The occurrence and development of cancer are closely related to dysregulation of cholesterol metabolism.Therefore,targeting cholesterol metabolism presents a novel diagnosis and treatment strategy for cancer.In this s...The occurrence and development of cancer are closely related to dysregulation of cholesterol metabolism.Therefore,targeting cholesterol metabolism presents a novel diagnosis and treatment strategy for cancer.In this study,a nanosystem(AVA-COD@Fe)exhibiting dual enzymatic activity was developed through a biomimetic mineralization approach.Cholesterol oxidase(COD)facilitated the consumption of cholesterol,thereby impairing the migratory capacity of tumor cells and diminishing resilience on oxidative stress.Concurrently,COD catalyzed the production of hydrogen peroxide(H2O2),which compensated for inadequate levels of tumor cells,thereby enhancing ferroptosis and ultimately inhibiting tumor growth and metastasis.Meanwhile,as an immune sensitizer,avasimibe altered cholesterol distribution,and promoted the infiltration and vitality of cytotoxic T lymphocytes into tumors jointly with immunogenic cell death(ICD)induced by ferroptosis,and enhanced anti-tumor immunity.To elicit significant immune memory effects,this nanosystem was further combined with the anti-programmed cell death protein ligand-1 antibody,which effectively inhibited the growth of both primary and metastatic tumors,and demonstrated a robust systemic anti-tumor immune response.This study addressed modulation of tumor cell cholesterol metabolism as a strategic entry point for tumor suppression,significantly curtailing tumor progression,and activating systemic immune responses,thereby offering a new perspective for future cancer therapies.展开更多
Background:The clinical value of heterogeneous sub-populations of circulating tumor cells(CTCs)in pancreatic ductal adenocarcinoma(PDAC)remains unclear.Methods:Peripheral blood samples were obtained from 67 PDAC patie...Background:The clinical value of heterogeneous sub-populations of circulating tumor cells(CTCs)in pancreatic ductal adenocarcinoma(PDAC)remains unclear.Methods:Peripheral blood samples were obtained from 67 PDAC patients.CTCs were isolated by employing CD45 negative enrichment technique and further characterized for epithelial to mesenchymal transition(EMT)or human equilibrative nucleoside transporter-1(hENT-1).The relationships between CTCs sub-phenotypes with clinicopathological factors or post-operative recurrence in PDAC patients were analyzed.Results:EMT related CTCs could be isolated and identified from the 81%of patients(54/67),and both the total count(median:5 vs.17/mL,P<0.0001)and M-CTC percentage(median:0.2 vs.0.345,P=0.0244)of CTCs could differentiate local/regional with metastatic disease.Multivariate analysis showed that both AJCC stage(P=0.025)and M-CTC percentage(P=0.001)were independent prognostic indicators of recurrence free survival(RFS)in resected patients.Moreover,Kaplan-Meier survival analysis showed that M-CTC after 2 courses of chemotherapy was significantly associated with inferior RFS(49.5 weeks vs.undefined,P=0.0288).No significant correlation in hENT-1 expression was found between CTCs and matched tumor tissues,and further multivariate analysis suggested hENT-1 expression in CTCs as independent prognostic factor for RFS(P=0.016).Patients with low hENT-1 expression in CTCs had decreased RFS(32 weeks vs.undefined,P=0.0337).Conclusions:CTCs could be the promising diagnostic biomarkers in PDAC patients,and phenotypic profiling of CTCs based on EMT or hENT-1 could help establish novel prognostic biomarkers in resected patients undergoing adjuvant gemcitabine-based chemotherapy.展开更多
We investigate a class of ecological models with local-nonlocal diffusions and different free boundaries.This is PartⅠof a two-part series,in which the existence,uniqueness,regularity and estimates of global solution...We investigate a class of ecological models with local-nonlocal diffusions and different free boundaries.This is PartⅠof a two-part series,in which the existence,uniqueness,regularity and estimates of global solution is studied.The spreading-vanishing dichotomy,criteria governing spreading and vanishing,long-time behavior of solution and the estimation of the spreading speed when spreading happens will be studied in the separate PartⅡ.展开更多
基金supported by the National Natural Science Foundation of China(No.32571629)the Natural Science Foundation of Liaoning Province(Nos.2024011874-JH4/4800,2023-MS-198,and 2023011989-JH3/4600)+1 种基金Scientific Research Projects of Liaoning Provincial Department of Education(Nos.LJ212410163004 and LJKMZ20221786)Career Development Support Program for Young and Middle-aged Teachers(No:ZQN202208)of Shenyang Pharmaceutical University.
