Sleep deprivation(SD)is a widespread issue that disrupts the lives of millions of people.These effects ini-tiate as changes within neurons,specifically at the DNA and RNA level,leading to disruptions in neuronal plast...Sleep deprivation(SD)is a widespread issue that disrupts the lives of millions of people.These effects ini-tiate as changes within neurons,specifically at the DNA and RNA level,leading to disruptions in neuronal plasticity and the dysregulation of various cognitive functions,such as learning and memory.Nucleic acid epigenetic modifications that could regulate gene expression have been reported to play crucial roles in this process.However,there is a lack of comprehensive research on the correlation of SD with nucleic acid epigenetic modifications.In the current study,we aimed to systematically investigate the landscape of modifications in DNA as well as in small RNA molecules across multiple tissues,including the heart,liver,kidney,lung,hippocampus,and spleen,in response to chronic sleep deprivation(CSD).Using liquid chromatography-tandem mass spectrometry(LC-MS/MS)analysis,we characterized the dynamic changes in DNA and RNA modification profiles in different tissues of mice under CSD stress.Specifically,we ob-served a significant decrease in the level of 5-methylcytosine(5mC)and a significant increase in the level of 5-hydroxymethylcytosine(5hmC)in the kidney in CSD group.Regarding RNA modifications,we observed an overall increased trend for most of these significantly changed modifications across six tis-sues in CSD group.Our study sheds light on the significance of DNA and RNA modifications as crucial epigenetic markers in the context of CSD-induced stress.展开更多
Chronic kidney disease(CKD)is an increasingly prevalent medical condition associated with high mortality and cardiovascular complications.The intricate interplay between kidney dysfunction and subsequent metabolic dis...Chronic kidney disease(CKD)is an increasingly prevalent medical condition associated with high mortality and cardiovascular complications.The intricate interplay between kidney dysfunction and subsequent metabolic disturbances may provide insights into the underlying mechanisms driving CKD onset and progression.Herein,we proposed a large-scale plasma metabolite identification and quantification system that combines the strengths of targeted and untargeted metabolomics technologies,i.e.,widely-targeted metabolomics(WT-Met)approach.WT-Met method enables large-scale identification and accurate quantification of thousands of metabolites.We collected plasma samples from 21 healthy controls and 62CKD patients,categorized into different stages(22 in stages 1-3,20 in stage 4,and 20 in stage 5).Using LC-MS-based WT-Met approach,we were able to effectively annotate and quantify a total of 1431metabolites from the plasma samples.Focusing on the 539 endogenous metabolites,we identified 399significantly altered metabolites and depicted their changing patterns from healthy controls to end-stage CKD.Furthermore,we employed machine-learning to identify the optimal combination of metabolites for predicting different stages of CKD.We generated a multiclass classifier consisting of 7 metabolites by machine-learning,which exhibited an average AUC of 0.99 for the test set.In general,amino acids,nucleotides,organic acids,and their metabolites emerged as the most significantly altered metabolites.However,their patterns of change varied across different stages of CKD.The 7-metabolite panel demonstrates promising potential as biomarker candidates for CKD.Further exploration of these metabolites can provide valuable insights into their roles in the etiology and progression of CKD.展开更多
The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is non-immunogenic, which consists of the stellate cells, fibroblasts, immune cells, extracellular matrix, and some other immune suppressive molecu...The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is non-immunogenic, which consists of the stellate cells, fibroblasts, immune cells, extracellular matrix, and some other immune suppressive molecules. This low tumor perfusion microenvironment with physical dense fibrotic stroma shields PDAC from traditional antitumor therapies like chemotherapy and various strategies that have been proven successful in other types of cancer. Immunotherapy has the potential to treat minimal and residual diseases and prevent recurrence with minimal toxicity, and studies in patients with metastatic and nonresectable disease have shown some efficacy. In this review, we highlighted the main components of the pancreatic tumor microenvironment, and meanwhile, summarized the advances of some promising immunotherapies for PDAC, including checkpoint inhibitors, chimeric antigen receptors T cells, and cancer vaccines. Based on our previous researches, we specifically discussed how granulocyte-macrophage colony stimulating factor based pancreatic cancer vaccine prime the pancreatic tumor microenvironment, and introduced some novel immunoadjuvants, like the stimulator of interferon genes.展开更多
