To flourish,cancers greatly depend on their surrounding tumor microenvironment(TME),and cancer-associated fibroblasts(CAFs)in TME are critical for cancer occurrence and progression because of their versatile roles in ...To flourish,cancers greatly depend on their surrounding tumor microenvironment(TME),and cancer-associated fibroblasts(CAFs)in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling,maintenance of sternness,blood vessel formation,modulation of tumor metabolism,immune response,and promotion of cancer cell proliferation,migration,invasion,and therapeutic resistance.CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta,phosphoinositide 3-kinase/AKT/mammalian target of rapamycin,mitogen-activated protein kinase,Wnt,Janus kinase/signal transducers and activators of transcription,epidermal growth factor receptor,Hippo,and nuclear factor kappa-light-chain-enhancer of activated B cells,etc.,signaling pathways.These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy.Therefore,a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers.Herein,in this review,we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials.Further,we hypothesize three potential targeting strategies,including,namely,epithelial-mesenchymal common targets,sequential target perturbation,and crosstalk-directed signaling targets,paving the way for CAF-directed or host cell-directed antitumor therapy.展开更多
Pancreatic ductal adenocarcinoma(PDAC) is one of the most intractable malignancy, with an only 6% 5-year relative survival rate. The dismal therapeutic effect is attributed to the chemotherapy resistance and unique pa...Pancreatic ductal adenocarcinoma(PDAC) is one of the most intractable malignancy, with an only 6% 5-year relative survival rate. The dismal therapeutic effect is attributed to the chemotherapy resistance and unique pathophysiology with abundant inflammatory cytokines and abnormal hyperplasia of extracellular matrix(ECM). Based on the theory that bone marrow mesenchymal stem cells(BM-MSCs) can influence the tumorous microenvironment and malignant growth of PDAC, we employed exosomes(Exos) derived from BM-MSCs as PDAC-homing vehicles to surpass the restrictions of pathological ECM and increase the accumulation of therapeutics in tumor site. To overcome chemoresistance of PDAC, paclitaxel(PTX) and gemcitabine monophosphate(GEMP)-an intermediate product of gemcitabine metabolismd-were loaded in/on the purified Exos. In this work, the Exo delivery platform showed superiorities in homing and penetrating abilities, which were performed on tumor spheroids and PDAC orthotopic models. Meanwhile, the favorable anti-tumor efficacy in vivo and in vitro, plus relatively mild systemic toxicity, was found. Loading GEMP and PTX, benefitting from the naturally PDAC selectivity, the Exo platform we constructed performs combined functions on excellent penetrating, anti-matrix and overcoming chemoresistance(Scheme 1). Worth expectantly, the Exo platform may provide a prospective approach for targeted therapies of PDAC.展开更多
Glioblastoma multiforme(GBM)is the most aggressive and common malig-nant primary brain tumor.Patients with GBM often have poor prognoses,with a median survival of∼15 months.Enhanced understanding of the molecular bio...Glioblastoma multiforme(GBM)is the most aggressive and common malig-nant primary brain tumor.Patients with GBM often have poor prognoses,with a median survival of∼15 months.Enhanced understanding of the molecular biology of central nervous system tumors has led to modifications in their classifications,the most recent of which classified these tumors into new categories and made some changes in their nomenclature and grading system.This review aims to give a panoramic view of the last 3 years’findings in glioblastoma characterization,its heterogeneity,and current advances in its treatment.Several molecular parameters have been used to achieve an accurate and personalized characterization of glioblastoma in patients,including epigenetic,genetic,transcriptomic and metabolic features,as well as age-and sex-related patterns and the involvement of several noncoding RNAs in glioblastoma progression.Astrocyte-like neural stem cells and outer radial glial-like cells from the subven-tricular zone have been proposed as agents involved in GBM of IDH-wildtype origin,but this remains controversial.Glioblastoma metabolism is characterized by upregulation of the PI3K/Akt/mTOR signaling pathway,promotion of the gly-colytic flux,maintenance of lipid storage,and other features.This metabolism also contributes to glioblastoma’s resistance to conventional therapies.Tumor heterogeneity,a hallmark of GBM,has been shown to affect the genetic expresion,modulation of metabolic pathways,and immune system evasion.GBM’s aggressive invasion potential is modulated by cell-to-cell crosstalk within the tumor microenvironment and altered expressions of specific genes,such as ANXA2,GBP2,FN1,PHIP,and GLUT3.Nevertheless,the rising number of active clinical trials illustrates the efforts to identify new targets and drugs to treat this malignancy.Immunotherapy is still relevant for research purposes,given the amount of ongoing clinical trials based on this strategy to treat GBM,and neoantigen and nucleic acid-based vaccines are gaining import展开更多
