Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified n...Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified novel kinesin light chain 2(KLC2)mutations in CML-myeloid blast phase patients.We aimed to examine the functional role of KLC2 mutations in leukemogenesis.Methods:To evaluate the biological role of KLC2 mutants(MT)in CML cells,we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot,immunofluorescence,cell proliferation,differentiation,and apoptosis;Tyrosine kinase inhibitor(TKI)-drug activities;and clonogenic assays for in vitro functional analyses.We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells(BMCs)to evaluate their clonogenic and self-renewal abilities ex vivo.Furthermore,we examined tumorigenic activity and drug efficacy in the K562 xenograft model.Results:KLC2-MT overexpression in BCR::ABL1-positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential,decreased imatinib sensitivity,and reduced apoptosis.Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology.In the K562 xenograft model,KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy.Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3(STAT3)activation and nuclear accumulation in imatinib-treated CML cells.KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2(SMAD2);however,the latter impaired transforming growth factor-beta(TGF-β)–mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.Conclusions:This study demonstrates the biological and functional importance of KLC2 mutation in CML cells,potentially enabling the development of better treatment strategies for CML patients carrying KLC2 mutations and providing enhanced understanding of the disease progression.展开更多
BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese med...BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.展开更多
To the Editor,We have read the article by Gener-Ricos et al.titled"NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage",published in Cancer[1].This retrospective,cr...To the Editor,We have read the article by Gener-Ricos et al.titled"NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage",published in Cancer[1].This retrospective,cross-sectional pilot study provides valuable insights into the clinicopathological features and treatment outcomes of patients with NPM1-mutated myeloid neoplasms(MNs)with less than 20%bone marrow blasts[1].展开更多
Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,ven...Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,venetoclax plus azacitidine(VEN-AZA)or intensive chemotherapy(IC)]on post-transplant outcomes remains inconclusive.This multicenter,retrospective study compared the post-transplant outcomes between patients receiving VEN-AZA and those receiving IC before allo-HSCT.Methods:This study was based on the transplant database of TROPHY group.Consecutive adverse-risk AML patients receiving allo-HSCT from January 2021 to June 2023 were screened in five Chinese transplant centers.Patients were categorized into VEN-AZA group if they received venetoclax combined with azacitidine as first-line therapy followed by allo-HSCT.Patients who received first-line therapy consisting of a mainstay treatment of cytarabine and anthracycline followed by allo-HSCT were categorized into IC group.Results:In the total cohort,the 3-year probabilities of overall survival,leukemia-free survival,and event-free survival were better in the IC group than VEN-AZA group,particularly for patients with ASXL1 mutations or SF3B1 mutations.However,the survival of the VEN-AZA group was not superior to that of IC group in patients aged≥55 years or those with the hematopoietic cell transplantation-comorbidity index scores≥1 before allo-HSCT.After propensity score matching(median age:VEN-AZA group:57 years;IC group:55 years),only the probability of overall survival for the IC group was better than that of VEN-AZA group(93.6%vs.78.0%,P=0.034)at the 1-year follow-up;however,all of the other clinical outcomes were comparable between the VEN-AZA and IC groups.The TP53 mutation was independently associated with post-transplant relapse and survival.Conclusions:Our results suggest that IC remains the cornerstone of therapy,whereas VEN-AZA may also be used in younger patients and medically fit patients with adverse-risk AML who are receiving allo-HSCT in CR1.展开更多
Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially...Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.展开更多
A series of cyclopropane-1,1-diamide derivatives containing imidazo[1,2-a]pyridine were synthesized.The inhibitory effects of these compounds on FLT3-ITD kinase and their anti-proliferative activities against two acut...A series of cyclopropane-1,1-diamide derivatives containing imidazo[1,2-a]pyridine were synthesized.The inhibitory effects of these compounds on FLT3-ITD kinase and their anti-proliferative activities against two acute myeloid leukemia cell lines expressing FLT3-ITD were evaluated.With focused on the different substitutions of imidazo[1,2-a]pyridine,a preliminary exploration of the structure-activity relationship was conducted for 22 compounds.The results revealed that most compounds exhibited certain inhibitory effects on FLT3-ITD kinase with IC_(50) values below 0.5μmol·L^(-1).Among them,N-(4-fluorophenyl)-N-(4-(7-((2-morpholinoethyl)carbamoyl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide(12a)demonstrated the most potent FLT3-ITD kinase inhibitory activity and the strongest anti-proliferative effect on the MV4-11 and MOLM-13 cell lines expressing FLT3-ITD with IC50 values of 0.06 and 0.2μmol·L^(-1),respectively.Moreover,compound 12a did not exhibit anti-proliferative activity against cell lines without FLT3 mutations,such as THP-1,HCT-116,A549,HepG2,K562,and MCF-7,and it displayed non-cytotoxicity towards normal human renal tubular epithelial cells(HK-2),human liver progenitor cells(HepaRG),and HEK293(human embryonic kidney cells).Although 12a exhibits inferior inhibitory activity against FLT3-ITD kinase and anti-tumor cell proliferation compared to C abozantinib in this study,it can provide a reference for further research into FLT3-ITD inhibitors.展开更多
