Objective:The aim of this study was to investigate the inhibitory effect of apogossypolone (ApoG2) on subcutaneous implants of human LNCaP prostatic carcinoma cells, and explore its mechanism. Methods:To establish hum...Objective:The aim of this study was to investigate the inhibitory effect of apogossypolone (ApoG2) on subcutaneous implants of human LNCaP prostatic carcinoma cells, and explore its mechanism. Methods:To establish human LNCaP prostatic carcinoma cell line subcutaneous xenograft models and observe the inhibitory effect of ApoG2 on the tumor model. Immunohistochemistry was employed to observe the expression of Bcl-2, PCNA, CD31, caspase-3 and-8 in tumor tissues. The microvessel density was calculated. Results:ApoG2 could obviously inhibit the growth of subcutaneous prostatic carcinoma implant. ApoG2 decreased the expression of PCNA and CD31, and increased the expression of caspases-3,-8 in tumor tissues. Conclusion:ApoG2 has an inhibitory effect on prostatic carcinoma implants.展开更多
Background:Gastric cancer(GC)is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets.Claudin-9(CLDN9)has been demonstrated to be upregulated in various c...Background:Gastric cancer(GC)is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets.Claudin-9(CLDN9)has been demonstrated to be upregulated in various cancers.However,its prognostic value,biological function,and regulatory mechanisms in GC remain unclear.Therefore,this study aimed to elucidate the role of CLDN9 in GC progression and its underlying mechanisms.Methods:We utilized consensus cluster,random survival forest,and multivariate Cox regression analyses to identify CLDN9 in GC.Subsequently,we evaluated the mRNA and protein levels of CLDN9 in GC using quantitative real-time polymerase chain reaction(PCR)(qRT-PCR),Western blotting(WB),and immunohistochemistry(IHC).Furthermore,the role of CLDN9 in GC progression was investigated using a series of functional in vivo and in vitro experiments.Finally,we elucidated the molecular mechanisms of CLDN9 using bioinformatics,molecular biology,animal models,and patient tissue specimens.Results:Two GC subtypes with survival and functional differences were identified based on glycolytic metabolic genes in the Cancer Genome Atlas(TCGA)-Stomach adenocarcinoma(STAD)dataset.A prognostic risk score was calculated using seven genes to assess the overall survival(OS)in GC.Using random survival forest and multivariate Cox analyses,we identified CLDN9 as the key gene linked to the glycolytic subtype and prognosis of GC.CLDN9 expression was significantly upregulated in patients with GC as well as in GC cells.CLDN9 knockdown inhibited tumor proliferation,invasion,and metastasis both in vivo and in vitro.Mechanistically,CLDN9 was found to regulate lactate dehydrogenase A(LDHA)expression and promote glycolytic metabolism by activating the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/hypoxia-inducible factor 1-alpha(HIF1α)signaling pathway.Additionally,lactate,a glycolytic metabolite,enhanced programmed cell death ligand 1(PD-L1)lactylation and stability,which suppressed anti-tumor immunity in CD8t T cells,thereby contributing to GC progression.Conclusions:CLDN9 expression is associated with GC development and progression.Mechanistically,CLDN9 enhances the glycolysis pathway and facilitates PD-L1 lactylation through the PI3K/AKT/HIF1αsignaling pathway,thereby suppressing anti-tumor immunity in CD8t T cells.CLDN9 has the potential to serve as a novel prognostic marker and therapeutic target for GC.展开更多
Background:Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2(HER2)-positive gastric cancer.However,the inevitable occurrence of acquired trastuzumab resistance limits the drug b...Background:Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2(HER2)-positive gastric cancer.However,the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit,and there is currently no effective reversal measure.Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves,while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking.This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients.Methods:Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing.Bioinformatics were used to analyze cell subtypes,metabolic pathways,and molecular signaling pathways.Changes in microenvironmental indicators(such as macrophage,angiogenesis,and metabolism)were verified by immunofluorescence(IF)and immunohistochemical(IHC)analyses.Finally,a multi-scale agent-based model(ABM)was constructed.The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM.Results:Based on transcriptome sequencing,molecular biology,and in vivo experiments,we found that the level of glutamine metabolism in trastuzumabresistant HER2-positive cells was increased,and glutaminase 1(GLS1)was significantly overexpressed.Meanwhile,tumor-derived GLS1 microvesicles drove M2macrophage polarization.Furthermore,angiogenesis promoted trastuzumab resistance.IHC showed high glutamine metabolism,M2 macrophage polarization,and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nudemice.Mechanistically,the cell division cycle 42(CDC42)promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B(NF-κB)p65 and drove GLS1microvesicle secretion through IQmotif-containing GTPase-activating protein 1(IQGAP1).Based on the ABM and in vivo experiments,we confirmed that the combination of anti-glutamine metabolism,anti-angiogenesis,and pro-M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2-positive gastric cancer.Conclusions:This study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism,M2 macrophage polarization,and pro-angiogenic function of macrophages,leading to acquired trastuzumab resistance in HER2-positive gastric cancer.A combination of anti-glutamine metabolism,anti-angiogenesis,and pro-M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.展开更多
