BACKGROUND The utility of D-dimer(DD)as a biomarker for acute aortic dissection(AD)is recognized.Yet,its predictive value for in-hospital mortality remains uncertain and subject to conflicting evidence.AIM To conduct ...BACKGROUND The utility of D-dimer(DD)as a biomarker for acute aortic dissection(AD)is recognized.Yet,its predictive value for in-hospital mortality remains uncertain and subject to conflicting evidence.AIM To conduct a meta-analysis of AD-related in-hospital mortality(ADIM)with elevated DD levels.METHODS We searched PubMed,Scopus,Embase,and Google Scholar for AD and ADIM literature through May 2022.Heterogeneity was assessed using I2 statistics and effect size(hazard or odds ratio)analysis with random-effects models.Sample size,study type,and patients’mean age were used for subgroup analysis.The significance threshold was P<0.05.RESULTS Thirteen studies(3628 patients)were included in our study.The pooled prevalence of ADIM was 20%(95%CI:15%-25%).Despite comparable demographic characteristics and comorbidities,elevated DD values were associated with higher ADIM risk(unadjusted effect size:1.94,95%CI:1.34-2.8;adjusted effect size:1.12,95%CI:1.05-1.19,P<0.01).Studies involving patients with a mean age of<60 years exhibited an increased mortality risk(effect size:1.43,95%CI:1.23-1.67,P<0.01),whereas no significant difference was observed in studies with a mean age>60 years.Prospective and larger sample size studies(n>250)demonstrated a heightened likelihood of ADIM associated with elevated DD levels(effect size:2.57,95%CI:1.30-5.08,P<0.01 vs effect size:1.05,95%CI:1.00-1.11,P=0.05,respectively).CONCLUSION Our meta-analysis shows elevated DD increases in-hospital mortality risk in AD patients,highlighting the need for larger,prospective studies to improve risk prediction models.展开更多
Acute myeloid leukemia （AML） is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity t...Acute myeloid leukemia （AML） is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow （BM） niche is critical to the maintenance and retention of hematopoietic stem cells （HSC）, including leukemia stem cells （LSC）, and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy- induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDFI/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors.展开更多
Allelic loss of the short arm of chromosome 1 has been observed frequently in a wide spectrum of cancers,most frequently in oligodendroglioma.In our previous studies,we evaluated 177 oligodendroglial tumor samples and...Allelic loss of the short arm of chromosome 1 has been observed frequently in a wide spectrum of cancers,most frequently in oligodendroglioma.In our previous studies,we evaluated 177 oligodendroglial tumor samples and identified the AJAP1 gene(formerly Shrew1) in the consensus region of deletion.AJAP1 is a transmembrane protein found in adheren junctions and functions to inhibit glioma cell adhesion and migration.Whereas a putative tumor suppressor gene,we did not detect AJAP1 gene mutations.In subsequent studies,we found that AJAP1 was underexpressed in oligodendrogliomas relative to normal brain tissues.Bioinformatic analysis revealed the presence of CpG islands in the promoter of AJAP1.Methylation analysis of the AJAP1 promoter identified hypermethylation in 21% of oligodendrogliomas(n = 27),and the degree of methylation correlated with low levels of AJAP1 expression(P = 0.045).The AJAP1 promoter was also highly methylated in a wide spectrum of cell lines(n = 22),including cell lines of glioblastoma.Analysis of the National Cancer Institute's REMBRANDT dataset,which contains 343 glioma samples,indicated that low AJAP1 gene expression was associated with decreased survival.Thus,both genetic(gene deletion) and epigenetic alterations(promoter methylation) are likely mechanisms that inactivate the putative tumor suppressor AJAP1 in gliomas,which contributes to poor prognosis.展开更多
Receptor tyrosine kinases(RTKs),a category of transmembrane receptors,have gained significant clinical attention in oncology due to their central role in cancer pathogenesis.Genetic alterations,including mutations,amp...Receptor tyrosine kinases(RTKs),a category of transmembrane receptors,have gained significant clinical attention in oncology due to their central role in cancer pathogenesis.Genetic alterations,including mutations,amplifications,and overexpression of certain RTKs,are critical in creating environments conducive to tumor development.Following their discovery,extensive research has revealed how RTK dysregulation contributes to oncogenesis,with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation,survival and progression.These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer.As a result,RTKs have emerged as primary targets in anticancer therapeutic development.Over the past two decades,this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors(TKIs),now effectively utilized in treating various cancer types.In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer.We explored the various alterations and overexpression of specific receptors across different malignancies,with special attention dedicated to the examination of current RTK inhibitors,highlighting their role as potential targeted therapies.By integrating the latest research findings and clinical evidence,we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.展开更多
To the Editor:As of July 4,2021,the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)pandemic has affected>0.18 billion individuals and caused>3.9milliondeaths worldwide.ll Currently,the only method to...To the Editor:As of July 4,2021,the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)pandemic has affected>0.18 billion individuals and caused>3.9milliondeaths worldwide.ll Currently,the only method to radically overcome this pandemic is extensive vaccination.However,the clinical trials assessing most vaccines against SARS-CoV-2 have excluded patients with hematological tumors.展开更多
Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metab...Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN,and identified the activation of RAS/MAPK pathway,leading to increased stability and higher levels of MCL-1 protein,as a major acquired mechanism of VEN resistance.展开更多
Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hemato...Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy;we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.展开更多
In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment,acute myeloid leukemia(AML)cells continuously adjust their metabolic state.To meet the biochemical demands of their ...In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment,acute myeloid leukemia(AML)cells continuously adjust their metabolic state.To meet the biochemical demands of their increased proliferation,AML cells strongly depend on mitochondrial oxidative phosphorylation(OXPHOS).Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation(FAO),which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance.For targeting these metabolic vulnerabilities of AML cells,inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential.Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells,enabling them to acquire resistance against OXPHOS and FAO inhibitors.These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors.Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.展开更多
Objective To investigate the effects of red orpiment on cell morphology, expression of promyelocytic leukemia (PML) mRNA and its protein localization in NB4 and HL-60 cell lines.Methods Cell morphology was assayed b...Objective To investigate the effects of red orpiment on cell morphology, expression of promyelocytic leukemia (PML) mRNA and its protein localization in NB4 and HL-60 cell lines.Methods Cell morphology was assayed by Wright's staining and fluorescence staining, while PML mRNA expression was determined by RT-PCR. PML protein localization by evaluated by immunofluorescence staining. Results The typical apoptosis was found in NB4 and HL-60 cells after treatment with red orpiment. The fusion protein was no longer observed in NB4 cells, PML protein was relocated, and then degraded. In HL-60 cells, PML protein underwent a similar progress. The expression of promyelocytic leukemia (PML) mRNA was not changed in the treated cells.Conclusion Red orpiment inhibits the proliferation of leukemia cells by inducing them to undergo apoptosis.展开更多
Acute myeloid leukemia(AML)is historically associated with poor prognosis,especially in older AML patients unfit for intensive chemotherapy.The development of Venetoclax,a potent oral BH3(BCL-2 homology domain 3)mimet...Acute myeloid leukemia(AML)is historically associated with poor prognosis,especially in older AML patients unfit for intensive chemotherapy.The development of Venetoclax,a potent oral BH3(BCL-2 homology domain 3)mimetic,has transformed the AML treatment.However,the short duration of response and development of resistance remain major concerns.Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens.In this review,we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies.Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations.Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.展开更多
文摘BACKGROUND The utility of D-dimer(DD)as a biomarker for acute aortic dissection(AD)is recognized.Yet,its predictive value for in-hospital mortality remains uncertain and subject to conflicting evidence.AIM To conduct a meta-analysis of AD-related in-hospital mortality(ADIM)with elevated DD levels.METHODS We searched PubMed,Scopus,Embase,and Google Scholar for AD and ADIM literature through May 2022.Heterogeneity was assessed using I2 statistics and effect size(hazard or odds ratio)analysis with random-effects models.Sample size,study type,and patients’mean age were used for subgroup analysis.The significance threshold was P<0.05.RESULTS Thirteen studies(3628 patients)were included in our study.The pooled prevalence of ADIM was 20%(95%CI:15%-25%).Despite comparable demographic characteristics and comorbidities,elevated DD values were associated with higher ADIM risk(unadjusted effect size:1.94,95%CI:1.34-2.8;adjusted effect size:1.12,95%CI:1.05-1.19,P<0.01).Studies involving patients with a mean age of<60 years exhibited an increased mortality risk(effect size:1.43,95%CI:1.23-1.67,P<0.01),whereas no significant difference was observed in studies with a mean age>60 years.Prospective and larger sample size studies(n>250)demonstrated a heightened likelihood of ADIM associated with elevated DD levels(effect size:2.57,95%CI:1.30-5.08,P<0.01 vs effect size:1.05,95%CI:1.00-1.11,P=0.05,respectively).CONCLUSION Our meta-analysis shows elevated DD increases in-hospital mortality risk in AD patients,highlighting the need for larger,prospective studies to improve risk prediction models.
基金funding from Guangzhou Pearl River of Science & Technology New Star (Grant No. 2011J2200069)supported in part by grants from the National Institutes of Health (Grant No. P01 CA055164)+2 种基金MD Anderson Cancer Center Support (Grant No. CA016672)the Paul and Mary Haas Chair in Genetics to Michael Andreeffby the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center to Bing Z. Carter
文摘Acute myeloid leukemia （AML） is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow （BM） niche is critical to the maintenance and retention of hematopoietic stem cells （HSC）, including leukemia stem cells （LSC）, and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy- induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDFI/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors.
