Background:Busulfan(BU)is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell(HSC)transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells.The suscep...Background:Busulfan(BU)is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell(HSC)transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells.The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU.Different susceptibilities were demonstrated in genetically diverse(GD)mice in our preliminary research.Methods:Three strains of GD mice with different susceptibilities to BU-i nduced HSC injury were used for screening biological markers of HSC injury susceptibility in urine.The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins.Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme-l inked immunoassay(ELISA).Results:Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence,apoptosis,and angiogenesis;whereas the differential proteins of the high-susceptible strain were enriched for the regulation of bone marrow microenvironment pathways,those of low-susceptible strain were enriched for the proapoptotic effect of GTPase pathways.Based on protein abundance differences,several urinary proteins that may be indicative of susceptibility were screened,and ELISA validation results showed that angiotensin-converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning.Conclusions:This study indicates that urinary protein levels can reflect differences in susceptibility to BU-i nduced HSC injury.Using GD mice to construct genetic difference models will provide preclinical data for screening BU-related biological markers.展开更多
Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig’s disease in the United States,Charcot’s disease in France,and motor neuron disease in the UK.The loss of motor n...Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig’s disease in the United States,Charcot’s disease in France,and motor neuron disease in the UK.The loss of motor neurons causes muscle wasting,paralysis,and eventually death,which is commonly related to respiratory failure,within 3-5 years after onset of the disease.Although there are a limited number of drugs approved for amyotrophic lateral sclerosis,they have had little success at treating the associated symptoms,and they cannot reverse the course of motor neuron degeneration.Thus,there is still a lack of effective treatment for this debilitating neurodegenerative disorder.Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers,particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons.Stem cell therapies may also be able to re-establish the motor control of voluntary muscles.Here,we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis.We focus on MN progenitor cells derived from fetal central nervous system tissue,embryonic stem cells,and induced pluripotent stem cells.In our recent studies,we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well,differentiate into motor neurons,and extend axons into the host white matter,not only in the rostrocaudal direction,but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord.Furthermore,the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis,particularly as a variety of stem cell derivatives,including induced pluripotent stem cells,are being considered for clinical trials for various diseases.展开更多
Background:Myelodysplastic syndrome(MDS)is a group of disorders involving he-mopoietic dysfunction leading to leukemia.Although recently progress has been made in identifying underlying genetic mutations,many question...Background:Myelodysplastic syndrome(MDS)is a group of disorders involving he-mopoietic dysfunction leading to leukemia.Although recently progress has been made in identifying underlying genetic mutations,many questions still remain.Animal models of MDS have been produced by introduction of specific mutations.However,there is no spontaneous mouse model of MDS,and an animal model to simulate natu-ral MDS pathogenesis is urgently needed.Methods:In characterizing the genetically diverse mouse strains of the Collaborative Cross(CC)we observed that one,designated JUN,had abnormal hematological traits.This strain was thus further analyzed for phenotypic and pathological iden-tification,comparing the changes in each cell population in peripheral blood and in bone marrow.Results:In a specific-pathogen free environment,mice of the JUN strain are rela-tively thin,with healthy appearance.However,in a conventional environment,they become lethargic,develop wrinkled yellow hair,have loose and light stools,and are prone to infections.We found that the mice were cytopenic,which was due to abnor-mal differentiation of multipotent bone marrow progenitor cells.These are common characteristics of MDS.Conclusions:A mouse strain,JUN,was found displaying spontaneous myelodysplas-tic syndrome.This strain has the advantage over existing models in that it develops MDS spontaneously and is more similar to human MDS than genetically modified mouse models.JUN mice will be an important tool for pathogenesis research of MDS and for evaluation of new drugs and treatments.展开更多