BACKGROUND CD155 is an immune checkpoint protein in cancers and interacts with ligands to regulate the immune microenvironment.The expression of CD155 is correlated with the prognosis and pathological features of brea...BACKGROUND CD155 is an immune checkpoint protein in cancers and interacts with ligands to regulate the immune microenvironment.The expression of CD155 is correlated with the prognosis and pathological features of breast cancer.AIM To investigate the expression status of CD155 and the association with exhausted CD4+helper and CD8+cytotoxic tumor infiltrating lymphocytes(TILs)and PD-L1 in the breast cancer microenvironment.METHODS One hundred and twenty-six breast cancer patients with invasive ductal breast cancer were consecutively recruited into this study.Immunohistochemistry was used to detect the expression CD155,PD-L1 and PD-1 on tumor-infiltrating immune cells and tumor cells in the microenvironment.RESULTS The proportion of patients with CD155 expression was higher in triple negative breast cancer(72.7%)than in Luminal A patients(22.2%,P<0.05).Patients with positive CD155 expression had a higher percentage of CD4+/PD-1+helper TILs(30%)than patients with negative CD155 expression(21%,P<0.05).Patients with positive CD155 expression also had higher cell counts of exhausted CD4+TILs[47 vs 20/high-power fields(HPF)]and unexhausted CD8+TILs(30 vs 17/HPF)than patients with negative expression(P<0.05).CD155 expression was correlated with increased PD-L1 expression in immune cells,0.8%and 0.02%immune cells expressed PD-L1 in patients with positive and negative CD155 expression,respectively(P<0.05).CONCLUSION CD155 was related to an inhibitory immune breast cancer microenvironment.CD155 was associated with a high proportion of exhausted CD4+and unexhausted CD8+TILs and high PD-L1 expression in immune cells.展开更多
BACKGROUND Hypertension(HTN)and type 2 diabetes mellitus(T2DM)are often coincident,and each condition is considered a risk factor for the other.Both occur frequently in the Inner Mongolia region of China.The reasons f...BACKGROUND Hypertension(HTN)and type 2 diabetes mellitus(T2DM)are often coincident,and each condition is considered a risk factor for the other.Both occur frequently in the Inner Mongolia region of China.The reasons for differences in risk between Han and Mongolian ethnic groups are not known.The LEPR gene and its polymorphism,rs1137101(Gln223Arg),are both considered risk factors for HTN and T2DM,but any role of rs1137101 in the occurrence of HTN+T2DM remains unclear for Mongolian and Han populations in the Inner Mongolia region.AIM To investigate the relationship between rs1137101 and the occurrence of HTN with T2DM in Mongolian and Han populations in Inner Mongolia METHODS A total of 2652 subjects of Han and Mongolian ethnic origins were enrolled in the current study,including 908 healthy controls,1061 HTN patients and 683 HTN patients with T2DM.RESULTS The association between the rs1137101 polymorphism and HTN with T2DM was analyzed,and differences between Han and Mongolian individuals assessed.There was a significant correlation between rs1137101 and HTN(co-dominant,dominant,over-dominant and log-additive models)and HTN+T2DM(co-dominant,dominant,over-dominant and log-additive models)after adjustment for sex and age in individuals of Mongolian origin.rs1137101 was significantly associated with HTN(co-dominant,recessive and log-additive models)and HTN+T2DM(codominant,dominant,over-dominant and log-additive models)in the Han Chinese population.CONCLUSION Mongolian and Han subjects from Inner Mongolia with HTN who had rs1137101 were protected against the development of T2DM.Allele A has the opposite impact on the occurrence of HTN in Mongolian and Han Chinese populations.展开更多
基金supported by the National Key R&D Program of China(Nos.2022YFC3400700,2022YFA0806600)the National Natural Science Foundation of China(Nos.22277093,22074110,21721005)+2 种基金the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University(No.JCRCGW-2022-008)the Wuhan Knowledge Innovation Project(No.2022020801010111)the Natural Science Foundation of Hubei Province(No.2022CFB569).
