Clear cell hepatocellular carcinoma(CCHCC)has hitherto been considered an uncommon, highly differentiated variant of hepatocellular carcinoma(HCC) with a relatively favorable prognosis. CCHCC is composed of mixtures o...Clear cell hepatocellular carcinoma(CCHCC)has hitherto been considered an uncommon, highly differentiated variant of hepatocellular carcinoma(HCC) with a relatively favorable prognosis. CCHCC is composed of mixtures of clear and/or acidophilic ground glass hepatocytes with excessive glycogen and/or fat and shares histology, clinical features and etiology with common HCCs. Studies in animal models of chemical, hormonal and viral hepatocarcinogenesis and observations in patients with chronic liver diseases prone to develop HCC have shown that the majority of HCCs are preceded by, or associated with, focal or diffuse excessive storage of glycogen(glycogenosis) which later may be replaced by fat(lipidosis/steatosis). In ground glass cells, the glycogenosis is accompanied by proliferation of the smooth endoplasmic reticulum, which is closely related to glycogen particles and frequently harbors the hepatitis B surface antigen(HBs Ag).From the findings in animal models a sequence of changes has been established, commencing with preneoplastic glycogenotic liver lesions, often containing ground glass cells, and progressing to glycogen-poor neoplasms via various intermediate stages, including glycogenotic/lipidotic clear cell foci, clear cell hepatocellular adenomas(CCHCA) rich in glycogen and/or fat, and CCHCC. A similar process seems to take place in humans, with clear cells frequently persisting in CCHCC and steatohepatitic HCC, which presumably represent intermediate stages in the development rather than particular variants of HCC. During the progression of the preneoplastic lesions,the clear and ground glass cells transform into cells characteristic of common HCC. The sequential cellular changes are associated with metabolic aberrations, which start with an activation of the insulin signaling cascade resulting in preneoplastic hepatic glycogenosis. The molecular and metabolic changes underlying the glycogenosis/lipidosis are apparently responsible for the dramatic metabolic shift from gluconeogenesis to the pentose ph展开更多
On-tissue chemical derivatization(OTCD)effectively enhances ionization efficiency of low abundant and poorly ionized functional molecules to improve detection sensitivity and coverage of mass spectrometry imaging(MSI)...On-tissue chemical derivatization(OTCD)effectively enhances ionization efficiency of low abundant and poorly ionized functional molecules to improve detection sensitivity and coverage of mass spectrometry imaging(MSI).Combination OTCD and MSI provides a novel strategy for visualizing previously undisclosed metabolic heterogeneity in tumor.Herein,we present a method to visualize heterogeneous metabolism of oxylipins within tumor by coupling OTCD with airflow-assisted desorption electrospray ionization(AFADESI)-MSI.Taking Girard’s P as a derivatization reagent,easily ionized hydrazide and quaternary amine groups were introduced into the structure of carbonyl metabolites via condensation reaction.Oxylipins,including 127 fatty aldehydes(FALs)and 71 oxo fatty acids(FAs),were detected and imaged in esophageal cancer xenograft with AFADESI-MSI after OTCD.Then t-distributed stochastic neighbor embedding and random forest were exploited to precisely locate the distribution of oxylipins in heterogeneous tumor tissue.With this method,we surprisingly found almost all FALs and oxo FAs significantly accumulated in the core region of tumor,and exhibited a gradual increase trend in tumor over time.These results reveal spatiotemporal heterogeneity of oxylipins in tumor progression,highlighting the value of OTCD combined with MSI to gain deeper insights into understanding tumor metabolism.展开更多
Non-alcoholic fatty liver disease(NAFLD)is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity.There is also substantial inter-individual variation and var...Non-alcoholic fatty liver disease(NAFLD)is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity.There is also substantial inter-individual variation and variable response to a different therapy.This heterogeneity of NAFLD is in turn influenced by various factors primarily demographic/dietary factors,metabolic status,gut microbiome,genetic predisposition together with epigenetic factors.The differential impact of these factors over a variable period of time influences the clinical phenotype and natural history.Failure to address heterogeneity partly explains the sub-optimal response to current and emerging therapies for fatty liver disease.Consequently,leading experts across the globe have recently suggested a change in nomenclature of NAFLD to metabolic-associated fatty liver disease(MAFLD)which can better reflect current knowledge of heterogeneity and does not exclude concomitant factors for fatty liver disease(e.g.alcohol,viral hepatitis,etc.).Precise identification of disease phenotypes is likely to facilitate clinical trial recruitment and expedite translational research for the development of novel and effective therapies for NAFLD/MAFLD.展开更多
