地方政策创新差异的整合性解释框架--基于互助养老政策创新的比较研究

地方政府作为政策创新的重要主体,其在实践中形成的政策创新各具特色,然而学界对地方政策创新差异的解释呈现为碎片化的图景。论文通过对重庆T区和D区互助养老政策创新进行案例比较研究,在理论与经验互构中提炼出地方政策创新差异的整合性解释框架。框架包含由政策创新空间、政策创新属性、政策创新行动者、政策创新目标等要素互动作用形成的四重机制。一是空间约束机制。上级政策规范的过程约束和绩效考核的结果约束共同决定政策创新空间约束强度,影响行动者自主决定政策创新方式及内容的自由,对其他要素均产生约束作用。二是属性影响机制。政策创新的风险性影响行动者的创新意愿,兼容性影响行动者的政策衔接选择,而这些潜在性影响受到政策创新空间的调节作用。三是能动创新机制。行动者在空间约束和属性影响之下,结合自身认知偏好,能动生成理性的政策创新目标。四是目标牵引机制。在创新目标的规范性指引下,行动者进一步将目标解释、具象化为政策创新内容。四重机制共同作用,最终形成地方政策创新差异。研究有助于系统透视地方政策创新差异形成的复杂机理,弥合政策创新研究的碎片化格局。

Single-arm trials for domestic oncology drug approvals in China

The urgent need for effective cancer treatments,particularly for advanced and relapsed cases in which standard therapies are inadequate,has spurred the development of innovative therapeutic drugs1,2.Among the strategies to expedite drug development,the use of single-arm trials(SATs)is emerging as a promising avenue with substantial potential to shorten drug approval timelines and accelerate market entry.

Comment on: “Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors”

In the ever-evolving landscape of cancer research and treatment,the quest for novel and non-invasive imaging techniques has become crucial for accurate diagnosis and effective therapy.This study[1]successfully developed a good manufacturing practices(GMP)grade ^(89)Zr-labeled anti-Claudin18.2(CLDN18.2)recombinant humanized antibody TST001.^(89)Zr-DFO-TST001 exhibited high radiochemical purity(>99%)and specific activity(24.15±1.34 GBq/mmol).It demonstrated good specificity and rapid tumor accumulation in vivo and in vivo.Through immuno-PET imaging,it enables non-invasive visualization and quantification of CLDN18.2 expression level in CLDN18.2-positive gastrointestinal tumor models.

中国国家药品监督管理局批准安罗替尼用于经两种系统化疗后疾病进展的晚期非小细胞肺癌的治疗

背景2018年5月8日,中国国家药品监督管理局(National Medical Products Administration,NMPA)批准了小分子多靶点抗血管抑制剂盐酸安罗替尼,用于既往经过至少两种系统化疗后疾病进展的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的治疗。概要中国NMPA审查了一项随机双盲、安慰剂对照的III期临床试验,该临床试验的主要终点为总生存期(overall survival,OS)。试验共纳入437例患者随机分组(2∶1)接受安罗替尼(n=294)或安慰剂(n=143)治疗,每日1次,连服2周,停药1周。表皮生长因子受体(epidermal growth factor receptor,EGFR)基因敏感突变或间变性淋巴瘤激酶(activating anaplasticlymphomakinase,ALK)阳性的患者须经过NMPA已批准的药物治疗后出现疾病进展。安罗替尼为中国NMPA批准的用于治疗既往经过两种及以上系统化疗后疾病进展的晚期NSCLC患者的首个药物。安罗替尼组的中位OS(9.46个月)较安慰剂组[6.37个月;风险比(hazard ratio,HR)=0.70,95%置信区间(confidence Interval,CI):0.55–0.89;双侧log-rank P=0.002]显著延长。安罗替尼组的客观缓解率(objective responserate,ORR)为9.2%,安慰剂组为0.7%。安罗替尼组的中位缓解持续时间(durationofresponse,DoR)为4.83个月,95%CI为3.31–6.97个月。安罗替尼的常见不良反应(adverse drug reactions,ADRs)包括高血压(67.4%)、手足综合征(43.9%)、咳血(14.0%)、促甲状腺激素(thyroid stimulating hormone,TSH)升高(46.6%)、心电图QT间期(corrected QT Interval,QTc)延长(26.2%)。结论安罗替尼显著延长了患者的OS,可作为经二线及以上化疗后晚期或转移性非小细胞肺癌的一种新的治疗方案。

Effects of Different NH_4^+/NO_3^- Ratio and Water Condition on Physiological Characteristics of Rice Seedlings

