A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and m...A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs.The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.展开更多
The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer cells.Worse still,despite PTT enhances immuno...The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer cells.Worse still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune cells.To solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor site.Upon irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ICD.Moreover,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic tumors.In vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.展开更多
As known,the benefits of photothermal therapy(PTT)are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins(HSPs).Then HSPs further trigger the formation of stress gran...As known,the benefits of photothermal therapy(PTT)are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins(HSPs).Then HSPs further trigger the formation of stress granules(SGs)that regulate protein expression and cell viability under various stress conditions.Inhibition of SG formation can sensitize tumor cells to PTT.Herein,we developed PEGylated pH(low)insertion peptide(PEG-pHLIP)-modified hollow copper sulfide nanoparticles(HCuS NPs)encapsulating the SG inhibitor ISRIB,with the phase-change material lauric acid(LA)as a gatekeeper,to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system(IL@H-PP).The nano medicine could specifically target slightly acidic tumor sites.Upon irradiation,IL@H-PP realized PTT,and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT,thereby increasing the antitumor effect and inducing potent immunogenic cell death(ICD).Moreover,IL@H-PP could promote the production of reactive oxygen species(ROS)by tumor-associated macrophages(TAMs),repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment.In vitro/vivo results revealed the potential of PTT combined with SG inhibitors,which provides a new paradigm for antitumor and antimetastases.展开更多
Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor ...Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor cells,circulating tumor DNA(ctDNA)is widely distributed in various body fluids,including peripheral blood and cerebrospinal fluid(CSF),as an alternative biomarker for tumor-associated analysis[1].Fortunately,genomic alterations of blood ctDNA and CSF ctDNA have been proven as prognostic markers in non-small cell lung cancer(NSCLC)patients with brain metastasis[2,3].展开更多
Large Eddy Simulation(LES) is performed to investigate the airfoil broadband noise reduction with wavy leading edge under anisotropic incoming turbulence. The anisotropic incoming turbulence is generated by a rod with...Large Eddy Simulation(LES) is performed to investigate the airfoil broadband noise reduction with wavy leading edge under anisotropic incoming turbulence. The anisotropic incoming turbulence is generated by a rod with a diameter of 10 mm. The incoming flow velocity is 40 m/s and the corresponding Reynolds numbers based on airfoil chord and rod diameter are about 397000 and 26000, respectively. The far-field acoustic field is predicted using an acoustic analogy method which has been validated by the experiment. A straight leading edge airfoil and a wavy leading edge airfoil are simulated. The results show that wavy leading edge increases the airfoil lift and drag whereas the lift and drag fluctuations are substantially reduced. In addition, wavy leading edge can significantly change the flow pattern around the leading edge and a pair of counter-rotating streamwise vortices stemming from each wavy leading edge peak are observed.An averaged noise reduction of 9.5 dB is observed with the wavy leading edge at the azimuthal angle of 90°. Moreover, the wavy leading edge can mitigate noise radiation at all the azimuthal angles without significantly changing the noise directivity. The underlying noise reduction mechanisms are then analyzed in detail.展开更多
Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through...Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer(d-SN38)-loaded nanoparticles(d-SN38@NPs/iRGD).Upon intravenous injection,d-SN38@NPs with high drug loading efficiency(33.92±1.33%)could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD.The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy.The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm,which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor.In vitro,coadministering iRGD with d-SN38@NPs+laser showed higher cellular uptake,apoptosis ratio and multicellular spheroid penetration.In vivo,d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor,leading to 60.89%of tumor suppression in 4 T1 tumor-bearing mouse model with a favorable toxicity profile.Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting,penetrating and retention,and empowers anticancer efficacy.展开更多
Insurmountable blood-brain barrier(BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease(AD).Poor accumulation of drugs in lesion sites and undesired effectivene...Insurmountable blood-brain barrier(BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease(AD).Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβ deposition or TAU protein need to be resolved urgently.Herein,a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD].DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions,and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma.Then exposed KLVFF can capture and carry Aβ to microglia,attenuating Aβ-induced neurotoxicity.Strikingly,rapamycin,an autophagy promoter,is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβ degradation and normalize inflammatory condition.This design altogether accelerates Aβ degradation and alleviates oxidative stress and excessive inflammatory response.Collectively,our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment,to achieve efficient AD therapy.展开更多
Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during t...Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during the neonatal period to provide early diagnosis and treatment[1].With a history of more than 60 years,NBS has advanced greatly due to technological progress resulting in significant improvement in the number of diseases covered by NBS and in screening efficiency[2-7].展开更多
Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the re...Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.展开更多