Thyroid carcinoma is one of the most common endocrine malignant diseases worldwide.With the rapid development of medical technology,early and effective diagnostic methods could be able to improve the survival rate and...Thyroid carcinoma is one of the most common endocrine malignant diseases worldwide.With the rapid development of medical technology,early and effective diagnostic methods could be able to improve the survival rate and quality of life of patients suffering from the disease.Considering the complexity of cancer,some specific detection method is desired for diagnosis and treatment.Mass spectrometry imaging(MSI)is an emerging technique for acquiring molecular information from biological tissues without staining and labeling,including qualitative,quantitative and spatial distribution information.Over the past several decades,MSI has been widely used for pharmacological monitoring,biomolecular imaging of cells and tissues.In this review,we introduce the tumor progression and histological characteristics of thyroid cancer,and focus mainly on the preparation of biological specimens for MSI and mass spectrometry(MS)analysis,as well as the recent progress in MS and MSI-based thyroid cancer research.This review thoroughly discusses the importance of MS and MSI for clinical diagnosis,identification and prognosis of thyroid cancer,and provides some new clues for molecular mechanisms research and tumor metastasis.展开更多
Objective:To classify the subtypes of metabolic-associated fatty liver disease(MAFLD)and provide new insights into the heterogeneity of MAFLD.Methods:Electronic medical records(EMR)of MAFLD diagnosed in accordance wit...Objective:To classify the subtypes of metabolic-associated fatty liver disease(MAFLD)and provide new insights into the heterogeneity of MAFLD.Methods:Electronic medical records(EMR)of MAFLD diagnosed in accordance with the diagnostic criteria of Hubei Provincial Hospital of Traditional Chinese Medicine from 2016-2020 were included in the study.for physical annotation,and the data on each clinical phenotype was normalized according to corresponding aspirational standards.The MAFLD heterogeneous medical record network(HEMnet)was constructed using sex,age,disease diagnosis,symptoms,and Western medicine prescriptions as nodes and the co-occurrence times between phenotypes as edges.K-means clustering was used for disease classification.Relative risk(RR)was used to assess the specificity of each phenotype.Statistical methods were used to compare differences in laboratory indicators among subtypes.Results:A total of patients(12,626)with a mean age of 55.02(±14.21)years were included in the study.MAFLD can be divided into five subtypes:digestive diseases(C0),mental disorders and gynecological diseases(C1),chronic liver diseases and decompensated complications(C2),diabetes mellitus and its complications(C3),and immune joint system diseases(C4).Conclusions:Patients with MAFLD experience various symptoms and complications.The classification of MAFLD based on the HEMnet method is highly reliable.展开更多
Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is now the most prevalent chronic liver disease worldwide,with an increasing incidence rate.MAFLD is a heterogeneous disease that can have a low or...Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is now the most prevalent chronic liver disease worldwide,with an increasing incidence rate.MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course.Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases.However,it remains unclear whether the RNA N1-methyladenosine(m1A)modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD.Materials and methods:To address this issue,we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing(scRNA-seq)data to pinpoint m1A regulators in the network.This was followed by a description of the immune landscape,pathway enrichment analysis,and molecular subtyping.Results:The expression patterns of m1A regulatory genes stratify MAFLD into two molecular subtypes,Cluster 1 and Cluster 2.These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics,which suggest different immune-inflammatory responses in the liver.Notably,Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD.Through intersection analysis of weighted gene co-expression network analysis(WGCNA)and m1A regulatory genes,three true hub genes(ALKBH1,YTHDC1,and YTHDF3)were identified,all of which were strongly correlated with infiltrating immune cells.The specific signaling pathways involved in the three core genes were derived from genomic variation analysis.Furthermore,scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types,with endothelial cells,macrophages,and monocytes showing the most significant differences between MAFLD and normal controls.The cell-cell communication network between immune cells and nonparenchymal cells was extremely sophisticated and changed significantly in MAFLD.展开更多