[Objective] This study aimed to further explore the dynamics of related physiological indexes of rice seedlings under different NH4＋ /NO3- ratio and different water condition. [Method] Under the hydroponic condition in laboratory, 3 NH4＋/NO3- ratios （0/100, 50/50 and 100/0） and 2 water conditions （＋PEG,-PEG） were designed for Fengliangyou 7203. [Result] The root-canopy ratio of rice seedlings increased under any of the NH4＋/NO3- ratios and water conditions. Under water stress, the root-canopy ratio of rice seedlings changed most greatly at the NH4＋/NO3- ratio of 0/ 100; the overall water potential of rice seedlings reached the lowest at the NH4＋/ NO3- ratio of 100/0; and the changes of water potential and xylem flow pH were relatively stable at the NH4＋/NO3- ratio of 50/50. Under the condition of no water stress, the growth of rice seedlings was best at the NH4＋/NO3- ratio of 50/50, followed by the NH4＋/NO3- ratios of 0/100 and 100/0. [Conclusion] This study will pro- vide a basis for understanding the relationship between water potential and xylem flow.

Effects of Comprehensive Control Technology on Heavy Metal Content and Rice Yield in Northern Guangdong Province

In order to explore the application effect of the comprehensive control technology of"soil conditioning-organic planting-foliar control"in the rice area of northern Guangdong,the effects of combined application of different dosages of soil conditioner,bio-organic fertilizer and foliar control agent on heavy metal contents and yields of early and late rice were investigated based on field experiments.The results showed that different treatments of early rice and late rice all increased the yield.The yield increase rates of treatments 2,3 and 4 reached 4.9%,7.2%and 8.7%in early rice,respectively,and those in late rice reached 7.7%,7.8%and 9.7%,respectively.And the cadmium contents of early rice and late rice in treatments 2,3 and 4 were significantly reduced below the safe value.Taking into account factors such as cost,yield increase rate,and heavy metal compliance rate,the recommended application rate for early and late rice is conventional fertilization+soil conditioner 6000 kg/hm^(2)+bio-organic fertilizer 1800 kg/hm^(2)+foliar control agent 6000 ml/hm^(2).

Effects of Nutrients on Growth and Yield of Shatian Pomelo Trees with Huanglongbing

[Objectives]In order to effectively alleviate Huanglongbing of Shatian pomelo trees,a nutrient preparation was developed and its effect on the growth and yield of Shatian pomelo was explored.[Methods]A field experiment was carried out with four treatments:control group,nutrient solution group,agent group,and nutrient solution+agent group,and the liquids were infused into the fruit trees through the trunk using a hanging bag.[Results]Through field trials,it was found that the nutrient solution treatment of fruit trees significantly increased the leaf chlorophyll content and nitrogen content,which increased by 17%and 12%compared with the control group,respectively,reaching(70.80±1.57)and(5.53±0.1)mg/kg,respectively;and the combined application of the nutrient solution and powder agents greatly alleviated the symptoms of Huanglongbing in Shatian pomelo plants,and significantly improved the bacterial disease index,photosynthetic intensity and yield,which increased by 152%,158%and 213.53%respectively,reaching(371.00±7.22),(406.67±7.09)and 23.15 kg/hm^2.[Conclusions]The use of the nutrient solution and agents greatly alleviated the symptoms of Huanglongbing of Shatian pomelo plants,and significantly improved the chlorophyll content,nitrogen content,bacterial disease index and photosynthetic intensity.Meanwhile,the number of fruit per plant and the weight of single fruit were better than other treatment groups and the control group,the technical operation was simple and the effect was obvious.This provides a certain reference basis for the prevention and control measures of Huanglongbing in Shatian pomelo plants.

Study on the Passivation Effect of Ca-Si Soil Conditioner on Heavy Metal Absorption by Rice

[Objectives] In order to solve the problem of heavy metal pollution in paddy fields,field experiments were carried out to study the effect of Ca-Si soil conditioner on heavy metal remediation in paddy fields. [Methods] A conventional planting mode( CK) was used as the control,and a Ca-Si soil conditioner( Ca-Si) treatment was set to analyze the differences in soil pH and heavy metal contents in different treatments. [Results]The content of cadmium in the paddy field exceeded the soil pollution risk control value of agricultural land by 59. 33%. The Ca-Si soil conditioner increased the pH value of paddy field soil by 0. 58 unit. The fixation rates of Ca-Si soil conditioner on chromium,arsenic,cadmium and plumbum reached 75. 96%,14. 09%,18. 93% and 7. 81% compared with the CK,respectively,and the available cadmium and lead contents were reduced by 82. 35% and 80. 00%,respectively. [Conclusions]This study provides ideas and references for the remediation of heavy metal pollution in paddy soil.