Relapse remains the worst life-threatening complications after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in patients with acute myeloid leukemia(AML),whose prognosis has been historically dismal.Giv...Relapse remains the worst life-threatening complications after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in patients with acute myeloid leukemia(AML),whose prognosis has been historically dismal.Given the rapid development of genomics and immunotherapies,the interference strategies for AML recurrence have been changing these years.More and more novel targeting agents that have received the U.S.Food and Drug Administration(FDA)approval for de novo AML treatment have been administrated in the salvage or maintenance therapy of post-HSCT relapse.Targeted strategies that regulate the immune microenvironment of and optimize the graft versus leukemia(GVL)effect of immune cells are gradually improved.Such agents not only have been proven to achieve clinical benefits from a single drug,but if combined with classic therapies,can significantly improve the poor prognosis of AML patients who relapse after allo-HSCT.This review will focus on currently available and promising upcoming agents and also discuss the challenges and limitations of targeted therapies in the allogeneic hematopoietic stem cell transplantation community.展开更多
RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies.The mutation,isoform(KRAS,HRAS,and NRAS),position,and type of substitution vary depending ...RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies.The mutation,isoform(KRAS,HRAS,and NRAS),position,and type of substitution vary depending on the tissue types.Despite decades of developing RAS-targeted therapies,only small subsets of these inhibitors are clinically effective,such as the allelespecific inhibitors against KRASG12C.Targeting the remaining RAS mutants would require further experimental elucidation ofRAS signal transduction,RASaltered metabolism,and the associated immune microenvironment.This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants,including KRAS allele-specific inhibitors,combination therapies,immunotherapies,and metabolism-associated therapies.展开更多
Adjuvant therapies for breast cancer have achieved great success in recent years and early breast cancer is now a curable or chronic disease. Targeted therapies, including endocrine therapy and human epidermal growth ...Adjuvant therapies for breast cancer have achieved great success in recent years and early breast cancer is now a curable or chronic disease. Targeted therapies, including endocrine therapy and human epidermal growth factor receptor-2 targeted therapy, marked a new era of breast cancer treatment. However, except for chemotherapy, an efficient drug treatment to improve the overall survival of breast cancer patients is still lacking for triple negative breast cancer. Furthermore, a certain proportion of breast cancer patients present with resistance to drug therapy, making it much more difficult to control the deterioration of the disease. Recently, altered energy metabolism has become one of the hallmarks of cancer, including breast cancer, and it may be linked to drug resistance. Targeting cellular metabolism is becoming a promising strategy to overcome drug resistance in cancer therapy. This review discusses metabolic reprogramming in breast cancer and the possible complex mechanism of modulation. We also summarize the recent advances in metabolic therapy targeted glycolysis, glutaminolysis and fatty acids synthesis in breast cancer.展开更多
Biofilms are special microbial communities produced by many microorganisms,such as bacteria,viruses,and fungi.Biofilms enable the microorganisms to possess the capacity against a diversity of stressful environments.Ye...Biofilms are special microbial communities produced by many microorganisms,such as bacteria,viruses,and fungi.Biofilms enable the microorganisms to possess the capacity against a diversity of stressful environments.Yet,biofilm formation often causes tough challenges in clinical infections,food quality,and environmental issues,however,the formation mechanism of biofilms are still incompletely understood which seriously impedes the development of new strategies to eradicate biofilms in different niches.In this study,we sought to explore the regulatory role of manganese(Mn^(2+))on small-molecule metabo-lism of biofilm formation in Escherichia coli(E.coli).Using structural imaging assay combined with precision-targeted metabolomics method,to investigate how biofilm formation responded to various concentrations of Mn^(2+),we found that Mn^(2+)could inhibit biofilm formation through the regulation of phenotypic morphology and metabolic reprogramming.Collectively,our work discovered 16 differential functional metabolites and associated three metabolic pathways involving glycolysis,TCA cycle,and tryptophan metabolism that were changed mostly by Mn^(2+)during biofilm formation,which can differentiate biofilms from the relevant planktonic cells.Altogether,this study demonstrated that Mn^(2+)can inhibit biofilm formation to regulate metabolic reprogramming and micro-structure,such effort provides novel insight into the regulation of metabolic features of biofilm formation,which enables the development of new strategies to eradicate biofilm formation for addressing the challenging problems in different areas by targeting the regulation of Mn^(2+)to the biosynthesis and expres-sions of functional metabolites produced by different microorganisms.展开更多