OBJECTIVE Gastric cancer is one of the most common malignant tumors,and the incidence rate is the highest in all kinds of tumors in China.However,it remains unclear that how signifi.cantly gastric cells are dependent ...OBJECTIVE Gastric cancer is one of the most common malignant tumors,and the incidence rate is the highest in all kinds of tumors in China.However,it remains unclear that how signifi.cantly gastric cells are dependent on glycolysis,and which type of gastric cells are sensitive to glycolysis inhibition.In this study,several kind of gastric cancer cell lines were used as the research object,and the metabolic characteristics of different cell lines were systematically analyzed to provide theoretical support for the accurate treatment of gastric cancer.METHODS We examined the energy metabolism of four gastric cancer cell lines(MGC-803,SGC-7901,HGC-27 and BGC-823) by using glycolysis inhibitor,2-deoxy-D-glucose(2-DG) and inhibitor of oxidative phosphorylation,oligomycin.Oxygen consumption rates(OCR) and L-lactate were also measured with an XF96 Analyzer(Seahorse Biosciences) to deter.mine the significance of metabolism of oxidative phosphorylation and aerobic glycolysisin gastric cells.In addition,western blot was used to detect the contribution of AMP-activated protein kinase(AMPK),and anti-apoptotic proteins(Bcl-2 and survivin) to clarify the mechanism of death or survival of gastric cancer cells treated by 2-DG or oligomycin.RESULTS In this study,it was shown that the growth of gastric cell lines were suppressed by 2-DG.However,the sensitivity to 2-DG was quite different among cell lines:IC 50 of 2-DG was from 3.28 mmol·L^(-1)(MGC-803) to 15.57 mmol·L^(-1)(BGC-823).MGC-803 was relatively sensitive to 2-DG(IC 50:3.28 mmol·L^(-1)),consumed more glucose and produced more lactate(waste product of glycolysis) than the three other cell lines.Consequently,MGC-803 could be more dependent on glycolysis than other cell lines,which was further confirmed by the fact that glucose(+) FCS(-) medium showed more growth and survival than glucose(-) FCS(+) medium.Alternatively,BGC-823,most resistant to 2-DG(IC50:15.57 mmol · L-1),was most sensitive to oligomycin,and showed more growth and survival in glucose(-) FCS(+) medium than 展开更多
基金partly supported by a grant from the Deutsche Forschungsgemeinschaft(RI2695/1-1)
文摘Clear cell hepatocellular carcinoma(CCHCC)has hitherto been considered an uncommon, highly differentiated variant of hepatocellular carcinoma(HCC) with a relatively favorable prognosis. CCHCC is composed of mixtures of clear and/or acidophilic ground glass hepatocytes with excessive glycogen and/or fat and shares histology, clinical features and etiology with common HCCs. Studies in animal models of chemical, hormonal and viral hepatocarcinogenesis and observations in patients with chronic liver diseases prone to develop HCC have shown that the majority of HCCs are preceded by, or associated with, focal or diffuse excessive storage of glycogen(glycogenosis) which later may be replaced by fat(lipidosis/steatosis). In ground glass cells, the glycogenosis is accompanied by proliferation of the smooth endoplasmic reticulum, which is closely related to glycogen particles and frequently harbors the hepatitis B surface antigen(HBs Ag).From the findings in animal models a sequence of changes has been established, commencing with preneoplastic glycogenotic liver lesions, often containing ground glass cells, and progressing to glycogen-poor neoplasms via various intermediate stages, including glycogenotic/lipidotic clear cell foci, clear cell hepatocellular adenomas(CCHCA) rich in glycogen and/or fat, and CCHCC. A similar process seems to take place in humans, with clear cells frequently persisting in CCHCC and steatohepatitic HCC, which presumably represent intermediate stages in the development rather than particular variants of HCC. During the progression of the preneoplastic lesions,the clear and ground glass cells transform into cells characteristic of common HCC. The sequential cellular changes are associated with metabolic aberrations, which start with an activation of the insulin signaling cascade resulting in preneoplastic hepatic glycogenosis. The molecular and metabolic changes underlying the glycogenosis/lipidosis are apparently responsible for the dramatic metabolic shift from gluconeogenesis to the pentose ph
基金supported by the National Natural Science Foundation of China(No.21927808)the Chinese Academy of Medical Science(CAMS)Innovation Fund for Medical Sciences(CIFMS,Nos.2022-I2M-2-002 and 2021-1-I2M-028).