Venetoclax(Vene),a BCL-2 inhibitor,is widely used as a chemotherapeutic drug in acute myeloid leukemia(AML).However,its treatment specificity for leukemia cells is limited,often leading to side effects and treatment r...Venetoclax(Vene),a BCL-2 inhibitor,is widely used as a chemotherapeutic drug in acute myeloid leukemia(AML).However,its treatment specificity for leukemia cells is limited,often leading to side effects and treatment resistance.In this study,we utilized L-phenylalanine as an efficient nanocarrier to enhance the delivery of Vene,forming the complex Vene@8P6.This complex was then applied to AML mouse models and human AML cell lines.The in vitro analysis showed that THP-1 and HL60 cells rapidly absorbed the Vene@8P6 nanoparticles.This absorption resulted in severe DNA damage,increased reactive oxygen species(ROS)production,elevated apoptosis rates,and decreased cell proliferation compared to the administration of Vene alone.In vivo studies demonstrated that Vene@8P6 more efficiently targeted leukemia cells than normal hematopoietic cells within the bone marrow and other major organs in AML mice,as evidenced by bioluminescence imaging and flow cytometry analysis.Furthermore,Vene@8P6 treatment resulted in reduced drug side effects and improved therapeutic efficacy in AML mice.Overall,Vene@8P6 represents a novel and efficient therapeutic agent for AML,offering enhanced leukemia target specificity,reduced side effects,and improved treatment outcomes.展开更多
Liver fibrosis,a hallmark pathological endpoint of chronic aging-related liver diseases,remains a clinical challenge with limited therapeutic options.In healthy liver,myeloid cells constitute<5%of total hepatic imm...Liver fibrosis,a hallmark pathological endpoint of chronic aging-related liver diseases,remains a clinical challenge with limited therapeutic options.In healthy liver,myeloid cells constitute<5%of total hepatic immune cells,primarily comprising tissue-resident Kupffer cells.However,during aging or chronic injury,bone marrow-derived myeloid cell recruitment increases by two-to threefold in murine fibrotic models,reaching 15%-20% of intrahepatic immune populations.These infiltrating myeloid subsets exhibit functional plasticity,dynamically differentiating into pro-inflammatory mac-rophages or fibrosis-promoting Kupffer-like cells,contingent upon chemokine gradi-ents(e.g.,CCL2/CCR2 axis)and damage-associated molecular patterns(DAMPs).This review systematically examines the regulatory mechanisms of myeloid cells in liver fibrogenesis,with particular emphasis on their developmental origins,hepatic recruit-ment dynamics,functional heterogeneity,and pathogenic contributions to fibrosis.Furthermore,signaling pathways involving myeloid cells in liver fibrosis and therapeu-tic approaches modulating their differentiation and recruitment are discussed in this review.展开更多
Objective:To evaluate the immune function and safety of Venetoclax combined with Azacitidine in the treatment of elderly patients with acute myeloid leukemia(AML).Methods:Sixty-eight elderly AML patients who visited t...Objective:To evaluate the immune function and safety of Venetoclax combined with Azacitidine in the treatment of elderly patients with acute myeloid leukemia(AML).Methods:Sixty-eight elderly AML patients who visited the hospital from January 2021 to December 2024 were selected as samples and randomly divided into two groups.Group A was treated with Venetoclax and Azacitidine,while Group B was treated with Azacitidine alone.Immune indicators,inflammatory factors,tumor markers,and adverse reactions were compared between the two groups.Results:The levels of CD3+,CD4+,and CD8+in Group A were higher than those in Group B(P<0.05).The tumor necrosis factor-α(TNF-α)level in Group A was lower than that in Group B,while the interferon-γ(IFN-γ)level was higher(P<0.05).The levels of cyclooxygenase-2(COX-2),lactate dehydrogenase(LDH),and vascular endothelial growth factor(VEGF)in Group A were lower than those in Group B(P<0.05).The adverse reaction rate in Group A was lower than that in Group B(P<0.05).Conclusion:The combination of Venetoclax and Azacitidine in the treatment of elderly AML patients can improve immune function,inhibit inflammation,delay disease progression,and is safe and efficient.展开更多
The clinical efficacy of immunotherapy in acute myeloid leukemia(AML)remains significantly limited by early relapse and treatment-associated toxicities.This review examines recent advances in antibody-and cell-based i...The clinical efficacy of immunotherapy in acute myeloid leukemia(AML)remains significantly limited by early relapse and treatment-associated toxicities.This review examines recent advances in antibody-and cell-based immunotherapies for AML,focusing on established targets(CD33,CD123,and CLL1)as well as emerging targets(including CD7,CD70,CD38,and FLT3).Therapeutic modalities discussed include immunoconjugates,bispecific T-cell engagers and chimeric antigen receptor T(CAR-T)cells.Furthermore,we summarize the current challenges impeding the success of immunotherapy in AML and propose strategies to enhance its efficacy.These include combination therapies,structural optimization of CAR constructs,functional enhancement of CAR-T cells,identification of novel targets,and the development of next-generation cellular therapies.Collectively,these approaches aim to offer new insights for improving immunotherapeutic outcomes in AML.展开更多
BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disru...BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disrupted by chromosomal translocations in hematological malignancies.AIM To characterize RUNX1 gene rearrangements and copy number variations in newly diagnosed adult AML patients,with an emphasis on the impact of clinical and laboratory features on the outcome.METHODS Fluorescence in situ hybridization was used to test RUNX1 gene alterations in 77 newly diagnosed adult AML cases.NPM1,FLT3/ITD,FLT3/TKD,and KIT mutations were tested by PCR.Prognostic clinical and laboratory findings were studied in relation to RUNX1 alterations.RESULTS RUNX1 abnormalities were detected by fluorescence in situ hybridization in 41.6%of patients:20.8%had translocations,22.1%had amplification,and 5.2%had deletion.Translocations prevailed in AML-M2(P=0.019)with a positive expression of myeloperoxidase(P=0.031),whereas deletions dominated in M4 and M5 subtypes(P=0.008)with a positive association with CD64 expression(P=0.05).The modal chromosomal number was higher in cases having amplifications(P=0.007)and lower in those with deletions(P=0.008).RUNX1 abnormalities were associated with complex karyotypes(P<0.001)and were mutually exclusive of NPM1 mutations.After 44 months of follow-up,RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.CONCLUSION RUNX1 abnormalities were mutually exclusive of NPM1 mutations.RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.展开更多