Allogeneic red blood cell(RBC)transfusion is commonly performed in medical practice because of its efficacy and low-risk level.However,pre-transfusion tests are susceptible to monoclonal antibody(mAb)interference.1 Cu...Allogeneic red blood cell(RBC)transfusion is commonly performed in medical practice because of its efficacy and low-risk level.However,pre-transfusion tests are susceptible to monoclonal antibody(mAb)interference.1 Currently,mAb therapies are being developed to treat many diseases,such as cancer.However,certain mAbs,such as anti-CD38mAb and anti-CD47mAb,can bind to RBC membranes;this binding interferes with pre-transfusion tests.2 CD47 has gained considerable attention in recent years because of its potential as a therapeutic target for hematologic malignancies and solid tumors.3 The binding of anti-CD47mAb to RBCs may lead to false-positive results in pan-agglutination tests and cause delays and risks in establishing compatible RBCs for transfusion.展开更多
With the development of tyrosine kinase inhibitor(TKI)resistance,finding the novel effective chemotherapeutic agent is of seminal importance for chronic myelogenous leukemia(CML)treatment.This study aims to find the e...With the development of tyrosine kinase inhibitor(TKI)resistance,finding the novel effective chemotherapeutic agent is of seminal importance for chronic myelogenous leukemia(CML)treatment.This study aims to find the effective anti-leukemic candidates and investigate the possible underlying mechanism.We synthesized the novel coumarin derivatives and evaluated their anti-leukemic activity.Cell viability assay revealed that compound DBH2 exhibited the potent inhibitory activity on the proliferation of CML K562 cells and TKI resistant K562 cells.Morphological observation and flow cytometry confirmed that DBH2 could selectively induce cell apoptosis and cell cycle arrest at G2/M phase of the K562 cells,which was further confirmed on the bone marrow cells from CML transgenic model mice and CD34+bone marrow leukemic cells from CML patients.Treatments of DBH2 in combination with imatinib could prolong the survival rate of SCL-tTA-BCR/ABL transgenic model mice significantly.Quantitative RT-PCR revealed that DBH2 inhibited the expression of STAT3 and STAT5 in K562 cells,and caspase-3 knockout alleviated the DBH2 induced apoptosis.Furthermore,DBH2 could induce the expression of PARP1 and ROCK1 in K562 cells,which may play the important role in caspase-dependent apoptosis.Our results concluded that coumarin derivative DBH2 serves as a promising candidate for the CML treatment,especially in the combination with imatinib for the TKI resistant CML,and STAT/caspase-3 pathway was involved in the molecular mechanism of anti-leukemic activity of DBH2.展开更多
To the Editor:The evolution and widespread distribution of antibiotic-resistant elements in bacterial pathogens is eroding our ability to control infections with existing antibiotics.Staphylococcus aureus(S.aureus)and...To the Editor:The evolution and widespread distribution of antibiotic-resistant elements in bacterial pathogens is eroding our ability to control infections with existing antibiotics.Staphylococcus aureus(S.aureus)and Methicillin-resistant S.aureus(MRSA)have acquired alarming broad-spectrum antibiotic resistance resulting in hospital-and community-associated infections,which has been responsible for significant morbidities and deaths worldwide.1 It is estimated that the number of deaths caused by antibiotic resistance may exceed 10 million per year by 2050.展开更多
文摘Objective:The aim of this study was to investigate the inhibitory effect of apogossypolone (ApoG2) on subcutaneous implants of human LNCaP prostatic carcinoma cells, and explore its mechanism. Methods:To establish human LNCaP prostatic carcinoma cell line subcutaneous xenograft models and observe the inhibitory effect of ApoG2 on the tumor model. Immunohistochemistry was employed to observe the expression of Bcl-2, PCNA, CD31, caspase-3 and-8 in tumor tissues. The microvessel density was calculated. Results:ApoG2 could obviously inhibit the growth of subcutaneous prostatic carcinoma implant. ApoG2 decreased the expression of PCNA and CD31, and increased the expression of caspases-3,-8 in tumor tissues. Conclusion:ApoG2 has an inhibitory effect on prostatic carcinoma implants.