文摘On-tissue chemical derivatization(OTCD)effectively enhances ionization efficiency of low abundant and poorly ionized functional molecules to improve detection sensitivity and coverage of mass spectrometry imaging(MSI).Combination OTCD and MSI provides a novel strategy for visualizing previously undisclosed metabolic heterogeneity in tumor.Herein,we present a method to visualize heterogeneous metabolism of oxylipins within tumor by coupling OTCD with airflow-assisted desorption electrospray ionization(AFADESI)-MSI.Taking Girard’s P as a derivatization reagent,easily ionized hydrazide and quaternary amine groups were introduced into the structure of carbonyl metabolites via condensation reaction.Oxylipins,including 127 fatty aldehydes(FALs)and 71 oxo fatty acids(FAs),were detected and imaged in esophageal cancer xenograft with AFADESI-MSI after OTCD.Then t-distributed stochastic neighbor embedding and random forest were exploited to precisely locate the distribution of oxylipins in heterogeneous tumor tissue.With this method,we surprisingly found almost all FALs and oxo FAs significantly accumulated in the core region of tumor,and exhibited a gradual increase trend in tumor over time.These results reveal spatiotemporal heterogeneity of oxylipins in tumor progression,highlighting the value of OTCD combined with MSI to gain deeper insights into understanding tumor metabolism.
文摘Non-alcoholic fatty liver disease(NAFLD)is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity.There is also substantial inter-individual variation and variable response to a different therapy.This heterogeneity of NAFLD is in turn influenced by various factors primarily demographic/dietary factors,metabolic status,gut microbiome,genetic predisposition together with epigenetic factors.The differential impact of these factors over a variable period of time influences the clinical phenotype and natural history.Failure to address heterogeneity partly explains the sub-optimal response to current and emerging therapies for fatty liver disease.Consequently,leading experts across the globe have recently suggested a change in nomenclature of NAFLD to metabolic-associated fatty liver disease(MAFLD)which can better reflect current knowledge of heterogeneity and does not exclude concomitant factors for fatty liver disease(e.g.alcohol,viral hepatitis,etc.).Precise identification of disease phenotypes is likely to facilitate clinical trial recruitment and expedite translational research for the development of novel and effective therapies for NAFLD/MAFLD.
基金The Natural Science Foundation of Guangdong Province,China(2021A1515010171)Natural Science Foundation of Shanxi Province of China(201901D111210)+2 种基金2019 Platform Base Special Project of Shanxi Province(201905D121002)Shanxi Medical University Innovation and Entrepreneurship Fund for College Students(2020181)Shenzhen Science and Technology Innovation Commission(KCXFZ202002011008124)
文摘Thyroid carcinoma is one of the most common endocrine malignant diseases worldwide.With the rapid development of medical technology,early and effective diagnostic methods could be able to improve the survival rate and quality of life of patients suffering from the disease.Considering the complexity of cancer,some specific detection method is desired for diagnosis and treatment.Mass spectrometry imaging(MSI)is an emerging technique for acquiring molecular information from biological tissues without staining and labeling,including qualitative,quantitative and spatial distribution information.Over the past several decades,MSI has been widely used for pharmacological monitoring,biomolecular imaging of cells and tissues.In this review,we introduce the tumor progression and histological characteristics of thyroid cancer,and focus mainly on the preparation of biological specimens for MSI and mass spectrometry(MS)analysis,as well as the recent progress in MS and MSI-based thyroid cancer research.This review thoroughly discusses the importance of MS and MSI for clinical diagnosis,identification and prognosis of thyroid cancer,and provides some new clues for molecular mechanisms research and tumor metastasis.
基金supported by grants from the Key project Natural Science Foundation of Hubei Province(No.2020CFA023)Project of the State Administration of Traditional Chinese Medicine(No Z155080000004):Key Laboratory of Liver and Kidney Treatment of Chronic Liver Diseases.
