Dihydroartemisinin(DHA),a first-line antimalarial drug,has demonstrated great anticancer effects in many types of tumors,including liver cancer,glioblastoma,and pancreatic cancer.Due to its abilities to induce program...Dihydroartemisinin(DHA),a first-line antimalarial drug,has demonstrated great anticancer effects in many types of tumors,including liver cancer,glioblastoma,and pancreatic cancer.Due to its abilities to induce programmed cell death(PCD;apoptosis,autophagy and ferroptosis),inhibit tumor metastasis and angiogenesis,and modulate the tumor microenvironment,DHA could become an antineoplastic agent in the foreseeable future.However,the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages,including poor stability,low aqueous solubility,and short plasma halflife.To overcome these drawbacks,nanoscale drug delivery systems(NDDSs),such as polymeric nanoparticles(NPs),liposomes,and metal-organic frameworks(MOFs),have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy.Based on the beneficial properties of NDDSs,including enhanced stability and solubility of the drug,prolonged circulation time and selective accumulation in tumors,the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA.This reviewfirst summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines,aiming to provide inspiration for further application of DHA as an anticancer drug.展开更多
β-Poly(L-malic acid)(PMLA)is a water-soluble biopolymer used in food,medicine and other industries.To date,the biosynthesis pathway of PMLA has not been fully elucidated.In this study,we sequenced the transcriptom e ...β-Poly(L-malic acid)(PMLA)is a water-soluble biopolymer used in food,medicine and other industries.To date,the biosynthesis pathway of PMLA has not been fully elucidated.In this study,we sequenced the transcriptom e of strain Aureobasidium melanogenum under 20 g/L CaCO_(3) addition.The resulting sequencing reads were assembled and annotated for the differentially expressed genes(DEGs)analysis and novel transcripts identification.The result indicated that with the CaCO_(3) addition,the tricarboxylic cycle(TCA)cycle and glyoxylate pathway were up-regulated,and it also found that a non-ribosomal peptide synthetase(NRPS)like protein was highly expressed.The DEGs analysis showed a high expression level of malate dehydrogenase(MDHC)and phosphoenolpyruvate carboxykinase(PCKA)in the CaCO_(3) group,which indicated a cytosolic malate activity.We speculated that the malate should be transported to or synthesized in the cytoplasm,which was then polymerized to PMLA by the NRPS-like protein,accompanied by the up-regulated TCA cycle providing ATP for the polymerization.Depending on the analysis,we assumed that an NRPS-like protein,the TCA cycle,and the cytosolic malate together are contributing to the PMLA biosynthesis.展开更多
To the Editor:Allogeneic hemopoietic stem cell transplantation(allo-HSCT)represents the only long-term survival treatment choice for patients with myelodysplastic syndromes(MDS)and MDS/myeloproliferative neoplasm(MPN)...To the Editor:Allogeneic hemopoietic stem cell transplantation(allo-HSCT)represents the only long-term survival treatment choice for patients with myelodysplastic syndromes(MDS)and MDS/myeloproliferative neoplasm(MPN).Unfortunately,post-hemopoietic stem cell transplantation(HSCT)relapse remains a cause of treatment failure and the results of salvage treatments are poor.Developing better conditioning regimens is urgently needed.Previous studies have shown synergistic antileukemic effects between decitabine(DEC)and idarubicin(IDA).[1]In an attempt to design a conditioning strategy with very low toxicity but considerable myelosuppressive activity and potential immune-enhancing effects for patients with high-risk MDS and MDS/MPN,we combined DEC and IDA with busulfan,cyclophosphamide,andudarabine for a modied myeloablative regimen in this prospective,multicenter cohort study(hereafter referred to as the“DEC/IDA study”).展开更多
Accumulating evidence suggests that a reduction in the number of Foxp3^(+) regulatory T cells(Tregs)contributes to the pathogenesis of acute graft-versus-host disease(aGVHD),which is a major adverse complication that ...Accumulating evidence suggests that a reduction in the number of Foxp3^(+) regulatory T cells(Tregs)contributes to the pathogenesis of acute graft-versus-host disease(aGVHD),which is a major adverse complication that can occur after allogeneic hematopoietic stem cell transplantation(allo-HSCT).However,the precise features and mechanism underlying the defects in Tregs remain largely unknown.In this study,we demonstrated that Tregs were more dramatically decreased in bone marrow compared with those in peripheral blood from aGVHD patients and