Gastroenterology(GE) used to be considered a subspecialty of internal medicine. Today, GE is generally recognized as a wide-ranging specialty incorporating capacities, such as hepatology, oncology and interventional e...Gastroenterology(GE) used to be considered a subspecialty of internal medicine. Today, GE is generally recognized as a wide-ranging specialty incorporating capacities, such as hepatology, oncology and interventional endoscopy, necessitating GEexpert differentiation. Although the European Board of Gastroenterology and Hepatology has defined specific expertise areas in Advanced endoscopy, hepatology, digestive oncology and clinical nutrition, training for the latter topic is lacking in the current hepatogastroenterology(HGE) curriculum. Given its relevance for HGE practice, and being at the core of gastrointestinal functioning, there is an obvious need for training in nutrition and related issues including the treatment of disease-related malnutrition and obesity and its associated metabolic derangements. This document aims to be a starting point for the integration of nutritional expertise in the HGE curriculum, allowing a central role in the management of malnutrition and obesity. We suggest minimum endpoints for nutritional knowledge and expertise in the standard curriculum and recommend a focus period of training in nutrition issues in order to produce well-trained HGE specialists. This article provides a road map for the organization of such a training program. We would highly welcome the World Gastroenterology Organisation, the European Board of Gastroenterology and Hepatology, the American Gastroenterology Association and other(inter)national Gastroenterology societies support the necessary certifications for this item in the HGE-curriculum.展开更多
2017年10月16日,美国神经重症监护学会(Neurocritical Care Society,NCS)发布了目标温度管理(targeted temperature management,TTM)实施循证指南(以下称2017 NCS指南)。指南编辑委员会基于人群-干预-比较-结果(population-intervention...2017年10月16日,美国神经重症监护学会(Neurocritical Care Society,NCS)发布了目标温度管理(targeted temperature management,TTM)实施循证指南(以下称2017 NCS指南)。指南编辑委员会基于人群-干预-比较-结果(population-intervention-comparison-outcome,PICO),针对TTM的诱发和维持、寒战和并发症这3个方面、共16个相关临床问题进行了阐述与讨论。2017 NCS指南旨在协助采用TTM手段进行监护的神经重症监护医师更好地开展TTM。同时,本文在对2017 NCS指南进行解读的基础上,将该指南与2017年法国重症监护室TTM指南、2015年加拿大心脏骤停后TTM指南、2016年中国心脏骤停后目标温度管理专家共识和2015年神经重症低温治疗中国专家共识进行比较和分析,以帮助临床医师更好地了解TTM在神经重症监护中的应用进展。展开更多
基金This study was supported by the National Natural Science Foundation of China(Nos.82071124,82002884,and 81772898)Sichuan Science and Technology Program(Nos.2021YFS0194,2021YFH0143,and 2019YFS0361)Science and Technology Program of Chengdu City(No.2019YF0501151SN).
文摘To flourish,cancers greatly depend on their surrounding tumor microenvironment(TME),and cancer-associated fibroblasts(CAFs)in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling,maintenance of sternness,blood vessel formation,modulation of tumor metabolism,immune response,and promotion of cancer cell proliferation,migration,invasion,and therapeutic resistance.CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta,phosphoinositide 3-kinase/AKT/mammalian target of rapamycin,mitogen-activated protein kinase,Wnt,Janus kinase/signal transducers and activators of transcription,epidermal growth factor receptor,Hippo,and nuclear factor kappa-light-chain-enhancer of activated B cells,etc.,signaling pathways.These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy.Therefore,a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers.Herein,in this review,we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials.Further,we hypothesize three potential targeting strategies,including,namely,epithelial-mesenchymal common targets,sequential target perturbation,and crosstalk-directed signaling targets,paving the way for CAF-directed or host cell-directed antitumor therapy.
基金the support from National Science Fund for Distinguished Young Scholars(grant No.81425023,China)National Natural Science Foundation of China(grant No.81872808)Program of Shanghai Academic Research Leader(18XD1400500,China)
文摘Pancreatic ductal adenocarcinoma(PDAC) is one of the most intractable malignancy, with an only 6% 5-year relative survival rate. The dismal therapeutic effect is attributed to the chemotherapy resistance and unique pathophysiology with abundant inflammatory cytokines and abnormal hyperplasia of extracellular matrix(ECM). Based on the theory that bone marrow mesenchymal stem cells(BM-MSCs) can influence the tumorous microenvironment and malignant growth of PDAC, we employed exosomes(Exos) derived from BM-MSCs as PDAC-homing vehicles to surpass the restrictions of pathological ECM and increase the accumulation of therapeutics in tumor site. To overcome chemoresistance of PDAC, paclitaxel(PTX) and gemcitabine monophosphate(GEMP)-an intermediate product of gemcitabine metabolismd-were loaded in/on the purified Exos. In this work, the Exo delivery platform showed superiorities in homing and penetrating abilities, which were performed on tumor spheroids and PDAC orthotopic models. Meanwhile, the favorable anti-tumor efficacy in vivo and in vitro, plus relatively mild systemic toxicity, was found. Loading GEMP and PTX, benefitting from the naturally PDAC selectivity, the Exo platform we constructed performs combined functions on excellent penetrating, anti-matrix and overcoming chemoresistance(Scheme 1). Worth expectantly, the Exo platform may provide a prospective approach for targeted therapies of PDAC.
