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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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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    

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Heterogeneity of chronic obstructive pulmonary disease: from phenotype to genotype

null

《医学前沿（英文）》 2013年 第7卷 第4期   页码 425-432 doi: 10.1007/s11684-013-0295-x

摘要：

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality throughout the world and is mainly characterized by persistent airflow limitation. Given that multiple systems other than the lung can be impaired in COPD patients, the traditional FEV1/FVC ratio shows many limitations in COPD diagnosis and assessment. Certain heterogeneities are found in terms of clinical manifestations, physiology, imaging findings, and inflammatory reactions in COPD patients; thus, phenotyping can provide effective information for the prognosis and treatment. However, phenotypes are often based on symptoms or pathophysiological impairments in late-stage COPD, and the role of phenotypes in COPD prevention and early diagnosis remains unclear. This shortcoming may be overcome by the potential genotypes defined by the heterogeneities in certain genes. This review briefly describes the heterogeneity of COPD, with focus on recent advances in the correlations between genotypes and phenotypes. The potential roles of these genotypes and phenotypes in the molecular mechanisms and management of COPD are also elucidated.

关键词： chronic obstructive pulmonary disease     heterogeneity     phenotype     genotype     prediction    

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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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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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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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Computational modeling of fracture in concrete: A review

Luthfi Muhammad Mauludin, Chahmi Oucif

《结构与土木工程前沿（英文）》 2020年 第14卷 第3期   页码 586-598 doi: 10.1007/s11709-020-0573-z

摘要： This paper presents a review of fracture modeling of concrete. The complex material, such as concrete, has been widely used in construction industries and become trending issue in the last decades. Based on comprehensive literature review, there are two main approaches considered to-date of concrete fracture modeling, such as macroscopic and micromechanical models. The purpose of this review is to provide insight comparison from different techniques in modeling of fracture in concrete which are available. In the first section, an overview of fracture modeling in general is highlighted. Two different approaches both of macroscopic and micromechanical models will be reviewed. As heterogeneity of concrete material is major concern in micromechanical-based concrete modeling, one section will discuss this approach. Finally, the summary from all of reviewed techniques will be pointed out before the future perspective is given.

关键词： concrete fracture     macroscopic     micromechanical     heterogeneity    

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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    

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Analysis of stress and failure in rock specimens with closed and open flaws on the surface

《结构与土木工程前沿（英文）》 2021年 第15卷 第5期   页码 1222-1237 doi: 10.1007/s11709-021-0773-1

摘要： The influence of closed and open surface flaws on the stress distribution and failure in rock specimens is investigated. Heterogeneous finite element models are developed to simulate the compression tests on flawed rock specimens. The simulated specimens include those with closed flaws and those with open flaws on the surface. Systematic analyses are conducted to investigate the influences of the flaw inclination, friction coefficient and the confining stress on failure behavior. Numerical results show significant differences in the stress, displacement, and failure behavior of the closed and open flaws when they are subjected to pure compression; however, their behaviors under shear and tensile loads are similar. According to the results, when compression is the dominant mode of stress applied to the flaw surface, an open flaw may play a destressing role in the rock and relocate the stress concentration and failure zones. The presented results in this article suggest that failure at the rock surface may be managed in a favorable manner by fabricating open flaws on the rock surface. The insights gained from this research can be helpful in managing failure at the boundaries of rock structures.

关键词： surface flaw     heterogeneity     circular hole     numerical modeling     relative displacement    

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Bacteria-mediated tumor-targeted delivery of tumstatin (54-132) significantly suppresses tumor growth