Background:Acute Myeloid Leukemia(AML)is a highly aggressive clonal hematological malignancy with limited treatment options.This study aimed to evaluate the therapeutic potential of nigericin,a polyether ionophore der...Background:Acute Myeloid Leukemia(AML)is a highly aggressive clonal hematological malignancy with limited treatment options.This study aimed to evaluate the therapeutic potential of nigericin,a polyether ionophore derived from Streptomyces DASNCL-29,as a mitochondrial-targeted agent for AML treatment.Methods:Nigericin was isolated from Streptomyces DASNCL-29 and characterized via chromatography and NMR.Its cytotoxicity was tested in MOLM13(sensitive and venetoclax-resistant)and HL60(sensitive and cytarabine-resistant)cells using the MTT assay.Mitochondrial dysfunction was assessed by measuring reactive oxygen species(ROS),mitochondrial membrane potential(Δψm),and mitochondrial mass.Apoptosis was evaluated with Annexin V/PI assays and immunoblotting,while proteomic analysis was conducted using Liquid Chromatography-Tandem Mass Spectrometry(LC-MS/MS)to identify differentially regulated proteins.Results:Nigericin demonstrated potent cytotoxicity with IC50 values of 57.02 nM in MOLM13-sensitive,35.29 nM in MOLM13-resistant,20.49 nM in HL60-sensitive,and 1.197 nM in HL60-cytarabine-resistant cells.Apoptosis was confirmed by Annexin V/PI staining and caspase-3/PARP cleavage,along with MCL-1 downregulation.Mitochondrial dysfunction was evident from increased ROS,reducedΔψm,and decreased mitochondrial mass.Proteomic profiling identified 264 dysregulated proteins,including a 3.8-fold upregulation of Succinate Dehydrogenase[Ubiquinone]Flavoprotein Subunit A(SDHA).Conclusion:Nigericin induces apoptosis in AML cells by disrupting mitochondrial function and enhancing oxidative stress.Its nanomolar potency highlights the need for further mechanistic studies and in vivo evaluations to explore its potential in AML treatment.展开更多
BACKGROUND The prognosis for acute myeloid leukemia(AML)remains poor,underscoring the need for a deeper understanding of its underlying molecular mechanisms.AIM To assess the significance of SOX11 gene expression in t...BACKGROUND The prognosis for acute myeloid leukemia(AML)remains poor,underscoring the need for a deeper understanding of its underlying molecular mechanisms.AIM To assess the significance of SOX11 gene expression in the clinical features,response to treatment,and survival outcomes of adult patients with AML.METHODS This retrospective study enrolled 102 adults with AML.SOX11 gene expression in bone marrow samples was measured using real-time PCR.Data were correlated to the patients’clinical features,response to treatment,and survival rates.RESULTS Increased SOX11 expression was significantly associated with the presence of the FLT3-ITD mutation(P<0.001),the FAB-M2 subtype(P=0.008),and cytogenetic abnormalities(P=0.011).However,no significant association was found between SOX11 expression and other clinical laboratory parameters,complete remission,disease-free survival,or overall survival.CONCLUSION SOX11 expression may serve as a marker to identify specific subsets of AML patients who could benefit from intensive targeted chemotherapy.展开更多
Myristica is a classic traditional Chinese medicine widely used for leukemia treatment.However,its main active ingredients and underlying mechanisms of action remain poorly understood.In this study,we comprehensively ...Myristica is a classic traditional Chinese medicine widely used for leukemia treatment.However,its main active ingredients and underlying mechanisms of action remain poorly understood.In this study,we comprehensively investigated the mechanisms by which Myristica exerted effects on radiation-induced myeloid leukemia(RIML)using molecular docking and network pharmacology.The active ingredients in Myristica were further identified via TCMSP database,potential Myristica-related targets were extracted from GEO,GeneCards,OMIM,and DisGeNET databases,a protein-protein interaction(PPI)network was constructed to screen key targets(followed by GO and KEGG enrichment analyses),and finally the binding affinity between active compounds and key targets was verified.The screening results identified 9 active substances,including Kudos,isoguaiacin,galbacin,and others.Topological analysis of the PPI network revealed that PARP1,ESR1,MTOR,MDM2,HIF1A,and ALB were key targets.GO enrichment analysis showed that these targets were mainly involved in biological processes such as DNA repair,cell cycle regulation,apoptosis,and oxidative stress response.KEGG pathway enrichment analysis indicated that Myristica might exert anti-leukemia effects by regulating signaling pathways such as PI3K-Akt,mTOR,and HIF-1.展开更多
Adverse-risk acute myeloid leukemia(AML)is a therapeutic challenge despite advances in risk stratification.Unmet needs persist in high-risk molecular subgroups,such as AML with myelodysplasia-related changes,TP53 muta...Adverse-risk acute myeloid leukemia(AML)is a therapeutic challenge despite advances in risk stratification.Unmet needs persist in high-risk molecular subgroups,such as AML with myelodysplasia-related changes,TP53 mutations,or rearrangements involving NUP98,NUP214,or FUS::ERG.These subtypes are associated with poor responses to conventional induction therapies and high relapse rates.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)remains the cornerstone of consolidation for eligible patients;however,due to high relapse rates,regimenrelated toxicity,and variable responses across genetic subtypes,optimal transplant timing,conditioning regimens(e.g.,busulfan-or melphalan-based protocols),and bridging strategies require further refinement.Meanwhile,post-transplant maintenance therapies,such as hypomethylating agents or targeted drugs,are one emerging area under investigation for relapse prevention.In this perspective,we review the latest advances in allo-HSCT strategies for adverse-risk AML and highlight the importance of molecularly-guided approaches to improve outcomes in these aggressive subtypes.展开更多
Non-alcoholic fatty liver disease(NAFLD)is a progressive disease.Without effective interventions,NAFLD can gradually develop to non-alcoholic steatohepatitis,fatty liver fibrosis,liver cirrhosis and even hepatocellula...Non-alcoholic fatty liver disease(NAFLD)is a progressive disease.Without effective interventions,NAFLD can gradually develop to non-alcoholic steatohepatitis,fatty liver fibrosis,liver cirrhosis and even hepatocellular carcinoma.It is still to investigate the precise molecular mechanism behind the pathophysiology of NAFLD.Triggering receptor expressed on myeloid cells 2(TREM2)can sense tissue injury and mediate immune remodeling,thereby inducing phagocytosis,lipid metabolism,and metabolic transfer,promoting cell survival and combating inflammatory activation.NAFLD might develop as a result of TREM2's regulatory role.We here briefly summarize the biological characteristics of TREM2 and its functions in the disease progression of NAFLD.Moreover,we propose to broaden the therapeutic strategy for NAFLD by targeting TREM2.展开更多
