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Proteins moonlighting in tumor metabolism and epigenetics

Lei Lv, Qunying Lei

《医学前沿（英文）》 2021年第15卷第3期页码 383-403 doi: 10.1007/s11684-020-0818-1

摘要： Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

关键词： moonlighting function tumor metabolism epigenetics

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Research progress on FASN and MGLL in the regulation of abnormal lipid metabolism and the relationshipbetween tumor invasion and metastasis

Jingyue Zhang, Yawen Song, Qianqian Shi, Li Fu

《医学前沿（英文）》 2021年第15卷第5期页码 649-656 doi: 10.1007/s11684-021-0830-0

摘要： Tumorigenesis involves metabolic reprogramming and abnormal lipid metabolism, which is manifested by increased endogenous fat mobilization, hypertriglyceridemia, and increased fatty acid synthesis. Fatty acid synthase (FASN) is a key enzyme for the synthesis of fatty acids, and monoacylglycerol esterase (MGLL) is an important metabolic enzyme that converts triglycerides into free fatty acids. Both enzymes play an important role in lipid metabolism and are associated with tumor-related signaling pathways, the most common of which is the PI3K–AKT signaling pathway. They can also regulate the immune microenvironment, participate in epithelial–mesenchymal transition, and then regulate tumor invasion and metastasis. Current literature have shown that these two genes are abnormally expressed in many types of tumors and are highly correlated with tumor migration and invasion. This article introduces the structures and functions of FASN and MGLL, their relationship with abnormal lipid metabolism, and the mechanism of the regulation of tumor invasion and metastasis and reviews the research progress of the relationship of FASN and MGLL with tumor invasion and metastasis.

关键词： FASN MGLL lipid metabolism tumor invasion metastasis

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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

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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

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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

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Vanadium metabolism investigation using substance flow and scenario analysis

Fangfang ZHANG, Huiquan LI, Bo CHEN, Xue GUAN, Yi ZHANG

《环境科学与工程前沿（英文）》 2014年第8卷第2期页码 256-266 doi: 10.1007/s11783-013-0585-1

摘要： Vanadium is a vital strategic resource, and vanadium metabolism is an important part of the national socio-economic system of China. This study conducts accounting and scenario analysis on the life cycle of vanadium metabolism in China. Based on the characteristics of vanadium life cycle and substance flow analysis (SFA) framework, we present a quantitative evaluation of a static anthropogenic vanadium life cycle for the year 2010. Results show that anthropogenic vanadium consumption, stocks, and new domestic scrap are at 98.2, 21.2, and 4.1 kt, respectively; new scrap is usually discarded. The overall utilization ratio of vanadium is 32.2%. A large amount of vanadium is stockpiled into tailings, debris, slags, and other spent solids. A scenario analysis was conducted to analyze the future developmental trend of vanadium metabolism in China based on the SFA framework and the qualitative analysis of technology advancement and socio-economic development. The baseline year was set as 2010. Several indicators were proposed to simulate different scenarios from 2010 to 2030. The scenario analysis indicates that the next 20 years is a critical period for the vanadium industry in China. This paper discusses relevant policies that contribute to the improvement of sustainable vanadium utilization in China.

关键词： metabolism vanadium industry substance flow analysis scenario analysis

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Insulin resistance and the metabolism of branched-chain amino acids

null

《医学前沿（英文）》 2013年第7卷第1期页码 53-59 doi: 10.1007/s11684-013-0255-5

摘要：

Insulin resistance (IR) is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders. IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network. Branched-chain amino acids (BCAAs), namely valine, leucine and isoleucine, are among the nine essential amino acids, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency. Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight, it is only recently that BCAAs are found to be closely associated with IR. This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.