Background Fragile X syndrome(FXS).caused by CGG-repeat expansion in FMR1 promoter,is one of the most common causes of mental retardation.Individuals with full mutation and premutation alleles have a high risk of psyc...Background Fragile X syndrome(FXS).caused by CGG-repeat expansion in FMR1 promoter,is one of the most common causes of mental retardation.Individuals with full mutation and premutation alleles have a high risk of psychophysiological disorder and of having affected offspring.Frequencies of FMR1 alleles in general newborns have been reported in Caucasians but have not been investigated in the large-scale population in the mainland of China.Methods The sizes of FMRI CGG-repeats were analyzed in 51,661 newborns(28,114 males and 23,547 females)and also in a cohort of 33 children diagnosed with developmental delay using GC-rich polymerase chain reaction(PCR)and triple repeat primed PCR.Results The frequency of CGG repeats>100 was 1/9371 in males and 1/5887 in females,and the frequency of CGG repeats>54 was 1/1561 in males and 1/1624 in females.FMRJ full mutation and premutation were identified in 27.27%of children who had Ages and Stages Questionnaire scores less than two standard deviations from the cutoff value.Conclusions Our study revealed the prevalence of FXS in China and improved the sample databases of FXS,suggesting that the prevalence of FXS in Chinese is higher than estimated previously and that FXS screening can be advised to high-risk families.展开更多
ZnO films coated with reduced graphene oxide(RGO-ZnO) were prepared by a simple chemical approach. The graphene oxide(GO) films transferred onto ZnO films by spin coating were reduced to RGO films by two steps(exposed...ZnO films coated with reduced graphene oxide(RGO-ZnO) were prepared by a simple chemical approach. The graphene oxide(GO) films transferred onto ZnO films by spin coating were reduced to RGO films by two steps(exposed to hydrazine vapor for 12 h and annealed at 600 °C). The crystal structures, electrical and photoluminescence properties of RGO-ZnO films on quartz substrates were systematically studied. The SEM images illustrated that RGO layers have successfully been coated on the ZnO films very tightly. The PL properties of RGO-ZnO were studied. PL spectra show two sharp peaks at 390 nm and a broad visible emission around 490 nm.The resistivity of RGO-ZnO films was measured by a Hall measurement system, RGO as nanofiller considerably decrease the resistivity of ZnO films. An electrode was fabricated, using RGO-ZnO films deposited on Si substrate as active materials, for super capacitor application. By comparison of different results, we conclude that the RGOZnO composite material couples possess the properties of super capacitor.展开更多
The authors regret that there were some picture errors in Fig.4A and data errors Fig.7A owing to the mistakes of copying and pasting in the process of assembling figures and making a dia-gram.The raw data of correct i...The authors regret that there were some picture errors in Fig.4A and data errors Fig.7A owing to the mistakes of copying and pasting in the process of assembling figures and making a dia-gram.The raw data of correct images of group b in Fig.4A and values of high dose in Fig.7A are provided in the supporting information,and the authors revise Figs.4 and 7 as below.The revisions do not affect any results and conclusions of the current work.The authors apologize for any inconvenience caused to the journal and readers.展开更多
Background:Glutaric acidemia type I(GA-I)is a rare metabolic disorder caused by mutation of the glutaryl-CoA dehydrogenase(GCDH)gene.The occurrence of rhabdomyolysis with GA-I is extremely rare.Methods:We reported a c...Background:Glutaric acidemia type I(GA-I)is a rare metabolic disorder caused by mutation of the glutaryl-CoA dehydrogenase(GCDH)gene.The occurrence of rhabdomyolysis with GA-I is extremely rare.Methods:We reported a child with recurrent rhabdomyolysis and undiagnosed glutaric acidemia type I(GA-I).And a literature review was performed.Results:A 4.5-year-old girl was admitted to our hospital due to recurrent rhabdomyolysis for 3 times within three years.At the third admission,she was diagnosed with GA-I by biochemical testing and mutation analysis.The girl was found to have a serine to leucine replacement mutation of the GCDH gene in exon 8 at position 764.Other three patients with rhabdomyolysis and GA-I were discovered by literature searching.Conclusion:This report highlights that patients with GA-I may have an increased risk of rhabdomyolysis.展开更多
Immune checkpoint inhibitors(ICIs)are gradually replacing chemotherapy as the cornerstone of the treatment of advanced malignant tumors because of their long-lasting and significant effect in different tumor types and...Immune checkpoint inhibitors(ICIs)are gradually replacing chemotherapy as the cornerstone of the treatment of advanced malignant tumors because of their long-lasting and significant effect in different tumor types and greatly prolonging the survival time of patients.However,not all patients can respond to ICIs,and even rapid tumor growth after treatment with ICI has been observed in a number of clinical studies.This rapid progression phenomenon is called hyper-progressive disease(HPD).The occurrence of HPD is not uncommon.Past statistics show that the incidence of HPD is 4%-29% in different tumor types,and the progression-free survival and overall survival of patients with HPD are significantly shorter than those of the non-HPD progressor group.With the deepening of the study of HPD,we have established a preliminary understanding of HPD,but the diagnostic criteria of HPD are still not unified,and the addition of biomarkers may break this dilemma.In addition,quite a few immune cells have been found to be involved in the occurrence and development of HPD in the tumor microenvironment,indicating that the molecular mechanism of HPD may be triggered by a variety of ongoing events at the same time.In this review,we summarize past findings,including case reports,clinical trials,and fundamental research;compare the diagnostic criteria,incidence,and clinical prognostic indicators of HPD in different studies;and explore the molecular mechanism and future research direction of HPD.展开更多
基金supported by the National Natural Science Foundation of China(82173762,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,China)the Fundamental of Research Funds for the Central Universities.