Acute myeloid leukemia(AML)is a heterogeneous malignancy with heterogeneity,and 35%-45%of patients are refractory to first-line treatment[e.g.,standard chemotherapy and hematopoietic stem cell transplantation(HSCT)]or...Acute myeloid leukemia(AML)is a heterogeneous malignancy with heterogeneity,and 35%-45%of patients are refractory to first-line treatment[e.g.,standard chemotherapy and hematopoietic stem cell transplantation(HSCT)]or relapse after treatment.Patients with refractory/relapsed(R/R)AML have a dismal prognosis and are ralely cured with conventional treatment(1),indicating the need for new therapeutic strategies to improve outcomes.展开更多
Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underp...Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.展开更多
Background:The role of 1,25-dihydroxyvitamin D3(1,25-(OH)_(2)D_(3))in cancer prevention and treatment is an emerging topic of interest.However,its effects on the stemness of acute myeloid leukemia(AML)cells are poorly...Background:The role of 1,25-dihydroxyvitamin D3(1,25-(OH)_(2)D_(3))in cancer prevention and treatment is an emerging topic of interest.However,its effects on the stemness of acute myeloid leukemia(AML)cells are poorly understood.Methods:The proliferation and differentiation of AML cells(HL60 and NB4)were investigated by the CCK-8 assay,immunocytochemical staining,and flow cytometry.The abilities of HL60 and NB4 cells to form spheres were examined by the cell sphere formation assay.In addition,the levels of stemness-associated markers(SOX2,Nanog,OCT4,and c-Myc)in HL60 and NB4 cells were measured by western blotting and quantitative real-time polymerase chain reaction.Moreover,we obtainedβ-catenin-interacting protein 1(ICAT)-knockout and ICAT-overexpressing HL-60 cells using gene editing and lentiviral infection techniques and investigated the role of ICAT in modulating the stemness-inhibiting effects of 1,25-(OH)_(2)D_(3)using the aforementioned experimental methods.Finally,we validated our findings in vivo using NOD/SCID mice.Results:1,25-(OH)_(2)D_(3)inhibited the proliferation and stemness of AML cells(HL60 and NB4)and induced their differentiation into monocytes.Additionally,the knockdown of ICAT in HL60 cells attenuated the inhibitory effects of 1,25-(OH)_(2)D_(3)on proliferation and stemness and suppressed the expression of stemness markers.Conversely,overexpression of ICAT enhanced the aforementioned inhibitory effects of 1,25-(OH)_(2)D_(3).Consistently,in NOD/SCID mice,1,25-(OH)_(2)D_(3)suppressed tumor formation by HL-60 cells,and the effects of ICAT knockdown or overexpression on 1,25-(OH)_(2)D_(3) aligned with the in vitro findings.Conclusion:1,25-(OH)_(2)D_(3)inhibits AML cell stemness,possibly through modulation of the ICAT-mediated Wnt/β-catenin signaling pathway.展开更多
Therapy-related myeloid neoplasms are neoplastic processes arising as a result of chemotherapy, radiation therapy, or a combination of these modalities given for a primary condition. The disease biology varies based o...Therapy-related myeloid neoplasms are neoplastic processes arising as a result of chemotherapy, radiation therapy, or a combination of these modalities given for a primary condition. The disease biology varies based on the etiology and treatment modalities patients receive for their primary condition. Topoisomerase II inhibitor therapy results in balanced translocations. Alkylating agents, characteristically, give rise to more complex karyotypes and mutations in p53. Other etiologies include radiation therapy, high-dose chemotherapy with autologous stem cell transplantation and telomere dysfunction. Poor-risk cytogenetic abnormalities are more prevalent than they are in de novo leukemias and the prognosis of these patients is uniformly dismal. Outcome varies according to cytogenetic risk group. Treatment recommendations should be based on performance status and karyotype. An in-depth understanding of risk factors that lead to the development of therapy-related myeloid neoplasms would help developing risk-adapted treatment protocols and monitoring patients after treatment for the primary condition, translating into reduced incidence, early detection and timely treatment.展开更多
基金supported by grants from the Ministry of Science and Technology,Taiwan(MOST108-2314-B-182-006,MOST109-2314-B-182-071:Lee-Yung Shih)the Ministry of Health and Welfare,Taiwan(MOHW110-TDU-B-212-134011:Lee-Yung Shih)+3 种基金Chang Gung Memorial Hospital(CMRPG3D1524,OMRPG3E0031:Lee-Yung Shih)the Grant-in-Aid for the Japan Society for the Promotion of Science(JSPS)KAKENHI(JP19H05656:Seishi Ogawa,22K16320:Yotaro Ochi)the Japan Agency for Medical Research and Development(AMED)(JP19cm0106501h0004,JP19ck0106250h0003:Seishi Ogawa)the Ministry of Education,Culture,Sports,Science and Technology of Japan(MEXT)(hp200138,hp210167:Seishi Ogawa)。
文摘Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified novel kinesin light chain 2(KLC2)mutations in CML-myeloid blast phase patients.We aimed to examine the functional role of KLC2 mutations in leukemogenesis.Methods:To evaluate the biological role of KLC2 mutants(MT)in CML cells,we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot,immunofluorescence,cell proliferation,differentiation,and apoptosis;Tyrosine kinase inhibitor(TKI)-drug activities;and clonogenic assays for in vitro functional analyses.We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells(BMCs)to evaluate their clonogenic and self-renewal abilities ex vivo.Furthermore,we examined tumorigenic activity and drug efficacy in the K562 xenograft model.Results:KLC2-MT overexpression in BCR::ABL1-positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential,decreased imatinib sensitivity,and reduced apoptosis.Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology.In the K562 xenograft model,KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy.Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3(STAT3)activation and nuclear accumulation in imatinib-treated CML cells.KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2(SMAD2);however,the latter impaired transforming growth factor-beta(TGF-β)–mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.Conclusions:This study demonstrates the biological and functional importance of KLC2 mutation in CML cells,potentially enabling the development of better treatment strategies for CML patients carrying KLC2 mutations and providing enhanced understanding of the disease progression.