基金supported by grants from the National Natural Science Foundation of China(Nos.82273204 and 81972471)the Guangdong Medical Science and Technology Program(No.A2023077)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2023A1515110952)the China Postdoctoral Science Foundation(Nos.2023M744024 and 2023M734015).
文摘Background:Gastric cancer(GC)is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets.Claudin-9(CLDN9)has been demonstrated to be upregulated in various cancers.However,its prognostic value,biological function,and regulatory mechanisms in GC remain unclear.Therefore,this study aimed to elucidate the role of CLDN9 in GC progression and its underlying mechanisms.Methods:We utilized consensus cluster,random survival forest,and multivariate Cox regression analyses to identify CLDN9 in GC.Subsequently,we evaluated the mRNA and protein levels of CLDN9 in GC using quantitative real-time polymerase chain reaction(PCR)(qRT-PCR),Western blotting(WB),and immunohistochemistry(IHC).Furthermore,the role of CLDN9 in GC progression was investigated using a series of functional in vivo and in vitro experiments.Finally,we elucidated the molecular mechanisms of CLDN9 using bioinformatics,molecular biology,animal models,and patient tissue specimens.Results:Two GC subtypes with survival and functional differences were identified based on glycolytic metabolic genes in the Cancer Genome Atlas(TCGA)-Stomach adenocarcinoma(STAD)dataset.A prognostic risk score was calculated using seven genes to assess the overall survival(OS)in GC.Using random survival forest and multivariate Cox analyses,we identified CLDN9 as the key gene linked to the glycolytic subtype and prognosis of GC.CLDN9 expression was significantly upregulated in patients with GC as well as in GC cells.CLDN9 knockdown inhibited tumor proliferation,invasion,and metastasis both in vivo and in vitro.Mechanistically,CLDN9 was found to regulate lactate dehydrogenase A(LDHA)expression and promote glycolytic metabolism by activating the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/hypoxia-inducible factor 1-alpha(HIF1α)signaling pathway.Additionally,lactate,a glycolytic metabolite,enhanced programmed cell death ligand 1(PD-L1)lactylation and stability,which suppressed anti-tumor immunity in CD8t T cells,thereby contributing to GC progression.Conclusions:CLDN9 expression is associated with GC development and progression.Mechanistically,CLDN9 enhances the glycolysis pathway and facilitates PD-L1 lactylation through the PI3K/AKT/HIF1αsignaling pathway,thereby suppressing anti-tumor immunity in CD8t T cells.CLDN9 has the potential to serve as a novel prognostic marker and therapeutic target for GC.