文摘A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs.The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.
基金supported by National Natural Science Foundation of China(No.82173762)Research Funds of Sichuan Science and Technology Department(Nos.2022JDJQ0050,2022YFS0334)111 Project(No.B18035)。
文摘The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer cells.Worse still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune cells.To solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor site.Upon irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ICD.Moreover,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic tumors.In vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.
文摘目的探讨静脉溶栓与抗血小板治疗在卒中预警综合征(stroke warning syndrome,SWS)患者中的有效性及安全性以及SWS患者转归的影响因素。方法回顾性纳入2018年6月1日至2023年12月31日兵器工业五二一医院收治的SWS患者。部分患者给予阿替普酶静脉溶栓,然后进行口服抗血小板治疗;部分患者仅接受抗血小板治疗。主要观察指标为发病后90 d时改良Rankin量表评分,0~2分定义为转归良好。结果共纳入35例SWS患者,男性26例(74.3%),年龄(58.29±11.06)岁。19例(54.3%)接受静脉溶栓,27例(77.1%)90 d时转归良好。静脉溶栓组与仅抗血小板治疗组人口统计学、基线资料以及转归良好均差异无统计学意义。静脉溶栓组有1例出现新发卒中,1例出现短暂性脑缺血发作。转归良好组与转归不良组ABCD2评分、收缩压、低密度脂蛋白胆固醇、空腹血糖、发作时最高美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale,NIHSS)评分以及症状持续时间差异有统计学意义(P均<0.05)。结论静脉溶栓与仅抗血小板药治疗SWS的效果相近。ABCD2评分、收缩压、低密度脂蛋白胆固醇、空腹血糖、发作时最高NIHSS评分以及症状持续时间可能是SWS患者转归的影响因素。
基金supported by the National Natural Science Foundation of China(82173762,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022YFS0334,2022JDJQ0500,China)+1 种基金111 Project(B18035,China)the Fundamental of Research Funds for the Central Universities。
文摘As known,the benefits of photothermal therapy(PTT)are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins(HSPs).Then HSPs further trigger the formation of stress granules(SGs)that regulate protein expression and cell viability under various stress conditions.Inhibition of SG formation can sensitize tumor cells to PTT.Herein,we developed PEGylated pH(low)insertion peptide(PEG-pHLIP)-modified hollow copper sulfide nanoparticles(HCuS NPs)encapsulating the SG inhibitor ISRIB,with the phase-change material lauric acid(LA)as a gatekeeper,to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system(IL@H-PP).The nano medicine could specifically target slightly acidic tumor sites.Upon irradiation,IL@H-PP realized PTT,and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT,thereby increasing the antitumor effect and inducing potent immunogenic cell death(ICD).Moreover,IL@H-PP could promote the production of reactive oxygen species(ROS)by tumor-associated macrophages(TAMs),repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment.In vitro/vivo results revealed the potential of PTT combined with SG inhibitors,which provides a new paradigm for antitumor and antimetastases.
文摘Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor cells,circulating tumor DNA(ctDNA)is widely distributed in various body fluids,including peripheral blood and cerebrospinal fluid(CSF),as an alternative biomarker for tumor-associated analysis[1].Fortunately,genomic alterations of blood ctDNA and CSF ctDNA have been proven as prognostic markers in non-small cell lung cancer(NSCLC)patients with brain metastasis[2,3].