基金Supported by the Provincial Key Cultivation Laboratory for Digestive Disease Research,No.2021SYS13Shanxi Province’s“Si Ge Yi Pi”Science and Technology Driven Medical Innovation Project,No.2021MX03Shanxi Provincial Basic Research Program,No.202403021222423.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.
文摘To the Editor,We have read the article by Gener-Ricos et al.titled"NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage",published in Cancer[1].This retrospective,cross-sectional pilot study provides valuable insights into the clinicopathological features and treatment outcomes of patients with NPM1-mutated myeloid neoplasms(MNs)with less than 20%bone marrow blasts[1].
基金supported by the Beijing Natural Science Foundation(No.Z230016)the National Key Research and Development Program of China(No.2022YFC 2502606)+4 种基金the Major Program of the National Natural Science Foundation of China(No.82293630)the Peking University Medicine Fund for the World’s Leading Discipline or Discipline Cluster Development(No.71003Y3035)the Plan Project of Tongzhou Municipal Science and Technology(No.KJ2024CX045)the National Natural Science Foundation of China(No.82170208)the Fundamental Research Funds for the Central Universities。
文摘Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,venetoclax plus azacitidine(VEN-AZA)or intensive chemotherapy(IC)]on post-transplant outcomes remains inconclusive.This multicenter,retrospective study compared the post-transplant outcomes between patients receiving VEN-AZA and those receiving IC before allo-HSCT.Methods:This study was based on the transplant database of TROPHY group.Consecutive adverse-risk AML patients receiving allo-HSCT from January 2021 to June 2023 were screened in five Chinese transplant centers.Patients were categorized into VEN-AZA group if they received venetoclax combined with azacitidine as first-line therapy followed by allo-HSCT.Patients who received first-line therapy consisting of a mainstay treatment of cytarabine and anthracycline followed by allo-HSCT were categorized into IC group.Results:In the total cohort,the 3-year probabilities of overall survival,leukemia-free survival,and event-free survival were better in the IC group than VEN-AZA group,particularly for patients with ASXL1 mutations or SF3B1 mutations.However,the survival of the VEN-AZA group was not superior to that of IC group in patients aged≥55 years or those with the hematopoietic cell transplantation-comorbidity index scores≥1 before allo-HSCT.After propensity score matching(median age:VEN-AZA group:57 years;IC group:55 years),only the probability of overall survival for the IC group was better than that of VEN-AZA group(93.6%vs.78.0%,P=0.034)at the 1-year follow-up;however,all of the other clinical outcomes were comparable between the VEN-AZA and IC groups.The TP53 mutation was independently associated with post-transplant relapse and survival.Conclusions:Our results suggest that IC remains the cornerstone of therapy,whereas VEN-AZA may also be used in younger patients and medically fit patients with adverse-risk AML who are receiving allo-HSCT in CR1.
基金Supported by Shanxi Provincial Key Research and Development Plan Project,No.2020ZDLSF01-02Doctor Foundation of the Second Affiliated Hospital of Xi’an Medical University,No.X2Y-R11.
文摘Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.
文摘A series of cyclopropane-1,1-diamide derivatives containing imidazo[1,2-a]pyridine were synthesized.The inhibitory effects of these compounds on FLT3-ITD kinase and their anti-proliferative activities against two acute myeloid leukemia cell lines expressing FLT3-ITD were evaluated.With focused on the different substitutions of imidazo[1,2-a]pyridine,a preliminary exploration of the structure-activity relationship was conducted for 22 compounds.The results revealed that most compounds exhibited certain inhibitory effects on FLT3-ITD kinase with IC_(50) values below 0.5μmol·L^(-1).Among them,N-(4-fluorophenyl)-N-(4-(7-((2-morpholinoethyl)carbamoyl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide(12a)demonstrated the most potent FLT3-ITD kinase inhibitory activity and the strongest anti-proliferative effect on the MV4-11 and MOLM-13 cell lines expressing FLT3-ITD with IC50 values of 0.06 and 0.2μmol·L^(-1),respectively.Moreover,compound 12a did not exhibit anti-proliferative activity against cell lines without FLT3 mutations,such as THP-1,HCT-116,A549,HepG2,K562,and MCF-7,and it displayed non-cytotoxicity towards normal human renal tubular epithelial cells(HK-2),human liver progenitor cells(HepaRG),and HEK293(human embryonic kidney cells).Although 12a exhibits inferior inhibitory activity against FLT3-ITD kinase and anti-tumor cell proliferation compared to C abozantinib in this study,it can provide a reference for further research into FLT3-ITD inhibitors.