that bone marrow Treg defects were negatively associated with hematopoietic reconstitution.Tregs from aGVHD patients exhibited multiple defects,including the instability of Foxp3 expression,especially in response to IL-12,impaired suppressor function,decreased migratory capacity,and increased apoptosis.Transcriptional profiling revealed the downregulation of Lkb1,a previously identified critical regulator of murine Treg identity and metabolism,and murine Lkb1-regulated genes in Tregs from aGVHD patients.Foxp3 expression in human Tregs could be decreased and increased by the knockdown and overexpression of the Lkb1 gene,respectively.Furthermore,a loss-of-function assay in an aGVHD murine model confirmed that Lkb1 deficiency could impair Tregs and aggravate disease severity.These findings reveal that Lkb1 downregulation contributes to multiple defects in Tregs in human aGVHD and highlight the Lkb1-related pathways that could serve as therapeutic targets that may potentially be manipulated to mitigate aGVHD.展开更多
Hemorrhagic cystitis(HC)is a common complication of allogeneic hematopoietic stem cell transplantation(HSCT).The incidence is about 7%to 68%,and some patients have to suffer a long period of frequent,urgent,and painfu...Hemorrhagic cystitis(HC)is a common complication of allogeneic hematopoietic stem cell transplantation(HSCT).The incidence is about 7%to 68%,and some patients have to suffer a long period of frequent,urgent,and painful urination,which brings great pain.This study aimed to analyze risk factors of HC and its effect on patient survival.We collected the medical records of 859 patients who underwent HSCT at our hospital between August 2016 and August 2020.Patients with and without HC were matched using propensity score matching at a 1:1 ratio based on sex,age,and diagnosis,and logistic regression analyses were used to identify factors associated with HC.We used Kaplan–Meier curves to analyze the survival rates of patients in the HC and non-HC groups.We also analyzed the relationship between BK viral load and the occurrence of HC using receiver operating characteristic curve(ROC)analysis.After propensity score matching,there were 131 patients each in the HC and non-HC groups.In the HC group,89 patients(67.9%)had mild HC(stage II°)and 43(32.1%)had severe HC(stage III–IV).The median interval between stem cell transplantation and HC development was 31(3–244)days.Univariate analysis indicated that donor age,hematopoietic stem cell source,HLA,acute graft-versus-host disease,busulfan,anti-thymocyte globulin(ATG),total body irradiation,cytomegalovirus(CMV)(urine),and BK polyomavirus(BKV)(urine)were significantly associated with HC.ATG,CMV(urine),and BKV(urine)were independent risk factors for HC based on the multivariate analysis.The Kaplan–Meier survival analysis showed no significant difference between the HC and non-HC groups(P=0.14).The 1-and 2-year survival rates in the HC group were 78.4%and 69.6%,respectively,and the corresponding rates in the non-HC group were 84.4%and 80.7%,respectively.ROC analysis indicated that a urine BKV load of 1×10^(7) copies/mL was able to stratify the risk of HC.In conclusion,when the BKV load is>1×10^(7),we needtobe aware of the potential for the development of HC.展开更多
Invasive fungal diseases(IFDs)are major and lethal infectious complications for patients with neutropenia after chemotherapy.Prophylaxis with intravenous and oral suspended itraconazole(200 mg Q12h intravenously×...Invasive fungal diseases(IFDs)are major and lethal infectious complications for patients with neutropenia after chemotherapy.Prophylaxis with intravenous and oral suspended itraconazole(200 mg Q12h intravenously×2 days followed by 5 mg/kg·d orally in twice)or oral suspension of posaconazole(200 mg Q8h)was administered for preventing IFDs.The only 2 episodes of proven IFDs were not included after propensity-score matching(PSM),while the incidence of possible IFDs was 8.2%(9/110)in itraconazole group and 1.8%(2/110)in posaconazole group,respectively(P=.030).In clinical failure analysis,the failure rate of posaconazole group was lower as compared to the itraconazole group(2.7%vs 10.9%,P=.016).Both intravenous-oral itraconazole and posaconazole suspension are effective in preventing IFDs,while posaconazole suspension seems more tolerable.展开更多