Mitochondria-specific near-infrared photoactivation of peroxynitrite upconversion luminescent nanogenerator for precision cancer gas therapy

Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment.However,there are limitations,including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision,associated with gas therapy.In this study,we developed a series of photoactivatable nitric oxide(NO)donors NRh-R-NO(R=Me,Et,Bn,iPr,and Ph)based on an N-nitrosated upconversion luminescent rhodamine scaffold.Under the irradiation of 808 nm light,only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence(FUCL)signal at 740 nm,ascribed to lower N-N bond dissociation energy.We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy,including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation,the superoxide anion O_(2)^(⋅−)produced by the photodynamic therapy(PDT)effect of NRh-Ph,and highly toxic peroxynitrite anion(ONOO‒)generated from the co-existence of NO and O_(2)^(⋅−).After mild nano-modification,the nanogenerator(NRh-Ph-NO NPs)empowered with superior biocompatibility could target mitochondria.Under an 808 nm laser irradiation,NRh-Ph-NO NPs could induce NO/ROS to generate RNS,causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation,which further induced tumor immunogenic cell death(ICD).In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy,demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging.Collectively,this versatile strategy defines the targeted RNS-mediated cancer therapy.

Linker gadolinium as charge channel and singlet oxygen activation site in graphitic carbon nitride for enhancing photocatalytic decomposition of tetracycline

Reactive oxygen species are essential in photocatalytic water treatment.In this paper,Gd doped carbon nitride(CN)photocatalysts were prepared by simple thermal polymerization for the photocatalytic degradation of tetracycline under visible light irradiation.The photodegradation rate of 1.OGdCN is as high as 95%in 18 min,and the photocatalytic performance is much higher than that of CN.The improvement of photocatalytic performance is mainly attributed to the fact that Gd ion implantation directly provides active sites for oxygen activation and induces the formation of N vacancies.The results of characterizations show that the introduction of Gd in CN can improve the conversion ability of activated oxygen,carrier separation and energy band structure adjustment.Therefore,1.0GdCN photocatalyst can be employed for efficient photocatalytic synthesis of tetracycline.Furthermore,three ways of photocatalytic degradation of tetracycline were revealed by high performance liquid chromatographymass spectrometry.This work provides insights into the doping strategy of CN to improve the production of reactive oxygen species for environmental remediation.

Full-spectrum Bi@SrTiO_(3) for bi-directional promotion effects on photocatalytic redox reaction:Insight into intermediates and mechanism

The development of full-spectrum photocatalysts active in the near-infrared(NIR)region has gained increasing attention for deleterious pollutant removal.The integration of plasmonic metals with semico nductors is an effective way to widen the light re sponse range of photocatalysts due to the strong light absorption and fast plasmonic energy transfer of the localized surface plasmon resonance(LSPR).In this work,the full-spectrum responsive Bi@SrTiO_(3) was prepared via facile solvothermal chemical reduction.The optimal Bi@SrTiO_(3) achieves exceptional photocatalytic Cr(VI)reduction efficiency and tetracycline degradation,realizing bi-directional promotion effects on redox reaction.According to density functional theory(DFT)simulations,the extraordinary photocatalytic performance is attributed to the tunable builtin electric field(IEF)of the Ohmic contact.The favorable adaptability in real water and high stability of BSTO-25 were proved by experime ntal results.And the po ssible photocatalytic mechanism was proposed based on theoretical calculation and experimental results.Furthermore,the non-toxicity of the BSTO-25 was evaluated by E.coli cultivation,which further proves the feasibility of treating wastewater with BSTO-25.This work provides a new perspective on constructing full-spectrum-driven photocatalysts for applications dealing with environmental remediation.

Identification and characterization of human hematopoietic mesoderm

The embryonic mesoderm comprises heterogeneous cell subpopulations with distinct lineage biases.It is unclear whether a bias for the human hematopoietic lineage emerges at this early developmental stage.In this study,we integrated single-cell transcriptomic analyses of human mesoderm cells from embryonic stem cells and embryos,enabling us to identify and define the molecular features of human hematopoietic mesoderm(HM)cells biased towards hematopoietic lineages.We discovered that BMP4 plays an essential role in HM specification and can serve as a marker for HM cells.Mechanistically,BMP4 acts as a downstream target of HDAC1,which modulates the expression of BMP4 by deacetylating its enhancer.Inhibition of HDAC significantly enhances HM specification and promotes subsequent hematopoietic cell differentiation.In conclusion,our study identifies human HM cells and describes new mechanisms for human hematopoietic development.