文摘The occurrence and development of cancer are closely related to dysregulation of cholesterol metabolism.Therefore,targeting cholesterol metabolism presents a novel diagnosis and treatment strategy for cancer.In this study,a nanosystem(AVA-COD@Fe)exhibiting dual enzymatic activity was developed through a biomimetic mineralization approach.Cholesterol oxidase(COD)facilitated the consumption of cholesterol,thereby impairing the migratory capacity of tumor cells and diminishing resilience on oxidative stress.Concurrently,COD catalyzed the production of hydrogen peroxide(H2O2),which compensated for inadequate levels of tumor cells,thereby enhancing ferroptosis and ultimately inhibiting tumor growth and metastasis.Meanwhile,as an immune sensitizer,avasimibe altered cholesterol distribution,and promoted the infiltration and vitality of cytotoxic T lymphocytes into tumors jointly with immunogenic cell death(ICD)induced by ferroptosis,and enhanced anti-tumor immunity.To elicit significant immune memory effects,this nanosystem was further combined with the anti-programmed cell death protein ligand-1 antibody,which effectively inhibited the growth of both primary and metastatic tumors,and demonstrated a robust systemic anti-tumor immune response.This study addressed modulation of tumor cell cholesterol metabolism as a strategic entry point for tumor suppression,significantly curtailing tumor progression,and activating systemic immune responses,thereby offering a new perspective for future cancer therapies.
文摘Background:The clinical value of heterogeneous sub-populations of circulating tumor cells(CTCs)in pancreatic ductal adenocarcinoma(PDAC)remains unclear.Methods:Peripheral blood samples were obtained from 67 PDAC patients.CTCs were isolated by employing CD45 negative enrichment technique and further characterized for epithelial to mesenchymal transition(EMT)or human equilibrative nucleoside transporter-1(hENT-1).The relationships between CTCs sub-phenotypes with clinicopathological factors or post-operative recurrence in PDAC patients were analyzed.Results:EMT related CTCs could be isolated and identified from the 81%of patients(54/67),and both the total count(median:5 vs.17/mL,P<0.0001)and M-CTC percentage(median:0.2 vs.0.345,P=0.0244)of CTCs could differentiate local/regional with metastatic disease.Multivariate analysis showed that both AJCC stage(P=0.025)and M-CTC percentage(P=0.001)were independent prognostic indicators of recurrence free survival(RFS)in resected patients.Moreover,Kaplan-Meier survival analysis showed that M-CTC after 2 courses of chemotherapy was significantly associated with inferior RFS(49.5 weeks vs.undefined,P=0.0288).No significant correlation in hENT-1 expression was found between CTCs and matched tumor tissues,and further multivariate analysis suggested hENT-1 expression in CTCs as independent prognostic factor for RFS(P=0.016).Patients with low hENT-1 expression in CTCs had decreased RFS(32 weeks vs.undefined,P=0.0337).Conclusions:CTCs could be the promising diagnostic biomarkers in PDAC patients,and phenotypic profiling of CTCs based on EMT or hENT-1 could help establish novel prognostic biomarkers in resected patients undergoing adjuvant gemcitabine-based chemotherapy.
基金Supported by NSFC Grants(Grant Nos.12171120,11971128)。
文摘We investigate a class of ecological models with local-nonlocal diffusions and different free boundaries.This is PartⅠof a two-part series,in which the existence,uniqueness,regularity and estimates of global solution is studied.The spreading-vanishing dichotomy,criteria governing spreading and vanishing,long-time behavior of solution and the estimation of the spreading speed when spreading happens will be studied in the separate PartⅡ.