文摘Objective:To classify the subtypes of metabolic-associated fatty liver disease(MAFLD)and provide new insights into the heterogeneity of MAFLD.Methods:Electronic medical records(EMR)of MAFLD diagnosed in accordance with the diagnostic criteria of Hubei Provincial Hospital of Traditional Chinese Medicine from 2016-2020 were included in the study.for physical annotation,and the data on each clinical phenotype was normalized according to corresponding aspirational standards.The MAFLD heterogeneous medical record network(HEMnet)was constructed using sex,age,disease diagnosis,symptoms,and Western medicine prescriptions as nodes and the co-occurrence times between phenotypes as edges.K-means clustering was used for disease classification.Relative risk(RR)was used to assess the specificity of each phenotype.Statistical methods were used to compare differences in laboratory indicators among subtypes.Results:A total of patients(12,626)with a mean age of 55.02(±14.21)years were included in the study.MAFLD can be divided into five subtypes:digestive diseases(C0),mental disorders and gynecological diseases(C1),chronic liver diseases and decompensated complications(C2),diabetes mellitus and its complications(C3),and immune joint system diseases(C4).Conclusions:Patients with MAFLD experience various symptoms and complications.The classification of MAFLD based on the HEMnet method is highly reliable.
基金This work was funded by the National Natural Science Foundation of China(82000620,81870449)GuangDong Basic and Applied Basic Research Foundation(2023A1515010583)+1 种基金China Postdoctoral Science Foundation(2022M723610)Natural Science Foundation of Xinjiang Uyghur Autonomous Region(2020D01C006).
文摘Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is now the most prevalent chronic liver disease worldwide,with an increasing incidence rate.MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course.Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases.However,it remains unclear whether the RNA N1-methyladenosine(m1A)modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD.Materials and methods:To address this issue,we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing(scRNA-seq)data to pinpoint m1A regulators in the network.This was followed by a description of the immune landscape,pathway enrichment analysis,and molecular subtyping.Results:The expression patterns of m1A regulatory genes stratify MAFLD into two molecular subtypes,Cluster 1 and Cluster 2.These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics,which suggest different immune-inflammatory responses in the liver.Notably,Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD.Through intersection analysis of weighted gene co-expression network analysis(WGCNA)and m1A regulatory genes,three true hub genes(ALKBH1,YTHDC1,and YTHDF3)were identified,all of which were strongly correlated with infiltrating immune cells.The specific signaling pathways involved in the three core genes were derived from genomic variation analysis.Furthermore,scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types,with endothelial cells,macrophages,and monocytes showing the most significant differences between MAFLD and normal controls.The cell-cell communication network between immune cells and nonparenchymal cells was extremely sophisticated and changed significantly in MAFLD.
基金supported by National Natural Science Foundation of China(81502952)
文摘OBJECTIVE Gastric cancer is one of the most common malignant tumors,and the incidence rate is the highest in all kinds of tumors in China.However,it remains unclear that how signifi.cantly gastric cells are dependent on glycolysis,and which type of gastric cells are sensitive to glycolysis inhibition.In this study,several kind of gastric cancer cell lines were used as the research object,and the metabolic characteristics of different cell lines were systematically analyzed to provide theoretical support for the accurate treatment of gastric cancer.METHODS We examined the energy metabolism of four gastric cancer cell lines(MGC-803,SGC-7901,HGC-27 and BGC-823) by using glycolysis inhibitor,2-deoxy-D-glucose(2-DG) and inhibitor of oxidative phosphorylation,oligomycin.Oxygen consumption rates(OCR) and L-lactate were also measured with an XF96 Analyzer(Seahorse Biosciences) to deter.mine the significance of metabolism of oxidative phosphorylation and aerobic glycolysisin gastric cells.In addition,western blot was used to detect the contribution of AMP-activated protein kinase(AMPK),and anti-apoptotic proteins(Bcl-2 and survivin) to clarify the mechanism of death or survival of gastric cancer cells treated by 2-DG or oligomycin.RESULTS In this study,it was shown that the growth of gastric cell lines were suppressed by 2-DG.However,the sensitivity to 2-DG was quite different among cell lines:IC 50 of 2-DG was from 3.28 mmol·L^(-1)(MGC-803) to 15.57 mmol·L^(-1)(BGC-823).MGC-803 was relatively sensitive to 2-DG(IC 50:3.28 mmol·L^(-1)),consumed more glucose and produced more lactate(waste product of glycolysis) than the three other cell lines.Consequently,MGC-803 could be more dependent on glycolysis than other cell lines,which was further confirmed by the fact that glucose(+) FCS(-) medium showed more growth and survival than glucose(-) FCS(+) medium.Alternatively,BGC-823,most resistant to 2-DG(IC50:15.57 mmol · L-1),was most sensitive to oligomycin,and showed more growth and survival in glucose(-) FCS(+) medium than
