Acyl-CoA synthetase long chain family member 5(ACSL5),is a member of the acyl-CoA synthetases(ACSs)family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs.The dysregulation of ACSL5...Acyl-CoA synthetase long chain family member 5(ACSL5),is a member of the acyl-CoA synthetases(ACSs)family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs.The dysregulation of ACSL5 has been reported in some cancers,such as glioma and colon cancers.However,little is known about the role of ACSL5 in acute myeloid leukemia(AML).We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors.ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients.In AML cells,the ACSL5 knockdown inhibited cell growth both in vitro and in vivo.Mechanistically,the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a.Additionally,triacsin c,a pan-ACS family inhibitor,inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199,the FDA approved BCL-2 inhibitor for AML therapy.Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.展开更多
This study aimed to investigate the prevalence,clinical characteristics,and prognostic impact of 1p32.3 deletion in patients with newly diagnosed multiple myeloma (MM).A retrospective analysis was conducted on 411 pat...This study aimed to investigate the prevalence,clinical characteristics,and prognostic impact of 1p32.3 deletion in patients with newly diagnosed multiple myeloma (MM).A retrospective analysis was conducted on 411 patients with newly diagnosed MM;among which,270 received bortezomib-based therapies,and 141 received thalidomide-based therapies.Fluorescence in situ hybridization (FISH) was performed to detect six cytogenetic abnormalities,namely,del(1p32.3),gain(1q21),del(17p13),del(13q14),t(4;14),and t(11;14).Results showed that 8.3% of patients with MM were detected with del(1p32.3) and had significantly more bone marrow plasma cells (P =0.025),higher β2-microglobulin levels (P =0.036),and higher lactate dehydrogenase levels (P =0.042) than those without del(1p32.3).Univariate analysis showed that patients with del(1p32.3) under thalidomide-based therapies were strongly associated with short progression-free survival (PFS) (median PFS 11.6 vs.31.2 months,P =0.002) and overall survival (OS) (median OS 16.8 vs.45.9 months,P < 0.001).Multivariate analysis revealed that del(1p32.3) remained a powerful independent factor with worse PFS (P =0.006) and OS (P =0.016) for patients under thalidomide-based treatments.Patients with del(1 p32.3) under bortezomib-based treatments tended to have short PFS and OS.In conclusion,del(1p32.3) is associated with short PFS and OS in patients with MM who received thalidomide-or bortezomib-based treatments.展开更多
Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for se...Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for second near-infrared(NIR-Ⅱ) fluorescence imaging-guided photoimmunotherapy.Firstly,a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor(D-A-D) backbone was synthesized.Then,the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1(JPC) and T7 ligand-modified PEG5k-DSPE.T7 can cross the BBB for tumor-targeted delivery of JPC and MRP.JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells.MRP could generate NIR-Ⅱ fluorescence to navigate 808 nm laser,induce a photothermal effect to trigger in-situ antigen release at the tumor site,and ultimately elicit antitumor immunogenicity.Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo.The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.展开更多
Abivertinib,a third-generation tyrosine kinase inhibitor,is originally designed to target epidermal growth factor receptor(EGFR)-activating mutations.Previous studies have shown that abivertinib has promising antitumo...Abivertinib,a third-generation tyrosine kinase inhibitor,is originally designed to target epidermal growth factor receptor(EGFR)-activating mutations.Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer.However,abivertinib also exhibited high inhibitory activity against Bruton’s tyrosine kinase and Janus kinase 3.Given that these kinases play some roles in the progression of megakaryopoiesis,we speculate that abivertinib can affect megakaryocyte(MK)differentiation and platelet biogenesis.We treated cord blood CD34+hematopoietic stem cells,Meg-01 cells,and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis.Our in vitro results showed that abivertinib impaired the CFU-MK formation,proliferation of CD34+HSC-derived MK progenitor cells,and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation.These results suggested that megakaryopoiesis was inhibited by abivertinib.We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice,which suggested that thrombopoiesis was also inhibited.Thus,these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.展开更多
基金supported by the key international cooperation projects of the National Natural Science Foundation of China(No.81820108004)the major projects of the Zhejiang Provincial Department of Science and Technology(No.2021C03123)the Pediatric Leukemia Diagnosis and Therapeutic Technology Research Center of Zhejiang Province(No.JBZX-201904).