文摘Sleep deprivation(SD)is a widespread issue that disrupts the lives of millions of people.These effects ini-tiate as changes within neurons,specifically at the DNA and RNA level,leading to disruptions in neuronal plasticity and the dysregulation of various cognitive functions,such as learning and memory.Nucleic acid epigenetic modifications that could regulate gene expression have been reported to play crucial roles in this process.However,there is a lack of comprehensive research on the correlation of SD with nucleic acid epigenetic modifications.In the current study,we aimed to systematically investigate the landscape of modifications in DNA as well as in small RNA molecules across multiple tissues,including the heart,liver,kidney,lung,hippocampus,and spleen,in response to chronic sleep deprivation(CSD).Using liquid chromatography-tandem mass spectrometry(LC-MS/MS)analysis,we characterized the dynamic changes in DNA and RNA modification profiles in different tissues of mice under CSD stress.Specifically,we ob-served a significant decrease in the level of 5-methylcytosine(5mC)and a significant increase in the level of 5-hydroxymethylcytosine(5hmC)in the kidney in CSD group.Regarding RNA modifications,we observed an overall increased trend for most of these significantly changed modifications across six tis-sues in CSD group.Our study sheds light on the significance of DNA and RNA modifications as crucial epigenetic markers in the context of CSD-induced stress.
基金supported by the National Key R&D Program of China(Nos.2022YFC3400700,2022YFA0806600)the Key Research and Development Project of Hubei Province(No.2023BCB094)+1 种基金the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University(No.JCRCGW-2022-008)the Key Laboratory of Hubei Province(No.2021KFY005)。
文摘Chronic kidney disease(CKD)is an increasingly prevalent medical condition associated with high mortality and cardiovascular complications.The intricate interplay between kidney dysfunction and subsequent metabolic disturbances may provide insights into the underlying mechanisms driving CKD onset and progression.Herein,we proposed a large-scale plasma metabolite identification and quantification system that combines the strengths of targeted and untargeted metabolomics technologies,i.e.,widely-targeted metabolomics(WT-Met)approach.WT-Met method enables large-scale identification and accurate quantification of thousands of metabolites.We collected plasma samples from 21 healthy controls and 62CKD patients,categorized into different stages(22 in stages 1-3,20 in stage 4,and 20 in stage 5).Using LC-MS-based WT-Met approach,we were able to effectively annotate and quantify a total of 1431metabolites from the plasma samples.Focusing on the 539 endogenous metabolites,we identified 399significantly altered metabolites and depicted their changing patterns from healthy controls to end-stage CKD.Furthermore,we employed machine-learning to identify the optimal combination of metabolites for predicting different stages of CKD.We generated a multiclass classifier consisting of 7 metabolites by machine-learning,which exhibited an average AUC of 0.99 for the test set.In general,amino acids,nucleotides,organic acids,and their metabolites emerged as the most significantly altered metabolites.However,their patterns of change varied across different stages of CKD.The 7-metabolite panel demonstrates promising potential as biomarker candidates for CKD.Further exploration of these metabolites can provide valuable insights into their roles in the etiology and progression of CKD.
基金Lei Zheng is supported by NIH grant R01 CA169702,NIH grant R01 CA197296,The Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins,National Cancer Institute Specialized Programs of Research Excellence in Gastrointestinal Cancers grant F50 CA062924,Sidney Kimmel Comprehensive Cancer Center grant P30 CA006973.