基金supported by the National Natural Science Foundation of China (Nos.51776174,51476134,51276149 and 11602290)State Key Laboratory of Aerodynamics of China Aerodynamics Research and Development Center (No.SKLA20160201)+1 种基金Key Laboratory of Aerodynamic Noise Control of China Aerodynamics Research and Development Center (No.ANCL20170201)China-Europe IMAGE (Innovative Methodologies and Technologies for Reducing Aircraft Noise Generation and Emission) program (No.688971-IMAGE-H2020MG-20141015)
文摘Large Eddy Simulation(LES) is performed to investigate the airfoil broadband noise reduction with wavy leading edge under anisotropic incoming turbulence. The anisotropic incoming turbulence is generated by a rod with a diameter of 10 mm. The incoming flow velocity is 40 m/s and the corresponding Reynolds numbers based on airfoil chord and rod diameter are about 397000 and 26000, respectively. The far-field acoustic field is predicted using an acoustic analogy method which has been validated by the experiment. A straight leading edge airfoil and a wavy leading edge airfoil are simulated. The results show that wavy leading edge increases the airfoil lift and drag whereas the lift and drag fluctuations are substantially reduced. In addition, wavy leading edge can significantly change the flow pattern around the leading edge and a pair of counter-rotating streamwise vortices stemming from each wavy leading edge peak are observed.An averaged noise reduction of 9.5 dB is observed with the wavy leading edge at the azimuthal angle of 90°. Moreover, the wavy leading edge can mitigate noise radiation at all the azimuthal angles without significantly changing the noise directivity. The underlying noise reduction mechanisms are then analyzed in detail.
基金the financial support from National Natural Science Foundation of China(Nos.8196113800982071915)+3 种基金Research Funds of Sichuan Science and Technology Department(No.19YYJC2250,China)111 Project(No.B18035,China)Fundamental Research Funds for the Central UniversitiesNatural Science Foundation of Heilongjiang Province of China(No.YQ2019H004)
文摘Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer(d-SN38)-loaded nanoparticles(d-SN38@NPs/iRGD).Upon intravenous injection,d-SN38@NPs with high drug loading efficiency(33.92±1.33%)could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD.The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy.The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm,which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor.In vitro,coadministering iRGD with d-SN38@NPs+laser showed higher cellular uptake,apoptosis ratio and multicellular spheroid penetration.In vivo,d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor,leading to 60.89%of tumor suppression in 4 T1 tumor-bearing mouse model with a favorable toxicity profile.Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting,penetrating and retention,and empowers anticancer efficacy.
基金supported by National Natural Science Foundation of China (No. 81872806)111 Project (No. B18035, China)the Fundamental of Research Funds for the Central University (China)。
文摘Insurmountable blood-brain barrier(BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease(AD).Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβ deposition or TAU protein need to be resolved urgently.Herein,a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD].DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions,and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma.Then exposed KLVFF can capture and carry Aβ to microglia,attenuating Aβ-induced neurotoxicity.Strikingly,rapamycin,an autophagy promoter,is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβ degradation and normalize inflammatory condition.This design altogether accelerates Aβ degradation and alleviates oxidative stress and excessive inflammatory response.Collectively,our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment,to achieve efficient AD therapy.
文摘Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during the neonatal period to provide early diagnosis and treatment[1].With a history of more than 60 years,NBS has advanced greatly due to technological progress resulting in significant improvement in the number of diseases covered by NBS and in screening efficiency[2-7].
基金supported by the Foundation of the State Key Laboratory of Aerodynamics(Grant No.SKLA2019040302)the National Natural Science Foundation of China(Grant No.11872038).
基金supported by National Natural Science Foundation of China(81961138009,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(No.2020YFS0570,China)+2 种基金111 Project(B18035,China)the Fundamental Research Funds for the Central Universities(China)the Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China(China)。
文摘Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.
基金supported by the Key Research and Development Program of Zhejiang Province(2017C03009 to Q.S.)the National Key Research and Development Program of China(2017YFC1001703 to Q.S.)Q.S.was also supported by the Fundamental Research Funds for the Central Universities(2014QNA6002).
文摘Background Fragile X syndrome(FXS).caused by CGG-repeat expansion in FMR1 promoter,is one of the most common causes of mental retardation.Individuals with full mutation and premutation alleles have a high risk of psychophysiological disorder and of having affected offspring.Frequencies of FMR1 alleles in general newborns have been reported in Caucasians but have not been investigated in the large-scale population in the mainland of China.Methods The sizes of FMRI CGG-repeats were analyzed in 51,661 newborns(28,114 males and 23,547 females)and also in a cohort of 33 children diagnosed with developmental delay using GC-rich polymerase chain reaction(PCR)and triple repeat primed PCR.Results The frequency of CGG repeats>100 was 1/9371 in males and 1/5887 in females,and the frequency of CGG repeats>54 was 1/1561 in males and 1/1624 in females.FMRJ full mutation and premutation were identified in 27.27%of children who had Ages and Stages Questionnaire scores less than two standard deviations from the cutoff value.Conclusions Our study revealed the prevalence of FXS in China and improved the sample databases of FXS,suggesting that the prevalence of FXS in Chinese is higher than estimated previously and that FXS screening can be advised to high-risk families.
