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Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanismsand strategies

《医学前沿（英文）》   页码 805-822 doi: 10.1007/s11684-023-1025-7

摘要： Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

关键词： CTLA-4     PD-1     PD-L1     immune checkpoint blockade (ICB)     metabolic reprogramming     combined tumor therapeutic strategies    

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Molecular mechanisms and therapeutic strategies of vulnerable atherosclerotic plaques

Wen-Qiang CHEN MD, Yun ZHANG MD, PhD, FACC,

《医学前沿（英文）》 2010年 第4卷 第1期   页码 36-42 doi: 10.1007/s11684-010-0020-y

摘要： Vulnerable atherosclerotic plaque rupture leading to thrombosis is the major cause of acute coronary syndrome (ACS). Studies on the pathophysiologic mechanism of both ACS and plaque stabilizing treatment are driving the development of animal models of vulnerable plaque. In our laboratory, we established animal models of plaque rupture and thrombosis in rabbits and mice that are similar to human plaque rupture. Potential mechanisms involved in plaque vulnerability were studied from the inflammation-immunity, proliferation-apoptosis, oxidative stress and biomechanics aspects. Imaging markers and biomarkers were used to detect vulnerable plaques, including high frequency duplex ultrasound, intravascular ultrasound (IVUS), intravascular ultrasound elastography, magnetic resonance imaging (MRI) and inflammatory markers. Effective gene and drug strategies to treat vulnerable plaques were explored.

关键词： vulnerable plaque     animal models     mechani-sm     detection     treatment    

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Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies

Guangbiao Zhou, Saijuan Chen, Zhu Chen

《医学前沿（英文）》 2020年 第14卷 第2期   页码 117-125 doi: 10.1007/s11684-020-0773-x

摘要： Since the outbreak of the COVID-19 pandemic in early December 2019, 81 174 confirmed cases and 3242 deaths have been reported in China as of March 19, 2020. The Chinese people and government have contributed huge efforts to combat this disease, resulting in significant improvement of the situation, with 58 new cases (34 were imported cases) and 11 new deaths reported on March 19, 2020. However, as of March 19, 2020, the COVID-19 pandemic continues to develop in 167 countries/territories outside of China, and 128 665 confirmed cases and 5536 deaths have been reported, with 16 498 new cases and 817 new deaths occurring in last 24 hours. Therefore, the world should work together to fight against this pandemic. Here, we review the recent advances in COVID-19, including the insights in the virus, the responses of the host cells, the cytokine release syndrome, and the therapeutic approaches to inhibit the virus and alleviate the cytokine storm. By sharing knowledge and deepening our understanding of the virus and the disease pathogenesis, we believe that the community can efficiently develop effective vaccines and drugs, and the mankind will eventually win this battle against this pandemic.

关键词： COVID-19     SARS-CoV-2     pathogenesis     evidence-based medicine     control and therapeutic strategies    

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Therapeutic effect of medical glue combined with the great omentum in severe tunica muscularis injury

REN Peitu, LU Baochun, RUAN Xinxian, CHEN Zhiliang, MA Yuliang, FU Hong

《医学前沿（英文）》 2008年 第2卷 第2期   页码 143-146 doi: 10.1007/s11684-008-0027-9

摘要： Twenty-seven patients with severe colon trauma treated in the Shaoxing People’s Hospital from 1995 to 2006 were retrospectively analyzed. The patients with severe tunica muscularis injury were treated by medical glue combined with the greater omentum during operations. The initial result was encouraging. All patients were cured with no anastomotic leakage or abscess. Therefore, reasonable use of medical glue combined with the greater omentum can not only improve the curative rate but also reduces postoperative complications for patients with colon injury.

关键词： abscess     initial     muscularis     anastomotic     medical    

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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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Circulating microRNAs in cardiovascular diseases: from biomarkers to therapeutic targets

null

《医学前沿（英文）》 2014年 第8卷 第4期   页码 404-418 doi: 10.1007/s11684-014-0379-2

摘要：

microRNAs (miRNAs) are a class of conserved, short, non-coding RNAs that have important and potent capacities to regulate gene expression at the posttranscriptional level. In the past several years, the aberrant expressions of miRNAs in the cardiovascular system have been widely reported, and the crucial roles of some special miRNAs in heart development and pathophysiology of various cardiovascular diseases have been gradually recognized. Recently, it was discovered that miRNAs are presented in peripheral circulation abundantly and stably. This has raised the possibility of using circulating miRNAs as biomarkers for diseases. Furthermore, some studies demonstrated that circulating miRNAs may serve as novel extracellular communicators of cell-cell communication. These discoveries not only reveal the functions of circulating miRNAs in cardiovascular system but also inform the development of miRNAs therapeutic strategies. In this review, we discuss the potential roles of circulating miRNAs in a variety of cardiovascular diseases from biomarkers to therapeutic targets to clearly understand the roles of circulating miRNAs in cardiovascular system.

关键词： microRNA     cardiovascular disease     biomarkers     therapeutic target    

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

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    

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Brown and beige fat: the metabolic function, induction, and therapeutic potential

null

《医学前沿（英文）》 2015年 第9卷 第2期   页码 162-172 doi: 10.1007/s11684-015-0382-2

摘要：

Adipose tissue is an important organ for energy homeostasis. White adipose tissue stores energy in the form of triglycerides, whereas brown adipocytes and recently identified beige adipocytes are specialized in dissipating energy by thermogenesis or contribution to dispose glucose and clear triglycerides in blood. The inverse correlation between the brown adipose tissue activity and body mass suggests its protective role against body fat accumulation. Thus, recruitment and activation of brown or beige adipose tissue become particularly appealing targets for increasing energy expenditure. Angiogenesis and sympathetic nerve signals are the fundamental determinants for brown and beige adipose tissue development, as well as for their metabolic functions. Secretary factors including BMPs can induce the development, the activation of brown or beige adipose tissue, which seem to be promising for therapeutic development.

关键词： brown adipocyte     beige adipocyte     metabolism     obesity    

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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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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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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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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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Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-likecells enriched 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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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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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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标题 作者 时间 类型 操作

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanismsand strategies

期刊论文

Molecular mechanisms and therapeutic strategies of vulnerable atherosclerotic plaques

Wen-Qiang CHEN MD, Yun ZHANG MD, PhD, FACC,

期刊论文

Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies

Guangbiao Zhou, Saijuan Chen, Zhu Chen

期刊论文

Therapeutic effect of medical glue combined with the great omentum in severe tunica muscularis injury

REN Peitu, LU Baochun, RUAN Xinxian, CHEN Zhiliang, MA Yuliang, FU Hong

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

Circulating microRNAs in cardiovascular diseases: from biomarkers to therapeutic targets

null

期刊论文

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

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

期刊论文

Brown and beige fat: the metabolic function, induction, and therapeutic potential

null

期刊论文

Heterogeneity of the tumor immune microenvironment and clinical interventions

期刊论文

Proteins moonlighting in tumor metabolism and epigenetics

Lei Lv, Qunying Lei

期刊论文

Complex interplay between tumor microenvironment and cancer therapy

null

期刊论文

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

期刊论文

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

null

期刊论文

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

null

期刊论文

Natural killer cell lines in tumor immunotherapy

null

期刊论文