmental changes in the subacute and chronic phases of ischemic stroke after stem cell transplantation. Herein, induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) were transplanted into the ischemic brain established by middle cerebral artery occlusion surgery. Positron emission tomography imaging and neurological tests were applied to evaluate the metabolic and neurofunctional alterations of rats transplanted with stem cells. Quantitative proteomics was employed to investigate the protein expression profiles in iPSCs-transplanted brain in the subacute and chronic phases of stroke. Compared with NSCs-transplanted rats, significantly increased glucose metabolism and neurofunctional scores were observed in iPSCs-transplanted rats. Subsequent proteomic data of iPSCs-transplanted rats identified a total of 39 differentially expressed proteins in the subacute and chronic phases, which are involved in various ischemic stroke-related biological processes, including neuronal survival, axonal remodeling, antioxidative stress, and mitochondrial function restoration. Taken together, our study indicated that iPSCs have a positive therapeutic effect in ischemic stroke and emphasized the wide-ranging microenvironmental changes in the subacute and chronic phases.

关键词: ischemic stroke     microenvironment     induced pluripotent stem cells (iPSCs)     positron emission tomography (PET)     quantitative proteomics    

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

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    

Microenvironmental time-activity patterns in Chongqing, China

Yu ZHAO, Shuxiao WANG, Gangcai CHEN, Fei WANG, Kristin AUNAN, Jiming HAO

《环境科学与工程前沿(英文)》 2009年 第3卷 第2期   页码 200-209 doi: 10.1007/s11783-009-0010-y

摘要: An investigation using recall questionnaires was conducted in winter and autumn 2006 to evaluate the time-activity patterns in Chongqing, China. The average time spent in seven microenvironments (MEs) including outdoors, transit, living room, bedroom, kitchen, classroom/office, and other indoors were found to be about 3.5, 1.1, 2.5, 9.7, 1.4, 4.2, and 1.7 h per day, respectively. According to the results of a nonparametric test, the sampling period and day of week were significant for the variation of the time spent in all MEs except for transit and outdoors. The time budget was analyzed using a general linear model (GLM), which exhibited significant variability by demographic factors such as gender, age, residence, education, and household income.

关键词: time-activity patterns     microenvironment     general linear model (GLM)     Chongqing     China    

The “Traditional Chinese medicine regulating liver regeneration” treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data

Ling Dai, Xiang Gao, Zhihua Ye, Hanmin Li, Xin Yao, Dingbo Lu, Na Wu

《医学前沿(英文)》 2021年 第15卷 第3期   页码 495-505 doi: 10.1007/s11684-020-0790-9

摘要: On the basis of real-world clinical data, the study aimed to explore the effect and mechanisms of the treatment plan of “traditional Chinese medicine (TCM) regulating liver regeneration.” A total of 457 patients with HBV-related liver failure were retrospectively collected. The patients were divided into three groups: the modern medicine control group (MMC group), patients treated with routine medical treatment; the control group combining traditional Chinese and Western medicine (CTW), patients treated with routine medical treatment plus the common TCM formula; and the treatment group of “TCM regulating liver regeneration” (RLR), patients treated with both routine medical treatment and the special TCM formula of RLR. After 8 weeks of treatment, the mortality of patients in the RLR group (12.31%) was significantly lower than those in the MMC (50%) and CTW (29.11%) groups. Total bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups ( <0.05). In addition, there were significant differences in the expression of several cytokines related to liver regeneration in the RLR group compared with the MMC group. RLR treatment can decrease jaundice, improve liver function, and significantly reduce the mortality in patients with HBV-related liver failure. The mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.

关键词: hepatitis B virus-related liver failure     traditional Chinese medicine     liver regeneration     liver regeneration microenvironment     cytokines    

纳米技术——一种针对促肿瘤中性粒细胞的肺癌治疗新策略 Review

张健, 蒋莎莎, 李仕林, 江继鹏, 梅婕, 陈延东, 马永富, 刘阳, 刘颖​​​​​​​

《工程(英文)》 2023年 第27卷 第8期   页码 106-126 doi: 10.1016/j.eng.2022.11.006

摘要:

原发性肺癌和转移性肺癌都是肺部恶性肿瘤,两者都威胁着患者的生命,但各自的发病机制不同。肿瘤的发生和发展涉及肿瘤细胞与宿主微环境之间的交流,中性粒细胞是肿瘤微环境(TME)中最丰富的免疫细胞,它们参与炎症环境的形成,并通过其抗肿瘤和促肿瘤能力影响患者的生存。中性粒细胞可根据不同的标准分为不同的类别,常见的类别包括 N1 抗肿瘤中性粒细胞和 N2 免疫抑制中性粒细胞。中性粒细胞的抗肿瘤作用是通过活性氧、肿瘤坏死因子相关的细胞凋亡诱导配体、高级糖化终产物受体-胰蛋白酶 G 等因素共同作用以及调节其他免疫细胞的活动共同介导的。中性粒细胞作为肿瘤促进因子,也可通过影响包括癌症发生、血管生成、癌细胞增殖和侵袭能力等过程,促进肺癌的发展和转移,并在其他癌症的肺转移中发挥类似作用。纳米技术的快速发展为针对中性粒细胞的癌症治疗提供了新策略。

关键词: 肺癌     转移     中性粒细胞     肿瘤微环境     纳米技术    

标题 作者 时间 类型 操作

Complex interplay between tumor microenvironment and cancer therapy

null

期刊论文

Nanovaccines for remodeling the suppressive tumor microenvironment: New horizons in cancer immunotherapy

Kai Shi, Matthew Haynes, Leaf Huang

期刊论文

Heterogeneity of the tumor immune microenvironment and clinical interventions

期刊论文

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma

期刊论文

Distinct immune escape and microenvironment between RG-like and pri-OPC-like glioma revealed by single-cell

期刊论文

Intratumor heterogeneity, microenvironment, and mechanisms of drug resistance in glioma recurrence and

Zhaoshi Bao, Yongzhi Wang, Qiangwei Wang, Shengyu Fang, Xia Shan, Jiguang Wang, Tao Jiang

期刊论文

Immunometabolism: a new dimension in immunotherapy resistance

期刊论文

Translational medicine in hepatocellular carcinoma

null

期刊论文

Immunological effects of nano-enabled hyperthermia for solid tumors: opportunity and challenge

期刊论文

Quantitative proteomics revealed extensive microenvironmental changes after stem cell transplantation in ischemic stroke

期刊论文

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

Hui QIU, Hui ZHANG, Zuohua FENG

期刊论文

Microenvironmental time-activity patterns in Chongqing, China

Yu ZHAO, Shuxiao WANG, Gangcai CHEN, Fei WANG, Kristin AUNAN, Jiming HAO

期刊论文

The “Traditional Chinese medicine regulating liver regeneration” treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data

Ling Dai, Xiang Gao, Zhihua Ye, Hanmin Li, Xin Yao, Dingbo Lu, Na Wu

期刊论文

纳米技术——一种针对促肿瘤中性粒细胞的肺癌治疗新策略

张健, 蒋莎莎, 李仕林, 江继鹏, 梅婕, 陈延东, 马永富, 刘阳, 刘颖​​​​​​​

期刊论文

李小年:仿生策略构筑催化反应微环境(2019年5月24日)

2021年04月22日

会议视频