基金the National Natural Science Foundation of China(No.52173150 to J.Wu)the National Natural Science Foundation of China(No.82370164 to C.Chen)+5 种基金Guangzhou Science and Technology Program City-University Joint Funding Project(No.2023A03J0001 to J.Wu)the Affiliated Qingyuan Hospital of Guangzhou Medical University Open Project Fund(No.202301–211 to J.Wu)Sanming Project of Medicine in Shenzhen(No.SZSM201911004 to D.Lin and M.Zhao)National Natural Science Foundation of China(No.92268205 to D.Lin)Doctoral Scientific Research Foundation of Changzhi Medical College,China(to Z.Zhao)Post-doctoral Science Foundation(No.2022M723670 to L.Wang)。
文摘Venetoclax(Vene),a BCL-2 inhibitor,is widely used as a chemotherapeutic drug in acute myeloid leukemia(AML).However,its treatment specificity for leukemia cells is limited,often leading to side effects and treatment resistance.In this study,we utilized L-phenylalanine as an efficient nanocarrier to enhance the delivery of Vene,forming the complex Vene@8P6.This complex was then applied to AML mouse models and human AML cell lines.The in vitro analysis showed that THP-1 and HL60 cells rapidly absorbed the Vene@8P6 nanoparticles.This absorption resulted in severe DNA damage,increased reactive oxygen species(ROS)production,elevated apoptosis rates,and decreased cell proliferation compared to the administration of Vene alone.In vivo studies demonstrated that Vene@8P6 more efficiently targeted leukemia cells than normal hematopoietic cells within the bone marrow and other major organs in AML mice,as evidenced by bioluminescence imaging and flow cytometry analysis.Furthermore,Vene@8P6 treatment resulted in reduced drug side effects and improved therapeutic efficacy in AML mice.Overall,Vene@8P6 represents a novel and efficient therapeutic agent for AML,offering enhanced leukemia target specificity,reduced side effects,and improved treatment outcomes.
基金National Key Research and Development Program of China,Grant/Award Number:2021YFA0804903National Natural Science Foundation of China,Grant/Award Number:882171545 and 91949125The Start-up Fund for Distinguished Research Fellows,the International Institute of Health Medicine,Zhejiang University,Grant/Award Number:Q22005。
文摘Liver fibrosis,a hallmark pathological endpoint of chronic aging-related liver diseases,remains a clinical challenge with limited therapeutic options.In healthy liver,myeloid cells constitute<5%of total hepatic immune cells,primarily comprising tissue-resident Kupffer cells.However,during aging or chronic injury,bone marrow-derived myeloid cell recruitment increases by two-to threefold in murine fibrotic models,reaching 15%-20% of intrahepatic immune populations.These infiltrating myeloid subsets exhibit functional plasticity,dynamically differentiating into pro-inflammatory mac-rophages or fibrosis-promoting Kupffer-like cells,contingent upon chemokine gradi-ents(e.g.,CCL2/CCR2 axis)and damage-associated molecular patterns(DAMPs).This review systematically examines the regulatory mechanisms of myeloid cells in liver fibrogenesis,with particular emphasis on their developmental origins,hepatic recruit-ment dynamics,functional heterogeneity,and pathogenic contributions to fibrosis.Furthermore,signaling pathways involving myeloid cells in liver fibrosis and therapeu-tic approaches modulating their differentiation and recruitment are discussed in this review.
文摘Objective:To evaluate the immune function and safety of Venetoclax combined with Azacitidine in the treatment of elderly patients with acute myeloid leukemia(AML).Methods:Sixty-eight elderly AML patients who visited the hospital from January 2021 to December 2024 were selected as samples and randomly divided into two groups.Group A was treated with Venetoclax and Azacitidine,while Group B was treated with Azacitidine alone.Immune indicators,inflammatory factors,tumor markers,and adverse reactions were compared between the two groups.Results:The levels of CD3+,CD4+,and CD8+in Group A were higher than those in Group B(P<0.05).The tumor necrosis factor-α(TNF-α)level in Group A was lower than that in Group B,while the interferon-γ(IFN-γ)level was higher(P<0.05).The levels of cyclooxygenase-2(COX-2),lactate dehydrogenase(LDH),and vascular endothelial growth factor(VEGF)in Group A were lower than those in Group B(P<0.05).The adverse reaction rate in Group A was lower than that in Group B(P<0.05).Conclusion:The combination of Venetoclax and Azacitidine in the treatment of elderly AML patients can improve immune function,inhibit inflammation,delay disease progression,and is safe and efficient.
基金supported by grants from the National High Technology Research and Development Program of China(No.2021YFA1101500)the National Natural Science Foundation of China(No.81873427 and No.82070217)the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital(No.2024ZHANCHI12)。
文摘The clinical efficacy of immunotherapy in acute myeloid leukemia(AML)remains significantly limited by early relapse and treatment-associated toxicities.This review examines recent advances in antibody-and cell-based immunotherapies for AML,focusing on established targets(CD33,CD123,and CLL1)as well as emerging targets(including CD7,CD70,CD38,and FLT3).Therapeutic modalities discussed include immunoconjugates,bispecific T-cell engagers and chimeric antigen receptor T(CAR-T)cells.Furthermore,we summarize the current challenges impeding the success of immunotherapy in AML and propose strategies to enhance its efficacy.These include combination therapies,structural optimization of CAR constructs,functional enhancement of CAR-T cells,identification of novel targets,and the development of next-generation cellular therapies.Collectively,these approaches aim to offer new insights for improving immunotherapeutic outcomes in AML.