文摘The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is non-immunogenic, which consists of the stellate cells, fibroblasts, immune cells, extracellular matrix, and some other immune suppressive molecules. This low tumor perfusion microenvironment with physical dense fibrotic stroma shields PDAC from traditional antitumor therapies like chemotherapy and various strategies that have been proven successful in other types of cancer. Immunotherapy has the potential to treat minimal and residual diseases and prevent recurrence with minimal toxicity, and studies in patients with metastatic and nonresectable disease have shown some efficacy. In this review, we highlighted the main components of the pancreatic tumor microenvironment, and meanwhile, summarized the advances of some promising immunotherapies for PDAC, including checkpoint inhibitors, chimeric antigen receptors T cells, and cancer vaccines. Based on our previous researches, we specifically discussed how granulocyte-macrophage colony stimulating factor based pancreatic cancer vaccine prime the pancreatic tumor microenvironment, and introduced some novel immunoadjuvants, like the stimulator of interferon genes.
基金Supported by Beijing Municipal Committee of Science and Technology,No.Z181100001718090 and Z19110006619041Beijing Municipal Administration of Hospitals,No.PX2018029Beijing Shijitan Hospital,Capital Medical University,No.2017-KF01.
文摘BACKGROUND CD155 is an immune checkpoint protein in cancers and interacts with ligands to regulate the immune microenvironment.The expression of CD155 is correlated with the prognosis and pathological features of breast cancer.AIM To investigate the expression status of CD155 and the association with exhausted CD4+helper and CD8+cytotoxic tumor infiltrating lymphocytes(TILs)and PD-L1 in the breast cancer microenvironment.METHODS One hundred and twenty-six breast cancer patients with invasive ductal breast cancer were consecutively recruited into this study.Immunohistochemistry was used to detect the expression CD155,PD-L1 and PD-1 on tumor-infiltrating immune cells and tumor cells in the microenvironment.RESULTS The proportion of patients with CD155 expression was higher in triple negative breast cancer(72.7%)than in Luminal A patients(22.2%,P<0.05).Patients with positive CD155 expression had a higher percentage of CD4+/PD-1+helper TILs(30%)than patients with negative CD155 expression(21%,P<0.05).Patients with positive CD155 expression also had higher cell counts of exhausted CD4+TILs[47 vs 20/high-power fields(HPF)]and unexhausted CD8+TILs(30 vs 17/HPF)than patients with negative expression(P<0.05).CD155 expression was correlated with increased PD-L1 expression in immune cells,0.8%and 0.02%immune cells expressed PD-L1 in patients with positive and negative CD155 expression,respectively(P<0.05).CONCLUSION CD155 was related to an inhibitory immune breast cancer microenvironment.CD155 was associated with a high proportion of exhausted CD4+and unexhausted CD8+TILs and high PD-L1 expression in immune cells.
基金Supported by National Natural Science Foundation of China,No.81260058.
文摘BACKGROUND Hypertension(HTN)and type 2 diabetes mellitus(T2DM)are often coincident,and each condition is considered a risk factor for the other.Both occur frequently in the Inner Mongolia region of China.The reasons for differences in risk between Han and Mongolian ethnic groups are not known.The LEPR gene and its polymorphism,rs1137101(Gln223Arg),are both considered risk factors for HTN and T2DM,but any role of rs1137101 in the occurrence of HTN+T2DM remains unclear for Mongolian and Han populations in the Inner Mongolia region.AIM To investigate the relationship between rs1137101 and the occurrence of HTN with T2DM in Mongolian and Han populations in Inner Mongolia METHODS A total of 2652 subjects of Han and Mongolian ethnic origins were enrolled in the current study,including 908 healthy controls,1061 HTN patients and 683 HTN patients with T2DM.RESULTS The association between the rs1137101 polymorphism and HTN with T2DM was analyzed,and differences between Han and Mongolian individuals assessed.There was a significant correlation between rs1137101 and HTN(co-dominant,dominant,over-dominant and log-additive models)and HTN+T2DM(co-dominant,dominant,over-dominant and log-additive models)after adjustment for sex and age in individuals of Mongolian origin.rs1137101 was significantly associated with HTN(co-dominant,recessive and log-additive models)and HTN+T2DM(codominant,dominant,over-dominant and log-additive models)in the Han Chinese population.CONCLUSION Mongolian and Han subjects from Inner Mongolia with HTN who had rs1137101 were protected against the development of T2DM.Allele A has the opposite impact on the occurrence of HTN in Mongolian and Han Chinese populations.