Objective:To investigate the risk factors for cytomegalovirus(CMV)infection within 100 days and the relationship between early CMV infection and 1-year relapse for patients with acute leukemia following allogeneic hem...Objective:To investigate the risk factors for cytomegalovirus(CMV)infection within 100 days and the relationship between early CMV infection and 1-year relapse for patients with acute leukemia following allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Three hundred fifty-nine patients with acute leukemia who received allo-HSCT at our center between January 2015 and January 2020 were retrospectively reviewed.Results:Of 359 patients,48.19%(173)patients experienced CMV infection within 100 days posttransplantation.In univariate and multivariate logistic analysis,haploidentical-related donor(HRD)(P<0.001;odds ratio[OR],5.542;95%confidence interval[CI],3.186–9.639),and ratio of CD3^(+)CD8^(+)cells in lymphocytes<14.825%(P<0.001;OR,3.005;95%CI,1.712–5.275)were identified as 2 independent risk factors.One-year relapse rate(RR)between the CMV infection group and the non-CMV infection group was not statistically significant(18.5%vs 19.9%,P=0.688).When we divided the total cohort into AML,ALL,and MAL subgroups,there were no significant differences as well(P=0.138;P=0.588;P=0.117;respectively).Conclusion:In conclusion,donor type(HRD)and the insufficient recovery of CD3^(+)CD8^(+)cells were independent risk factors for CMV infection within 100 days posttransplantation in patients with acute leukemia.CMV infection within 100 days did not influence the incidence of relapse in 1 year for patients with acute leukemia.展开更多
1.INTRODUCTION.Extramedullary leukemic infiltration can occur as a manifestation of relapse.It is,however,rare with fewer than 10 cases of cardiovascular relapse reported in the literature,and it often presents as mye...1.INTRODUCTION.Extramedullary leukemic infiltration can occur as a manifestation of relapse.It is,however,rare with fewer than 10 cases of cardiovascular relapse reported in the literature,and it often presents as myeloid sarcoma.1 We report a case of pericardial effusion presenting as an isolated extramedullary relapse(IEMR)of leukemia after allogeneic hematopoietic stem cell transplantation(allo-HSCT).展开更多
基金supported by the National Natural Science Foundation of China[51922111]the Science and Technology Development Fund,Macao SAR[File no.0124/2019/A3]Guangdong-Hong Kong-Macao Joint Laboratory of Optoelectronic and Magnetic Functional Materials[2019B121205002].
文摘Dihydroartemisinin(DHA),a first-line antimalarial drug,has demonstrated great anticancer effects in many types of tumors,including liver cancer,glioblastoma,and pancreatic cancer.Due to its abilities to induce programmed cell death(PCD;apoptosis,autophagy and ferroptosis),inhibit tumor metastasis and angiogenesis,and modulate the tumor microenvironment,DHA could become an antineoplastic agent in the foreseeable future.However,the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages,including poor stability,low aqueous solubility,and short plasma halflife.To overcome these drawbacks,nanoscale drug delivery systems(NDDSs),such as polymeric nanoparticles(NPs),liposomes,and metal-organic frameworks(MOFs),have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy.Based on the beneficial properties of NDDSs,including enhanced stability and solubility of the drug,prolonged circulation time and selective accumulation in tumors,the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA.This reviewfirst summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines,aiming to provide inspiration for further application of DHA as an anticancer drug.
基金the financial support of the Tianjin Municipal Science and Technology Commission(17PTGCCX00190,17PTSYJC00080,17YFCZZC00310,and 16YFXTSF00460)the Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control(ZXKF20180301).
文摘β-Poly(L-malic acid)(PMLA)is a water-soluble biopolymer used in food,medicine and other industries.To date,the biosynthesis pathway of PMLA has not been fully elucidated.In this study,we sequenced the transcriptom e of strain Aureobasidium melanogenum under 20 g/L CaCO_(3) addition.The resulting sequencing reads were assembled and annotated for the differentially expressed genes(DEGs)analysis and novel transcripts identification.The result indicated that with the CaCO_(3) addition,the tricarboxylic cycle(TCA)cycle and glyoxylate pathway were up-regulated,and it also found that a non-ribosomal peptide synthetase(NRPS)like protein was highly expressed.The DEGs analysis showed a high expression level of malate dehydrogenase(MDHC)and phosphoenolpyruvate carboxykinase(PCKA)in the CaCO_(3) group,which indicated a cytosolic malate activity.We speculated that the malate should be transported to or synthesized in the cytoplasm,which was then polymerized to PMLA by the NRPS-like protein,accompanied by the up-regulated TCA cycle providing ATP for the polymerization.Depending on the analysis,we assumed that an NRPS-like protein,the TCA cycle,and the cytosolic malate together are contributing to the PMLA biosynthesis.