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy.Targeted radionuclide therapy delivers radiation directly to tumor sites.LNC1004 is a fibroblast activation protein(FAP)-targeting radiopharmaceutical,conjugated with the albumin binder Evans Blue,which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies.Herein,we demonstrate that^(68)Ga/^(177)Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts.Radionuclide therapy with^(177)Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells.The combination of^(177)Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice,with mice showing 100%tumor rejection upon rechallenge.Immunohistochemistry,single-cell RNA sequencing(scRNA-seq),and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication,CD8^(+)T-cell activation and expansion,M1 macrophage counts,antitumor activity of neutrophils,and T-cell receptor diversity.A preliminary clinical study demonstrated that^(177)Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers.Further,scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment.This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation.In conclusion,our data supported the efficacy of immunotherapy combined with^(177)Lu-LNC1004 for cancer patients with FAP-positive tumors.

In vivo bioorthogonal labeling of rare-earth doped nanoparticles for improved NIR-II tumor imaging by extracellular vesiclemediated targeting

The development of efficient contrast agents for tumor-targeted imaging remains a critical challenge in the clinic.Herein,we proposed a tumor-derived extracellular vesicle(EV)-mediated targeting approach to improve in vivo tumor imaging using ternary downconversion nanoparticles(DCNPs)with strong near infrared II(NIR-II)luminescence at 1,525 nm.The EVs were metabolically engineered with azide group,followed by in vivo labeling of DCNPs through copper-free click chemistry.By taking advantage of the homologous targeting property of tumor derived EVs,remarkable improvement in the tumor accumulation(6.5%injection dose(ID)/g)was achieved in the subcutaneous colorectal cancer model when compared to that of individual DCNPs via passive targeting(1.1%ID/g).Importantly,such bioorthogonal labeling significantly increased NIR-II luminescence signals and prolonged the retention at tumor sites.Our work demonstrates the great potential of EVs-mediated bioorthogonal approach for in vivo labeling of NIR-II optical probes,which provides a robust tool for tumor-specific imaging and targeted therapy.

Superconducting Magnetic Energy Storage Integrated Current-source DC/DC Converter for Voltage Stabilization and Power Regulation in DFIG-based DC Power Systems

Unpredictable power fluctuation and fault ridethrough capability attract increased attention as two uncertain major factors in doubly-fed induction generators(DFIGs)integrated DC power system.Present solutions usually require complicated cooperation comprising multiple modules of energy storage,current control,and voltage stabilizer.To overcome the drawbacks of existing solutions,this paper proposes a superconducting magnetic energy storage(SMES)integrated currentsource DC/DC converter(CSDC).It is mainly composed of a current-source back-to-back converter,and the SMES is tactfully embedded in series with the intermediate DC link.The proposed SMES-CSDC is installed in front of the DC-DFIG to carry out its dual abilities of load voltage stabilization under multifarious transient disturbances and power regulation under wind speed variations.Compared with the existing DC protection devices,the SMES-CSDC is designed on the basis of unique current-type energy storage.It has the advantages of fast response,extensive compensation range,concise hardware structure,and straightforward control strategy.The feasibility of the SMESCSDC is implemented via a scaled-down experiment,and its effectiveness for DC-DFIG protection is verified by a large-scale DC power system simulation.

BaTiO_(3)@Au nanoheterostructure suppresses triple-negative breast cancer by persistently disrupting mitochondrial energy metabolism

Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic interventions demonstrated unsatisfactory therapeutic outcomes and potential systemic toxicity,resulting from the metabolic instability and limited targeting ability of inhibitors as well as complex tumor microenvironment.To address these limitations,here we developed a robust pyroelectric BaTiO_(3)@Au core–shell nanostructure(BTO@Au)to selectively and persistently block energy generation of tumor cells.Stimulated by near-infrared(NIR)laser,the Au shell could generate heat to activate the BaTiO_(3)core to produce reactive oxygen species(ROS)regardless of the constrained microenvironment,thus prominently inhibits mitochondrial oxidative phosphorylation(OXPHOS)and reduces ATP production to induce TNBC cell apoptosis.The therapeutic effects have been well demonstrated in vitro and in vivo,paving a new way for the development of metabolic interventions.