基金the National Natural Science Foundation of China(No.81741090)the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talentsthe National KePy R&D Program of China(Nos.2017YFC1001703 and 2018YFC1002700)。
基金supported by the National Natural Science Foundation of China(Nos.61464005,51562015)the Natural Science Foundation of Jiangxi Province(Nos.20143ACB21004,20151BAB212008,20171BAB216015)+2 种基金the Jiangxi Province Foreign Cooperation Projects,China(No.20151BDH80031)the Leader Training Object Project of Major Disciplines Academic and Technical of Jiangxi Province(No.20123BCB22002)the Key Technology R&D Program of the Jiangxi Provine of Science and Technology(No.20171BBE50053)
文摘ZnO films coated with reduced graphene oxide(RGO-ZnO) were prepared by a simple chemical approach. The graphene oxide(GO) films transferred onto ZnO films by spin coating were reduced to RGO films by two steps(exposed to hydrazine vapor for 12 h and annealed at 600 °C). The crystal structures, electrical and photoluminescence properties of RGO-ZnO films on quartz substrates were systematically studied. The SEM images illustrated that RGO layers have successfully been coated on the ZnO films very tightly. The PL properties of RGO-ZnO were studied. PL spectra show two sharp peaks at 390 nm and a broad visible emission around 490 nm.The resistivity of RGO-ZnO films was measured by a Hall measurement system, RGO as nanofiller considerably decrease the resistivity of ZnO films. An electrode was fabricated, using RGO-ZnO films deposited on Si substrate as active materials, for super capacitor application. By comparison of different results, we conclude that the RGOZnO composite material couples possess the properties of super capacitor.
文摘The authors regret that there were some picture errors in Fig.4A and data errors Fig.7A owing to the mistakes of copying and pasting in the process of assembling figures and making a dia-gram.The raw data of correct images of group b in Fig.4A and values of high dose in Fig.7A are provided in the supporting information,and the authors revise Figs.4 and 7 as below.The revisions do not affect any results and conclusions of the current work.The authors apologize for any inconvenience caused to the journal and readers.
基金This study was supported by the National Natural Science Foundation of China(81170664).
文摘Background:Glutaric acidemia type I(GA-I)is a rare metabolic disorder caused by mutation of the glutaryl-CoA dehydrogenase(GCDH)gene.The occurrence of rhabdomyolysis with GA-I is extremely rare.Methods:We reported a child with recurrent rhabdomyolysis and undiagnosed glutaric acidemia type I(GA-I).And a literature review was performed.Results:A 4.5-year-old girl was admitted to our hospital due to recurrent rhabdomyolysis for 3 times within three years.At the third admission,she was diagnosed with GA-I by biochemical testing and mutation analysis.The girl was found to have a serine to leucine replacement mutation of the GCDH gene in exon 8 at position 764.Other three patients with rhabdomyolysis and GA-I were discovered by literature searching.Conclusion:This report highlights that patients with GA-I may have an increased risk of rhabdomyolysis.
文摘Immune checkpoint inhibitors(ICIs)are gradually replacing chemotherapy as the cornerstone of the treatment of advanced malignant tumors because of their long-lasting and significant effect in different tumor types and greatly prolonging the survival time of patients.However,not all patients can respond to ICIs,and even rapid tumor growth after treatment with ICI has been observed in a number of clinical studies.This rapid progression phenomenon is called hyper-progressive disease(HPD).The occurrence of HPD is not uncommon.Past statistics show that the incidence of HPD is 4%-29% in different tumor types,and the progression-free survival and overall survival of patients with HPD are significantly shorter than those of the non-HPD progressor group.With the deepening of the study of HPD,we have established a preliminary understanding of HPD,but the diagnostic criteria of HPD are still not unified,and the addition of biomarkers may break this dilemma.In addition,quite a few immune cells have been found to be involved in the occurrence and development of HPD in the tumor microenvironment,indicating that the molecular mechanism of HPD may be triggered by a variety of ongoing events at the same time.In this review,we summarize past findings,including case reports,clinical trials,and fundamental research;compare the diagnostic criteria,incidence,and clinical prognostic indicators of HPD in different studies;and explore the molecular mechanism and future research direction of HPD.