基金Ministerio de Ciencia e Innovación,Grant/Award Number:PID2019-105010RB-I00Agencia de Innovación y Desarrollo de Andalucía,Grant/Award Numbers:BIO 267,UMA18-FEDERJA-220。
文摘Glioblastoma multiforme(GBM)is the most aggressive and common malig-nant primary brain tumor.Patients with GBM often have poor prognoses,with a median survival of∼15 months.Enhanced understanding of the molecular biology of central nervous system tumors has led to modifications in their classifications,the most recent of which classified these tumors into new categories and made some changes in their nomenclature and grading system.This review aims to give a panoramic view of the last 3 years’findings in glioblastoma characterization,its heterogeneity,and current advances in its treatment.Several molecular parameters have been used to achieve an accurate and personalized characterization of glioblastoma in patients,including epigenetic,genetic,transcriptomic and metabolic features,as well as age-and sex-related patterns and the involvement of several noncoding RNAs in glioblastoma progression.Astrocyte-like neural stem cells and outer radial glial-like cells from the subven-tricular zone have been proposed as agents involved in GBM of IDH-wildtype origin,but this remains controversial.Glioblastoma metabolism is characterized by upregulation of the PI3K/Akt/mTOR signaling pathway,promotion of the gly-colytic flux,maintenance of lipid storage,and other features.This metabolism also contributes to glioblastoma’s resistance to conventional therapies.Tumor heterogeneity,a hallmark of GBM,has been shown to affect the genetic expresion,modulation of metabolic pathways,and immune system evasion.GBM’s aggressive invasion potential is modulated by cell-to-cell crosstalk within the tumor microenvironment and altered expressions of specific genes,such as ANXA2,GBP2,FN1,PHIP,and GLUT3.Nevertheless,the rising number of active clinical trials illustrates the efforts to identify new targets and drugs to treat this malignancy.Immunotherapy is still relevant for research purposes,given the amount of ongoing clinical trials based on this strategy to treat GBM,and neoantigen and nucleic acid-based vaccines are gaining import
基金supported by the National Natural Science Foundation of China(Grant No.81302043)the Collaborative Innovation Center of Hematology,China
文摘Relapse remains the worst life-threatening complications after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in patients with acute myeloid leukemia(AML),whose prognosis has been historically dismal.Given the rapid development of genomics and immunotherapies,the interference strategies for AML recurrence have been changing these years.More and more novel targeting agents that have received the U.S.Food and Drug Administration(FDA)approval for de novo AML treatment have been administrated in the salvage or maintenance therapy of post-HSCT relapse.Targeted strategies that regulate the immune microenvironment of and optimize the graft versus leukemia(GVL)effect of immune cells are gradually improved.Such agents not only have been proven to achieve clinical benefits from a single drug,but if combined with classic therapies,can significantly improve the poor prognosis of AML patients who relapse after allo-HSCT.This review will focus on currently available and promising upcoming agents and also discuss the challenges and limitations of targeted therapies in the allogeneic hematopoietic stem cell transplantation community.
基金National Natural Science Foundation of China,Grant/Award Numbers:82072360,82102704,82072624,81872481Natural Science Foundation of Zhejiang Province,Grant/Award Number:LBY20H160002。
文摘RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies.The mutation,isoform(KRAS,HRAS,and NRAS),position,and type of substitution vary depending on the tissue types.Despite decades of developing RAS-targeted therapies,only small subsets of these inhibitors are clinically effective,such as the allelespecific inhibitors against KRASG12C.Targeting the remaining RAS mutants would require further experimental elucidation ofRAS signal transduction,RASaltered metabolism,and the associated immune microenvironment.This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants,including KRAS allele-specific inhibitors,combination therapies,immunotherapies,and metabolism-associated therapies.