《医学前沿（英文）》 2022年 第16卷 第6期   页码 873-882 doi: 10.1007/s11684-022-0925-2

摘要： Tumor growth is an angiogenesis-dependent process and accompanied by the formation of hypoxic areas. Tumstatin is a tumor-specific angiogenesis inhibitor that suppresses the proliferation and induces the apoptosis of tumorous vascular endothelial cells. VNP20009, an attenuated Salmonella typhimurium strain, preferentially accumulates in the hypoxic areas of solid tumors. In this study, a novel Salmonella-mediated targeted expression system of tumstatin (VNP-Tum5) was developed under the control of the hypoxia-induced J23100 promoter to obtain anti-tumor efficacy in mice. Treatment with VNP-Tum5 effectively suppressed tumor growth and prolonged survival in the mouse model of B16F10 melanoma. VNP-Tum5 exhibited a higher efficacy in inhibiting the proliferation and inducing the necrosis and apoptosis of B16F10 cells in vitro and in vivo compared with VNP (control). VNP-Tum5 significantly inhibited the proliferation and migration of mouse umbilical vascular endothelial cells to impede angiogenesis. VNP-Tum5 downregulated the expression of anti-vascular endothelial growth factor A, platelet endothelial cell adhesion molecule-1, phosphorylated phosphoinositide 3 kinase, and phosphorylated protein kinase B and upregulated the expression of cleaved-caspase 3 in tumor tissues. This study is the first to use tumstatin-transformed VNP20009 as a tumor-targeted system for treatment of melanoma by combining anti-tumor and anti-angiogenic effects.

关键词： Salmonella VNP20009     tumstatin     B16F10     melanoma     apoptosis     angiogenesis    

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A multiscale material model for heterogeneous liquid droplets in solid soft composites

《结构与土木工程前沿（英文）》 2021年 第15卷 第5期   页码 1292-1299 doi: 10.1007/s11709-021-0771-3

摘要： Liquid droplets in solid soft composites have been attracting increasing attention in biological applications. In contrary with conventional composites, which are made of solid elastic inclusions, available material models for composites including liquid droplets are for highly idealized configurations and do not include all material real parameters. They are also all deterministic and do not address the uncertainties arising from droplet radius, volume fraction, dispersion and agglomeration. This research revisits the available models for liquid droplets in solid soft composites and presents a multiscale computational material model to determine their elastic moduli, considering nearly all relevant uncertainties and heterogeneities at different length scales. The effects of surface tension at droplets interface, their volume fraction, size, size polydispersity and agglomeration on elastic modulus, are considered. Different micromechanical material models are incorporated into the presented computational framework. The results clearly indicate both softening and stiffening effects of liquid droplets and show that the model can precisely predict the effective properties of liquid droplets in solid soft composites.

关键词： liquid in solid     soft composite     computational modeling     multiscale model     heterogeneity    

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Endostatin specifically targets both tumor blood vessels and lymphatic vessels

Wei Zhuo, Yang Chen, Xiaomin Song, Yongzhang Luo

《医学前沿（英文）》 2011年 第5卷 第4期   页码 336-340 doi: 10.1007/s11684-011-0163-5

摘要： Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, was first identified as a potent angiogenic inhibitor. The anti-angiogenic function of endostatin has been well documented during the past decade. Recently, several studies demonstrated that endostatin also inhibits tumor lymphangiogenesis and lymphatic metastasis. However, the exact mechanism that endostatin executes its anti-angiogenic and anti-lymphangiogenic functions remains elusive. In the current mini-review, we briefly summarize recent novel findings, including the functions of endostatin targeting not only angiogenesis but also lymphangiogenesis, and the underlying mechanism by which endostatin internalization regulates its biological functions.

关键词： endostatin     angiogenesis     lymphangiogenesis     nystatin     internalization     tumor    

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标题 作者 时间 类型 操作

Heterogeneity of the tumor immune microenvironment and clinical interventions

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

Heterogeneity of chronic obstructive pulmonary disease: from phenotype to genotype

null

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

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

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

Kai Shi, Matthew Haynes, Leaf Huang

期刊论文

Computational modeling of fracture in concrete: A review

Luthfi Muhammad Mauludin, Chahmi Oucif

期刊论文

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

期刊论文

Analysis of stress and failure in rock specimens with closed and open flaws on the surface

期刊论文

Bacteria-mediated tumor-targeted delivery of tumstatin (54-132) significantly suppresses tumor growth

期刊论文

A multiscale material model for heterogeneous liquid droplets in solid soft composites

期刊论文

Endostatin specifically targets both tumor blood vessels and lymphatic vessels

Wei Zhuo, Yang Chen, Xiaomin Song, Yongzhang Luo

期刊论文