文摘Acyl-CoA synthetase long chain family member 5(ACSL5),is a member of the acyl-CoA synthetases(ACSs)family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs.The dysregulation of ACSL5 has been reported in some cancers,such as glioma and colon cancers.However,little is known about the role of ACSL5 in acute myeloid leukemia(AML).We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors.ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients.In AML cells,the ACSL5 knockdown inhibited cell growth both in vitro and in vivo.Mechanistically,the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a.Additionally,triacsin c,a pan-ACS family inhibitor,inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199,the FDA approved BCL-2 inhibitor for AML therapy.Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.
基金We would like to thank the patients who donated multiple myeloma specimens.This work was partially supported by the National Natural Science Foundation of China(Nos.81400080 and 81470305)Leukemia Research Innovation Team of Zhejiang Province(No.2011R50015).
文摘This study aimed to investigate the prevalence,clinical characteristics,and prognostic impact of 1p32.3 deletion in patients with newly diagnosed multiple myeloma (MM).A retrospective analysis was conducted on 411 patients with newly diagnosed MM;among which,270 received bortezomib-based therapies,and 141 received thalidomide-based therapies.Fluorescence in situ hybridization (FISH) was performed to detect six cytogenetic abnormalities,namely,del(1p32.3),gain(1q21),del(17p13),del(13q14),t(4;14),and t(11;14).Results showed that 8.3% of patients with MM were detected with del(1p32.3) and had significantly more bone marrow plasma cells (P =0.025),higher β2-microglobulin levels (P =0.036),and higher lactate dehydrogenase levels (P =0.042) than those without del(1p32.3).Univariate analysis showed that patients with del(1p32.3) under thalidomide-based therapies were strongly associated with short progression-free survival (PFS) (median PFS 11.6 vs.31.2 months,P =0.002) and overall survival (OS) (median OS 16.8 vs.45.9 months,P < 0.001).Multivariate analysis revealed that del(1p32.3) remained a powerful independent factor with worse PFS (P =0.006) and OS (P =0.016) for patients under thalidomide-based treatments.Patients with del(1 p32.3) under bortezomib-based treatments tended to have short PFS and OS.In conclusion,del(1p32.3) is associated with short PFS and OS in patients with MM who received thalidomide-or bortezomib-based treatments.
基金Financial supports from the National Natural Science Foundation of China (22074043, 22174047, 32050410287)Science and Technology Commission of Shanghai Municipality (20142202800, China)+1 种基金China Postdoctoral Science Foundation (2021M700157)Shanghai Post-Doctoral Excellence Program (2021424, China)
文摘Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for second near-infrared(NIR-Ⅱ) fluorescence imaging-guided photoimmunotherapy.Firstly,a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor(D-A-D) backbone was synthesized.Then,the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1(JPC) and T7 ligand-modified PEG5k-DSPE.T7 can cross the BBB for tumor-targeted delivery of JPC and MRP.JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells.MRP could generate NIR-Ⅱ fluorescence to navigate 808 nm laser,induce a photothermal effect to trigger in-situ antigen release at the tumor site,and ultimately elicit antitumor immunogenicity.Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo.The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.
基金supported by grants from National Natural Science Foundation of China(Nos.82070118 and 81820108004)and the Zhejiang Provincial Natural Science Foundation of China(Nos.LY 20H080008 and Y 19H080009).
文摘Abivertinib,a third-generation tyrosine kinase inhibitor,is originally designed to target epidermal growth factor receptor(EGFR)-activating mutations.Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer.However,abivertinib also exhibited high inhibitory activity against Bruton’s tyrosine kinase and Janus kinase 3.Given that these kinases play some roles in the progression of megakaryopoiesis,we speculate that abivertinib can affect megakaryocyte(MK)differentiation and platelet biogenesis.We treated cord blood CD34+hematopoietic stem cells,Meg-01 cells,and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis.Our in vitro results showed that abivertinib impaired the CFU-MK formation,proliferation of CD34+HSC-derived MK progenitor cells,and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation.These results suggested that megakaryopoiesis was inhibited by abivertinib.We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice,which suggested that thrombopoiesis was also inhibited.Thus,these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.