文摘Adjuvant therapies for breast cancer have achieved great success in recent years and early breast cancer is now a curable or chronic disease. Targeted therapies, including endocrine therapy and human epidermal growth factor receptor-2 targeted therapy, marked a new era of breast cancer treatment. However, except for chemotherapy, an efficient drug treatment to improve the overall survival of breast cancer patients is still lacking for triple negative breast cancer. Furthermore, a certain proportion of breast cancer patients present with resistance to drug therapy, making it much more difficult to control the deterioration of the disease. Recently, altered energy metabolism has become one of the hallmarks of cancer, including breast cancer, and it may be linked to drug resistance. Targeting cellular metabolism is becoming a promising strategy to overcome drug resistance in cancer therapy. This review discusses metabolic reprogramming in breast cancer and the possible complex mechanism of modulation. We also summarize the recent advances in metabolic therapy targeted glycolysis, glutaminolysis and fatty acids synthesis in breast cancer.
基金This work was supported by the National Key R&D Program of China(No.2017YFC1308600 and 2017YFC1308605)the National Natural Science Foundation of China Grants(No.31670031)the Startup Funding for Specialized Professorship Provided by Shanghai Jiao Tong University(No.WF220441502).
文摘Biofilms are special microbial communities produced by many microorganisms,such as bacteria,viruses,and fungi.Biofilms enable the microorganisms to possess the capacity against a diversity of stressful environments.Yet,biofilm formation often causes tough challenges in clinical infections,food quality,and environmental issues,however,the formation mechanism of biofilms are still incompletely understood which seriously impedes the development of new strategies to eradicate biofilms in different niches.In this study,we sought to explore the regulatory role of manganese(Mn^(2+))on small-molecule metabo-lism of biofilm formation in Escherichia coli(E.coli).Using structural imaging assay combined with precision-targeted metabolomics method,to investigate how biofilm formation responded to various concentrations of Mn^(2+),we found that Mn^(2+)could inhibit biofilm formation through the regulation of phenotypic morphology and metabolic reprogramming.Collectively,our work discovered 16 differential functional metabolites and associated three metabolic pathways involving glycolysis,TCA cycle,and tryptophan metabolism that were changed mostly by Mn^(2+)during biofilm formation,which can differentiate biofilms from the relevant planktonic cells.Altogether,this study demonstrated that Mn^(2+)can inhibit biofilm formation to regulate metabolic reprogramming and micro-structure,such effort provides novel insight into the regulation of metabolic features of biofilm formation,which enables the development of new strategies to eradicate biofilm formation for addressing the challenging problems in different areas by targeting the regulation of Mn^(2+)to the biosynthesis and expres-sions of functional metabolites produced by different microorganisms.
文摘Gastroenterology(GE) used to be considered a subspecialty of internal medicine. Today, GE is generally recognized as a wide-ranging specialty incorporating capacities, such as hepatology, oncology and interventional endoscopy, necessitating GEexpert differentiation. Although the European Board of Gastroenterology and Hepatology has defined specific expertise areas in Advanced endoscopy, hepatology, digestive oncology and clinical nutrition, training for the latter topic is lacking in the current hepatogastroenterology(HGE) curriculum. Given its relevance for HGE practice, and being at the core of gastrointestinal functioning, there is an obvious need for training in nutrition and related issues including the treatment of disease-related malnutrition and obesity and its associated metabolic derangements. This document aims to be a starting point for the integration of nutritional expertise in the HGE curriculum, allowing a central role in the management of malnutrition and obesity. We suggest minimum endpoints for nutritional knowledge and expertise in the standard curriculum and recommend a focus period of training in nutrition issues in order to produce well-trained HGE specialists. This article provides a road map for the organization of such a training program. We would highly welcome the World Gastroenterology Organisation, the European Board of Gastroenterology and Hepatology, the American Gastroenterology Association and other(inter)national Gastroenterology societies support the necessary certifications for this item in the HGE-curriculum.
文摘2017年10月16日,美国神经重症监护学会(Neurocritical Care Society,NCS)发布了目标温度管理(targeted temperature management,TTM)实施循证指南(以下称2017 NCS指南)。指南编辑委员会基于人群-干预-比较-结果(population-intervention-comparison-outcome,PICO),针对TTM的诱发和维持、寒战和并发症这3个方面、共16个相关临床问题进行了阐述与讨论。2017 NCS指南旨在协助采用TTM手段进行监护的神经重症监护医师更好地开展TTM。同时,本文在对2017 NCS指南进行解读的基础上,将该指南与2017年法国重症监护室TTM指南、2015年加拿大心脏骤停后TTM指南、2016年中国心脏骤停后目标温度管理专家共识和2015年神经重症低温治疗中国专家共识进行比较和分析,以帮助临床医师更好地了解TTM在神经重症监护中的应用进展。