Precise nanomedicine for intelligent therapy of cancer

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.

China National Medical Products Administration approval summary:anlotinib for the treatment of advanced non-small cell lung cancer after two lines of chemotherapy

Background:On May 8,2018,the China National Medical Products Administration(NMPA)approved anlotinib,an orally administered anti-angiogenesis inhibitor,for the treatment of patients with advanced non-small cell lung can-cer(NSCLC)who have progressed after treatment with two or more lines of prior systemic chemotherapy.Main body of the abstract:China NMPA reviewed and inspected a regional double-blinded,placebo-controlled,Phase III trial comparing the overall survival(OS)of NSCLC patients between the anlotinib and placebo arms.A total of 437 patients were randomized(2:1)to receive either anlotinib(n=294)or placebo(n=143)once daily on a 2-week on and 1-week off schedule.Patients with epidermal growth factor receptor(EGFR)or activating anaplastic lymphoma kinase(ALK)genomic tumor aberrations should have disease progression on NMPA-approved therapy.Anlotinib is the first NMPA-approved drug for patients with advanced NSCLC who have progressed on at least two lines of prior systemic chemotherapies in China.The approval was based on a statistically and clinically significant improvement in median OS with anlotinib(9.46 months)compared with placebo[6.37 months;hazard ratio(HR])=0.70,95%confidence interval(CI)=0.55-0.89;two-sided log-rank P=0.002].The confirmed objective response rate(ORR)was 9.2%in the anlotinib arm and 0.7%in the placebo arm.The median duration of response(DoR)was 4.83 months,with a 95%CI of 3.31-6.97 months.The toxicity profile of anlotinib was consistent with that of known anti-angiogenesis inhibitors.Common adverse drug reactions(ADRs)in anlotinib-treated patients included hypertension(67.4%),hand-foot syndrome(43.9%),hemoptysis(14.0%),thyroid stimulating hormone(TSH)elevation(46.6%),and corrected QT interval(QTc)prolongation(26.2%).Short conclusion:Anlotinib demonstrated a clinically significant OS prolongation as a novel therapeutic option for advanced or metastatic NSCLC following at least two lines of chemotherapy.

Hollow iron oxide nanoparticles as multidrug resistant drug delivery and imaging vehicles

Magnetic nanopartides have been used as drug delivery vehicles against a number of cancer cells. Most of these theranostic formulations have used solid iron oxide nanoparticles （SIONPs） loaded with chemotherapeutics as nano-carrier formulation for both magnetic resonance imaging （MRI） and cancer therapy. In this study, we applied the dopamine-plus-human serum albumin （HSA） method to modify hollow iron oxide nanoparticles （HIONPs） and encapsuated doxorubicin （DOX） within the hollow porous structure of the nano-carrier. The new delivery system can load more drug than solid iron oxide nanoparticles of the same core size using the same coating strategy. The HIONPs-DOX formulation also has a pH-dependent drug release behaviour. Compared with free DOX, the HIONPs-DOX were more effectively uptaken by the multidrug resistant OVCAR8- ADR cells and consequently more potent in killing drug resistant cancer cells. MRI phantom and cell studies also showed that the HIONPs-DOX can decrease the T2 MRI signal intensity and can be used as a MR/contrast agent while acting as a drug delivery vehicle. For the first time, the dual application of chemo drug transport and MR imaging using the HIONPs-DOX formulation was achieved against both DOX-sensitive and DOX-resistant cancer cells.

Metal-organic frameworks nanoswitch:Toward photo-controllable endo/lysosomal rupture and release for enhanced cancer RNA interference

Endo/lysosomal escape and gene release are two critical bottlenecks in gene delivery.Herein,a novel photo-controllable metal-organic frameworks(MOFs)nanoswitch is rationally designed for enhancing small interfering RNA(siRNA)delivery.One single laser triggers the“off-to-on”switching of MOFs nanocomplexes,inducing significant siRNA release accompanied by rapid MOFs dissociation into protonatable 2-methylimidazalo and osmotic rupturing Zn2+ions,which cooperatively contribute to remarkable endo/lysosomal rupture(∼90%).The simultaneous endo/lysosomal rupture and release enable a high spatio-temporal control on RNA interference for effective cancer therapy.Notably,the“off-to-on”switching also activates fluorescence recovery for real-time monitoring siRNA delivery.The nanoswitch could easily be extended to deliver other therapeutic agents(e.g.,DNA,protein,anticancer drug)for overcoming endo/lysosomal entrapment.