Objective:To evaluate cervical function and pregnancy outcomes after hysteroscopic resection of the complete uterine septum,duplicate cervix and vaginal septum with Metzenbaum scissors.Methods:Between January 2010 and...Objective:To evaluate cervical function and pregnancy outcomes after hysteroscopic resection of the complete uterine septum,duplicate cervix and vaginal septum with Metzenbaum scissors.Methods:Between January 2010 and December 2016,13 patients admitted to the Department of Obstetrics and Gynecology of Sir Run Run Shaw Hospital with complete uterine septum,duplicate cervix and vaginal septum,were enrolled into this study.The cervical and corporal septum was cut by Metzenbaum scissors,and residual septum was cut by micro scissors under hysteroscopy.The vaginal septum was cut with the unipolar electric knife.Results:The operation time was about 10±1.31 min.All the 13 patients present normal uterine cavities without scar formation under hysteroscopy at 3 months after operation,there was mild adhesions between anterior and posterior intrauterine wall on 2 cases.After operation,there were 13 pregnancies naturally conceived in 11 patients,10 deliveries.The live birth rate was 76.92%,the early miscarriage rate was 23.08%.The cesarean section ratewas 30%,the vaginal delivery ratewas 70%,and all were term births.Conclusion:The operation was simple,convenient,and fast,without any complications and cervical insufficiency.It was easy to have vaginal deliveries.展开更多
Background Clarifying the enrichment and response processes of triclosan(TCS)in hydrophytes is crucial for assessing the ecological risk of TCS in aquatic environments.This study delves into the chronic toxic effects ...Background Clarifying the enrichment and response processes of triclosan(TCS)in hydrophytes is crucial for assessing the ecological risk of TCS in aquatic environments.This study delves into the chronic toxic effects of TCS in floating plant Eichhornia crassipes(Mart.)Solms and submerged plant Hydrilla verticillata(L.f.)Royle exposed to TCS sediments through hydroponic experiments.Results The absorption abilities of hydrophytes to TCS were species-dependent.The concentration of TCS in the roots of E.crassipes was significantly higher than that in its leaves,while the absorption capacities of the leaves of H.verticillata to TCS were stronger than that in its roots.Furthermore,the physiological indexes,including chlorophyll concentration,soluble protein concentration,and antioxidant enzyme activities,showed a significant decrease with the exposure concentration and time of TCS.Although the chlorophyll and soluble protein concentrations and the antioxidant enzyme activities in the leaves were initially increased at a low concentration of TCS(at 7 days of exposure),they decreased significantly over time.Compared to the leaves,the physiological indexes of the roots were more sensitive to the ecotoxicological effects of TCS.The inhibition effects of TCS on H.verticillata were signifi-cantly higher than those on E.crassipes,which may be associated with the absorbing abilities of TCS and the growth characteristics of the plants.Pearson’s correlation analysis found a significant negative correlation between the TCS concentrations and the antioxidant enzyme activities in the plants.Conclusions This study highlighted the differences in the uptake and enrichment process and toxic effects of TCS by different aquatic plants.Compared with E.crassipes,H.verticillata is more sensitive to TCS toxicity.展开更多
Extreme temperature events have affected Chinese city residents more frequently and intensively since the early 2000 s, but few studies have identified the impacts of extreme temperature on mortality in different city...Extreme temperature events have affected Chinese city residents more frequently and intensively since the early 2000 s, but few studies have identified the impacts of extreme temperature on mortality in different city clusters of China. This study first used a distributed lag,nonlinear model to estimate the county/district-specific effects of extreme temperature on nonaccidental and cardiovascular mortality. The authors then applied a multivariate meta-analysis to pool the estimated effects in order to derive regional temperature–mortality relationship in three large city clusters—the Beijing-Tianjin-Hebei(BTH)region, the Yangtze River Delta(YRD), and the Pearl River Delta(PRD), which represent northern and southern regions. With 0–3 days' lag, the strongest heat-related mortality effect was observed in the BTH region(with relative risk(RR) of 1.29; 95% confidence interval(CI):1.13–1.47), followed by the YRD(RR = 1.25; 95% CI:1.13–1.35) and the PRD(RR = 1.14; 95% CI: 1.01–1.28)areas. With 0–21 days' lag, the cold effect was pronounced in all city clusters, with the highest extreme cold-related mortality risk found in the PRD area(RR = 2.27; 95% CI:1.63–3.16), followed by the YRD area(RR = 1.85; 95%CI: 1.56–2.20) and BTH region(RR = 1.33; 95% CI:0.96–1.83). People in the southern regions tended to be more vulnerable to cold stress, but the northern population was more sensitive to heat stress. By examining the effects of extreme temperature in city clusters of different regions,our findings underline the role of adaptation towards heat and cold, which has important implications for public health policy making and practice.展开更多