基金supported by grants from the Tianjin Health Science and Technology Project(No.TJWJ2022MS001)Clinical research project of Tianjin Society of Hematology and Regenerative Medicine(No.2022 TSHRM08004)+3 种基金Key Project of Tianjin Natural Science Foundation(No.20JCZDJC00410)CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-073)Haihe Laboratory of Cell Ecosystem Innovation Fund(No.22HHXBSS00034)National Natural Science Foundation of China(Nos.82070192,8230012348,and 82170217)
文摘To the Editor:Allogeneic hemopoietic stem cell transplantation(allo-HSCT)represents the only long-term survival treatment choice for patients with myelodysplastic syndromes(MDS)and MDS/myeloproliferative neoplasm(MPN).Unfortunately,post-hemopoietic stem cell transplantation(HSCT)relapse remains a cause of treatment failure and the results of salvage treatments are poor.Developing better conditioning regimens is urgently needed.Previous studies have shown synergistic antileukemic effects between decitabine(DEC)and idarubicin(IDA).[1]In an attempt to design a conditioning strategy with very low toxicity but considerable myelosuppressive activity and potential immune-enhancing effects for patients with high-risk MDS and MDS/MPN,we combined DEC and IDA with busulfan,cyclophosphamide,andudarabine for a modied myeloablative regimen in this prospective,multicenter cohort study(hereafter referred to as the“DEC/IDA study”).
基金by grants from the National Basic Research Program of China(2015CB964402)the National Natural Science Foundation of China(81670171,81601369)+2 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-1-003 and 2018-I2M-HL-013)the Tianjin Science Funds for Distinguished Young Scholars(17JCJQJC45800)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2018PT32034 and 2019-RC-HL-013).
文摘Accumulating evidence suggests that a reduction in the number of Foxp3^(+) regulatory T cells(Tregs)contributes to the pathogenesis of acute graft-versus-host disease(aGVHD),which is a major adverse complication that can occur after allogeneic hematopoietic stem cell transplantation(allo-HSCT).However,the precise features and mechanism underlying the defects in Tregs remain largely unknown.In this study,we demonstrated that Tregs were more dramatically decreased in bone marrow compared with those in peripheral blood from aGVHD patients and that bone marrow Treg defects were negatively associated with hematopoietic reconstitution.Tregs from aGVHD patients exhibited multiple defects,including the instability of Foxp3 expression,especially in response to IL-12,impaired suppressor function,decreased migratory capacity,and increased apoptosis.Transcriptional profiling revealed the downregulation of Lkb1,a previously identified critical regulator of murine Treg identity and metabolism,and murine Lkb1-regulated genes in Tregs from aGVHD patients.Foxp3 expression in human Tregs could be decreased and increased by the knockdown and overexpression of the Lkb1 gene,respectively.Furthermore,a loss-of-function assay in an aGVHD murine model confirmed that Lkb1 deficiency could impair Tregs and aggravate disease severity.These findings reveal that Lkb1 downregulation contributes to multiple defects in Tregs in human aGVHD and highlight the Lkb1-related pathways that could serve as therapeutic targets that may potentially be manipulated to mitigate aGVHD.
基金the National Natural Science Foundation of China(81670171 and 82070192)Key Project of Tianjin Natural Science Foundation(20JCZDJC00410)thrombocytopenia funding from the Yeehong Business School of Shenyang Pharmaceutical University(Sansheng TCP Young Research Funding,No.57).