基金supported by the Anthony Bullock Ⅲ Research Fund and Cancer Center Support Grant CA016672 from the National Institutes of Health to the MD Anderson Cancer Center
文摘Allelic loss of the short arm of chromosome 1 has been observed frequently in a wide spectrum of cancers,most frequently in oligodendroglioma.In our previous studies,we evaluated 177 oligodendroglial tumor samples and identified the AJAP1 gene(formerly Shrew1) in the consensus region of deletion.AJAP1 is a transmembrane protein found in adheren junctions and functions to inhibit glioma cell adhesion and migration.Whereas a putative tumor suppressor gene,we did not detect AJAP1 gene mutations.In subsequent studies,we found that AJAP1 was underexpressed in oligodendrogliomas relative to normal brain tissues.Bioinformatic analysis revealed the presence of CpG islands in the promoter of AJAP1.Methylation analysis of the AJAP1 promoter identified hypermethylation in 21% of oligodendrogliomas(n = 27),and the degree of methylation correlated with low levels of AJAP1 expression(P = 0.045).The AJAP1 promoter was also highly methylated in a wide spectrum of cell lines(n = 22),including cell lines of glioblastoma.Analysis of the National Cancer Institute's REMBRANDT dataset,which contains 343 glioma samples,indicated that low AJAP1 gene expression was associated with decreased survival.Thus,both genetic(gene deletion) and epigenetic alterations(promoter methylation) are likely mechanisms that inactivate the putative tumor suppressor AJAP1 in gliomas,which contributes to poor prognosis.
基金funded by a grant of the Romanian Government(bursa Henri Coandă)funded by a grant from the Romanian Academy of Scientists 2023-2024+3 种基金funded by an international grant of the European Hematology Association(EHA-SWG Immunotherapy Project 2024–CAR NK cells for tumor associated macrophage immunomodulation—a new era of immunotherapy)by a bilateral collaboration grant between Romania and Moldova(PN-IVP8-8.3-ROMD-2023-0036)funded by a national grant of the Romanian Research Ministry–PNRR 2024-2026(PNRR/2022/C9/MCID/18,Contract No.760278/26.03.2024)supported in part by the R35 CA 197706 grant from the National Cancer Institute.
文摘Receptor tyrosine kinases(RTKs),a category of transmembrane receptors,have gained significant clinical attention in oncology due to their central role in cancer pathogenesis.Genetic alterations,including mutations,amplifications,and overexpression of certain RTKs,are critical in creating environments conducive to tumor development.Following their discovery,extensive research has revealed how RTK dysregulation contributes to oncogenesis,with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation,survival and progression.These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer.As a result,RTKs have emerged as primary targets in anticancer therapeutic development.Over the past two decades,this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors(TKIs),now effectively utilized in treating various cancer types.In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer.We explored the various alterations and overexpression of specific receptors across different malignancies,with special attention dedicated to the examination of current RTK inhibitors,highlighting their role as potential targeted therapies.By integrating the latest research findings and clinical evidence,we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.
文摘To the Editor:As of July 4,2021,the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)pandemic has affected>0.18 billion individuals and caused>3.9milliondeaths worldwide.ll Currently,the only method to radically overcome this pandemic is extensive vaccination.However,the clinical trials assessing most vaccines against SARS-CoV-2 have excluded patients with hematological tumors.
基金This study is partially supported by NIH R01CA235622(to MK).
文摘Despite high initial response rates,acute myeloid leukemia(AML)treated with the BCL-2-selective inhibitor venetoclax(VEN)alone or in combinations commonly acquires resistance.We performed gene/protein expression,metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN,and identified the activation of RAS/MAPK pathway,leading to increased stability and higher levels of MCL-1 protein,as a major acquired mechanism of VEN resistance.
文摘Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy;we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.
文摘In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment,acute myeloid leukemia(AML)cells continuously adjust their metabolic state.To meet the biochemical demands of their increased proliferation,AML cells strongly depend on mitochondrial oxidative phosphorylation(OXPHOS).Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation(FAO),which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance.For targeting these metabolic vulnerabilities of AML cells,inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential.Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells,enabling them to acquire resistance against OXPHOS and FAO inhibitors.These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors.Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.
基金ThisstudywaspartiallysupportedbytheNationalNaturalScienceFoundationofChina (No 36 970 32 8)
文摘Objective To investigate the effects of red orpiment on cell morphology, expression of promyelocytic leukemia (PML) mRNA and its protein localization in NB4 and HL-60 cell lines.Methods Cell morphology was assayed by Wright's staining and fluorescence staining, while PML mRNA expression was determined by RT-PCR. PML protein localization by evaluated by immunofluorescence staining. Results The typical apoptosis was found in NB4 and HL-60 cells after treatment with red orpiment. The fusion protein was no longer observed in NB4 cells, PML protein was relocated, and then degraded. In HL-60 cells, PML protein underwent a similar progress. The expression of promyelocytic leukemia (PML) mRNA was not changed in the treated cells.Conclusion Red orpiment inhibits the proliferation of leukemia cells by inducing them to undergo apoptosis.
文摘Acute myeloid leukemia(AML)is historically associated with poor prognosis,especially in older AML patients unfit for intensive chemotherapy.The development of Venetoclax,a potent oral BH3(BCL-2 homology domain 3)mimetic,has transformed the AML treatment.However,the short duration of response and development of resistance remain major concerns.Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens.In this review,we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies.Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations.Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.