Photodynamic therapy(PDT)has been widely used in cancer treatment.However,hypoxia in most solid tumors seriously restricts the efficacy of PDT.To improve the hypoxic microenvironment,we designed a novel mesoporous pla...Photodynamic therapy(PDT)has been widely used in cancer treatment.However,hypoxia in most solid tumors seriously restricts the efficacy of PDT.To improve the hypoxic microenvironment,we designed a novel mesoporous platinum(mPt)nanoplatform to catalyze hydrogen peroxide(H2 O2)within the tumor cells in situ without an extra enzyme.During the fabrication,the carboxy terminus of the photosensitizer chlorin e6(Ce6)was connected to the amino terminus of the bifunctional mercaptoaminopolyglycol(SH-PEG-NH2)by a condensation reaction,and then PEG-Ce6 was modified onto the mPt moiety via the mercapto terminal of SH-PEG-NH2.Material,cellular and animal experiments demonstrated that Pt@PEG-Ce6 catalyzed H2 O2 to produce oxygen(O2)and that Ce6 transformed O2 to generate reactive oxygen species(ROS)upon laser irradiation.The Pt@PEG-Ce6 nanoplatform with uniform diameter presented good biocompatibility and efficient tumor accumulation.Due to the high atomic number and good near-infrared absorption for Pt,this Pt@PEG-Ce6 nanoplatform showed computed tomography(CT)and photoacoustic(PA)dual-mode imaging ability,thus providing an important tool for monitoring the tumor hypoxic microenvironment.Moreover,the Pt@PEG-Ce6 nanoplatform reduced the expression of hypoxia-inducible factor-la(HIF-1α)and programmed death-1(PD-1)in tumors,discussing the relationship between hypoxia,PD-1,and PDT for the first time.展开更多
基金National Natural Scientific Foundation of ChinaGrant/Award Number:81972975+2 种基金National Human Diseases Animal Model Resource CenterNational Science Foundation for Young Scientists of ChinaGrant/Award Number:81703170。
文摘Background:Busulfan(BU)is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell(HSC)transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells.The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU.Different susceptibilities were demonstrated in genetically diverse(GD)mice in our preliminary research.Methods:Three strains of GD mice with different susceptibilities to BU-i nduced HSC injury were used for screening biological markers of HSC injury susceptibility in urine.The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins.Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme-l inked immunoassay(ELISA).Results:Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence,apoptosis,and angiogenesis;whereas the differential proteins of the high-susceptible strain were enriched for the regulation of bone marrow microenvironment pathways,those of low-susceptible strain were enriched for the proapoptotic effect of GTPase pathways.Based on protein abundance differences,several urinary proteins that may be indicative of susceptibility were screened,and ELISA validation results showed that angiotensin-converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning.Conclusions:This study indicates that urinary protein levels can reflect differences in susceptibility to BU-i nduced HSC injury.Using GD mice to construct genetic difference models will provide preclinical data for screening BU-related biological markers.
基金supported by the Stem Cell and Translation National Key Project(No.2016YFA0101403,to ZC)the National Natural Science Foundation of China(Nos.81973351,81661130160,81422014,81561138004,all to ZC)+7 种基金the Beijing Municipal Natural Science Foundation(No.5142005,to ZC)Beijing Talents Foundation(No.2017000021223TD03,to ZC)the Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-Year Plan(No.CIT&TCD20180333,to ZC)the Beijing Medical System High Level Talent Award(No.2015-3-063,to ZC)Beijing Municipal Health Commission Fund(No.PXM2020_026283_000005)Beijing One Hundred,Thousand,and Ten Thousand Talents Fund(No.2018A03,to ZC)the Royal Society-Newton Advanced Fellowship(No.NA150482,to ZC)the USA Veterans Administration(No.I01 RX002264-01A2,to PL).
文摘Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig’s disease in the United States,Charcot’s disease in France,and motor neuron disease in the UK.The loss of motor neurons causes muscle wasting,paralysis,and eventually death,which is commonly related to respiratory failure,within 3-5 years after onset of the disease.Although there are a limited number of drugs approved for amyotrophic lateral sclerosis,they have had little success at treating the associated symptoms,and they cannot reverse the course of motor neuron degeneration.Thus,there is still a lack of effective treatment for this debilitating neurodegenerative disorder.Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers,particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons.Stem cell therapies may also be able to re-establish the motor control of voluntary muscles.Here,we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis.We focus on MN progenitor cells derived from fetal central nervous system tissue,embryonic stem cells,and induced pluripotent stem cells.In our recent studies,we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well,differentiate into motor neurons,and extend axons into the host white matter,not only in the rostrocaudal direction,but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord.Furthermore,the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis,particularly as a variety of stem cell derivatives,including induced pluripotent stem cells,are being considered for clinical trials for various diseases.