文摘Hemorrhagic cystitis(HC)is a common complication of allogeneic hematopoietic stem cell transplantation(HSCT).The incidence is about 7%to 68%,and some patients have to suffer a long period of frequent,urgent,and painful urination,which brings great pain.This study aimed to analyze risk factors of HC and its effect on patient survival.We collected the medical records of 859 patients who underwent HSCT at our hospital between August 2016 and August 2020.Patients with and without HC were matched using propensity score matching at a 1:1 ratio based on sex,age,and diagnosis,and logistic regression analyses were used to identify factors associated with HC.We used Kaplan–Meier curves to analyze the survival rates of patients in the HC and non-HC groups.We also analyzed the relationship between BK viral load and the occurrence of HC using receiver operating characteristic curve(ROC)analysis.After propensity score matching,there were 131 patients each in the HC and non-HC groups.In the HC group,89 patients(67.9%)had mild HC(stage II°)and 43(32.1%)had severe HC(stage III–IV).The median interval between stem cell transplantation and HC development was 31(3–244)days.Univariate analysis indicated that donor age,hematopoietic stem cell source,HLA,acute graft-versus-host disease,busulfan,anti-thymocyte globulin(ATG),total body irradiation,cytomegalovirus(CMV)(urine),and BK polyomavirus(BKV)(urine)were significantly associated with HC.ATG,CMV(urine),and BKV(urine)were independent risk factors for HC based on the multivariate analysis.The Kaplan–Meier survival analysis showed no significant difference between the HC and non-HC groups(P=0.14).The 1-and 2-year survival rates in the HC group were 78.4%and 69.6%,respectively,and the corresponding rates in the non-HC group were 84.4%and 80.7%,respectively.ROC analysis indicated that a urine BKV load of 1×10^(7) copies/mL was able to stratify the risk of HC.In conclusion,when the BKV load is>1×10^(7),we needtobe aware of the potential for the development of HC.
基金the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS)[2021-I2M-1-017]and[2021-I2M-C&T-B-080]Haihe Laboratory of Cell Ecosystem Innovation Fund[HH22KYZX0036].
文摘Invasive fungal diseases(IFDs)are major and lethal infectious complications for patients with neutropenia after chemotherapy.Prophylaxis with intravenous and oral suspended itraconazole(200 mg Q12h intravenously×2 days followed by 5 mg/kg·d orally in twice)or oral suspension of posaconazole(200 mg Q8h)was administered for preventing IFDs.The only 2 episodes of proven IFDs were not included after propensity-score matching(PSM),while the incidence of possible IFDs was 8.2%(9/110)in itraconazole group and 1.8%(2/110)in posaconazole group,respectively(P=.030).In clinical failure analysis,the failure rate of posaconazole group was lower as compared to the itraconazole group(2.7%vs 10.9%,P=.016).Both intravenous-oral itraconazole and posaconazole suspension are effective in preventing IFDs,while posaconazole suspension seems more tolerable.
基金This work was funded by grants from the CAMS Innovation Fund for Medical Sciences(CIFMS)(grant numbers 2021-1-I2M-017 and 2021-I2M-C&T-B-080).
文摘Objective:To investigate the risk factors for cytomegalovirus(CMV)infection within 100 days and the relationship between early CMV infection and 1-year relapse for patients with acute leukemia following allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Three hundred fifty-nine patients with acute leukemia who received allo-HSCT at our center between January 2015 and January 2020 were retrospectively reviewed.Results:Of 359 patients,48.19%(173)patients experienced CMV infection within 100 days posttransplantation.In univariate and multivariate logistic analysis,haploidentical-related donor(HRD)(P<0.001;odds ratio[OR],5.542;95%confidence interval[CI],3.186–9.639),and ratio of CD3^(+)CD8^(+)cells in lymphocytes<14.825%(P<0.001;OR,3.005;95%CI,1.712–5.275)were identified as 2 independent risk factors.One-year relapse rate(RR)between the CMV infection group and the non-CMV infection group was not statistically significant(18.5%vs 19.9%,P=0.688).When we divided the total cohort into AML,ALL,and MAL subgroups,there were no significant differences as well(P=0.138;P=0.588;P=0.117;respectively).Conclusion:In conclusion,donor type(HRD)and the insufficient recovery of CD3^(+)CD8^(+)cells were independent risk factors for CMV infection within 100 days posttransplantation in patients with acute leukemia.CMV infection within 100 days did not influence the incidence of relapse in 1 year for patients with acute leukemia.
基金supported by Tianjin Municipal Science and Technology Commission Grant(21JCZDJC01170)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-C&T-B-080,2021-I2M-1-017)+1 种基金Haihe Laboratory of Cell Ecosystem Innovation Fund(22HHXBSS00036)to S.F.Youth Program of National Natural Science Foundation of China 81900182)to Y.S.
文摘1.INTRODUCTION.Extramedullary leukemic infiltration can occur as a manifestation of relapse.It is,however,rare with fewer than 10 cases of cardiovascular relapse reported in the literature,and it often presents as myeloid sarcoma.1 We report a case of pericardial effusion presenting as an isolated extramedullary relapse(IEMR)of leukemia after allogeneic hematopoietic stem cell transplantation(allo-HSCT).