关键词： branched-chain amino acids leucine isoleucine valine insulin resistance

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Anaerobic ammonia oxidizing bacteria: ecological distribution, metabolism, and microbial interactions

Dawen Gao, Xiaolong Wang, Hong Liang, Qihang Wei, Yuan Dou, Longwei Li

《环境科学与工程前沿（英文）》 2018年第12卷第3期 doi: 10.1007/s11783-018-1035-x

摘要： Anammox (ANaerobic AMMonia OXidation) is a newly discovered pathway in the nitrogen cycle. This discovery has increased our knowledge of the global nitrogen cycle and triggered intense interest for anammox-based applications. Anammox bacteria are almost ubiquitous in the suboxic zones of almost all types of natural ecosystems and contribute significant to the global total nitrogen loss. In this paper, their ecological distributions and contributions to the nitrogen loss in marine, wetland, terrestrial ecosystems, and even extreme environments were reviewed. The unique metabolic mechanism of anammox bacteria was well described, including the particular cellular structures and genome compositions, which indicate the special evolutionary status of anammox bacteria. Finally, the ecological interactions among anammox bacteria and other organisms were discussed based on substrate availability and spatial organizations. This review attempts to summarize the fundamental understanding of anammox, provide an up-to-date summary of the knowledge of the overall anammox status, and propose future prospects for anammox. Based on novel findings, the metagenome has become a powerful tool for the genomic analysis of communities containing anammox bacteria; the metabolic diversity and biogeochemistry in the global nitrogen budget require more comprehensive studies.

关键词： Anammox Metabolism Metagenome Ecological distribution Microbial interactions

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Metabolism and immunity in breast cancer

Deyu Zhang, Xiaojie Xu, Qinong Ye

《医学前沿（英文）》 2021年第15卷第2期页码 178-207 doi: 10.1007/s11684-020-0793-6

摘要： Breast cancer is one of the most common malignancies that seriously threaten women’s health. In the process of the malignant transformation of breast cancer, metabolic reprogramming and immune evasion represent the two main fascinating characteristics of cancer and facilitate cancer cell proliferation. Breast cancer cells generate energy through increased glucose metabolism. Lipid metabolism contributes to biological signal pathways and forms cell membranes except energy generation. Amino acids act as basic protein units and metabolic regulators in supporting cell growth. For tumor-associated immunity, poor immunogenicity and heightened immunosuppression cause breast cancer cells to evade the host’s immune system. For the past few years, the complex mechanisms of metabolic reprogramming and immune evasion are deeply investigated, and the genes involved in these processes are used as clinical therapeutic targets for breast cancer. Here, we review the recent findings related to abnormal metabolism and immune characteristics, regulatory mechanisms, their links, and relevant therapeutic strategies.

关键词： breast cancer metabolism immunity cancer stem cells

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Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives

null

《医学前沿（英文）》 2012年第6卷第1期页码 67-78 doi: 10.1007/s11684-012-0176-8

摘要：

Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004. Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment, recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy, resulting in tumor recurrence in patients after several months of treatment. Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues, which fosters tumor cells to become more aggressive and metastatic. In 2001, Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers. At present, normalizing the disorganized tumor vasculature, rather than disrupting or blocking them, has emerged as a new option for anticancer therapy. Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies, proteins, peptides, small molecules, and pericytes resulted in decreased tumor size and reduced metastasis. However, current tumor vascular normalizing drugs display moderate anticancer efficacy. Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization, growth, and metastasis. Therefore, multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization. To this end, the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics, as well as the integration of Western medicine with traditional Chinese medicine, may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.

关键词： angiogenesis vasculogenesis neovascularization tumor vasculature normalization traditional Chinese medicine

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Dynamic simulation of urban water metabolism under water environmental carrying capacity restrictions