基金National Science and Technology Major Project,Grant/Award Number:2017ZX10304402Peking Union Medical College,Grant/Award Number:3332020050。
文摘Background:Myelodysplastic syndrome(MDS)is a group of disorders involving he-mopoietic dysfunction leading to leukemia.Although recently progress has been made in identifying underlying genetic mutations,many questions still remain.Animal models of MDS have been produced by introduction of specific mutations.However,there is no spontaneous mouse model of MDS,and an animal model to simulate natu-ral MDS pathogenesis is urgently needed.Methods:In characterizing the genetically diverse mouse strains of the Collaborative Cross(CC)we observed that one,designated JUN,had abnormal hematological traits.This strain was thus further analyzed for phenotypic and pathological iden-tification,comparing the changes in each cell population in peripheral blood and in bone marrow.Results:In a specific-pathogen free environment,mice of the JUN strain are rela-tively thin,with healthy appearance.However,in a conventional environment,they become lethargic,develop wrinkled yellow hair,have loose and light stools,and are prone to infections.We found that the mice were cytopenic,which was due to abnor-mal differentiation of multipotent bone marrow progenitor cells.These are common characteristics of MDS.Conclusions:A mouse strain,JUN,was found displaying spontaneous myelodysplas-tic syndrome.This strain has the advantage over existing models in that it develops MDS spontaneously and is more similar to human MDS than genetically modified mouse models.JUN mice will be an important tool for pathogenesis research of MDS and for evaluation of new drugs and treatments.
基金supported by the Department of Education of Zhejiang Province,China(Y201534677).
文摘Objective:To evaluate cervical function and pregnancy outcomes after hysteroscopic resection of the complete uterine septum,duplicate cervix and vaginal septum with Metzenbaum scissors.Methods:Between January 2010 and December 2016,13 patients admitted to the Department of Obstetrics and Gynecology of Sir Run Run Shaw Hospital with complete uterine septum,duplicate cervix and vaginal septum,were enrolled into this study.The cervical and corporal septum was cut by Metzenbaum scissors,and residual septum was cut by micro scissors under hysteroscopy.The vaginal septum was cut with the unipolar electric knife.Results:The operation time was about 10±1.31 min.All the 13 patients present normal uterine cavities without scar formation under hysteroscopy at 3 months after operation,there was mild adhesions between anterior and posterior intrauterine wall on 2 cases.After operation,there were 13 pregnancies naturally conceived in 11 patients,10 deliveries.The live birth rate was 76.92%,the early miscarriage rate was 23.08%.The cesarean section ratewas 30%,the vaginal delivery ratewas 70%,and all were term births.Conclusion:The operation was simple,convenient,and fast,without any complications and cervical insufficiency.It was easy to have vaginal deliveries.
基金supported by the National Natural Science Foundation of China(31971515)the Fund for National Key Research and Development Plan of China(2019YFC1804100)+1 种基金the Fund for Strategic Priority Research Program of the Chinese Academy of Sciences(XDA28010503)the Major Project of Shenyang Institute of Applied Ecology,Chinese Academy of Sciences(IAEMP202201).
文摘Background Clarifying the enrichment and response processes of triclosan(TCS)in hydrophytes is crucial for assessing the ecological risk of TCS in aquatic environments.This study delves into the chronic toxic effects of TCS in floating plant Eichhornia crassipes(Mart.)Solms and submerged plant Hydrilla verticillata(L.f.)Royle exposed to TCS sediments through hydroponic experiments.Results The absorption abilities of hydrophytes to TCS were species-dependent.The concentration of TCS in the roots of E.crassipes was significantly higher than that in its leaves,while the absorption capacities of the leaves of H.verticillata to TCS were stronger than that in its roots.Furthermore,the physiological indexes,including chlorophyll concentration,soluble protein concentration,and antioxidant enzyme activities,showed a significant decrease with the exposure concentration and time of TCS.Although the chlorophyll and soluble protein concentrations and the antioxidant enzyme activities in the leaves were initially increased at a low concentration of TCS(at 7 days of exposure),they decreased significantly over time.Compared to the leaves,the physiological indexes of the roots were more sensitive to the ecotoxicological effects of TCS.The inhibition effects of TCS on H.verticillata were signifi-cantly higher than those on E.crassipes,which may be associated with the absorbing abilities of TCS and the growth characteristics of the plants.Pearson’s correlation analysis found a significant negative correlation between the TCS concentrations and the antioxidant enzyme activities in the plants.Conclusions This study highlighted the differences in the uptake and enrichment process and toxic effects of TCS by different aquatic plants.Compared with E.crassipes,H.verticillata is more sensitive to TCS toxicity.