基金National Natural Science Foundation of China,Grant/Award Number:82073325。
文摘Background:Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2(HER2)-positive gastric cancer.However,the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit,and there is currently no effective reversal measure.Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves,while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking.This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients.Methods:Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing.Bioinformatics were used to analyze cell subtypes,metabolic pathways,and molecular signaling pathways.Changes in microenvironmental indicators(such as macrophage,angiogenesis,and metabolism)were verified by immunofluorescence(IF)and immunohistochemical(IHC)analyses.Finally,a multi-scale agent-based model(ABM)was constructed.The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM.Results:Based on transcriptome sequencing,molecular biology,and in vivo experiments,we found that the level of glutamine metabolism in trastuzumabresistant HER2-positive cells was increased,and glutaminase 1(GLS1)was significantly overexpressed.Meanwhile,tumor-derived GLS1 microvesicles drove M2macrophage polarization.Furthermore,angiogenesis promoted trastuzumab resistance.IHC showed high glutamine metabolism,M2 macrophage polarization,and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nudemice.Mechanistically,the cell division cycle 42(CDC42)promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B(NF-κB)p65 and drove GLS1microvesicle secretion through IQmotif-containing GTPase-activating protein 1(IQGAP1).Based on the ABM and in vivo experiments,we confirmed that the combination of anti-glutamine metabolism,anti-angiogenesis,and pro-M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2-positive gastric cancer.Conclusions:This study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism,M2 macrophage polarization,and pro-angiogenic function of macrophages,leading to acquired trastuzumab resistance in HER2-positive gastric cancer.A combination of anti-glutamine metabolism,anti-angiogenesis,and pro-M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.
文摘Allogeneic red blood cell(RBC)transfusion is commonly performed in medical practice because of its efficacy and low-risk level.However,pre-transfusion tests are susceptible to monoclonal antibody(mAb)interference.1 Currently,mAb therapies are being developed to treat many diseases,such as cancer.However,certain mAbs,such as anti-CD38mAb and anti-CD47mAb,can bind to RBC membranes;this binding interferes with pre-transfusion tests.2 CD47 has gained considerable attention in recent years because of its potential as a therapeutic target for hematologic malignancies and solid tumors.3 The binding of anti-CD47mAb to RBCs may lead to false-positive results in pan-agglutination tests and cause delays and risks in establishing compatible RBCs for transfusion.
基金This project was reviewed and approved by the ethical committee of Tangdu Hospital,Air Force Medical University(No.201903-87).
文摘With the development of tyrosine kinase inhibitor(TKI)resistance,finding the novel effective chemotherapeutic agent is of seminal importance for chronic myelogenous leukemia(CML)treatment.This study aims to find the effective anti-leukemic candidates and investigate the possible underlying mechanism.We synthesized the novel coumarin derivatives and evaluated their anti-leukemic activity.Cell viability assay revealed that compound DBH2 exhibited the potent inhibitory activity on the proliferation of CML K562 cells and TKI resistant K562 cells.Morphological observation and flow cytometry confirmed that DBH2 could selectively induce cell apoptosis and cell cycle arrest at G2/M phase of the K562 cells,which was further confirmed on the bone marrow cells from CML transgenic model mice and CD34+bone marrow leukemic cells from CML patients.Treatments of DBH2 in combination with imatinib could prolong the survival rate of SCL-tTA-BCR/ABL transgenic model mice significantly.Quantitative RT-PCR revealed that DBH2 inhibited the expression of STAT3 and STAT5 in K562 cells,and caspase-3 knockout alleviated the DBH2 induced apoptosis.Furthermore,DBH2 could induce the expression of PARP1 and ROCK1 in K562 cells,which may play the important role in caspase-dependent apoptosis.Our results concluded that coumarin derivative DBH2 serves as a promising candidate for the CML treatment,especially in the combination with imatinib for the TKI resistant CML,and STAT/caspase-3 pathway was involved in the molecular mechanism of anti-leukemic activity of DBH2.
基金This work was supported by Science and Technology Development Foundations of the Fourth Military Medical University(No.4241122094,X.Q.)。
文摘To the Editor:The evolution and widespread distribution of antibiotic-resistant elements in bacterial pathogens is eroding our ability to control infections with existing antibiotics.Staphylococcus aureus(S.aureus)and Methicillin-resistant S.aureus(MRSA)have acquired alarming broad-spectrum antibiotic resistance resulting in hospital-and community-associated infections,which has been responsible for significant morbidities and deaths worldwide.1 It is estimated that the number of deaths caused by antibiotic resistance may exceed 10 million per year by 2050.