文摘BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disrupted by chromosomal translocations in hematological malignancies.AIM To characterize RUNX1 gene rearrangements and copy number variations in newly diagnosed adult AML patients,with an emphasis on the impact of clinical and laboratory features on the outcome.METHODS Fluorescence in situ hybridization was used to test RUNX1 gene alterations in 77 newly diagnosed adult AML cases.NPM1,FLT3/ITD,FLT3/TKD,and KIT mutations were tested by PCR.Prognostic clinical and laboratory findings were studied in relation to RUNX1 alterations.RESULTS RUNX1 abnormalities were detected by fluorescence in situ hybridization in 41.6%of patients:20.8%had translocations,22.1%had amplification,and 5.2%had deletion.Translocations prevailed in AML-M2(P=0.019)with a positive expression of myeloperoxidase(P=0.031),whereas deletions dominated in M4 and M5 subtypes(P=0.008)with a positive association with CD64 expression(P=0.05).The modal chromosomal number was higher in cases having amplifications(P=0.007)and lower in those with deletions(P=0.008).RUNX1 abnormalities were associated with complex karyotypes(P<0.001)and were mutually exclusive of NPM1 mutations.After 44 months of follow-up,RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.CONCLUSION RUNX1 abnormalities were mutually exclusive of NPM1 mutations.RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.
文摘Background:Acute Myeloid Leukemia(AML)is a highly aggressive clonal hematological malignancy with limited treatment options.This study aimed to evaluate the therapeutic potential of nigericin,a polyether ionophore derived from Streptomyces DASNCL-29,as a mitochondrial-targeted agent for AML treatment.Methods:Nigericin was isolated from Streptomyces DASNCL-29 and characterized via chromatography and NMR.Its cytotoxicity was tested in MOLM13(sensitive and venetoclax-resistant)and HL60(sensitive and cytarabine-resistant)cells using the MTT assay.Mitochondrial dysfunction was assessed by measuring reactive oxygen species(ROS),mitochondrial membrane potential(Δψm),and mitochondrial mass.Apoptosis was evaluated with Annexin V/PI assays and immunoblotting,while proteomic analysis was conducted using Liquid Chromatography-Tandem Mass Spectrometry(LC-MS/MS)to identify differentially regulated proteins.Results:Nigericin demonstrated potent cytotoxicity with IC50 values of 57.02 nM in MOLM13-sensitive,35.29 nM in MOLM13-resistant,20.49 nM in HL60-sensitive,and 1.197 nM in HL60-cytarabine-resistant cells.Apoptosis was confirmed by Annexin V/PI staining and caspase-3/PARP cleavage,along with MCL-1 downregulation.Mitochondrial dysfunction was evident from increased ROS,reducedΔψm,and decreased mitochondrial mass.Proteomic profiling identified 264 dysregulated proteins,including a 3.8-fold upregulation of Succinate Dehydrogenase[Ubiquinone]Flavoprotein Subunit A(SDHA).Conclusion:Nigericin induces apoptosis in AML cells by disrupting mitochondrial function and enhancing oxidative stress.Its nanomolar potency highlights the need for further mechanistic studies and in vivo evaluations to explore its potential in AML treatment.
文摘BACKGROUND The prognosis for acute myeloid leukemia(AML)remains poor,underscoring the need for a deeper understanding of its underlying molecular mechanisms.AIM To assess the significance of SOX11 gene expression in the clinical features,response to treatment,and survival outcomes of adult patients with AML.METHODS This retrospective study enrolled 102 adults with AML.SOX11 gene expression in bone marrow samples was measured using real-time PCR.Data were correlated to the patients’clinical features,response to treatment,and survival rates.RESULTS Increased SOX11 expression was significantly associated with the presence of the FLT3-ITD mutation(P<0.001),the FAB-M2 subtype(P=0.008),and cytogenetic abnormalities(P=0.011).However,no significant association was found between SOX11 expression and other clinical laboratory parameters,complete remission,disease-free survival,or overall survival.CONCLUSION SOX11 expression may serve as a marker to identify specific subsets of AML patients who could benefit from intensive targeted chemotherapy.
基金National Natural Science Foundation of China (82104246)Postdoctoral Fellowship Program of CPSF (GZB20230996)+2 种基金Natural Science Basic Research Program of Shaanxi (2025JC-YBMS-917)Research Foundation of Air Force Medical University (2024JC054)Xijing Innovation Research Institute Joint Fund Project (LHJJ2023-YX16)。
文摘Myristica is a classic traditional Chinese medicine widely used for leukemia treatment.However,its main active ingredients and underlying mechanisms of action remain poorly understood.In this study,we comprehensively investigated the mechanisms by which Myristica exerted effects on radiation-induced myeloid leukemia(RIML)using molecular docking and network pharmacology.The active ingredients in Myristica were further identified via TCMSP database,potential Myristica-related targets were extracted from GEO,GeneCards,OMIM,and DisGeNET databases,a protein-protein interaction(PPI)network was constructed to screen key targets(followed by GO and KEGG enrichment analyses),and finally the binding affinity between active compounds and key targets was verified.The screening results identified 9 active substances,including Kudos,isoguaiacin,galbacin,and others.Topological analysis of the PPI network revealed that PARP1,ESR1,MTOR,MDM2,HIF1A,and ALB were key targets.GO enrichment analysis showed that these targets were mainly involved in biological processes such as DNA repair,cell cycle regulation,apoptosis,and oxidative stress response.KEGG pathway enrichment analysis indicated that Myristica might exert anti-leukemia effects by regulating signaling pathways such as PI3K-Akt,mTOR,and HIF-1.
