Objective： The aim of the study was to compare the hematologic toxicity of gemcitabine between fixed-dose rate （FDR） infusion and 30-minute standard infusion in the treatment of malignancy. Methods： The 25 maligna...Objective： The aim of the study was to compare the hematologic toxicity of gemcitabine between fixed-dose rate （FDR） infusion and 30-minute standard infusion in the treatment of malignancy. Methods： The 25 malignancy patients confirmed by histopathology or cytology received single-agent gemcitabine or gemcitabine in combination with other chemo- therapeutic agents. These patients were randomly divided into gemcitabine 1000 mg/m2 on dl, d8 at a rate of 10 mg/m2/min arm （FDR arm） or 30 rain arm （standard arm）, every 21 days one cycle. Hematologic toxicity was evaluated at the end of each cycle. Results： The 13 of 25 patients received gemcitabine FDR therapy, a total of 28 cycles was completed, and 32 cycles in the others （12 of 25 patients） with the standard arm. All patients were evaluable for hematologic toxicity. The result showed that the grades 3-4 leucopenia was significantly different between the two arms （14.3% vs 0, P 〈 0.05）, and no significant differences of neutropenia, thrombocytopenia and hemoglobin suppression of grades 3-4 （14.3% vs 3.1%, 10.7% vs 3.1%, 3.6% vs 9.4%, P 〉 0.05, respectively） were observed between the two arms, no grade 4 of hemoglobin suppression was observed. Conclusion： Hematologic toxicity of gemcitabine therapy at a fixed-dose rate for malignancy is tolerable.展开更多
Background:Recurrence and metastasis remain significant challenges in lung adenocarcinoma(LUAD)after radical resection.The mechanisms behind the recurrence and metastasis of LUAD remain elusive,and deregulated cellula...Background:Recurrence and metastasis remain significant challenges in lung adenocarcinoma(LUAD)after radical resection.The mechanisms behind the recurrence and metastasis of LUAD remain elusive,and deregulated cellular metabolism is suspected to play a significant role.This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase(NNMT)in LUAD.Methods:Untargeted metabolomic analyses were performed to detect metabolism irregularities.Single-cell RNA sequencing(RNA-seq)databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment.The biological functions of NNMT were investigated both in vitro and in vivo,with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms.Finally,single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.Results:Untargeted metabolomic analyses revealed metabolic aberrations in amino acids,organic acids,lipids,and nicotinamide pathways,which are linked to metastasis of non-small cell lung cancer.NNMT is a key enzyme in nicotinamide metabolism,and we found the bulk tissue mRNA level of NNMT gene was inversely associated with LUAD metastasis.NNMT was proved to be predominantly expressed in cancer-associated fibroblasts(CAFs)within the stromal regions of LUAD,and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD.The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments,which confirmed that NNMT negatively regulated the metastasispromoting properties of CAFs in LUAD.Mechanistically,the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle,resulting in heightened methylation at H3K4me3.This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs,including those encoding collagens,integrins,laminins,and matrix metalloproteinases,thereby facilitating cancer cell invasion and metastasis.Reanalysis of single-cell RNA-seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT’s negative regulation of these genes in CAFs.Conclusions:This study provides novel insights into the metabolic and epigenetic regulatory functions of NNMT in CAFs,expanding the current understanding of LUAD metastasis regulation and suggesting potential avenues for future research and therapeutic development.展开更多
基金Supported by the grants of the National Natural Science Foundation of China(No.30872591)Shanghai Science and Technology Commission(No.02.04.11.006)
文摘Objective： The aim of the study was to compare the hematologic toxicity of gemcitabine between fixed-dose rate （FDR） infusion and 30-minute standard infusion in the treatment of malignancy. Methods： The 25 malignancy patients confirmed by histopathology or cytology received single-agent gemcitabine or gemcitabine in combination with other chemo- therapeutic agents. These patients were randomly divided into gemcitabine 1000 mg/m2 on dl, d8 at a rate of 10 mg/m2/min arm （FDR arm） or 30 rain arm （standard arm）, every 21 days one cycle. Hematologic toxicity was evaluated at the end of each cycle. Results： The 13 of 25 patients received gemcitabine FDR therapy, a total of 28 cycles was completed, and 32 cycles in the others （12 of 25 patients） with the standard arm. All patients were evaluable for hematologic toxicity. The result showed that the grades 3-4 leucopenia was significantly different between the two arms （14.3% vs 0, P 〈 0.05）, and no significant differences of neutropenia, thrombocytopenia and hemoglobin suppression of grades 3-4 （14.3% vs 3.1%, 10.7% vs 3.1%, 3.6% vs 9.4%, P 〉 0.05, respectively） were observed between the two arms, no grade 4 of hemoglobin suppression was observed. Conclusion： Hematologic toxicity of gemcitabine therapy at a fixed-dose rate for malignancy is tolerable.
基金National Natural Science Foundation of China,Grant/Award Numbers:92059203,82173386National Key R&D Program of China,Grant/Award Number:2023YFF0723500+3 种基金Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer,Chinese Academy of Medical Sciences,Grant/Award Number:2021RU002Medical and Health Science and Technology Innovation project,Grant/Award Number:2021-I2M-002Beijing Nova Program,Grant/Award Number:20230484314Innovation Fund for Excellent PhD student of Peking University Health Science Center,Grant/Award Number:2022-58。
文摘Background:Recurrence and metastasis remain significant challenges in lung adenocarcinoma(LUAD)after radical resection.The mechanisms behind the recurrence and metastasis of LUAD remain elusive,and deregulated cellular metabolism is suspected to play a significant role.This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase(NNMT)in LUAD.Methods:Untargeted metabolomic analyses were performed to detect metabolism irregularities.Single-cell RNA sequencing(RNA-seq)databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment.The biological functions of NNMT were investigated both in vitro and in vivo,with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms.Finally,single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.Results:Untargeted metabolomic analyses revealed metabolic aberrations in amino acids,organic acids,lipids,and nicotinamide pathways,which are linked to metastasis of non-small cell lung cancer.NNMT is a key enzyme in nicotinamide metabolism,and we found the bulk tissue mRNA level of NNMT gene was inversely associated with LUAD metastasis.NNMT was proved to be predominantly expressed in cancer-associated fibroblasts(CAFs)within the stromal regions of LUAD,and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD.The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments,which confirmed that NNMT negatively regulated the metastasispromoting properties of CAFs in LUAD.Mechanistically,the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle,resulting in heightened methylation at H3K4me3.This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs,including those encoding collagens,integrins,laminins,and matrix metalloproteinases,thereby facilitating cancer cell invasion and metastasis.Reanalysis of single-cell RNA-seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT’s negative regulation of these genes in CAFs.Conclusions:This study provides novel insights into the metabolic and epigenetic regulatory functions of NNMT in CAFs,expanding the current understanding of LUAD metastasis regulation and suggesting potential avenues for future research and therapeutic development.