基金supported by the fund for Creative Research Groups of the National Natural Science Foundation of China (No. 41621061)State Key Laboratory of Earth Surface Processes and Resources Ecology
文摘Extreme temperature events have affected Chinese city residents more frequently and intensively since the early 2000 s, but few studies have identified the impacts of extreme temperature on mortality in different city clusters of China. This study first used a distributed lag,nonlinear model to estimate the county/district-specific effects of extreme temperature on nonaccidental and cardiovascular mortality. The authors then applied a multivariate meta-analysis to pool the estimated effects in order to derive regional temperature–mortality relationship in three large city clusters—the Beijing-Tianjin-Hebei(BTH)region, the Yangtze River Delta(YRD), and the Pearl River Delta(PRD), which represent northern and southern regions. With 0–3 days' lag, the strongest heat-related mortality effect was observed in the BTH region(with relative risk(RR) of 1.29; 95% confidence interval(CI):1.13–1.47), followed by the YRD(RR = 1.25; 95% CI:1.13–1.35) and the PRD(RR = 1.14; 95% CI: 1.01–1.28)areas. With 0–21 days' lag, the cold effect was pronounced in all city clusters, with the highest extreme cold-related mortality risk found in the PRD area(RR = 2.27; 95% CI:1.63–3.16), followed by the YRD area(RR = 1.85; 95%CI: 1.56–2.20) and BTH region(RR = 1.33; 95% CI:0.96–1.83). People in the southern regions tended to be more vulnerable to cold stress, but the northern population was more sensitive to heat stress. By examining the effects of extreme temperature in city clusters of different regions,our findings underline the role of adaptation towards heat and cold, which has important implications for public health policy making and practice.
基金supported by the National Program on Key Basic Research Project(Grant No.2014CB744504,China)the National Natural Science Foundation of China(Grant No.81530054)+1 种基金Guangdong Science and Technology Department(Grant No.2016ZC0086,China)Guangdong Science and Technology Department(Grant No.2017ZC0099,China)
文摘Photodynamic therapy(PDT)has been widely used in cancer treatment.However,hypoxia in most solid tumors seriously restricts the efficacy of PDT.To improve the hypoxic microenvironment,we designed a novel mesoporous platinum(mPt)nanoplatform to catalyze hydrogen peroxide(H2 O2)within the tumor cells in situ without an extra enzyme.During the fabrication,the carboxy terminus of the photosensitizer chlorin e6(Ce6)was connected to the amino terminus of the bifunctional mercaptoaminopolyglycol(SH-PEG-NH2)by a condensation reaction,and then PEG-Ce6 was modified onto the mPt moiety via the mercapto terminal of SH-PEG-NH2.Material,cellular and animal experiments demonstrated that Pt@PEG-Ce6 catalyzed H2 O2 to produce oxygen(O2)and that Ce6 transformed O2 to generate reactive oxygen species(ROS)upon laser irradiation.The Pt@PEG-Ce6 nanoplatform with uniform diameter presented good biocompatibility and efficient tumor accumulation.Due to the high atomic number and good near-infrared absorption for Pt,this Pt@PEG-Ce6 nanoplatform showed computed tomography(CT)and photoacoustic(PA)dual-mode imaging ability,thus providing an important tool for monitoring the tumor hypoxic microenvironment.Moreover,the Pt@PEG-Ce6 nanoplatform reduced the expression of hypoxia-inducible factor-la(HIF-1α)and programmed death-1(PD-1)in tumors,discussing the relationship between hypoxia,PD-1,and PDT for the first time.