Weihua ZENG,Bo WU,Ying CHAI

《环境科学与工程前沿（英文）》 2016年第10卷第1期页码 114-128 doi: 10.1007/s11783-014-0669-6

摘要： A revised concept for urban water metabolism (UWM) is presented in this study to address the inadequacies in current research on UWM and the problems associated with the traditional urban water metabolic process. Feedback loops can be analyzed to increase the water environmental carrying capacity (WECC) of the new urban water metabolism system (UWMS) over that of a traditional UWMS. An analysis of the feedback loops of an UWMS was used to construct a system dynamics (SD) model for the system under a WECC restriction. Water metabolic processes were simulated for different scenarios using the Tongzhou District in Beijing as an example. The results for the newly developed UWM case showed that a water environment of Tongzhou District could support a population of 1.1926 × 10 , an irrigation area of 375.521 km , a livestock of 0.7732 × 10 , and an industrial value added of ¥193.14 × 10 (i.e. about US$28.285× 10 ) in 2020. A sensitivity analysis showed that the WECC could be improved to some extent by constructing new sewage treatment facilities or by expanding the current sewage treatment facilities, using reclaimed water and improving the water circulation system.

关键词： urban water metabolism system (UWMS) system dynamic simulation water environmental carrying capacity (WECC) feedback loops bilateral control

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Expression profiles of genes and enzymes related to ascorbic acid metabolism in fruits of

Yingying CHEN,Zhihui ZHAO,Jin ZHAO,Mengjun LIU

《农业科学与工程前沿（英文）》 2016年第3卷第2期页码 131-136 doi: 10.15302/J-FASE-2016096

摘要： The fruit of Chinese jujube ( ) possesses extremely high concentrations of ascorbic acid (AsA). The accumulation of AsA, the expression patterns of the nine genes related to AsA metabolism as well as the activities of five enzymes involved in AsA synthesis, oxidation and recycling were investigated during fruit development in Mill. ‘Jinsixiaozao’. The results showed that the high level of AsA accumulation in jujube fruit is due to a contribution from both AsA biosynthesis and AsA recycling. It is suggested that L-galactono-1,4-lactone dehydrogenase, ascorbate peroxidase and monodehydro-ascorbate reductase are the crucial genes/enzymes of jujube AsA synthesis, oxidization and recycling, respectively. These results provide useful new insights into the regulatory mechanisms of AsA accumulation in Chinese jujube.

关键词： Chinese jujube ascorbic acid metabolism gene enzyme

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Natural killer cell lines in tumor immunotherapy

null

《医学前沿（英文）》 2012年第6卷第1期页码 56-66 doi: 10.1007/s11684-012-0177-7

摘要：

Natural killer (NK) cells are considered to be critical players in anticancer immunity. However, cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells. Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches, including activating autologous NK cells, expanding allogeneic NK cells, usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines. The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production. Additionally, genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity. In this review, NK cells in tumor immunotherapy are discussed, and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed.

关键词： natural killer cell natural killer cell line tumor immunotherapy genetic modification

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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

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carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor

《化学科学与工程前沿（英文）》 2022年第16卷第4期页码 536-545 doi: 10.1007/s11705-021-2067-5

摘要： Many scientific efforts have been made to penetrate the blood-brain barrier and target glioblastoma cells, but the outcomes have been limited. More attention should be given to local inhibition of recurrence after glioblastoma resection to meet real medical needs. A biodegradable wafer containing the chemotherapeutics carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU) was the only local drug delivery system approved for clinical glioblastoma treatment, but with a prolonged survival time of only two months and frequent side effects. In this study, to improve the sustained release and prolonged therapeutic effect of drugs for inhibiting tumor recurrence after tumor resection, both free BCNU and BCNU- poly (lactic-co-glycolic acid) (the ratio of lactic acid groups to glycolic acid groups is 75/25) nanoparticles were simultaneously loaded into natural extracellular matrix hydrogel from pigskin to prepare BCNU gels. The hydrogel was injected into the resection cavity of a glioblastoma tumor immediately after tumor removal in a fully characterized resection rat model. Free drugs were released instantly to kill the residual tumor cells, while drugs in nanoparticles were continuously released to achieve a continuous and effective inhibition of the residual tumor cells for 30 days. These combined actions effectively restricted tumor growth in rats. Thus, this strategy of local drug implantation and delivery may provide a reliable method to inhibit the recurrence of glioblastoma after tumor resection in vivo.

关键词： BCNU glioblastoma recurrence tumor resection nanoparticles hydrogel