基金supported by the National Natural Science Foundation of China(No.82170206,82470213)Shanghai Municipal Health Commission Project of Disciplines of Excellence(No.20224Z0002)National Research Center for Translational Medicine under grant number[No.NRCTM(SH)-2023-11]。
文摘Adverse-risk acute myeloid leukemia(AML)is a therapeutic challenge despite advances in risk stratification.Unmet needs persist in high-risk molecular subgroups,such as AML with myelodysplasia-related changes,TP53 mutations,or rearrangements involving NUP98,NUP214,or FUS::ERG.These subtypes are associated with poor responses to conventional induction therapies and high relapse rates.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)remains the cornerstone of consolidation for eligible patients;however,due to high relapse rates,regimenrelated toxicity,and variable responses across genetic subtypes,optimal transplant timing,conditioning regimens(e.g.,busulfan-or melphalan-based protocols),and bridging strategies require further refinement.Meanwhile,post-transplant maintenance therapies,such as hypomethylating agents or targeted drugs,are one emerging area under investigation for relapse prevention.In this perspective,we review the latest advances in allo-HSCT strategies for adverse-risk AML and highlight the importance of molecularly-guided approaches to improve outcomes in these aggressive subtypes.
基金Supported by Henan Province's"Double First-Class"Creation of Scientific Research in Traditional Chinese Medicine,No.HSRPDFCTCM-2023-7-23 and No.STG-ZYX02-202117National Traditional Chinese Medicine Clinical Research Base Scientific Research Special Project,No.2022JDZX098 and No.2022JDZX114+1 种基金National Natural Science Foundation of China,No.82205086The 9th China Association for Science and Technology Young Talent Support Project,No.2023QNRC001.
文摘Non-alcoholic fatty liver disease(NAFLD)is a progressive disease.Without effective interventions,NAFLD can gradually develop to non-alcoholic steatohepatitis,fatty liver fibrosis,liver cirrhosis and even hepatocellular carcinoma.It is still to investigate the precise molecular mechanism behind the pathophysiology of NAFLD.Triggering receptor expressed on myeloid cells 2(TREM2)can sense tissue injury and mediate immune remodeling,thereby inducing phagocytosis,lipid metabolism,and metabolic transfer,promoting cell survival and combating inflammatory activation.NAFLD might develop as a result of TREM2's regulatory role.We here briefly summarize the biological characteristics of TREM2 and its functions in the disease progression of NAFLD.Moreover,we propose to broaden the therapeutic strategy for NAFLD by targeting TREM2.
基金supported by the National Major Scientific and Technological Projects(No.2023ZD0501201)the Science and Technology Planning Project of Guangdong Province(No.2024A0505090015)+2 种基金the Clinical Research Project of Nanfang Hospital,Southern Medical University(No.2023CR007)the Science and Technology Project of Ganzhou City(No.GZ2024YLJ033)the National Natural Science Foundation of China(No.82170215)。
文摘Acute myeloid leukemia(AML)is a heterogeneous malignancy with heterogeneity,and 35%-45%of patients are refractory to first-line treatment[e.g.,standard chemotherapy and hematopoietic stem cell transplantation(HSCT)]or relapse after treatment.Patients with refractory/relapsed(R/R)AML have a dismal prognosis and are ralely cured with conventional treatment(1),indicating the need for new therapeutic strategies to improve outcomes.
文摘Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(2022B1515230007).
文摘Background:The role of 1,25-dihydroxyvitamin D3(1,25-(OH)_(2)D_(3))in cancer prevention and treatment is an emerging topic of interest.However,its effects on the stemness of acute myeloid leukemia(AML)cells are poorly understood.Methods:The proliferation and differentiation of AML cells(HL60 and NB4)were investigated by the CCK-8 assay,immunocytochemical staining,and flow cytometry.The abilities of HL60 and NB4 cells to form spheres were examined by the cell sphere formation assay.In addition,the levels of stemness-associated markers(SOX2,Nanog,OCT4,and c-Myc)in HL60 and NB4 cells were measured by western blotting and quantitative real-time polymerase chain reaction.Moreover,we obtainedβ-catenin-interacting protein 1(ICAT)-knockout and ICAT-overexpressing HL-60 cells using gene editing and lentiviral infection techniques and investigated the role of ICAT in modulating the stemness-inhibiting effects of 1,25-(OH)_(2)D_(3)using the aforementioned experimental methods.Finally,we validated our findings in vivo using NOD/SCID mice.Results:1,25-(OH)_(2)D_(3)inhibited the proliferation and stemness of AML cells(HL60 and NB4)and induced their differentiation into monocytes.Additionally,the knockdown of ICAT in HL60 cells attenuated the inhibitory effects of 1,25-(OH)_(2)D_(3)on proliferation and stemness and suppressed the expression of stemness markers.Conversely,overexpression of ICAT enhanced the aforementioned inhibitory effects of 1,25-(OH)_(2)D_(3).Consistently,in NOD/SCID mice,1,25-(OH)_(2)D_(3)suppressed tumor formation by HL-60 cells,and the effects of ICAT knockdown or overexpression on 1,25-(OH)_(2)D_(3) aligned with the in vitro findings.Conclusion:1,25-(OH)_(2)D_(3)inhibits AML cell stemness,possibly through modulation of the ICAT-mediated Wnt/β-catenin signaling pathway.
文摘Therapy-related myeloid neoplasms are neoplastic processes arising as a result of chemotherapy, radiation therapy, or a combination of these modalities given for a primary condition. The disease biology varies based on the etiology and treatment modalities patients receive for their primary condition. Topoisomerase II inhibitor therapy results in balanced translocations. Alkylating agents, characteristically, give rise to more complex karyotypes and mutations in p53. Other etiologies include radiation therapy, high-dose chemotherapy with autologous stem cell transplantation and telomere dysfunction. Poor-risk cytogenetic abnormalities are more prevalent than they are in de novo leukemias and the prognosis of these patients is uniformly dismal. Outcome varies according to cytogenetic risk group. Treatment recommendations should be based on performance status and karyotype. An in-depth understanding of risk factors that lead to the development of therapy-related myeloid neoplasms would help developing risk-adapted treatment protocols and monitoring patients after treatment for the primary condition, translating into reduced incidence, early detection and timely treatment.
